    [Senate Hearing 113-]
    [From the U.S. Government Publishing Office]

      DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, AND EDUCATION, AND
              RELATED AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2014

                                  ----------

                            WEDNESDAY, MAY 15, 2013

                                           U.S. Senate,
               Subcommittee of the Committee on Appropriations,
                                                        Washington, DC.
        The subcommittee met at 2:30 p.m., in room SD-138, Dirksen
    Senate Office Building, Hon. Tom Harkin (chairman) presiding.
        Present: Senators Harkin, Mikulski, Moran, Cochran, Shelby,
    and Boozman.

                    DEPARTMENT OF HEALTH AND HUMAN SERVICES

                         National Institutes of Health

    STATEMENT OF FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR
    ACCOMPANIED BY:
            ANTHONY S. FAUCI, M.D., DIRECTOR, NATIONAL INSTITUTE OF ALLERGY
                AND INFECTIOUS DISEASES
            GARY H. GIBBONS, M.D., DIRECTOR, NATIONAL HEART, LUNG, AND
                BLOOD INSTITUTE
            RICHARD J. HODES, M.D., DIRECTOR, NATIONAL INSTITUTE ON AGING
            STORY C. LANDIS, Ph.D., DIRECTOR, NATIONAL INSTITUTE FOR
                NEUROLOGICAL DISORDERS AND STROKE
            HAROLD E. VARMUS, M.D., DIRECTOR, NATIONAL CANCER INSTITUTE

                    OPENING STATEMENT OF SENATOR TOM HARKIN

        Senator Harkin. The Senate Appropriations Subcommittee on
    Labor, Health and Human Services, and Education will please
    come to order.
        Today, we are privileged to have with us, again, as my
    longtime compatriot Arlen Specter used to say, ``The crown
    jewel of the Federal Government.'' That is our National
    Institutes of Health (NIH) here today for our budget hearing.
        So, Dr. Collins, we welcome you back to the subcommittee,
    and also, in alphabetical order, Dr. Tony Fauci, Director of
    the National Institute of Allergy and Infectious Diseases; Dr.
    Gary Gibbons, Director of the National Heart, Lung, and Blood
    Institute; Dr. Richard Hodes, Director of the National
    Institute on Aging; Dr. Story Landis, Director of the National
    Institute for Neurological Disorders and Stroke; Dr. Harold
    Varmus, Director of the National Cancer Institute.
        This is a perilous moment for NIH and, indeed, for the
    future of biomedical research in this country. Since fiscal
    year 2003, the end of the 5-year doubling effort, NIH funding
    has dropped in real terms by 22 percent. In other words, the
    purchasing power of NIH's appropriations has fallen by more
    than one-fifth over the past decade.
        This year, fiscal year 2013, NIH funding will drop in
    actual dollars by $1.7 billion below last year's level, almost
    entirely because of sequestration.
        As a result, NIH will award 700 fewer new research project
    grants this year than it did last. That means 700 fewer
    opportunities to investigate and possibly find the cures for
    cancer and Alzheimer's and diabetes and any number of diseases.
        Perhaps even more alarming, a researcher's chance of
    getting a grant approved by NIH will drop to just 16 percent.
    That is the lowest success rate in the history of NIH.
        That comes at the time when the potential for scientific
    breakthroughs has perhaps never been better. At the National
    Cancer Institute, the success rate will be just 12 percent. At
    other institutes, below 10 percent. That's abysmal.
        When you have less than a 1-in-10 chance of getting a
    grant, that's when our best and brightest young minds start
    asking, ``What's the point? Maybe I need to find a different
    career.''
        It's no wonder that some are saying our Nation's status as
    the undisputed world leader in biomedical research is under
    threat.
        The President's budget request offers a welcome response to
    this disturbing decline. His budget calls for $31.1 billion for
    NIH in fiscal year 2014, which would not only reverse all of
    the cuts that are occurring this year but result in an increase
    over the fiscal year 2012 level. Included in that increase is
    $40 million to the new Brain Research through Advancing
    Innovative Neurotechnologies (BRAIN) Initiative, which I'm sure
    we'll hear more about.
        And I read your testimony last night, you mention that,
    both Dr. Collins and, I'm sure, Dr. Landis.
        So I want to do everything I can to help boost NIH's budget
    this year. I suspect that many Senators on the other side of
    the aisle also agree with this. NIH enjoys more bipartisan
    support than perhaps any other Agency in the entire Labor-HHS
    appropriations bill.
        But here's a problem. At the same time some of my
    colleagues are requesting a strong commitment to NIH funding,
    they also want sequestration to continue in fiscal year 2014.
    Some even want deeper cuts to nondefense discretionary spending
    next year to pay for some more increases in defense spending.
        There simply is no way to square these two priorities. I
    can promise you, if sequestration stays in effect next year,
    there's no chance that we will get close to the President's
    request for NIH, let alone back to the fiscal year 2012 level.
    It just won't happen.
        We are not going to savage other functions in education,
    health, labor, Centers for Disease Control and Prevention, and
    others, which are already at minimal levels. I will not get
    engaged in pitting NIH against other worthwhile endeavors in
    this appropriations bill.
        This is just one of the many reasons why we need to replace
    sequestration with a mix of targeted, responsible spending
    cuts, not just blind cuts to everything, and, yes, increased
    revenue.
        This sort of balanced approach is the only way NIH will
    have the resources it needs to realize the enormous scientific
    opportunities that we'll hear about shortly from our witnesses.
        First, I'll yield to Senator Moran for his opening
    statement.

                        STATEMENT OF SENATOR JERRY MORAN

        Senator Moran. Mr. Chairman, thank you very much, and let
    me thank you and your staff for the continual effort for us to
    work together to find a path forward on a Labor-H bill. I very
    much appreciate the attitude and approach that our staffs, and
    you and I, are taking.
        And I appreciate Dr. Collins and the other center directors
    being here today. This is a highlight, I think, for our
    subcommittee as we hear of some of the most recent and exciting
    developments as we face the challenges that disease provides.
        Science and research are the foundation of innovation,
    growth in our economy, and the solution to a myriad of issues
    that confront the health and well-being of our Nation. NIH
    funding biomedical research is the catalyst behind many of the
    advances that are now helping Americans live longer and
    healthier lives.
        Because of the Federal investment in biomedical research,
    U.S. cancer rates are now falling 1 percent each year, with
    each 1-percent decline saving our Nation about $500 billion.
        The U.S. death rate from heart disease and stroke have
    declined more than 60 percent in the last half century. And
    between 1997 and 2006, the death rate among adults with
    diabetes declined 23 percent.
        However, health advances aside, and they are paramount, the
    reduction of healthcare costs in the future may be one of the
    most significant contributions to society that medical research
    provides.
        As baby boomers age, the cost of healthcare will continue
    to increase. For example, a study led by the economists at the
    RAND Corporation stated that the cost of dementia care is
    projected to double over the next 30 years, surpassing
    healthcare expenses for both heart disease and cancer. Without
    a way to prevent or cure or effectively treat dementia, it will
    be difficult, if not impossible, to rein in costs.
        But science has confronted similar health challenges in the
    past and has prevailed. In the mid-20th century, economists
    predicted polio would cost taxpayers $100 billion a year to
    treat patients in iron lung hotels. In the face of this
    challenge, medical research produced a solution to this
    devastating disease, and polio is now on the verge of being
    eradicated worldwide.
        In the next few years, we confront difficult spending
    choices. And I believe we must prioritize our Federal
    commitment to NIH. It is crucial that our next generation of
    biomedical researchers, the ones who will develop better and
    more cost-effective healthcare, remain in the scientific
    research field.
        Without adequate and sustained Federal support for medical
    research, trainees will be driven from medical fields, or into
    the arms of our global competitors.
        Last year, China's Government pledged to increase basic
    research investment by 26 percent and will contribute more than
    $300 billion to biotechnology over the next 5 years.

                               PREPARED STATEMENT

        In the last 5 years, China's percentage of science and
    engineering degrees earned by university students was more than
    double those earned here in the United States. Without
    continued investment in NIH, we jeopardize our current
    scientific progress, risk losing a generation of scientists,
    and stunt our Nation's global competitiveness.
        This is not a time to waver on America's commitment to NIH
    and to the health of all Americans.
        Mr. Chairman, thank you, and I look forward to working with
    you on these priorities.
        [The statement follows:]

                   Prepared Statement of Senator Jerry Moran

        Thank you, Mr. Chairman. I appreciate Dr. Collins and the other
    Center Directors being here today to discuss funding for the National
    Institutes of Health (NIH).
        Science and research are the foundation of innovation, growth in
    our economy, and the solution to the myriad of issues that confront the
    health and well-being of our Nation. NIH-funded biomedical research is
    the catalyst behind many of the advances that are now helping Americans
    live longer and healthier lives. Because of the Federal investment in
    biomedical research, U.S. cancer death rates are now falling 1 percent
    each year, with each 1-percent decline saving our Nation about $500
    billion. U.S. death rates from heart disease and stroke have declined
    more than 60 percent in the last half-century. Between 1997 and 2006,
    the death rate among adults with diabetes declined by 23 percent.
        However, health advances aside--and they are paramount--the
    reduction of healthcare costs in the future may be one of the most
    significant contributions to society from medical research. As baby
    boomers age, the cost of healthcare will continue to increase. For
    example, a study led by economists at the RAND Corporation stated that
    the cost of dementia care is projected to double over the next 30
    years, surpassing healthcare expenses for both heart disease and
    cancer. Without a way to prevent, cure, or effectively treat dementia,
    it will be difficult, if not impossible, to rein in costs. But science
    has confronted similar healthcare challenges in the past and prevailed.
    In the mid-20th century, economists predicted polio would cost
    taxpayers $100 billion a year to treat patients in ``iron lung
    hotels.'' In the face of this challenge, medical research produced a
    solution to this devastating disease. Polio is now on the verge of
    being eradicated worldwide.
        In the next few years as we confront difficult spending choices, I
    believe we must prioritize our Federal commitment to NIH. It is crucial
    that our next generation of biomedical researchers, the ones who will
    develop better and more cost-effective healthcare, remain in the
    scientific research field. Without adequate and sustained Federal
    support for medical research, trainees will be driven from the medical
    field or into the arms of our global competitors. Last year, China's
    Government pledged to increase basic research investment by 26 percent
    and will contribute more than $300 billion into biotechnology over the
    next 5 years. In the last 5 years, China's percentage of science and
    engineering degrees earned by university students was more than double
    those earned by U.S. students.
        Without continued investment in the NIH we jeopardize our current
    scientific progress, risk losing a generation of scientists, and stunt
    our Nation's global competitiveness. This is not the time to waiver on
    America's commitment to the NIH and the health of all Americans.
        Thank you, Mr. Chairman.

        Senator Harkin. Thank you very much, Senator Moran.
        And we welcome back again Dr. Francis Collins, the 16th
    Director of the National Institutes of Health, a physician and
    geneticist noted for discoveries of disease genes and his
    leadership of the Human Genome Project, of which he was the
    director from 1993 to 2008. Dr. Collins received a B.S. from
    the University of Virginia, his Ph.D. from Yale, and an M.D.
    from University of North Carolina at Chapel Hill.
        Dr. Collins, your statement will be made part of the record
    in its entirety. And, again, the floor is yours. Please proceed
    as you so desire.

                  SUMMARY STATEMENT OF DR. FRANCIS S. COLLINS

        Dr. Collins. Well, good afternoon, Mr. Chairman and members
    of the subcommittee. I'm very pleased to be here with my
    colleagues to present the President's budget request for the
    National Institutes of Health for fiscal year 2014.
        This panel has a long history of supporting NIH's mission
    to seek fundamental knowledge and apply it in ways that enhance
    human health, lengthen life, and reduce suffering.
        My sincere thanks to you, Mr. Chairman, for your strong
    commitment to supporting biomedical research over these years.
    NIH and millions of patients are grateful for that leadership.
        But I'm here today to talk about the Administration's
    fiscal year 2014 budget request of $31.331 billion, which is a
    $471 million, or 1.5 percent, increase over fiscal year 2012.
    This budget request will enhance NIH's ability to support
    cutting-edge research and training of the scientific workforce,
    with the ultimate goal of speeding up development of new ways
    to improve human health.
        This request allocates resources to areas of extraordinary
    promise while allowing flexibility to pursue unplanned
    scientific opportunities and address unforeseen health needs.
        But even with these tremendous scientific opportunities
    before us, and our hopes for your support in fiscal year 2014,
    we cannot ignore the current fiscal situation. As the chairman
    has just said, this is a perilous moment.
        As you know, and despite this subcommittee's best efforts
    to avert it, sequestration took effect on March 27. Frankly,
    this has already dealt a devastating blow to NIH and to the
    entire biomedical research enterprise.
        We're absorbing a $1.7 billion cut to our budget--and
    without action by this Congress, that will result, from the
    sequester, in a loss of $19 billion over the next 10 years.

                              NIH PURCHASING POWER

        This graph that I'm showing you shows in blue the
    appropriated levels to NIH and the effects of inflation in
    orange. So including the sequester, which you can see
    identified by this red arrow, that leads to a significant
    downturn in fiscal year 2013, and which we hope will turn back
    up again with the President's budget proposal for 2014, almost
    22 percent of the purchasing power for research has been lost
    versus 10 years ago, as you stated, Mr. Chairman.
        The consequences are stark. Look back at 2003. At that
    point, as a direct result of the efforts of this subcommittee,
    NIH was supporting a total of 38,216 research project grants.
    Now, a decade later, with all the scientific opportunity in
    front of us, that number has fallen by more than 3,300 grants.
    And the drop is particularly severe in fiscal year 2013, where
    we'll be funding 700 fewer new and competing research project
    grants done in fiscal year 2012. Which of those grants might
    have led to the next big discovery in cancer research or
    launched a career of a promising young scientist? We will never
    know.
        The paradox of my directorship at this time of
    unprecedented scientific opportunity, when we should be making
    progress by leaps and bounds towards curing human disease, is
    that our resources are suffering a historic downturn.
        This cut in support in biomedical research in the U.S. is
    particularly troubling when one considers the investments being
    made in the rest of the world, as Senator Moran has referred
    to.

                  WORLDWIDE INVESTMENT IN BIOMEDICAL RESEARCH

        This bar graph is really quite striking, and I don't think
    anyone can look at it without being troubled by its
    significance. It shows the relative increases in support for
    biomedical research by countries around the globe. And you will
    notice the United States stands out on this graph in a very
    troubling way.
        Mr. Chairman, I cannot gloss over the severity of this
    situation. The potential damage to scientific momentum,
    economic growth, and morale is profound.
        Despite these trying times, NIH has continued to pursue our
    mission and has been accelerating scientific discovery in
    several key areas, and I'd like to highlight a couple of those.

                        CANCER: DECREASE IN DEATH RATES

        Let's consider cancer. One person dies from cancer every
    minute in the United States. NIH research has contributed to
    real progress with cancer death rates falling by 1 percent per
    year for the last 15 years, as already cited by Senator Moran.
    Economists estimate that each 1 percent drop is saving the U.S.
    $500 billion, making this an extremely good investment. But we
    are actually positioned to do much more.

                         THE CANCER GENOME ATLAS (TCGA)

        The Cancer Genome Atlas, or TCGA, is a coordinated effort
    to accelerate our understanding of the molecular basis of
    cancer using dramatic advances in genome sequencing
    technologies to carry out comprehensive analysis of more than
    20 types of cancer. By identifying the molecular changes in a
    cancer cell, as compared to a healthy cell of the same
    individual, we are gaining a better understanding of the
    driving forces behind the disease.

                     NIH-FUNDED RESEARCH MAJOR DEVELOPMENTS

        For example, very recently, NIH-funded researchers reported
    a major development. And in a study widely reported in the news
    media, they discovered that the genetic profile of a deadly
    form of uterine cancer closely resembles the profiles of the
    most lethal ovarian and breast cancers. This result has
    dramatic implications for prognosis and treatment.
        And this breakthrough, and others like it, is leading to
    the identification of new therapies tailored to the patient's
    unique genetic profile that can empower personalized
    interventions, and precision medicine instead of one-size-fits-
    all chemotherapy.

                             STEM CELL ADVANCEMENTS

        Another example of how NIH-supported research is advancing
    biomedical discovery is in the area of stem cells. Induced
    pluripotent stem cells, also known as iPS cells, are
    revolutionizing the way we study disease. iPS cells are mature
    cells typically derived from a patient's skin that researchers
    can reprogram back to an immature state. These cells can then
    be programmed into a wide variety of cell types, including
    liver cells, neurons, or blood cells.

        This means we can start with a skin biopsy from a patient
    and then re-create that same individual's disease in a Petri
    dish. We can learn molecular details about the disease and even
    test potential drugs to see if they are likely to be safe and
    effective. It may one day even be possible to use these cells
    therapeutically. You can imagine how this might work, for
    instance, for a disease of the blood, such as sickle cell
    anemia. But we're not stopping there.

                      NEW INITIATIVES IN FISCAL YEAR 2014

        I'd like now to focus on a landmark new scientific endeavor
    that we're planning for fiscal year 2014. Neurological and
    psychiatric disorders such as Alzheimer's disease, Parkinson's
    disease, autism, schizophrenia, epilepsy, and traumatic brain
    injury inflict a tremendous toll on society yet their
    underlying pathology has remained largely unknown due to the
    enormous complexity of the human brain.
        This complexity, built on 86 billion neurons--that's what
    you got up there--each with thousands of connections was once
    thought to be beyond the reach of scientific understanding.
    Today, however, tremendous strides in neuroscience have created
    new opportunities for unlocking these mysteries and have placed
    us in the position of proposing a truly bold new initiative.

                                BRAIN INITIATIVE

        And so in fiscal year 2014, NIH will begin its support of
    the Brain Research through Advancing Innovative
    Neurotechnologies, B-R-A-I-N, the BRAIN Initiative. The goal of
    this initiative is to accelerate the development and
    application of new technologies that will enable researchers to
    produce dynamic pictures of the brain that show how individual
    brain cells and complex neural circuits interact, all at the
    speed of thought.
        To do that, we need to be able to record signals in much
    greater numbers of brain cells at a much more rapid pace than
    is currently possible. And while recent innovations like
    functional magnetic resonance imaging (MRI) have contributed
    substantially to our expanding knowledge of the brain,
    significant breakthroughs on how we treat neurological and
    psychiatric disease will require a new generation of tools.
        By measuring activity at the scale of circuits and networks
    in living organisms, we can begin to translate data into models
    that will decode sensory experience, motor activity, and
    potentially even memory, emotion, and thought. So how do we set
    about doing this?

                            HUMAN CONNECTOME PROJECT

        Another major NIH initiative has already laid the
    groundwork for mapping the human brain, the Human Connectome
    Project. This is an image, a noninvasive image, of a healthy
    human being, using a new kind of MRI. This connectome depends
    upon a dramatic set of advances in MRI scanning, giving this 3-
    D picture of a wiring diagram of nerve cells in your brain.
        Interestingly, this proves that you are more than just your
    deoxyribonucleic acid (DNA). Environmental factors and life
    experiences work in concert with genetics to create your unique
    neural connections. And this is where the BRAIN Initiative
    comes in. It is designed to develop technologies that are
    capable of recording the activity of hundreds of thousands of
    neurons in real time, allowing us to determine the way in which
    brain circuits actually function.

                        BRAIN INITIATIVE: LONG-TERM PLAN

        The BRAIN Initiative is ambitious, and the details of a
    plan that will stretch over a decade or more are being worked
    out. But we must begin now. The BRAIN Initiative will provide a
    better understanding of the roots of human neurological
    disorders, revolutionize the field of neuroscience, and set the
    stage for major advances in diseases that will catalyze the
    development of new treatments and cures.

                              DR. COLLINS' SUMMARY

        So, to sum up, today I've told you about the tremendous
    scientific progress we've already made and a few of the many
    fantastic opportunities that lie on the horizon. However, I
    need to drive home, again, the impact of sequestration.
        Let me close by putting a human face on exactly who is at
    risk during these trying fiscal times.

                           FUTURE OF YOUNG SCIENTISTS

        I recently met with Dina, one of my former superstar
    students, who spent 2 years working in my lab at NIH before
    deciding to go on to graduate school. She's now finishing her
    Ph.D. at MIT and has done spectacular work in developmental
    biology. But she sees what is happening to biomedical research
    in the United States, and she is sufficiently worried about her
    own future to begin to consider other options quite seriously.
        In fact, many of her contemporaries have begun looking for
    options outside of science or outside of this country. She
    wrote me these words after our recent meeting: ``Many of my
    role models--top scientists with amazing ideas and the
    potential to change the world--are unable to get funding. I
    can't erase the fear that this is my future.''

                              PREPARED STATEMENTS

        This is a defining moment. My fear is that we're putting an
    entire generation of U.S. scientists at risk. And if they go
    away, they won't come back.
        Sequestration is compromising the future of biomedical
    research and slowing improvement in the health of all
    Americans.
        So, thank you, Mr. Chairman. I look forward to answering
    any questions you and this committee may have.
        [The statements follows:]

             Prepared Statement of Francis S. Collins, M.D., Ph.D.

        Good afternoon, Mr. Chairman and distinguished members of the
    subcommittee. I am Francis S. Collins, M.D., Ph.D., and I am the
    Director of the National Institutes of Health (NIH). Accompanying me
    today are: Anthony S. Fauci, M.D., Director of the National Institute
    of Allergy and Infectious Diseases; Gary H. Gibbons, M.D., Director of
    the National Heart, Lung, and Blood Institute; Richard J. Hodes, M.D.,
    Director of the National Institute on Aging; Story C. Landis, Ph.D.,
    Director of the National Institute for Neurological Disorders and
    Stroke; and Harold E. Varmus, M.D., Director of the National Cancer
    Institute.
        It is an honor to appear before you today to present the
    Administration's fiscal year 2014 budget request for the NIH.
        NIH's mission is to seek fundamental knowledge about the nature and
    behavior of living systems and to apply that knowledge to enhance human
    health, lengthen life, and reduce illness and disability. I can report
    to you that NIH leadership, employees, and grantees continue to believe
    passionately in our mission.
        NIH has been advancing our understanding of health and disease for
    more than a century, and scientific and technological breakthroughs
    generated by NIH-supported research are behind much of the gains this
    country has enjoyed in public health. For example, deaths from heart
    attack have fallen by more than 60 percent over the past 40 years;
    deaths from stroke by more than 70 percent. HIV/AIDS treatment and
    prevention may now enable us to envision the first AIDS-free generation
    since this virus emerged more than 30 years ago. More than 90 percent
    of children diagnosed today with the most common form of childhood
    leukemia will survive. NIH research has given us vaccines for cervical
    cancer, influenza, and meningitis. We can look forward to a future in
    which advanced prevention and treatment strategies such as these allow
    everyone to have a much better chance of living a long and healthy
    life.
        I would like to begin today by highlighting just a few areas in
    which NIH-supported research is opening up extraordinary new
    opportunities to improve the health of the American public.
        Let's consider cancer. One person dies from cancer every minute in
    the United States--that equates to 1,500 deaths every day, the
    equivalent of five crashing jumbo jets.\1\ NIH research has contributed
    to real progress, with cancer death rates falling by 1 percent per year
    for the past 15 years--but we aim to do much more. With the National
    Cancer Institute (NCI) and the National Human Genome Research Institute
    (NHGRI) as leads, NIH established The Cancer Genome Atlas (TCGA) as a
    coordinated effort to accelerate our understanding of the molecular
    basis of cancer, using dramatic advances in genome sequencing
    technologies to carry out comprehensive genomic analysis of more than
    20 types of cancer. By identifying the molecular changes in a cancer
    cell as compared to a healthy cell of the same individual, we are
    gaining a better understanding of the driving forces behind the
    disease. That is leading to identification of new drug targets, as well
    as of subsets of disease with different responses to therapy that can
    empower personalized interventions instead of one-size-fits-all
    chemotherapy. As an example, a TCGA research network of investigators
    recently identified promising new therapeutic targets in squamous cell
    carcinoma of the lung, the second most common form of lung cancer,
    including three families of enzymes that act as molecular switches.\2\
    These findings lay the foundation for the development and
    implementation of advanced diagnostics and treatments for squamous cell
    cancer. Moreover, they underscore the value and promise of our Nation's
    investment in TCGA.
        Another new and exciting area of basic research is the Human
    Microbiome Project. Microbes inhabit many parts of the human body and
    have often had a bad reputation for causing sickness. But more often
    than not, they actually contribute to the health of their human hosts.
    In a 5-year endeavor supported by the NIH Common Fund, 200 scientists
    at 80 institutions sequenced the genomes of bacteria from multiple body
    sites of 250 individuals, with striking results. The research showed
    that certain communities of bacteria help keep people healthy, whereas
    others appear to make people more susceptible to disease.\3\ When the
    bacterial population in the intestinal tract gets disrupted, chronic
    conditions such as obesity can result; this new understanding may
    provide us with novel ways to address this serious health threat. An
    unexpected result from another NIH-funded study was that poor diet is
    not the only contributor to malnutrition. In fact, a bad assortment of
    microbes in the gut can conspire with a nutrient deficient diet to lead
    to severe malnutrition.\4\
        A final example I want to provide of how NIH-supported research is
    accelerating scientific discovery is in the area of stem cells. Induced
    pluripotent stem (iPS) cell technology is revolutionizing the way we
    study disease, and holds the promise of dramatic advances in treatment.
    iPS cells are patient-derived cells, typically from skin, that
    scientists can reprogram back to an embryonic stem cell-like state.
    These cells can then be induced to turn on specific sets of genes to
    differentiate into a variety of cell types, including blood cells,
    liver cells, or neurons. This means researchers can re-create a
    patient's disease in a dish and screen drug compounds against the
    cells--rather than the patient--to determine drug toxicity and
    efficacy. But it's also possible that these cells could be used
    therapeutically, especially if an individual's genetic misspellings
    could be corrected in their own iPS cells, and then programmed and
    delivered to a tissue where they are sorely needed. Recent NIH-funded
    studies have developed copy-editing enzymes that are making it faster,
    easier, and cheaper to correct genetic typos. In 2011, researchers used
    a specially engineered copy-editing enzyme to find and correct the
    mutation that causes sickle cell anemia using iPS cells derived from a
    patient with the disease.\5\ Two very recent, groundbreaking
    discoveries along this same avenue are the development of the next
    generation methodology of ``find and replace'' enzymes that are making
    it much simpler to copy-edit the genome.\6\ \7\
        While these exciting findings have led to a much deeper
    understanding of health and human disease, much more work needs to be
    done in order to move these strategies and others like them out of the
    lab and into the clinic--and to do so as quickly as possible. To this
    end, the Administration's fiscal year 2014 budget request for the NIH
    is $31.331 billion, $471 million above the fiscal year 2012 level. This
    budget request reflects the President's and the Secretary's commitment
    to improving the health of the Nation and to maintaining our Nation's
    leadership in the life sciences. The request highlights investments in
    innovative research that will advance fundamental knowledge and speed
    the development of new therapies, diagnostics, and preventive measures
    to improve public health.
        The fiscal year 2014 budget request, a 1.5-percent increase over
    fiscal year 2012, will enhance NIH's ability to support cutting-edge
    research and training of the scientific workforce. Within the
    Administration's fiscal year 2014 budget, we will continue to increase
    Research Project Grants (RPGs), NIH's funding mechanism for
    investigator-initiated research. NIH expects to support 10,269
    competing RPGs in fiscal year 2014, an increase of 1,283 over fiscal
    year 2012 levels. For fiscal year 2014, NIH anticipates funding a total
    of 36,610 RPGs. The budget request allocates resources to areas of the
    most extraordinary promise for biomedical research, while maintaining
    the flexibility to pursue unplanned scientific opportunities and
    address unforeseen health needs.
        A major initiative for NIH in fiscal year 2014 will be in the area
    of Alzheimer's disease research. As many as 5.1 million Americans
    suffer this irreversible, progressive, and devastating brain disease
    that slowly destroys cognitive functions including memory and the
    ability to reason and think.\8\ At the same time, millions of American
    families struggle with the physical, emotional, and financial costs of
    caring for a loved one with Alzheimer's. A recently published NIH-
    supported study found the costs of caring for people with dementia in
    the United States in 2010 ranged from $157 billion to $215 billion.\9\
    This disease is not just a burden on our health, but also a burden on
    our economy.
        NIH, with the National Institute on Aging (NIA) taking the lead,
    currently supports a number of studies aimed at understanding,
    diagnosing, preventing, and treating Alzheimer's disease. In fiscal
    year 2014, NIA would plan to award a total of 591 new and competing
    RPGs, an increase of 277 from fiscal year 2012. This includes an $80
    million increase for Alzheimer's research.
        A seminal finding that has recently generated a lot of excitement
    is the discovery that the protein, tau, which appears to be in part
    responsible for the cognitive decline in Alzheimer's patients, spreads
    from neuron to neuron like an infection.\10\ This means that if
    researchers could find a way to prevent cell-to-cell transmission,
    perhaps by blocking tau with an antibody, the disease process could be
    halted. There is also growing evidence that successful treatment of
    Alzheimer's disease needs to happen very early in the course of the
    disease, perhaps even before any symptoms have appeared at all. This
    kind of Alzheimer's disease prevention is at the heart of new clinical
    trials being conducted by scientists at the Dominant Inherited
    Alzheimer's Network (DIAN), a NIA-funded international research
    partnership. One of the investigational drugs being tested is a
    monoclonal antibody that binds to certain forms of amyloid beta, a main
    constituent of the signature plaques in Alzheimer's disease. Trying to
    prevent Alzheimer's symptoms from ever occurring in individuals at very
    high genetic risk is a new strategy--one that we are eager to pursue in
    order to determine if early intervention can influence this terrible
    disease.
        With advancing scientific and technological capabilities, such as
    genome sequencing machines and high resolution medical imagers,
    biomedical researchers are generating huge amounts of data at an
    unprecedented pace. The need to integrate and analyze massively complex
    datasets is referred to as the Big Data challenge--a challenge that we
    must overcome to gain a deeper understanding of disease and develop the
    next generation of therapeutic targets.
        Managing Big Data is a critical part of translating scientific
    discoveries into clinical applications. To address this challenge, NIH
    is developing the Big Data to Knowledge (BD2K) program, which will be
    launched in fiscal year 2014. BD2K will support four programmatic
    efforts: (1) facilitate the broad use and sharing of large, complex
    biomedical data sets through the development of policies, resources and
    standards; (2) develop and disseminate new analytical methods and
    software; (3) enhance training of data scientists, computer engineers,
    and bioinformaticians; and (4) establish Centers of Excellence to
    develop generalizable approaches that address important problems in
    biomedical analytics, computational biology, and medical informatics.
    In fiscal year 2014, NIH will invest at least $40 million in the BD2K
    program through the Common Fund, and each Big Data Center of Excellence
    will be funded at $2 million to $5 million per year for 3 to 5 years.
    As Big Data challenges in biomedical research are shared with other
    areas of scientific research such as energy and space research, BD2K
    will also require effective collaboration and coordination with other
    Government agencies tackling similar challenges, including the National
    Science Foundation and the Department of Energy, as well as privately
    funded efforts. With the proper investments and efforts, we will
    overcome the challenges associated with Big Data in order to accelerate
    the translation of bench to bedside applications.
        Another exciting new initiative I would like to tell you about is
    NIH's efforts to recruit and retain a diverse pool of scientific talent
    and creativity. NIH is strongly committed to maintaining a diverse
    biomedical research workforce and has supported programs to enhance the
    diversity of our workforce for more than 30 years in order to achieve
    this goal. While progress has been made in some areas, more work needs
    to be done. The centerpiece of the newest initiative is the BUilding
    Infrastructure Leading to Diversity (BUILD) Program that is designed to
    provide relatively under-resourced institutions with the opportunity to
    provide a series of rigorous, mentored research experiences to their
    students, many of whom are from backgrounds underrepresented in
    biomedical research, with the goal of facilitating entry of a more
    diverse pool of students into graduate programs for biomedical
    research.
        I want to emphasize that while all of these ambitious new
    scientific endeavors provide unprecedented promise for advancing human
    health, we cannot ignore the impact the sequester is having on
    groundbreaking medical research. The fiscal year 2013 reduction of $1.6
    billion, or 5.0 percent, is having a substantial impact on the
    scientific community. If the Budget Control Act-imposed caps on
    discretionary programs continue, and NIH funding is reduced
    proportionally over the next 10 years, funding will decline by about
    $19 billion. The consequences will be harmful to scientific progress
    and to American leadership in science. NIH-funded investigators are
    already feeling the effects as Institutes and Centers are forced to
    fund a lower percentage of grant applications. In fiscal year 2012, we
    funded 8,986 competing RPGs. In fiscal year 2013, our projection is
    8,283. This trend is also reflected in our total research portfolio--we
    expect to fund 34,902 RPGs this year compared to 36,259 in fiscal year
    2012. With this new reality, more and more investigators will be unable
    to pursue the bold ideas that NIH has traditionally supported.
        NIH plays a significant role in the U.S. economy by advancing
    scientific products and technologies that help maintain our Nation's
    role as a global innovation leader.\11\ At a time when global
    competition in the life sciences is intensifying, the American economy
    cannot afford to lose ground in scientific efforts that promote human
    health. Countries such as China and India are increasingly investing
    resources into biomedical science and technology. According to the
    Organization for Economic Cooperation and Development (OECD), in 2008,
    including both public and private sources, the U.S. invested 2.8
    percent of its GDP in research and development (R&D)--less than Israel,
    Japan, Korea, Sweden, and Switzerland. Moreover, the U.S. ranks only
    eighth in R&D as a share of GDP among countries in the OECD.\12\ China
    has made policy changes to invest heavily in the life sciences
    industry, moving them closer to becoming a world leader in science and
    technology by the end of the decade.\13\ Over the past decade,
    Singapore has also pursued a prominent role as a global leader in the
    life sciences. For example, their pharmaceutical industry R&D funding
    was five times greater than that of the U.S. in 2009, on a share of GDP
    basis. Despite these factors, the United States is by far the largest
    R&D performer globally, contributing $402 billion in 2009, accounting
    for about 31 percent of the global total.\14\
        But let me close on a more positive note. I began today by telling
    you about some exciting new initiatives NIH is planning for fiscal year
    2014. Now I want to tell you about our boldest new scientific
    endeavor--one that we are all very excited about.
        Neurological and psychiatric disorders such as Alzheimer's disease,
    Parkinson's disease, autism, schizophrenia, and traumatic brain injury
    inflict a tremendous toll on society, yet their underlying pathologies
    remain unknown due to the great complexity of the human brain. This
    complexity was once thought to be beyond the reach of scientific
    understanding. Today, however, tremendous strides in neuroscience have
    brought forward remarkable new opportunities for unlocking these
    mysteries.
        Indeed, neuroscience has made some extraordinary progress in recent
    years. For example, a group of NIH-supported researchers has developed
    a sophisticated neural interface that enables paralyzed people to move
    a robotic arm, using just their thoughts. Using this robotic arm
    system, 58-year-old Cathy Hutchinson recently was able to take a sip of
    coffee on her own for the first time since she'd been paralyzed more
    than 14 years earlier. A truly remarkable moment--but just a beginning,
    because we need a lot more of these moments for a whole lot more
    people.
        In fiscal year 2014, NIH will begin its support of the Brain
    Research through Advancing Innovative Neurotechnologies (BRAIN)
    Initiative, in order to develop a deeper understanding of brain
    function through the creation of new tools capable of examining the
    activity of millions of nerve cells, networks, and pathways in real
    time. By measuring activity at the scale of circuits and networks in
    living organisms, we can begin to translate data into models that will
    decode sensory experience, motor planning, and, potentially, even
    memory, emotion, and thought. NIH is embracing a collaborative approach
    in tackling this challenge, working with researchers from across the
    country, industry, foundations, and other Government agencies including
    the Defense Advanced Research Projects Agency and the National Science
    Foundation. In fiscal year 2014, NIH will invest $40 million in this
    initiative to leverage investment from a number of other sources,
    including private sector and leading philanthropies. We believe that
    successful completion of the BRAIN Initiative will revolutionize the
    field of neuroscience and set the stage for major advances in diseases
    such as Alzheimer's, Parkinson's, autism, schizophrenia, depression,
    and epilepsy.
        Granted, this is a very ambitious goal. But we at NIH have heard
    and overcome such skepticism before. Take the example of the Human
    Genome Project, which I had the privilege to lead. In its earliest
    days, back in the late 1980s, many questioned the wisdom of that
    proposal to sequence the 3 billion letters in the human genetic
    blueprint. Nearly everyone in the research community agreed that it
    would be fantastic to have a full readout of the human DNA instruction
    book. But skeptics argued that it could not be done because the tools
    and technologies didn't exist. In fact, they were right--we didn't have
    the necessary technologies. But, the opportunity for dramatic progress
    in genetics inspired a remarkable series of technical innovations.
    These tools enabled the Human Genome Project to be successfully
    completed in April 2003, ahead of schedule and under budget. Like the
    Human Genome Project, we envision the BRAIN Initiative will create
    data, tools, and technologies that will speed the efforts of many
    different types of researchers all around the world. Though this
    program will need to extend over many years, and we must be careful not
    to overpromise immediate medical benefits, BRAIN will eventually lead
    to scientific advances that will catalyze development of new treatments
    and cures.
        I have provided you today with a brief overview of NIH's past
    successes and continuing commitment to basic and translational science,
    as well as a glimpse into the critical role that NIH plays in our
    domestic and global economies. We have never witnessed a time of
    greater promise for advances in medicine than right now. With your
    support, the future of medicine will be very bright.
        This concludes my testimony, Mr. Chairman.
    ---------------------------------------------------------------------------
        \1\ http://cancergenome.nih.gov/PublishedContent/Files/pdfs/
    1.1.0_CancerGenomics_TCGA-Genomics-Brochure-508.pdf.
        \2\ http://www.nature.com/nature/journal/v489/n7417/pdf/
    nature11404.pdf.
        \3\ http://www.nature.com/nature/journal/v486/n7402/pdf/
    nature11209.pdf.
        \4\ http://www.sciencemag.org/content/339/6119/548.full.pdf.
        \5\ http://onlinelibrary.wiley.com/doi/10.1002/stem.718/pdf.
        \6\ http://www.sciencemag.org/content/326/5959/1501.full.pdf.
        \7\ http://www.sciencemag.org/content/339/6121/819.full.pdf.
        \8\ http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics.
        \9\ http://www.nejm.org/doi/pdf/10.1056/NEJMsa1204629.
        \10\ http://www.plosone.org/article/
    info%3Adoi%2F10.1371%2Fjournal.pone.0031302.
        \11\ http://www.unitedformedicalresearch.com/wp-content/uploads/
    2013/02/UMR_Impact_of_
    Sequestration_2013.pdf.
        \12\ http://www.itif.org/publications/winning-race-2012-memos-
    science-and-technology.
        \13\ http://www.itif.org/publications/leadership-decline-assessing-
    us-international-
    competitiveness-biomedical-research.
        \14\ http://www.nsf.gov/statistics/seind12/c4/c4s8.htm.
    ---------------------------------------------------------------------------
                                     ______

                  Prepared Statement of Anthony S. Fauci, M.D.

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Allergy
    and Infectious Diseases (NIAID) of the National Institutes of Health
    (NIH). The fiscal year 2014 NIAID budget of $4,578,813,000 includes an
    increase of $96,444,000 over the comparable fiscal year 2012 level of
    $4,482,369,000.
        NIAID conducts basic and clinical research with the ultimate goal
    of improving human health through the development of diagnostics,
    therapeutics, and vaccines for infectious diseases; and to increase our
    understanding of the immune system, how it protects us from infection
    and disease, and its role in immune-mediated diseases. NIAID also
    addresses the scientific challenges that arise from emerging and re-
    emerging infectious diseases, including influenza, HIV/AIDS,
    tuberculosis, and malaria.

                          INFECTIOUS DISEASES RESEARCH

        HIV/AIDS.--Through more than 30 years of supporting and conducting
    basic and clinical research, NIAID has provided the scientific
    foundation for groundbreaking interventions and strategies to treat and
    prevent HIV/AIDS, including combination antiretroviral therapy (ART),
    pre-exposure prophylaxis (PrEP), medical male circumcision, prevention
    of mother-to-child transmission (PMTCT), microbicides, and
    antiretroviral treatment as prevention. It is an exciting time in the
    domestic and global fight against HIV/AIDS, and NIAID continues to
    support research critical to a goal now within our reach: an AIDS-free
    generation. The NIAID-funded HPTN-052 clinical trial--the ``Science''
    magazine 2011 Breakthrough of the Year--conclusively demonstrated that
    treatment of the HIV-infected person in a stable heterosexual
    relationship with an uninfected partner dramatically reduces the
    likelihood of transmitting HIV to the uninfected partner. Recently,
    based upon results of the NIAID-funded iPrEx study and other research,
    the Food and Drug Administration (FDA) approved the ART combination
    drug Truvada as a prevention tool for uninfected adults at high risk
    of acquiring HIV. Ongoing NIAID studies of PrEP, microbicides, and
    PMTCT are exploring new strategies to limit HIV transmission in various
    populations; one study (TLC-Plus) is evaluating the feasibility of a
    community-level ``testing, link to care, and treatment'' strategy; and
    the new population-based ART study (PopART) will determine the effects
    of universal testing and immediate ART on HIV transmission.
        NIAID continues its longstanding efforts to develop an effective
    HIV vaccine. NIAID is currently investigating the reasons for the
    modest efficacy (31 percent protection) of the HIV vaccine candidates
    used in the RV-144 clinical trial conducted in Thailand several years
    ago, and will seek to achieve significantly better results with future
    vaccine candidates. In this regard, NIAID has funded two new HIV
    vaccine initiatives and also is moving into Phase I clinical trials to
    determine if passively transferred neutralizing antibodies can protect
    against HIV infection.
        Tuberculosis and Malaria.--Drug-resistant forms of tuberculosis
    (TB) are emerging worldwide, and co-infection with TB and HIV is a
    major cause of morbidity and mortality in the developing world. NIAID
    is helping to bring TB research into the 21st century by applying
    microbial genomic sequencing technologies, investing in the basic
    science underlying point-of-care diagnostics, supporting research to
    develop vaccine candidates, and engaging in public-private partnerships
    for drug development. These efforts are bearing fruit: NIAID
    researchers showed the potential of linezolid (originally developed for
    staphyloccocal infections) as a treatment for extensively drug-
    resistant TB, and FDA recently approved the first new TB drug
    (bedaquiline) in decades.
        NIAID continues its work to combat malaria. To counter the emerging
    resistance to artemesinin, a first-line malaria drug, NIAID scientists
    have identified a region in the genome of the parasite linked to
    artemesinin resistance. NIAID is pursuing its promising efforts to
    develop candidate malaria vaccines, including studies conducted at the
    NIH Clinical Center.
        Other Infectious Diseases of Domestic and Global Health
    Importance.--Events in the news remind us almost on a daily basis of
    the global threat of emerging and re-emerging infectious diseases.
    Paramount among these are seasonal influenza and potential pandemic
    influenza threats, such as the H7N9 influenza emerging in China. NIAID
    conducts research on the pathogenesis and transmissibility of
    influenza, and the emergence of epidemics and pandemics, with the goal
    of furthering the development of influenza diagnostics, therapeutics,
    and vaccines. We have made significant strides toward developing a
    universal influenza vaccine, which would obviate the need for annual
    influenza vaccination and enhance our ability to respond to the
    emergence of influenza pandemics. Though it will be years before this
    goal is achieved, NIAID grantees and scientists, including those at
    NIAID's Vaccine Research Center, have demonstrated success in animal
    models, and have begun Phase I trials in humans. In addition, the NIAID
    Human Immunology Project Consortium is characterizing human immune
    responses to improve vaccines and immunotherapeutics for a variety of
    infectious diseases, including influenza.
        NIAID scientists have developed an animal model to study the novel
    coronavirus recently identified in Saudi Arabia, and to evaluate
    potential treatments and vaccines. They have shown recently that a
    combination of two antiviral drugs, ribavirin and interferon, can
    inhibit replication of the virus in cell culture.
        Common microbial infections are increasingly becoming resistant to
    the drugs generally used to treat them. Methicillin-resistant
    ``Staphyloccus aureus'' (MRSA) has been a longstanding problem. Of
    particular concern is the recent emergence of other antibiotic-
    resistant organisms such as the carbapenem-resistant Enterobacteriaceae
    (CRE) including ``Klebsiella pneumoniae''. To address the challenge of
    antimicrobial resistance, NIAID continues its efforts in the
    development and testing of vaccines to prevent these infections, and in
    the evaluation of new and repurposed drugs to treat antimicrobial-
    resistant organisms. This year, NIAID will establish a leadership group
    for a national network to conduct clinical research on antibacterial
    resistance.
        We are witnessing rapid changes in the treatment of hepatitis C
    virus (HCV), a major cause of chronic liver disease and a common co-
    infection with HIV. Promising new HCV protease inhibitor drugs recently
    approved by FDA were developed with the help of NIAID and other NIH
    Institutes. NIAID also is collaborating with industry to develop new
    HCV therapeutics and vaccines, and to test approved drugs in
    individuals with HCV/HIV co-infection.
        NIAID biodefense research continues to build on our fundamental
    understanding of the biology of and immune response to microbes. Recent
    successes include FDA approval of a monoclonal antibody to treat
    anthrax and progress on vaccines against Ebola and other hemorrhagic
    fever viruses. NIAID biodefense research also addresses the global
    threat of emerging and re-emerging diseases, including the development
    of vaccines for dengue fever and animal models to study West Nile
    virus.

              RESEARCH ON IMMUNOLOGY AND IMMUNE-MEDIATED DISORDERS

        NIAID remains committed to basic and clinical research on the
    immune system and immune-mediated diseases, including the development
    and testing of adjuvants to enhance the immune response to vaccination.
    NIAID also supports groundbreaking studies in the treatment of food
    allergy, a significant concern for many Americans. Recently, NIAID-
    funded scientists found that oral egg immunotherapy can reduce and even
    eliminate allergic responses for extended periods in certain children.
    Similarly promising results showed that peanut immunotherapy given
    under the tongue can reduce the allergic response in adolescents and
    adults.

                                   CONCLUSION

        NIAID conducts critical research on infectious and immune-mediated
    diseases that ultimately will enable interventions to improve health
    domestically and worldwide. Understanding and developing
    countermeasures against microbes that threaten our public health is
    central to NIAID's mission. NIAID will continue to fund meritorious
    basic and clinical research with the ultimate goal of translating these
    discoveries into global public health benefits.
                                     ______

                  Prepared Statement of Gary H. Gibbons, M.D.

        Mr. Chairman and distinguished members of the subcommittee: I am
    pleased to present the President's budget request for the National
    Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of
    Health (NIH). The fiscal year 2014 budget of $3,098,508,000 includes an
    increase of $25,206,000 over the comparable fiscal year 2012 level of
    $3,073,302,000.
        NHLBI leads research and education programs to discover and apply
    knowledge to improve health by preventing and treating heart, lung, and
    blood diseases. It is a privilege to serve as NHLBI Director in this
    time of unprecedented opportunity in biomedical research. Today, I will
    discuss new opportunities to reduce health disparities, advance
    understanding of complex chronic diseases, and enhance clinical
    research.

                          HEALTH DISPARITIES RESEARCH

        The NHLBI portfolio includes studies of many diseases that impose
    strikingly disparate burdens on Americans from different walks of life.
    Understanding and alleviating health disparities has been a passion of
    mine throughout my career, and I am honored to lead an Institute with
    such a longstanding commitment to supporting work in that area. Many of
    you are familiar with the NHLBI's large epidemiological studies that
    focus on minority populations, including the Jackson Heart Study in
    African Americans, the Hispanic Community Health Study, the Multi-
    Ethnic Study of Atherosclerosis, which includes a sizeable cohort of
    Asian Americans, and the Strong Heart study in American Indians. Our
    recent investments in genotyping of diverse cohorts promise to shed
    critical light on biological differences in disease susceptibility as
    well as the interactions between genes and environment as determinants
    of health among all Americans. We also have an outstanding record of
    including substantial numbers of minorities in our clinical research,
    particularly in studies of high blood pressure, which appears with
    great frequency and often devastating complications in African
    Americans.
        Efforts to date have yielded progress that has benefited most
    people to some extent but, unfortunately, has done little to close the
    gaps that persist between the healthiest and least healthy segments of
    society. Because health disparities are complex and are clearly
    influenced not only by genetics but also by factors such as family,
    social community, and physical environment, we believe that they offer
    an excellent model for a new ``systems'' approach to our research
    strategy. Until recently scientists have had to consider such factors
    separately; for instance, one researcher might look at basic biological
    pathways or genetic factors, while another examines lifestyle choices
    and a third considers socioeconomic influences. This piecemeal approach
    provides a limited view of how disease occurs and, more important, how
    it can be prevented or managed effectively. To revolutionize our
    understanding of health and disease, we are now developing and
    exploiting new tools that enable consideration of many factors--
    biological, behavioral, environmental--together in a holistic way.
    That, I believe, is the path to future progress in preventing and pre-
    empting chronic heart, lung, and blood disorders. If we can develop the
    ``systems'' research model for health disparities research we can
    transform both science and medicine by applying it more broadly to
    other public health needs.

               A NEW PARADIGM FOR UNDERSTANDING COMPLEX DISEASES

        Let me give you one example of recent findings that highlight the
    value of a cross-disciplinary approach. We have known for decades that
    the foods we eat influence our risk of developing cardiovascular
    disease (CVD). Observational studies have taught us the value of so-
    called heart-healthy diets that emphasize fruits, vegetables, whole
    grains, fish, and ``good'' fats such as olive oil. Nevertheless,
    controversies persist about the potential harmful effects of red meat
    consumption. Scientists still don't know why certain foods increase or
    reduce the risk of CVD.
        Recently, a provocative series of NHLBI-funded studies provided
    some important new insights into the potential link between red meat
    consumption and atherosclerotic CVD. Researchers have shown that the
    bacteria that reside in our guts and metabolize L-carnitine, a
    substance found in red meat, may be an important culprit behind CVD.
    This interaction between diet and gut microbes leads to the production
    of TMAO (trimethylamine-N-oxide), an organic compound that circulates
    in the blood and promotes the ``clogging of arteries'' by inhibiting
    the removal of cholesterol from atherosclerotic plaque.
        This and other work is dramatically enhancing our view of how the
    trillions of microbes that co-exist in and around our bodies contribute
    to both health and disease. The research perfectly illustrates a
    ``systems'' approach that interactively integrates studies in mice as
    well as large-scale population science and smaller-scale human studies.
    It provides an entirely new and critical understanding of the dynamic
    interplay between the factors that predispose patients to CVD.

                          ENHANCING CLINICAL RESEARCH

        As we work to integrate our research efforts across multiple
    disciplines, we are placing particular emphasis on ensuring that our
    clinical research is robust. A major challenge is to enhance clinical
    trials, which provide critical evaluation of new preventive and
    therapeutic approaches but are, arguably, some of our most challenging
    and expensive undertakings. In recent years, the NHLBI has been
    exploring ways to make trials more efficient and more applicable to
    real-world clinical settings. Moving forward, we plan to build on past
    successes while capitalizing on new technologies and data sources, such
    as electronic medical records.
        For many years, the NHLBI has used a network model to increase the
    efficiency of clinical trials. Our networks have a strong track record
    of conducting multiple, multi-center, clinical trials using
    standardized operations and sustainable infrastructures that minimize
    the time required to start new studies. They span a wide range of
    topics, such as asthma, cardiovascular cell therapy, pediatric heart
    disease, heart failure, childhood obesity, and transfusion medicine. A
    major problem facing our healthcare system is the costly cycle of
    chronic disease care that is characterized by persistent debilitating
    symptoms, hospitalizations for acute exacerbations of the condition,
    eventual hospital discharge, and then subsequent re-hospitalizations.
    To address this clinical practice challenge, the NHLBI is supporting
    innovation in discovery science that holds promise for breaking this
    vicious cycle of chronic heart, lung, and blood disorders. In 2014, we
    will pilot a new network structure to evaluate treatment strategies for
    acute, serious lung conditions--such as exacerbations of chronic
    obstructive pulmonary disease--that require hospitalization. If the new
    model proves successful we will apply it to clinical trials of other
    chronic diseases that are treated in inpatient clinical settings.
        Another cost-effective strategy that the NHLBI has used very
    successfully is funding ancillary studies piggybacked onto trials to
    maximize return on investment. For example an NHLBI-funded clinical
    trial demonstrating that aspirin reduces the risk of heart attack also
    included ancillary studies that sought to identify new risk factors for
    CVD. These ancillary discovery science projects superimposed on the
    original clinical trial yielded strong evidence that elevated levels of
    a marker for inflammation called c-reactive protein are correlated with
    CVD events. The insights gained from the original clinical trial and
    subsequent ancillary studies have led to an innovative strategy to
    reduce CVD that targets the inflammatory process as a causative factor
    in heart attacks. Accordingly, the NHLBI recently funded the
    Cardiovascular Inflammation Reduction Trial to determine whether
    treatment with the anti-inflammation drug methotrexate, which is
    commonly prescribed for rheumatoid arthritis, reduces the risk of heart
    attacks and strokes. Taken together, these studies illustrate the
    NHLBI's ongoing efforts to enhance the efficiency and return-on-
    investment of our clinical trial portfolio so that advances in the
    practice of medicine are translated into healthier lives for all
    Americans.
        We also are pursuing new opportunities to conduct trials that are
    bigger, but simpler, with clinically relevant end points that leverage
    routine medical care and existing data in electronic medical records
    and registries. By using electronic health records data from real-world
    clinical practice, we hope not only to make trials more relevant to
    clinical practice, but also to make the results more robust and
    reproducible by including hundreds of thousands of participants. In
    fiscal year 2014, the Institute will explore the use of electronic
    medical records in clinical trials through a new initiative to compare
    the ability of two data sources, electronic health records and
    traditional prospective patient-based clinical and research data, to
    answer research questions about pediatric pulmonary vascular diseases.
    We anticipate that these innovations that enhance the cost-
    effectiveness of NHLBI's approach to supporting clinical research will
    yield additional new discoveries that have a dramatic impact on the
    health outcomes of patients with chronic heart, lung, and blood
    disorders.
                                     ______

                  Prepared Statement of Richard J. Hodes, M.D.

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute on Aging
    (NIA) of the National Institutes of Health (NIH). The fiscal year 2014
    budget includes $1,193,370,000, which is $72,979,000 more than the
    comparable fiscal year 2012 level of $1,120,391,000.
        More than 40 million people age 65 and older live in the United
    States, and data from the Federal Interagency Forum on Aging-Related
    Statistics indicate that their numbers will double by 2040. In less
    than 50 years, the number of ``oldest old''--people ages 85 and older--
    may quadruple. As record numbers of Americans reach older age, profound
    changes will occur in our health care and social systems.
        NIA leads the national effort to understand aging and to identify
    and develop interventions that will help older adults enjoy robust
    health and independence, remain physically active, and continue to make
    positive contributions to their families and communities. We support
    genetic, biological, clinical, behavioral, and social research related
    to the aging process, healthy aging, and diseases and conditions that
    often increase with age. We also carry out the crucial task of training
    the next generation of researchers who specialize in the issues of
    aging and old age. Finally, we support a vibrant program of basic,
    clinical, and translational research through our Intramural Research
    Program, which underwent a revision in 2013, to recognize new paradigms
    in the field of aging research and integrate laboratories and resources
    in a way that will more efficiently foster discovery.

             IMPROVING THE HEALTH AND WELL-BEING OF OLDER AMERICANS

        Life expectancy in the developed world has improved dramatically
    over the last century, and advances in public health and medicine are
    allowing people to stay healthier longer. But, since 1980, U.S. life
    expectancy, especially for women, has lagged behind other wealthy
    nations, and cross-national studies suggest that older Americans get
    sicker sooner than older Europeans. Similar disparities in health and
    longevity exist across geographical areas within the United States. NIA
    has established an initiative to identify and address the behaviors and
    social circumstances behind these differences.
        NIA-supported investigators are continuing to work to identify the
    optimal means to address the unique health needs of older individuals.
    For example, studies have shown that regular physical activity can
    improve physical performance in older people, and with the U.S. Surgeon
    General, NIA has launched its nationwide ``Go4Life'' campaign to
    motivate older Americans to engage in physical activity and exercise.
    However, definitive evidence that physical activity can prevent
    mobility disability is lacking, and NIA supports the Lifestyle
    Interventions and Independence for Elders Study to assess whether a
    specific physical activity program can prevent disability in sedentary
    older individuals.
        NIA-supported investigators are also testing interventions for
    health conditions common to old age. For example, the Centers for
    Disease Control and Prevention reports that fully half of older
    Americans have at least two chronic health conditions that compromise
    quality of life. NIA participates in a trans-NIH initiative to develop
    interventions to modify behavior and improve health outcomes among
    individuals with multiple chronic conditions. In addition, NIA supports
    research on rehabilitation from a number of acute and chronic
    conditions, including the development and pilot testing of a smart
    phone-based self-management system for older patients with heart
    failure and development of a unique biomaterial that can act as a
    temporary replacement for both bone and cartilage. Other ongoing
    studies include the ASPirin in Reducing Events in the Elderly (ASPREE)
    trial to determine whether the benefits of aspirin outweigh the risks
    in people over 70; testosterone supplementation to delay or prevent
    frailty in older men; exercise for mood, health, and cognition; and
    several interventions for menopausal symptoms.

                     THE FIGHT AGAINST ALZHEIMER'S DISEASE

        It is estimated that as many as 5 million people in the United
    States aged 65 and older currently have Alzheimer's disease (AD), and
    annual costs of care for dementia, of which Alzheimer's is the most
    common cause, have been calculated using data from the Health and
    Retirement Study at between $157 billion and $215 billion among people
    70 and older. Unless effective treatment or preventive interventions
    are identified, these numbers will rise significantly as the number of
    older Americans continues to increase. NIA has been a leader in the
    implementation of the National Alzheimer's Project Act and the
    development of the National Plan to Address Alzheimer's Disease. Recent
    initiatives have boosted support for AD research, including the NIH
    Director's allocation of an additional $50 million in fiscal year 2012
    and $40 million in fiscal year 2013 for the disease. In the fiscal year
    2014 President's budget request for NIA, $80 million of the increase
    planned for competing research project grants will be devoted to
    Alzheimer's disease projects, in response to recommendations of the
    Alzheimer's Disease Research Summit held in May 2012. The recent launch
    of the International Alzheimer's Disease Research Portfolio (IADRP), a
    publicly available database to capture the full spectrum of current AD
    research investments and resources throughout the world, will
    facilitate coordination of these efforts.
        One active and highly promising area of research is the
    identification and elucidation of risk and protective genes for AD. For
    example, a variation in TREM2, a gene involved in inflammation and
    immune response, was recently identified as a moderate risk factor for
    late-onset AD, and a variant of the BCHE gene has been associated with
    deposition of beta-amyloid in the brain--a pathologic hallmark of the
    disease. Other investigators found that in mice, ApoE-4, the best-known
    genetic risk factor for late-onset AD, is associated inflammation of
    the blood vessels that feed the brain involving a molecule called
    cyclophilin A, suggesting that cyclophilin A may be a viable drug
    target. Finally, investigators with the NIH-supported AD Genetics
    Consortium have identified a gene, ABCA7, which appears to be more
    strongly associated with AD in African Americans than in individuals of
    European ancestry. Further study is needed to confirm and extend this
    finding.
        NIH currently supports more than 35 clinical trials, including both
    pilot and large-scale trials, of a wide range of interventions to
    prevent, slow, or treat AD and/or cognitive decline; more than 40
    compounds are in preclinical development through the AD Translational
    Initiative. Funding for the groundbreaking Alzheimer's Disease
    Cooperative Study was renewed earlier this year, and several
    interventional studies are planned: a secondary prevention trial to
    test an amyloid-clearing drug in 1,000 symptom-free older volunteers
    with abnormal levels of brain amyloid accumulation; a randomized,
    controlled trial to find out if supervised aerobic exercise can
    influence cognitive decline, slow brain atrophy, or mitigate
    Alzheimer's pathology in older adults with mild cognitive impairment, a
    condition that often leads to AD; and a study to test the drug prazosin
    to help control agitation, a common symptom in AD patients.

                  UNDERSTANDING AGING AT THE MOST BASIC LEVEL

        NIA initiatives on the molecular mechanisms of aging, from in-depth
    study of single cells to the broad study of organisms at the systems
    level, continue to advance our understanding of the basic underpinnings
    of the aging process. The NIH Geroscience Interest Group (GSIG) was
    formed in 2012 to accelerate and coordinate efforts to promote
    discovery on the common risks and mechanisms behind age-related
    diseases and conditions. The GSIG has planned a number of initiatives
    for coming years, including informational activities, expansion of
    current initiatives to incorporate aging-related aims, and new trans-
    NIH funding initiatives. A GSIG workshop on inflammation and age-
    related diseases was held in September 2012, and a larger-scale
    workshop tentatively entitled ``Geroscience: Foundations for Delaying
    Chronic Disease and Increasing Healthspan'' is planned for fall 2013.

              EMPOWERING THE NEXT GENERATION OF AGING RESEARCHERS

        The need for health care professionals and research scientists who
    specialize in the unique needs of older individuals is becoming ever
    more urgent. Recently, NIA established the Grants for Early Medical/
    Surgical Subspecialists' Transition to Aging Research (GEMSSTAR)
    program to support physicians who seek to become clinician-scientists
    in geriatric aspects of their subspecialty. NIA has also established a
    program targeting undergraduate students from diverse backgrounds in
    order to advance their interest in and knowledge of aging issues.
                                     ______

                  Prepared Statement of Story C. Landis, Ph.D.

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of
    Neurological Disorders and Stroke (NINDS) of the National Institutes of
    Health (NIH). The fiscal year 2014 NINDS budget of $1,642,619,000
    includes an increase of $19,275,000 over the comparable fiscal year
    2012 level of $1,623,344,000.

                        COMBATING NEUROLOGICAL DISORDERS

        The NINDS mission is to reduce the burden of neurological disorders
    through research. For stroke, research on prevention and treatment led
    to reductions of the age-adjusted death rate by 36.9 percent and of the
    actual number of deaths by 22.9 percent from 1999 to 2009.\1\
        An intensive and inclusive NINDS planning process has identified
    the highest priority research investments to continue this progress
    against stroke. Experts across disciplines agreed that stroke clinical
    trials networks could accelerate progress. In response, NINDS is
    establishing a flexible stroke clinical trials network to conduct
    prevention, treatment, and recovery trials. With shared infrastructure,
    the network will better set priorities for studies, reduce cost and
    time in start-up, and therefore significantly improve efficiency. The
    network builds on lessons from the NeuroNEXT network, which expedites
    early phase clinical trials of new treatments, especially for rare
    diseases. NeuroNEXT uses a single Institutional Review Board and
    standard site contracts, which reduce time required to start a trial by
    months. It also accommodates projects from academic investigators or
    private partners. Trials for spinal muscular atrophy (SMA) biomarkers
    and secondary progressive multiple sclerosis are under way, and
    planning has begun for clinical trials of two therapies developed by
    the NIH Therapeutics for Rare and Neglected Disease Program.
        Reducing cognitive impairment from brain vascular disease is
    another priority that emerged from planning. Stroke itself is a major
    cause of dementia. Furthermore, the 7 million U.S. stroke survivors
    have an increased likelihood of cognitive problems, and the 13 million
    people with ``silent strokes'' \2\ may also be at risk. Vascular risk
    factors are also associated with Alzheimer's disease. In fact, there is
    a spectrum from pure vascular dementia to pure Alzheimer's disease,
    with most patients having contributions from both.\3\ This month a
    scientific workshop on Alzheimer's Related Dementias, part of the
    National Alzheimer's Project Act activities, focused on vascular
    dementia.
        Traumatic Brain Injury (TBI) is the leading cause of death and
    disability in children and young adults, common among the elderly, and
    a major concern for the military and veterans. New studies will address
    two reasons why more than 30 major clinical trials of interventions for
    TBI failed to demonstrate improved outcomes: classification schemes do
    not distinguish between different types of damage in different parts of
    brain that may respond differently to interventions, and large
    variations in outcomes among medical centers confound assessment of
    interventions in clinical trials. A study of 1,000 children will
    evaluate the effectiveness of six major critical care guidelines for
    severe, pediatric TBI that lack compelling evidence. Another
    prospective, observational, multi-center study of 5,000 adults and
    children with TBI will be coordinated with studies by the European
    Union and the Canadian Institute of Health Research to enhance the
    statistical power to detect differences. The research community has
    agreed upon standards through the NINDS TBI Common Data Elements
    program that will allow meaningful comparison across studies, and the
    Department of Defense and NIH-led Federal Interagency TBI Research
    informatics system (FITBIR) provides a database for sharing
    information. NIH is also addressing TBI through the Foundation for
    NIH's Sports and Health Research Program, with support from the
    National Football League. In December a workshop focused on Chronic
    Traumatic Encephalopathy (CTE), a neurodegenerative disorder that can
    follow repetitive mild brain trauma in sports and the military. Follow-
    up research solicitations are underway, and this public private
    partnership will address other key aspects of sports and health in the
    coming years.
        Epilepsy is another common disorder that affects people of all
    ages. Every 6 years since 2001, the Epilepsy Benchmarks process has
    brought NINDS, the research community, and non-governmental
    organizations together to establish research milestones and monitor
    progress. This April NINDS convened a major workshop to assess progress
    and set pathways forward. Previous Benchmarks guided investments that
    are now yielding important gene findings, advances in understanding how
    epilepsy develops, and attention to comorbidities, including Sudden
    Unexplained Death in Epilepsy (SUDEP). Future Benchmarks will focus on
    disease progression and modification, predictability of seizures and
    treatment response, and aspects of gender, ethnicity, and age (children
    and elderly), among other issues. Opportunities from other investments
    could also have a significant impact on epilepsy. The community is
    excited, for example, about advances in genetics, ``big data,'' and
    brain circuit analysis.
        Opportunities are also emerging for many other brain diseases,
    common and rare. Induced pluripotent stem cells derived from patients
    with Parkinson's disease, amyotrophic lateral sclerosis (ALS),
    Huntington's and other disorders allow laboratory testing of potential
    drugs. Biomarkers under development for Parkinson's, SMA, and other
    diseases will speed clinical testing. Brain stimulation therapies have
    proven benefit for Parkinson's disease, essential tremor, and dystonia,
    and show promise for diseases including epilepsy and Tourette syndrome.
    In research settings, brain machine interfaces enable paralyzed
    individuals to control a robotic arm and hand; development of practical
    devices is underway. Gene discoveries have led to mechanism targeted
    therapies that are now in the translational pipeline for many diseases,
    for example, muscular dystrophies, SMA, familial dysautonomia, and
    fragile X.

                               BASIC NEUROSCIENCE

        Researchers in academia and industry agree that basic science
    drives progress against disease. A few recent examples: genes
    discovered for epilepsy, ALS, and autism enable the dissection of
    underlying disease mechanisms, pointing to potential targets for
    therapy development. Research is also revealing unexpected ways that
    degeneration propagates in the brain, why acute pain can become
    chronic, and that serious disabilities in children born prematurely may
    be more reversible than expected. Science of the normal brain advanced
    this year on topics as diverse as the mechanisms of itch, how the brain
    clears waste, control of brain blood flow in infants, the influence of
    anesthetics on consciousness, and brain circuits for memory.
        NINDS relies on investigator-initiated research throughout its
    programs. Engaging the insight and ingenuity of the scientific
    community in this way is especially crucial for basic research. The
    Institute has also emphasized the importance of transparent reporting
    of research findings, stressing rigor and reproducibility. A June 2012
    NINDS workshop brought together representatives of all major
    stakeholders, which has already lead to changes within and outside the
    NIH, including policies of leading journals.\4\
        Technology can also empower investigators. Investment by the NIH
    and others, together with advances in optics, computer science, genetic
    engineering, and other disciplines, has led to promising technological
    strategies to study the activity of large numbers of brain cells and
    the intricacies of their connections. The Brain Research through
    Advancing Innovative Neurotechnologies (BRAIN) Initiative partners
    Federal agencies and private foundations in a coordinated program to
    develop and apply these emerging opportunities, including study of the
    human brain. This will ultimately revolutionize understanding of how
    networks of brain cells enable us to perceive, think, and act, and what
    goes wrong in diseases of the brain. A stellar committee of scientists
    will guide this initiative, with recommendations on first steps due
    this fall and a more complete plan the following summer. History
    suggests that the most important benefits of BRAIN will be those that
    we have not yet even imagined.
    ---------------------------------------------------------------------------
        \1\ ``Circulation'' 134:e6-245, 2013.
        \2\ ``Circulation'' 125:e2-e220, 2012.
        \3\ ``Neurology'' 72:368-74, 2009.
        \4\ e.g., ``Nature'' 490:187-91, 2012; ``Nature'' 496:398, 2013;
    ``Nature Neuroscience'' 16:1, 2013; 16:517, 2013.
    ---------------------------------------------------------------------------
                                     ______

                  Prepared Statement of Harold E. Varmus, M.D.

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Cancer Institute (NCI)
    of the National Institutes of Health (NIH). The fiscal year 2014 NCI
    budget of $5,125,951,000 includes an increase of $63,189,000 over the
    comparable fiscal year 2012 level of $5,062,762,000.

                       CANCER DEATHS CONTINUE TO DECLINE

        The 2013 Report to the Nation on the Status of Cancer shows that
    overall cancer death rates continued to decline in the United States
    among both men and women, among all major racial and ethnic groups, and
    for all of the most common cancer sites, including lung, colon and
    rectum, female breast, and prostate. However, death rates continued to
    increase for melanoma of the skin (among men) and for cancers of the
    liver, pancreas, and uterus. The Report also emphasizes the importance
    of human papilloma virus (HPV) infection as a cause of the growing
    number of cancers, and shows that incidence rates are increasing for
    HPV-associated oropharyngeal and anal cancers. Also noted was that HPV
    vaccination coverage remains disappointingly low, falling short of the
    U.S. Government's Healthy People 2020 target, and much lower than
    vaccination rates reported in several other countries.
        The continued decline in death rates for most cancers shows that
    our nation's investment in cancer research produces life-saving
    approaches to cancer control. However, there is still critical work to
    do, for example, in reducing tobacco exposure and obesity. Taken
    together, adverse health effects from cigarette smoking--including
    heart disease, stroke, and cancer--account for an estimated 443,000
    deaths every year in the U.S.; nearly 1 in 5 deaths that could have
    been prevented. Since tobacco is responsible for about 30 percent of
    all cancer deaths in the U.S. (approximately 174,000 preventable cancer
    deaths in 2013), NCI continues to support research into methods to
    encourage smoking cessation and to discourage initiation; behavioral
    modification; and effectiveness of tobacco control efforts. Obesity,
    another significant cause of disease and preventable death, is
    associated with heart disease, stroke, type 2 diabetes and at least
    eight types of cancers. NCI funds research on the molecular mechanisms
    of obesity and cancer, and has developed new initiatives that explore
    ways to prevent and control obesity as a cancer risk factor.

             NATIONAL CANCER INSTITUTE-SUPPORTED RESEARCH ADVANCES

        The past year has yielded significant advances across the spectrum
    of cancer research, including studies of cancer mechanisms, prevention,
    detection, and therapy. One cancer detection study showed that the
    protein fibulin-3 may be able to identify patients with mesothelioma,
    suggesting that it may be a promising biomarker for high-risk
    populations exposed to asbestos. Another study found a way to target
    mesothelin, a cell surface protein that is present in normal tissues
    but overexpressed in more than 90 percent of pancreatic cancers and
    mesotheliomas, as well as in lung and ovarian cancers. Currently, the
    NCI intramural program is conducting a Phase I study of SS1P, an
    immunotoxin that targets mesothelin and destroys cancer cells, with
    plans for a Phase II study under way.
        NCI is supporting research to identify the genetic drivers of
    cancer, and to advance adoption of precise tumor diagnosis and the
    development of targeted therapies. The two major genomics initiatives,
    involving hundreds of investigators nation-wide, are The Cancer Genome
    Atlas (TCGA) and the Therapeutically Applicable Research to Generate
    Effective Treatments (TARGET) initiative, focused on adult and
    pediatric cancers respectively. TCGA recently completed a study of lung
    squamous cell carcinoma that identified several potential therapeutic
    targets related to the initiation and progression of that disease.
    Another study examined nearly 400 endometrial (uterine) cancers and
    identified four new subtypes with several possible therapeutic targets.
    This study also found genomic similarities between endometrial and
    other cancers, including breast, ovarian, and colorectal. A TARGET
    study identified a subclass of acute lymphoblastic leukemia with high
    risk of recurrence associated with novel chromosomal translocations;
    these translocations represent exploitable therapeutic targets. Another
    TARGET study found few recurrent mutations among 240 cases of high-risk
    neuroblastoma, suggesting a limited number of targets for this
    pediatric disease.
        In 2011, one of several noteworthy achievements was FDA approval of
    a new class of drug, vemurafenib, for the treatment of metastatic
    melanoma. The drug targets mutant forms of the BRAF protein, which is
    mutated in about 60 percent of these patients, leading to inhibition of
    a key growth pathway in the tumor cell, the MAPK pathway. Although the
    drug can increase the lifespan of these patients, almost all patients
    eventually develop drug resistance and relapse. Recent observations
    from several research groups have indicated that drug resistance can
    arise by any of several mechanisms. Some resistance is attributable to
    activation of the MAPK pathway, which can result from further mutation
    of BRAF itself or changes in other genes in the MAPK pathway. In other
    cases, resistance seems to result from activation of parallel pathways.
    These findings are now leading to clinical trials testing the
    hypothesis that combining the BRAF inhibitor with drugs that have been
    shown in preclinical models to reduce development of these resistance
    mechanisms will lead to longer therapeutic responses.
        A potentially exciting therapeutic advance has come from
    immunotherapy research for B cell lymphoma being conducted at several
    institutions. The approach is to use genetic engineering to construct a
    chimeric antigen receptor (CAR) by combining parts from two different
    receptors, each with key immune functions, into one receptor that is
    then expressed by the patient's own normal T cells. Early-phase
    clinical trials with a receptor called anti-CD19 CAR, which works by
    directing T cells to the malignant B cells of the tumor, have resulted
    in several dramatic long-term responses in patients with advanced stage
    lymphoma.

                    PRECISION MEDICINE--APPROACHES TO CANCER

        Incorporation of genomics into cancer research and clinical trials
    constitutes a growing portion of the Institute's research portfolio. In
    the years ahead, NCI and the entire cancer research enterprise will
    extend studies of the pathogenetic roles for specific genomic changes
    in tumors and test more interventions that are based on genetic
    profiles of tumors. There are several ways in which NCI is expanding
    its pursuit of these goals, most notably by mandating that all NCI-
    sponsored clinical trials include tissue collection and genomic
    analysis. NCI is also developing new approaches that explore the
    relationship between a cancer patient's genomic data (genotype) and the
    behavior of each patient's tumor (phenotype). One such study is the
    Exceptional Responders initiative, which will begin with phenotypes--
    asking why a small number of patients respond very well to a particular
    regimen, while the same treatment fails in almost all others with the
    same cancer type. To probe this phenomenon, researchers will explore
    the genomic data (genotype) to look for clues as to why some patients
    enrolled in clinical trials respond to agents that do not benefit most
    patients in the same study. Some recently reported cases provide
    dramatic evidence for how a combination of molecular factors can
    explain why patients responded so well to therapy while comparable
    patients did not.
        An approach from the opposite perspective (genotype to phenotype)
    is the ``NCI MATCH'' study, which aims to screen about 3,000 patients
    with advanced cancers in an effort to find approximately 1,000 such
    cancers with genetic mutations for which new therapies, including some
    not yet approved for use, are made available by the pharmaceutical
    industry through collaborative arrangements. This approach will provide
    a level of genomic data far beyond what would typically be available
    when genotyping is limited to one or more mutations known to be
    associated with a particular cancer type. There is a great opportunity
    for investigator-initiated research to build on information that
    emerges from this kind of novel trial, leading to yet greater
    therapeutic insight.

                                 TARGETING RAS

        The Frederick National Laboratory for Cancer Research (FNLCR) is a
    federally Funded Research and Development Center (FFRDC) supported by
    NCI, providing a national resource with unique capabilities for the
    development of new technologies and the translation of basic science
    discoveries into novel agents for the prevention, diagnosis and
    treatment of cancer and AIDS. NCI is poised to launch a large-scale
    project targeting RAS, an oncogene known for decades to drive the
    development of many types of cancers and about a quarter of all cancers
    in the U.S., including more than 90 percent of pancreatic
    adenocarcinomas. However, despite that information, the cancer research
    community has failed to develop effective treatments. Now, with the
    knowledge of new chemical approaches to inhibit the RAS protein
    directly and a deeper understanding of how RAS signaling works, NCI is
    launching a large-scale project to develop therapeutic strategies
    against cancers driven by RAS through a national ``hub and spoke''
    model with scientific leaders, core facilities and important
    technologies at the FNLCR hub, and research led by investigators at
    companies, academic institutions and the NCI intramural research
    program at the spokes.
        We find ourselves at a time of tremendous opportunity in cancer
    research, building our knowledge of the genetic changes that cause
    cancer, and finding new ways to use this information to diagnose, treat
    and even prevent cancers. The President's budget for 2014 for the
    National Cancer Institute will support studies intended to foster the
    discoveries essential for this next frontier of cancer research.
                                     ______

        Prepared Statement of Thomas R. Insel, M.D., Director, National
                           Institute of Mental Health

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Mental
    Health (NIMH) of the National Institutes of Health (NIH). The fiscal
    year 2014 NIMH budget of $1,465,782,000 represents a decrease of
    $11,734,000 below the comparable fiscal year 2012 level of
    $1,477,516,000. In my statement, I will review the scope of mental
    disorders in the United States and their impact on public health, and I
    will outline examples of NIMH's research efforts designed to address
    this challenge.

                     PUBLIC HEALTH BURDEN OF MENTAL ILLNESS

        The National Institute of Mental Health (NIMH) is the lead Federal
    agency for research on mental and behavioral disorders, with a mission
    to transform the understanding and treatment of mental illnesses
    through basic and clinical research. The global burden of mental
    illness is enormous. An estimated 11 million American adults
    (approximately 5 percent of all adults) suffer from a seriously
    disabling mental illness each year.\1\ Mental disorders are the leading
    cause of disability in the United States and Canada, accounting for 28
    percent of all years of life lost to disability and premature mortality
    (Disability Adjusted Life Years or DALYs) for people age 15-49.\2\ The
    personal, social, and economic costs associated with these disorders
    are tremendous. A cautious estimate places the direct and indirect
    financial costs associated with mental illness in the U.S. at well over
    $300 billion annually, and it ranks as the third most costly medical
    condition in terms of overall healthcare expenditure, behind only heart
    conditions and traumatic injury.\3\ \4\ Even more concerning, the
    burden of illness for mental disorders is projected to sharply increase
    over the next 20 years.\5\
        NIMH-supported research has found that Americans with serious
    mental illness (SMI)--in which the ability to function in daily life is
    significantly impaired--die 8 years earlier than the general
    population.\6\ People with SMI experience chronic medical conditions
    and the risk factors that contribute to them more frequently and at
    earlier ages. There are low rates of prevention, detection, and
    intervention for chronic medical conditions and their risk factors
    among people with SMI, and this contributes to significant illness and
    earlier death.

                      PREDICTING AND PREVENTING PSYCHOSIS

        In the past, we viewed mental disorders as chronic conditions
    defined by their apparent symptoms, even though behavioral
    manifestations of illness are in fact the last indications--following a
    cascade of subtle brain changes--that something is wrong. We understand
    now that mental disorders are brain disorders, with specific symptoms
    rooted in abnormal patterns of brain activity. Moving forward, NIMH
    aims to support research on earlier diagnosis and quicker delivery of
    appropriate treatment, be it behavioral or pharmacological.
        The majority of people with serious mental illness (SMI)--in which
    the ability to function in daily life is significantly impaired--
    experience significant delays to seeking care--nearly 2 years, on
    average.\7\ \8\ Untreated SMI, particularly psychosis, poses an
    increased risk for using potentially life-threatening, self-
    administered treatments, such as legal or illicit substances,
    potentially resulting in death. When untreated psychosis is also
    accompanied by symptoms of paranoia and when it is associated with
    substance abuse, the risk of violence is increased. Importantly, the
    risk of violence is reduced with appropriate treatment.\9\ \10\
    Moreover, people with SMI are 11 times more likely than the general
    population to be victims of violence.\11\ Therefore, NIMH has planned
    several new research initiatives, ramping up the Institute's commitment
    to early treatment in order to reduce this period of untreated
    psychosis to less than 12 weeks. These initiatives propose two
    objectives: (a) improving detection of youth and young adults at high
    risk for psychosis; and (b) reducing the duration of untreated
    psychosis in community treatment settings.

                            IMPROVING PUBLIC HEALTH

        When violence is associated with mental illness, it is most often
    self-directed. Approximately 5 percent of individuals with
    schizophrenia will die by suicide during their lifetime, a rate 50-fold
    greater than the general population.\12\ Furthermore, suicide is the
    10th leading cause of death in the United States, accounting for the
    loss of more than 38,000 American lives each year, more than double the
    number of lives lost to homicide.\13\ NIMH is spearheading several
    initiatives intended to reduce and prevent suicide, such as taking a
    lead role with The National Action Alliance for Suicide Prevention, a
    public-private partnership tasked with developing the next National
    Strategy for Suicide Prevention. Alongside the Jed Foundation, NIMH is
    co-chairing the Action Alliance's Research Task Force (RTF), which is
    developing a National Research Agenda to reduce suicide morbidity
    (attempts) and mortality (deaths) by at least 20 percent in 5 years,
    and 40 percent or more in 10 years. The RTF aims to release the Agenda
    in September 2013.
        One of the most notable and disturbing increases in suicide over
    the past decade has occurred among the Nation's returning military
    veterans. To counter this trend, NIMH has partnered with the Department
    of the Army to conduct the Army Study to Assess Risk and Resilience in
    Servicemembers (Army STARRS) Project--the largest study of mental
    health risk and resilience ever conducted among military personnel.
    Army STARRS seeks to identify factors that both protect soldiers'
    mental health and those that put a soldier's mental health at risk. The
    goal is to provide empirical evidence to help the Army develop targeted
    prevention and treatment strategies. Army STARRS has established a data
    enclave that integrates the administrative records of the 1.6 million
    soldiers who served between 2004 and 2009. In addition, Army STARRS
    includes a series of studies involving soldiers currently serving on
    active duty. Most of these studies have now finished enrolling subjects
    and the data are being analyzed.
        NIMH, along with other NIH Institutes and the Departments of
    Defense, Education, and Veterans Affairs are contributing to the
    development of the National Research Action Plan (NRAP), pursuant to
    Executive Order, ``Improving Access to Mental Health Services for
    Veterans, Service Members, and Military Families'' (http://
    www.whitehouse.gov / the-press-office / 2012 / 08 / 31/executive-order-
    improving-
    access-mental-health-services-veterans-service). NRAP will
    strategically inform planning for future federally funded research
    related to mental health and traumatic brain injury among veterans and
    soldiers. NRAP will address post-traumatic stress disorder, depression,
    suicide prevention, and some aspects of substance abuse prevention and
    treatment.

                      THE FUTURE OF MENTAL HEALTH RESEARCH

        On April 2, President Obama proposed the Brain Research through
    Advancing Innovative Neurotechnologies (BRAIN) Initiative (http://
    www.nih.gov/science/brain/index.htm), a bold plan not only to transform
    our fundamental understanding of the brain, but also to revolutionize
    both our approach to brain research and our understanding of brain
    disorders. BRAIN will encourage the development of innovative
    technology necessary for monitoring the activity of millions of brain
    cells simultaneously and translate that activity into circuit diagrams
    and algorithms. This effort will advance our understanding of how the
    brain works and fails to work, and how it can be repaired.
        Research has taught us to detect diseases early and intervene
    quickly to preempt later stages of illness. This year, we will avert
    1.1 million deaths from heart disease because we have not waited for a
    heart attack to diagnose and treat coronary artery disease.\14\ Our
    best hope of reducing mortality from mental illness and other brain
    disorders will come from realizing that just like other medical
    disorders, we need to diagnose and intervene before the symptoms become
    manifest. Our investments today ensure a healthy tomorrow.
    ---------------------------------------------------------------------------
        \1\ Substance Abuse and Mental Health Services Administration.
    ``Results from the 2009 National Survey on Drug Use and Health: Mental
    Health Findings'' (Office of Applied Studies, NSDUH Series H-39, HHS
    Publication No. SMA 10-4609). Rockville, MD: Substance Abuse and Mental
    Health Services Administration, 2010.
        \2\ The World Health Organization. ``The global burden of disease:
    2004 update,'' Table A2: Burden of disease in DALYs by cause, sex and
    income group in WHO regions, estimates for 2004. Geneva, Switzerland:
    WHO, 2008.
        \3\ Insel TR. Assessing the economic cost of serious mental
    illness. ``Am J Psychiatry.'' 2008 Jun;165(6):663-5.
        \4\ Soni A. ``The Five Most Costly Conditions, 1996 and 2006:
    Estimates for the U.S. Civilian Noninstitutionalized Population.''
    Statistical Brief #248. July 2009. Agency for Healthcare Research and
    Quality, Rockville, MD.
        \5\ Bloom DE, Cafiero ET, Jane-Llopis E, Abrahams-Gessel S, Bloom
    LR, Fathima S, Feigl AB, Gaziano T, Mowafi M, Pandya A, Prettner K,
    Rosenberg L, Seligman B, Stein A, Weinstein C. ``The Global Economic
    Burden of Non-communicable Diseases.'' Geneva, Switzerland: World
    Economic Forum, 2011.
        \6\ Druss BG, Zhao L, Von Esenwein S, Morrato EH, Marcus SC.
    Understanding excess mortality in persons with mental illness: 17-year
    follow up of a nationally representative U.S. survey. ``Med Care.''
    2011 Jun;49(6):599-604.
        \7\ Wang PS, Berglund PA, Olfson M, Kessler RC. Delays in initial
    treatment contact after first onset of a mental disorder. ``Health Serv
    Res.'' 2004 Apr;39(2):393-415.
        \8\ Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T.
    Association between duration of untreated psychosis and outcome in
    cohorts of first-episode patients. ``Arch Gen Psychiatry.'' 2005 Sep
    62:975-983.
        \9\ Swanson JW, Swartz MS, Van Dorn RA, Volavka J, Monahan J,
    Stroup TS, McEvoy JP, Wagner HR, Elbogen EB, Lieberman JA; CATIE
    investigators. Comparison of antipsychotic medication effects on
    reducing violence in people with schizophrenia. ``Br J Psychiatry.''
    2008 Jul;193(1):37-43.
        \10\ Steadman HJ, Mulvey EP, Monahan J, Robbins PC, Appelbaum PS,
    Grisso T, Roth LH, Silver E. Violence by people discharged from acute
    psychiatric inpatient facilities and by others in the same
    neighborhoods. ``Arch Gen Psychiatry.'' 1998 May;55(5):393-401.
        \11\ Teplin, LA, McClelland, GM, Abram, KM & Weiner, DA. Crime
    victimization in adults with severe mental illness: comparison with the
    National Crime Victimization Survey. ``Arch Gen Psychiatry,'' 2005,
    62(8), 911-921.
        \12\ Hor K. & Taylor M. Suicide and schizophrenia: a systematic
    review of rates and risk factors. ``J Psychopharmacol.'' 2010;24(4S):
    81-90.
        \13\ Centers for Disease Control and Prevention, National Center
    for Injury Prevention and Control. Web-based Injury Statistics Query
    and Reporting System (WISQARS): www.cdc.gov/ncipc/wisqars accessed May
    2013.
        \14\ Vital Statistics of the United States, CDC/National Center for
    Health Statistics. (2011, August). Age-adjusted Death Rates for
    Coronary Heart Disease (CHD). National Heart Lung and Blood Institute.
    Retrieved January 23, 2013, from http://www.nhlbi.nih.gov/news/
    spotlight/
    success/conquering-cardiovascular-disease.html.
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                                     ______

      Prepared Statement of Martha J. Somerman, D.D.S., Ph.D., Director,
             National Institute of Dental and Craniofacial Research

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Dental and
    Craniofacial Research (NIDCR) of the National Institutes of Health
    (NIH). The fiscal year 2014 NIDCR budget of $411,515,000 includes an
    increase of $1,568,000 over the comparable fiscal year 2012 level of
    $409,947,000.
        When NIDCR was established as a research home for oral health in
    the mid-20th century, it focused primarily on oral infectious diseases
    like tooth decay and periodontal disease. Today, the Institute
    maintains a diverse and productive research portfolio that extends
    beyond infections in the mouth. In keeping with its mission to improve
    the Nation's oral health, the breadth of NIDCR-funded research includes
    basic science studies aiming to understand development, maintenance,
    and regeneration of tissues of the face and head; novel preventive,
    diagnostic, and treatment approaches for oral infections and oral
    cancer; investigating the role the mouth plays as an indicator of
    overall health; and community-led studies of issues related to dental
    care.

                       REALIZING PERSONALIZED ORAL HEALTH

        Personalized health, aiming to individualize care based on a
    person's unique genetic, environmental, and clinical profile, is not
    new: dentists and physicians have long recognized variations among
    patients, and they have provided customized care based on the history,
    environmental exposure, and behavioral components that shape a person's
    health. However, new technologies offer additional strategies. For
    example, the NIDCR investment in molecular diagnostics using saliva is
    a key step toward advancing personalized care. As a diagnostic fluid,
    saliva has long been recognized to have many advantages over blood.
    These include simple, non-invasive collection; the potential for lower
    testing costs; portability; and application at or near the site of
    patient care, maximizing convenience and allowing the results to be
    available immediately to the patient. Recent progress comes from NIDCR-
    supported scientists that developed a miniaturized, portable biochip
    that can analyze small volumes of saliva. During the first phase of
    this project, the researchers found promising predictive markers for
    cardiac events. Other research identified the presence, in saliva, of
    disease-related proteins and RNAs for oral cancers, Sjogren's syndrome,
    and conditions such as periodontal disease.
        Beyond supporting the development of molecular-based tools to
    individualize care, NIDCR appreciates the important role of behavior
    and environment in determining an individual's health status. As
    trusted providers in a private setting, dentists have an extraordinary
    opportunity to communicate to their patients the health risks of
    behaviors such as alcohol and tobacco use. NIDCR-funded projects are
    currently exploring how dental providers can help their patients by
    providing smoking-cessation advice.

                       PROGRESS IN ORAL DISEASES: CANCER

        The 5-year relative survival rate for oral and pharyngeal cancer is
    approximately 60 percent, which is among the lowest for all major
    cancers.\1\ This outlook is significantly worse for African Americans,
    who face a 5-year relative survival rate close to 40 percent. In
    addition to bringing behavioral science tools and expertise to bear on
    this problem, NIDCR aims to initiate and lead an NIH-wide effort in
    oral premalignancy identification and oral cancer prevention. The
    multi-pronged approach weaves together scientific advances in molecular
    profiling with clinical testing of the FDA-approved drug rapamycin for
    its effectiveness against certain cancers of the head and neck. Also,
    in fiscal year 2014 NIDCR will launch an initiative supporting research
    on a unique type of cell capable of initiating oral cancer, as
    therapies targeting these cells could potentially eliminate the
    ``root'' of the cancer.
        Infection with human papillomavirus (HPV) is an increasingly
    recognized risk factor for distinct forms of oral and pharyngeal
    cancer. NIDCR remains vigilant to this rising public health concern.
    The incidence of HPV-linked oral cancers in the United States has been
    increasing at a rapid rate--by 225 percent from 1998 to 2004, and now
    37 percent of oral and pharyngeal cancers are HPV-associated
    cancers.\2\ Because the FDA-approved HPV vaccine Gardasil is effective
    against the particular strains of HPV implicated in oral cancers, NIDCR
    is supporting efforts to determine the potential benefit of this
    vaccine in preventing these terrible diseases.

                        PROGRESS IN ORAL DISEASES: PAIN

        NIDCR has a long-standing interest in the understanding and
    management of chronic pain. In 2012, the Institute launched the second
    phase of Orofacial Pain: Prospective Evaluation and Risk Assessment
    (OPPERA), the first-ever large, prospective clinical study to identify
    risk factors for temporomandibular joint disorder (TMJD). OPPERA II
    will follow more than 3,000 initially pain-free individuals for three
    to 5 years. OPPERA II will build upon OPPERA I and further explore risk
    factors and genome-wide markers for chronic TMJD as well as for several
    frequently overlapping pain conditions. Also in 2012, NIDCR partnered
    with the National Institute of Neurological Disorders and Stroke to
    host a workshop focused on identifying innovative scientific approaches
    to the study of chronic overlapping pain conditions. Together, these
    efforts are expected to have an impact not only on TMJD, but also on
    other chronic pain conditions including fibromyalgia, irritable bowel
    syndrome, chronic headache, vulvodynia, and chronic fatigue syndrome.
    In addition, NIDCR co-sponsored a meeting in 2013 with two other NIH
    Institutes to explore opportunities to utilize contemporary and
    integrative approaches in understanding TMJ structure and function,
    including novel imaging and molecular diagnostic techniques.

                SYSTEMS APPROACHES TO UNDERSTANDING ORAL HEALTH

        Oral tissues and fluids have remarkable protective roles, dependent
    on human components and those of oral bacteria. The NIH Human
    Microbiome Project (HMP) has created unprecedented opportunity to learn
    much more. NIDCR is harnessing HMP knowledge and tools to define the
    overlapping and unique roles of the oral microbiota in oral diseases
    and immune function--such as in susceptibility to autoimmune diseases
    and cancer--and in other systemic conditions like metabolic syndrome, a
    cluster of co-occurring conditions including increased blood pressure,
    blood sugar levels, body fat, and cholesterol levels that can raise the
    risk of heart disease, stroke, and diabetes. NIDCR is investing
    resources in new approaches to understand the properties of the vast
    majority (more than 80 percent) of the microbial universe in our mouths
    that cannot be grown in the laboratory. These studies will provide
    insights into interactions among microbes and with human cells,
    potentially leading to the development of novel strategies for
    prevention, diagnosis, and treatment of oral diseases.
        Genome-wide association studies, or GWAS, are another example of
    the broad utility of systems approaches for investigating oral health
    biology. GWAS methods combine human genome sequencing and high-speed
    computing, to scan the entire genome for disease triggers and factors.
    In the realm of oral health, GWAS suggest that the risk for dental
    caries arises from interplay between genetic factors, home fluoride
    exposure levels, and in some cases, taste preferences. Further analyses
    may point to common risk factors for dental caries and other conditions
    such as diabetes and cardiovascular disease. NIDCR-funded genetic
    studies of craniofacial development and birth defects have yielded
    information on the causes of cleft lip and palate and craniosynostosis,
    and this research will continue to be a focus moving forward.

                     NEW DIRECTIONS IN ORAL HEALTH RESEARCH

        Minding workforce trends and the importance of interdisciplinary
    science to health promotion, NIDCR recognizes the need for
    investigators representing a range of scientific areas to conduct
    research in dental, oral, and craniofacial health. NIDCR is
    particularly engaged with the needs and contributions of practitioners,
    whose participation in research could cut the time it takes for
    laboratory research to be applied for patients. In 2005, NIDCR launched
    the Practice-Based Research Network, or PBRN, and the second, 7-year
    phase began in April 2012. This powerful ``real world'' research
    network is recruiting practitioners in every State--with a goal of
    involving at least 5,000--to propose and perform clinical studies on
    topics important to dentistry. Because the research is conducted by
    clinicians in their own practices, dentists are more likely to accept
    and adopt the findings. The expected result is nothing short of a
    transformation of dental practice--one that will yield more
    individualized and evidence-based treatment and prevention, to the
    benefit of millions of Americans.
    ---------------------------------------------------------------------------
        \1\ Siegel et al., (2013) Cancer statistics, 2013. ``CA: A Cancer
    Journal for Clinicians.'' 63 (1) 11-30.
        \2\ Gillison ML et al. (2012) ``JAMA'';307,693-703; Jemal A et al.
    (2013) ``J Natl Cancer Inst.''
    ---------------------------------------------------------------------------
                                     ______

      Prepared Statement of Griffin P. Rodgers, M.D., M.A.C.P., Director,
        National Institute of Diabetes and Digestive and Kidney Diseases

        Mr. Chairman and members of the committee: I am pleased to present
    the President's fiscal year 2014 Budget request for the National
    Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the
    National Institutes of Health (NIH). The fiscal year 2014 budget
    includes $1,811,786,000, which is $18,080,000 above the comparable
    fiscal year 2012 appropriation of $1,793,706,000. Complementing these
    funds is an additional $150,000,000 also available in fiscal year 2014
    from the Special Statutory Funding Program for Type 1 Diabetes
    Research. NIDDK supports research on a wide range of common, chronic,
    costly, and consequential diseases and health problems that affect
    millions of Americans. These include diabetes and other endocrine and
    metabolic diseases; digestive and liver diseases; kidney and urologic
    diseases; blood diseases; obesity; and nutrition disorders.

               TODAY'S BASIC SCIENCE FOR TOMORROW'S BREAKTHROUGHS

        NIDDK-supported basic science research is achieving remarkable
    advances and building the foundation for previously unimaginable
    strategies to improve health and quality of life. Among these advances,
    recent research into biological processes showed that two newly
    discovered molecules--irisin and TRPV4--regulate energy expenditure in
    mice. Irisin was shown to promote energy expenditure (calorie burning),
    and reduced obesity and type 2 diabetes. Mice genetically engineered to
    lack TRPV4 had increased energy expenditure without differences in food
    intake, physical activity, or body temperature. If these findings are
    extended to humans, administration of irisin or targeting of TRPV4
    could be potential new therapeutic approaches for obesity and type 2
    diabetes. In addition, newly identified brown fat progenitor cells and
    factors that regulate brown fat development may lead to new obesity
    therapies that coax cells in white fat tissue to burn calories faster,
    like brown fat. The microorganisms that inhabit the gastrointestinal
    tract are important factors in maintaining or tipping the balance
    between digestive health and disease. Investigators have also reported
    that early exposure to ``friendly'' microbes protects against
    inflammatory bowel disease in animal models. Investigating the
    different types of bacteria that reside in the intestines, researchers
    have discovered surprising links to diet, diversity with respect to age
    and geographic location, fatty liver disease, and antibiotic exposure.
    Scientists supported by our Institute have shown that pancreatic b
    cells can revert to an earlier developmental stage and lose their
    ability to produce insulin; thus, approaches that save cells that have
    regressed and restore them to become b cells again could be an
    effective way to treat type 2 diabetes. Other scientists have
    illuminated the complex system of regulation surrounding kidney
    fibrosis following injury, and identified potential targets for further
    strategies aimed at preventing and possibly reversing kidney fibrosis.
    For example, one molecule, called microRNA-21, was found to be highly
    elevated in two mouse models of kidney disease soon after injury but
    before fibrosis appeared. Mice engineered to lack the microRNA-21 gene
    showed diminished fibrosis in response to kidney injury. This molecule,
    which is found in humans with kidney injury, represents a potential
    target for antifibrotic therapies in kidney disease.
        NIDDK will continue support for basic research across the
    Institute's mission, to gain further insights into health and disease
    and propel new ideas for interventions. Areas of emerging opportunity
    include research on human b cells toward the goal of developing cell
    replacement therapies; genetic analyses to identify genes and gene
    regions associated with inflammatory bowel disease; identification of
    environmental triggers of type 1 diabetes in genetically susceptible
    newborns; and development of blood and urine tests to better predict
    patients who will have rapid progression of kidney disease or worsening
    of heart disease.

                       TRANSLATIONAL AND CLINICAL SCIENCE

        Through innovative design and rigorous testing of interventions--
    whether in the operating room, doctor's office, or home or community
    settings--NIDDK-supported researchers are improving lives with new
    approaches to prevent, treat, and reverse diseases and disorders. For
    example, investigators have recently reported that weight loss and
    increased physical fitness slow decline in mobility in overweight or
    obese adults with type 2 diabetes. Invasive and costly tests commonly
    performed in women before surgery for stress urinary incontinence may
    not be necessary--information that women and their physicians can
    consider in planning treatment. This could result in fewer unnecessary
    procedures and a savings in healthcare costs. Additional research has
    shown that interventions to prevent type 2 diabetes in people at high
    risk for the disease are a very cost-effective way to improve their
    health and quality-of-life.
        Because many diseases within our mission disproportionately affect
    certain populations, we will also continue to seek insights and answers
    to health disparities. As just a few examples of our many clinical
    studies, Institute-supported scientists are conducting two large-scale,
    long-term observational studies of chronic kidney disease (CKD), the
    Chronic Kidney Disease in Children (CKiD) Study and the Chronic Renal
    Insufficiency Cohort (CRIC) Study, to address a wide range of
    scientific questions focused on prediction and mechanisms of CKD
    progression in both children and adults. Several efforts are
    translating CKD research into improved clinical outcomes such as
    decision support interventions to improve renal replacement therapy
    preparation. Among multifaceted efforts to meet the challenge of
    obesity is a consortium studying lifestyle interventions for overweight
    and obese pregnant women, to improve the health of both mother and
    child. The Institute continues to support clinical studies for a range
    of liver diseases including a multicenter research network planning
    trials of different treatment strategies for hepatitis B, including
    comparative effectiveness research. The MERIT-UC study investigators
    are conducting a multicenter trial to investigate the safety and
    efficacy of methotrexate (a drug also used to treat some forms of
    cancer and rheumatoid arthritis) in adult patients with active
    ulcerative colitis. The Glycemia Reduction Approaches in Diabetes: A
    Comparative Effectiveness study has as its overarching goal to
    understand the relative effectiveness of different medications in
    combination with metformin, and whether introducing them sequentially
    or initially in combination is most effective in maintaining glycemic
    goals over time in patients with type 2 diabetes. To maximize the reach
    and benefits of interventions proven successful in clinical trials,
    NIDDK will sustain support for translational research.

               RECRUITING AND RETAINING DIVERSE SCIENTIFIC TALENT

        NIDDK will continue programs to train and support researchers at
    all stages of their careers, and to ensure that we benefit from the
    best scientific minds. This year, NIDDK held its 11th annual Network of
    Minority Research Investigators workshop to encourage and facilitate
    participation of underrepresented racial and ethnic minority groups in
    the conduct of biomedical research. Several NIDDK-sponsored programs
    provide opportunities for minority students to obtain research
    experience. For example, NIDDK's Short-Term Education Program for
    Underrepresented Persons, or STEP-UP, provides research education
    grants to seven institutions to coordinate three high school and four
    undergraduate STEP-UP programs that enable students to gain summer
    research experience and training. STEP-UP and the NIH Building
    Infrastructure Leading To Diversity (BUILD) Consortium will work to
    identify resources which may be shared and to exchange lessons learned/
    best practices.

      INTEGRATING SCIENCE-BASED INFORMATION INTO PRACTICE: EDUCATION AND
                                    OUTREACH

        NIDDK also will continue to support education, outreach, and
    awareness programs. In 2012, NIDDK, in collaboration with NLM, launched
    the LiverTox database--a free source of evidence-based information for
    healthcare professionals and for researchers studying liver injury
    associated with prescription and over-the-counter medications, herbal
    products, and dietary supplements. Likewise, in 2012, NIDDK
    collaborated with Home Box Office to develop ``The Weight of the
    Nation'' documentary series showing how obesity affects the Nation's
    health, and how interventions can turn the tide against obesity and its
    complications. In addition, NIDDK's National Kidney Disease Education
    Program collaborated with the American Diabetes Association's ``Live
    Empowered'' program, the National Coalition of Pastors' Spouses, and
    Chi Eta Phi Sorority, Incorporated, to kick off the first nationwide
    ``Kidney Sundays'' event to raise awareness of kidney disease risk
    factors among African Americans.
        In closing, NIDDK's future research investments will be guided by
    five principles: maintain a vigorous investigator-initiated research
    portfolio; support pivotal clinical studies and trials; preserve a
    stable pool of new investigators; foster research training and
    mentoring; and disseminate science-based knowledge through education
    and outreach programs.
                                     ______

     Prepared Statement of Judith H. Greenberg, Ph.D., Director, National
                     Institute of General Medical Sciences

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget for the National Institute of General Medical
    Sciences (NIGMS) of the National Institutes of Health (NIH). The fiscal
    year 2014 budget of $2,401,011,000 includes a decrease of $24,511,000
    below the comparable fiscal year 2012 level of $2,425,522,000.
        Basic discovery for better health is the past, present, and future
    of NIGMS. Today, amid the breakneck speed of progress in biomedical and
    information science technology, truly phenomenal opportunities for
    progress are at our doorstep.
        In one recent example of the merit of joining the biological and
    information sciences, scientists with the NIGMS-led NIH
    Pharmacogenomics Research Network (PGRN) devised a computer algorithm
    to sift through millions of reports to the U.S. Food and Drug
    Administration to predict dangerous, yet unsuspected interactions
    between medications such as those between antidepressants and a common
    blood-pressure medication. In another case, researchers with the
    Institute's flagship Protein Structure Initiative (PSI) solved the
    three-dimensional atomic structure of the molecule on the surface of
    brain cells that attaches to opioids and is centrally involved in
    pleasure, pain, addiction, depression, psychosis, and related
    conditions. By linking these conditions in molecular terms, the
    research may well lead to better, more targeted drug therapies for a
    range of brain-related conditions. A third example comes from
    investigators with the NIGMS-funded Models of Infectious Disease Agent
    Study (MIDAS) program. They showed that methicillin-resistant
    ``Staphylococcus aureus'', or MRSA, infections are better prevented
    when hospitals cooperate and coordinate their infection control
    procedures. This research points to policy-related measures that could
    have a significant impact on public health.

                         FROM BENCH TO BEDSIDE AND BACK

        For several decades, NIGMS has provided a home for research
    conducted in emergency care settings. The Institute's burn and trauma
    centers have made many discoveries that have been implemented
    clinically. These include the development of artificial skin for burn
    victims, nutritional standards for the care of severely injured
    patients, and new understanding of how inflammation affects injury and
    healing in people who have experienced severe physical trauma.
        This past year, NIGMS announced the formation of the Office of
    Emergency Care Medicine (OECR). This office is the culmination of
    several years of discussions between NIH and the emergency medicine
    community, and responds to reports about the Nation's emergency medical
    system issued in 2006 by the Institute of Medicine. Although OECR does
    not have funding authority, it will provide agency-wide coordination
    toward speeding diagnosis and improving care for the full spectrum of
    conditions that require emergency treatment.
        Another compelling example of the clinical relevance of NIGMS-
    supported basic research is the Developmental Genome Anatomy Project
    (DGAP), which employs a model of ``patient as laboratory.'' DGAP
    scientists identify abnormalities in the DNA of people with a disorder
    that is not well understood, and then follow up with laboratory studies
    to further probe the molecular defect in animal models. One exciting
    DGAP discovery is a prenatal diagnostics method that analyzes DNA in
    amniotic fluid using customized whole-genome sequencing.

                      BASIC DISCOVERIES FOR BETTER HEALTH

        NIGMS-supported research employs a range of non-human model
    organisms to ask and answer questions about human biology. One example
    is research to understand circadian rhythms, commonly known as the
    biological clock. The foundation of knowledge gathered over the years
    in this area of science is now coming together to help explain how
    various diseases and conditions are influenced by the time of day.
    Recent NIGMS-funded studies have shown that circadian rhythms have a
    major influence on the production of the basic units of metabolism such
    as amino acids, sugars, and fats. Researchers learned that about 60
    percent of these essential metabolites that sustain and promote cell
    health and growth are synchronized with the body's clock system. These
    findings are important because of their connection to other NIGMS-
    supported research established a link between circadian rhythms and
    chronic conditions like diabetes and obesity, which involve activities
    linked to time of day including eating, sleeping, and physical
    activity. Integrating knowledge from basic metabolism and circadian
    biology has implications for managing the many conditions related to
    our biological clocks.
        Aside from their use as models for basic cell biology, genetics,
    and metabolism, bacteria are a focus of study for NIGMS-supported
    researchers in another way: the study of bacterial communities called
    biofilms. Many individual microbes do not cause disease; indeed, they
    aid in normal digestion and perform other vital roles in the body. Yet,
    when some otherwise non-harmful strains of bacteria assemble into a
    film structure, they can clog medical devices like heart valves and
    catheters. Using powerful microscopes and time-lapse imaging, NIGMS-
    supported scientists watched biofilms form, as microbes joined together
    to create slimy ribbons that ensnared other bacteria as they traveled
    through narrow, fluid-filled tubes mimicking implanted medical devices.
    The researchers were surprised to learn just how fast this clogging
    occurred, and with no apparent warning. These research results could be
    used toward the development of clog-resistant medical devices.

                  ENABLING TECHNOLOGY THAT ADVANCES DISCOVERY

        Technology is a key driver of progress in biomedicine. NIGMS
    considers its support of resource development a vital component of the
    Institute's investment in allowing creative scientists to uncover new
    knowledge and make breakthrough discoveries.
        One example of NIGMS-supported resource development is the NIGMS
    Biomedical Technology Research Centers program, a synergistic
    interaction of technical and biomedical expertise. These Centers
    promote the widespread and routine application of pioneering
    technologies and methods, and apply them to a broad range of basic,
    translational, and clinical research efforts. The resources--ranging
    from electron microscopes to bioinformatics platforms to mass
    spectrometers and other technologies--are used by thousands of NIH-
    supported scientists each year.
        A second example is the Institute's investment in research on
    chemistry methods that can be used and re-purposed by both academia and
    industry. In one recent instance, scientists used NIGMS research funds
    to make a chemistry toolkit that can quickly and easily generate dozens
    or even hundreds of versions of a single molecule, toward the testing
    and refining of such molecules as potential drugs. This research is
    important because companies are unlikely to sponsor the development of
    broad-based resources like this. A key advantage of this new technique
    is that it simplifies complicated and potentially hazardous chemical
    reactions such that they can be automated and can be performed in a
    water-based environment without the use of harmful chemicals.

                            STRATEGY FOR THE FUTURE

        NIGMS has always planned strategically for the future, since
    biomedical research is a long-term commitment to supporting creative
    people to develop and test new ideas. Part of this process is keeping
    an eye on the evolution of biomedicine as new tools emerge and new
    disease threats come to light. In recent years, NIGMS has published
    companion strategic plans that chart the Institute's course for
    research and research training, noting the tight link between the two.
    The Institute continues to invest funds and resources toward activities
    that reflect the content of these plans. NIGMS strives for a healthy
    balance within its scientific portfolio between small projects that are
    conducted by individual scientists within their laboratories, and
    larger consortia (like the PGRN, PSI, and MIDAS) that enable
    researchers to work together on problems that call for a broader range
    of expertise, samples, and resources than can be managed reasonably and
    successfully by individual scientists.
        NIGMS is pleased that many of its research and research training
    efforts under way resonate so well with recommendations put forth last
    year by the NIH Advisory Committee to the Director on NIH's role in
    research training and in promoting a diverse biomedical workforce.
    Toward building a strong evidence base in workforce-related issues,
    NIGMS has funded grants that investigate factors contributing to gender
    and ethnic/racial disparity in workforce representation, to increase
    diversity. Emerging concepts include eliminating unconscious bias,
    career flexibility, and the value of good mentoring. This growing body
    of work will be pivotal to effecting change on a larger scale.
        NIGMS recognizes its vital role in supporting basic research for
    better health. In so doing, the Institute contributes in a sustained
    fashion to the health of the American people and to maintaining
    America's leadership role in science.
                                     ______

      Prepared Statement of Alan E. Guttmacher, M.D., Director, ``Eunice
        Kennedy Shriver'' National Institute of Child Health and Human
                                  Development

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the ``Eunice Kennedy Shriver''
    National Institute of Child Health and Human Development (NICHD). The
    fiscal year 2014 budget of $1,339,360,000 includes an increase of
    $20,417,000 over the comparable fiscal year 2012 level of
    $1,318,943,000.
        This past year, NICHD celebrated its 50th anniversary. Beyond
    celebrating past accomplishments, this milestone inspired the
    Institute, along with its many stakeholders, to identify compelling
    scientific opportunities for the next decade. The Institute's future
    research must build upon its strong foundation of scientific advances,
    from better understanding of the basic mechanisms that transform cells
    into healthy and effectively functioning individuals, to clinical
    studies that improve the health and well-being of women, children,
    families, and individuals with disabilities.

                             DEVELOPMENTAL BIOLOGY

        Research in developmental biology helps to explain how individuals
    develop and the origins of various diseases and conditions. Recently,
    NICHD-funded scientists found that pregnant women with epilepsy who
    took the prescription drug topiramate during their first trimester to
    prevent seizures were at a slightly increased risk of having babies
    with cleft lip. Intramural scientists recently used next-generation
    gene sequencing techniques to discover new brain regions in an animal
    model, once thought to be inert, which appear to be active in the
    pineal gland, which controls the body's 24-hour wake-sleep cycle and is
    integral to development. Advances in genetics and systems biology will
    shed new light on human development, and provide critical underpinnings
    for emerging fields such as regenerative medicine.

                  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE

        Complex interactions among biological and external factors,
    starting before conception, can influence health across the life
    course, and even across generations. NICHD researchers discovered a
    genetic pathway common to the rapid growth of healthy fetuses and the
    uncontrolled cell division of cancer, shedding light on both normal
    development and the genetic bases of common cancers. Understanding the
    developmental origins of health and disease will benefit from
    interdisciplinary and global studies and, ultimately, can be applied to
    prevent, treat, or even reverse chronic conditions such as obesity,
    diabetes, and cognitive deterioration.

                        PREGNANCY AND PREGNANCY OUTCOMES

        Achieving a better understanding of pregnancy processes and fetal
    development can pave the way for predicting and preventing poor
    pregnancy outcomes as well as improving lifelong health for both women
    and infants. A new NICHD-funded study reported that pregnant women's
    exposure to the flu was associated with a nearly four-fold increased
    risk that their children would develop bipolar disorder in adulthood.
    This information may encourage and increase the use of prevention
    strategies, such as the flu vaccine. Another study found that women who
    develop gestational diabetes during pregnancy can greatly decrease
    their risk of developing type 2 diabetes later in life by maintaining a
    healthy diet in the years following pregnancy. Targeted areas for
    future research include obtaining further understanding of how to
    promote healthy pregnancies and unraveling the complex causes of
    stillbirth and prematurity.

                                  REPRODUCTION

        Reproductive health is an essential element of personal well-being
    across the lifespan, and necessary to ensuring the health of future
    generations. NICHD-supported research found that the hormone progestin,
    often given as a first step in infertility treatment for polycystic
    ovary syndrome, unexpectedly decreased the odds of conception and
    giving birth. Discoveries such as this advance our understanding of
    what works in clinical practice and what may have unintended
    consequences and, at the same time, be used to identify potential new
    diagnostic and therapeutic targets for managing critical aspects of
    women's and men's reproductive health.

                             BEHAVIOR AND COGNITION

        Human behaviors can contribute to positive health outcomes or
    increase the risk of adverse ones. NICHD-funded researchers found that
    when the mind is at rest, the electrical signals by which brain cells
    communicate appear to travel in reverse, wiping out unimportant
    information, while sensitizing cells for future learning. NICHD
    research found that children who failed to acquire a particular math
    skill, number system knowledge, in first grade scored well behind their
    peers by seventh grade, pointing the way for targeted intervention when
    it matters most. In another study, seven-month old babies who were
    later diagnosed with autism took slightly longer to shift their gaze
    than babies who developed normally, which may provide an early clue to
    differences in their brain structure. Future basic and translational
    research that combines neuropsychological, behavioral, and social
    science perspectives will increase knowledge about the mechanisms that
    underlie typical and atypical behavior and cognition.

                         PLASTICITY AND REHABILITATION

        Plasticity, adaptive or maladaptive change at the cellular, tissue,
    organ, or system levels, is at the core of human development and
    rehabilitation. NICHD researchers have identified proteins in an animal
    model that help fuse early-stage cells and eventually develop into
    muscle cells. This finding has implications for understanding how to
    repair and rehabilitate muscle tissue and how specialized cells
    (osteoclasts) repair and maintain bones. The ongoing challenge for
    scientists will be to generate additional knowledge about the
    mechanisms of plasticity, and translate this knowledge into
    interventions that can help individuals remodel, maintain, or enhance
    functioning.

                              POPULATION DYNAMICS

        Individuals, families, and communities are all critical units,
    through which population-level factors interact with genetic and
    environmental variables, influencing individual health across the
    lifespan. An NICHD study demonstrated that the stresses of poverty
    (e.g., financial worries, inadequate child care), were shown to lead to
    impaired learning ability in children; high levels of stress hormones
    influence the developing circuitry of children's brains, impairing
    their executive functions. Another study, a landmark collaboration
    among NICHD, other NIH Institutes and Centers, Federal agencies, and
    private foundations, demonstrated that providing specialized housing
    vouchers that enabled low-income women and children to move from
    impoverished neighborhoods to those with relatively few poor residents
    reduced extreme obesity and diabetes over time. Over the next decade,
    research must continue to provide the comprehensive evidence needed for
    what works and how to scale programs at the population level,
    accounting for individual behaviors and biomedical factors, family and
    community characteristics, and social forces.

                               CONDUCT OF SCIENCE

        In the coming years, biomedical and biobehavioral researchers will
    need to work as transdisciplinary teams, manage massive amounts of
    data, and acquire new and diverse skill sets. The very breadth of
    NICHD's mission requires us to create, train, and support such teams to
    be able to fully translate our research advances into actions that
    improve the health of women, children, families, and individuals with
    disabilities.
                                     ______

    Prepared Statement of Paul A. Sieving, M.D., Ph.D., Director, National
                                 Eye Institute

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Eye Institute (NEI) of
    the National Institutes of Health (NIH). The fiscal year 2014 budget of
    $699,216,000 includes a decrease of $2,191,000 below the comparable
    fiscal year 2012 level of $701,407,000. As the director of the NEI, it
    is my privilege to report on the many research opportunities that exist
    to reduce the burden of eye disease.

                               STRATEGIC PLANNING

        ``The NEI Challenge to Identify Audacious Goals in Vision Research
    and Blindness Rehabilitation'' was a novel strategic planning
    initiative designed to identify innovative, groundbreaking long-term
    research goals. The challenge was open to anyone with an idea for a 10-
    year audacious research goal including scientists, engineers,
    clinicians, and the public. NEI used a new prize competition authority,
    from the America COMPETES Reauthorization Act of 2010, to attract
    attention and received more than 500 ideas for audacious goals. A
    Federal review panel selected 10 winning entries for further
    consideration. Then, more than 200 leading scientists and clinicians
    met to further develop these ideas at the NEI Audacious Goals
    Development Meeting held in February 2013. Afterwards, NEI announced an
    audacious goal (Regenerate Neurons and Neural Connections in the Eye
    and Visual System) and two high-priority areas (Molecular Therapy for
    Eye Disease and the Intersection of Aging and Biological Mechanisms of
    Eye Disease) at the Association for Research in Vision and
    Ophthalmology meeting on May 5. NEI is now identifying the necessary
    steps to boldly attack these research endeavors over the coming decade.

                                CLINICAL TRIALS

        This month, NEI-supported investigators published results of the
    Age-Related Eye Disease Study 2 (AREDS2), a large, multi-center
    clinical trial designed to refine the antioxidant and mineral
    supplement formulation that was evaluated in the original AREDS
    clinical trial. The original Age-related Eye Disease Study (AREDS)
    established that daily doses of vitamins C and E, beta-carotene, zinc,
    and copper slows the progression to advanced age-related macular
    degeneration (AMD), the leading cause of visual impairment and legal
    blindness in older Americans. AREDS2 was undertaken for three reasons.
    First, preliminary evidence indicated that Omega-3 fatty acids might be
    beneficial. Second, beta-carotene, used in AREDS, was found to increase
    lung cancer risk in cigarette smokers. Third, it was suggested that the
    rather high zinc level in AREDS might cause minor side effects, such as
    stomach upset. AREDS2 investigators found that adding Omega-3 fatty
    acids, replacing beta-carotene with two other carotenoids, lutein and
    zeaxanthin, and lowering zinc levels maintained, but did not improve
    the effectiveness of the original formulation. Thus, changing the
    carotenoid and lowering the zinc in original AREDS formulations offers
    an equally effective alternative with fewer side effects. The AREDS2
    study results provide physicians and patients with new information
    about delaying or preventing vision loss from AMD.
        In February 2013, the FDA approved the Argus II Retinal Prosthesis
    System, a medical device capable of restoring ambulatory vision to
    those blind from retinitis pigmentosa. Argus II consists of a miniature
    video camera that is mounted on a pair of glasses. A processing unit
    worn on a belt converts images captured by the camera into electrical
    impulses that are wirelessly transmitted to a 60-electrode grid
    implanted in the eye. Users perceive the electrical impulses as
    patterns of light that produce visual information. The Argus II,
    developed by Second Sight, Inc., was made possible through more than a
    decade of clinical trial support from NEI.

                             TRANSLATIONAL RESEARCH

        Retinitis pigmentosa (RP) is a group of rare, degenerative diseases
    that result from mutations in any one of 40 genes that function in rod
    photoreceptor cells in the retina. These cells form our peripheral
    vision and allow us to see in dim and dark environments. As RP
    progresses, patients experience night blindness and severely restricted
    visual fields. For reasons that are not understood, the loss of rods
    eventually leads to the degeneration and death of cones, the
    photoreceptor cells in the central portion of the retina that allow us
    to perceive fine visual detail and color. Without central vision, it is
    impossible to perform essential tasks of daily life such as reading,
    driving, walking without assistance, or recognizing faces and objects.
        Vision researchers have long sought a therapeutic approach that can
    address multiple RP genotypes. However, current efforts with gene
    therapy address only one specific gene defect at a time. In a highly
    novel approach that could be applied to most, if not all, forms of RP,
    NEI-supported investigators genetically reprogrammed rods to become
    cone-like cells in a rodent model of RP. This approach reduced rod cell
    function but preserved cone cells. Although such a treatment would
    leave patients with limited peripheral vision and night blindness, this
    would be preferable to the added debilitating loss of central vision
    for the estimated 200,000 Americans who live with RP.
        NEI-supported investigators have developed a potential new
    treatment to prevent proliferative vitreoretinopathy (PVR) a sight-
    threatening complication of retinal detachment that requires prompt
    surgical treatment. PVR occurs in about 10 percent of retinal
    detachments, resulting in permanent scarring of the retina. In this
    condition, retinal pigment epithelial (RPE) cells, which line the
    neural retina, migrate through the retinal detachment into the vitreous
    fluid where they rapidly multiply, dedifferentiate and contribute to
    the formation of an abnormal membrane on the surface of the retina.
    This membrane eventually contracts, pulling at the retina and forming a
    larger detachment. PVR causes heavy scarring of the retina and severe
    visual impairment. NEI investigators identified seven classes of
    biological growth factors and regulatory proteins that promote the
    proliferation and contraction of the RPE-derived membrane in an animal
    model of PVR. By inhibiting the expression of these biological factors,
    the investigators prevented PVR. This study provides insight into the
    causes of PVR and proof-of-concept for treating the condition.
        The cornea, the outer protective layer of the eye, is amazingly
    resilient to infection. By exposing cultured human corneal cells to
    bacteria, NEI researchers identified a class of peptides important in
    the cornea's defense against bacterial infection. Blocking these
    peptides in a rodent model led to a marked increase in corneal
    infections. Synthetic variations of these peptides effectively killed
    bacteria that lead to flesh-eating disease and strep throat, staph
    infections, diarrhea, and cystic fibrosis associated lung infections.
    The findings could lead to a powerful new class of low-cost antibiotics
    at a time when antibiotic resistance to existing agents is of growing
    concern.
                                     ______

       Prepared Statement of Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S.,
         Director, National Institute of Environmental Health Sciences

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of
    Environmental Health Sciences (NIEHS) of the National Institutes of
    Health (NIH). The fiscal year 2014 NIEHS budget of $691,348,000
    includes an increase of $7,051,000 from the comparable fiscal year 2012
    level of $684,297,000.

                                  INTRODUCTION

        In fiscally challenging times for science, NIEHS is finding
    innovative ways to maximize its investments through strategic planning,
    collaborative research, and focused translation of science. For
    example, NIEHS grantees have discovered a key mechanism by which
    dietary omega-3 fatty acids (fish oils) could reduce the growth and
    spread of cancer, which kills 580,000 Americans a year.\1\ New findings
    from the NIEHS Sister Study show that even moderate physical activity
    can reduce breast cancer risk,\2\ and that estrogen may help offset
    effects of obesity and alcohol on risk.\3\

                             COLLABORATIVE RESEARCH

        NIEHS develops and leads multi-disciplinary collaborations in areas
    such as the Gulf Oil spill, breast cancer and the environment,
    nanotechnology, bisphenol A, and science data management. In
    partnership with the Substance Abuse and Mental Health Services
    Administration, the NIEHS Gulf Long-term Follow-up (GuLF) Study of
    33,000 men and women will assess mental health trajectories, resiliency
    and coping, and mental healthcare needs of participants. NIEHS has
    invested $30 million from 2009 to date working with Federal partners
    and the Nation's leading researchers to fill data gaps and resolve
    controversies over the human health effects of exposure to low levels
    of BPA. Nearly 150 papers have resulted from this effort so far.\4\
    Recent observational human studies \5\ show that early life exposures
    to BPA can potentially lead to diseases or health problems in adulthood
    such as prostate and breast cancer, obesity, diabetes, and
    cardiovascular, neurobehavioral, and reproductive disorders. Work of
    the Engineered Nanomaterials Grand Opportunity (Nano GO) Consortium of
    13 laboratories now provides investigators with standardized methods
    for predicting the toxicity of selected nanomaterials.\6\ \7\ NIEHS is
    a partner in the new National Consortium for Data Science that aims to
    address the challenges of collecting, sharing, and using large, diverse
    datasets. At its recent summit, genomic and data scientists drafted
    recommendations for translating genomic data into better, more
    affordable healthcare by developing new ways to collect, manage,
    analyze, and apply massive amounts of data into tools for scientific
    discovery and economic growth.

                              SCIENTIFIC ADVANCES

        NIEHS's investigator-initiated research provides critical advances
    in environmental health and basic sciences. New findings suggest that
    Vitamin D may reduce the risk of uterine fibroids,\8\ a condition that,
    according to NIH, afflicts up to 80 percent of American women, causes
    more than 200,000 hysterectomies each year, and results in direct
    health costs of $2.1 billion. A recent study points to exposure to
    polybrominated diphenyl ethers in flame retardants as a factor in
    increased risk of Parkinson's disease.\9\ A new analysis of the
    scientific literature shows that exposure to increased levels of
    particulate matter during pregnancy can lead to greater risk of low
    birth weight babies,\10\ putting them at risk of poor health in
    childhood and adulthood.
        Exposure to toxic substances in the environment accrues huge costs
    in human suffering, and results in economic costs to individuals and
    society; NIEHS-funded studies illustrate this dual burden. Each year in
    Europe, 1.8 million children suffer unsafe prenatal methylmercury
    exposures that affect brain development, mostly from fish in mothers'
    diets. Preventing such exposures could save the European Union 8 to 9
    billion euros per year in lost earning potential of these children.\11\
    In a study of approximately 12.5 million elderly Medicare
    beneficiaries, researchers found a consistent increase in costly
    respiratory hospitalizations with increasing outdoor temperatures.\12\

                            STAKEHOLDER TRANSLATION

        Just as scientific rigor is required to generate sound research
    findings, vigorous approaches are needed to translate these findings to
    stakeholders. In 2012, NIEHS released a strategic plan that identifies
    key goals for the next 5 years that will provide the rubric for NIEHS
    to achieve its vision as a catalyst for the application of state-of-
    the-art biomedical research to the most critical environmental health
    problems. NIEHS ``talks the talk'' by committing to effective research
    translation in its strategic plan, and ``walks the walk'' through
    engagement and translation activities with the American public.
        Community Forums around the United States allow the public to raise
    environmental health concerns with the NIEHS director. In November
    2012, NIEHS held its first virtual Community Forum on environmental
    exposures and childhood obesity, using social media and webcasting to
    reach 600 viewers and spark 1.5 million tweets. In a March forum in
    Seattle, residents voiced concerns about a site along the Duwamish
    River that is one of the most polluted in the U.S., as well as home to
    low-income and recent immigrants, and fishing grounds of three
    Northwest Tribes. In February, the NIEHS-led Interagency Breast Cancer
    and Environmental Research Coordinating Committee released
    ``Prioritizing Prevention,'' recommendations for reducing environmental
    exposures and modifying lifestyle factors implicated in breast cancer.
        NIEHS provides critical Federal and global leadership to advance
    science on how the environment affects people's health to promote
    healthier lives.
    ---------------------------------------------------------------------------
        \1\ Zhang G, et al., Epoxy metabolites of docosahexaenoic acid
    (DHA) inhibit angiogenesis, tumor growth, and metastasis. Nature. April
    3, 2013. Published online at: http://www.pnas.org/content/early/2013/
    04/03/1304321110.
        \2\ McCullough LE, et al., Fat or fit: the joint effects of
    physical activity, weight gain, and body size on breast cancer risk.
    Cancer. Oct. 1, 2012, 118(19):4860-8. Published online at: http://
    www.ncbi.nlm.nih.gov/pubmed/22733561.
        \3\ Hong J, Holcomb VB, Kushiro K, Nunez NP. Estrogen inhibits the
    effects of obesity and alcohol on mammary tumors and fatty liver. 2011.
    Int J Oncol 39(6):1443-1453. Published online at: http://
    www.ncbi.nlm.nih.gov/pubmed/21850368.
        \4\ http://www.niehs.nih.gov/research/resources/bpa-related/
    index.cfm.
        \5\ Li D, et al., Occupational exposure to bisphenol-A (BPA) and
    the risk of self-reported male sexual dysfunction. Hum Reprod. 2010
    Feb;25(2):519-27. Published online at: http://www.ncbi.nlm.nih.gov/
    pubmed/19906654.
        \6\ Xia T, et al., Interlaboratory Evaluation of ``In Vitro''
    Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials:
    The NIEHS Nano GO Consortium. Environ Health Perspect. 2013 May 6.
    [Epub ahead of print] Published online at: http://www.ncbi.nlm.nih.gov/
    pubmed/23649538.
        \7\ Bonner JC, et al., Interlaboratory Evaluation of Rodent
    Pulmonary Responses to Engineered Nanomaterials: The NIEHS Nano Go
    Consortium. Environ Health Perspect. 2013 May 6. [Epub ahead of print]
    Published online at: http://www.ncbi.nlm.nih.gov/pubmed/23649427.
        \8\ Baird DD, Hill MC, Schectman JM, Hollis BW. 2013. Vitamin D and
    the risk of uterine fibroids. ``Epidemiology''; 24(3):447-453.
    Published online at: http://www.ncbi.nlm.nih.gov/pubmed/23493030.
        \9\ Bradner JM, et al., Exposure to the polybrominated diphenyl
    ether mixture DE-71 damages the nigrostriatal dopamine system: Role of
    dopamine handling neurotoxicity. Exp Neurol 2013, 241:138-147.
    Published online at: http://www.ncbi.nlm.nih.gov/pubmed/23287494.
        \10\ Dadvand P, et al., Maternal exposure to particulate air
    pollution and term birth weight: a multi-country evaluation of effect
    and heterogeneity. Environ Health Perspect; 2013 [Online 6 February
    2013]. Published online at: http://ehp.niehs.nih.gov/1205575/.
        \11\ Bellanger M, et al., Economic benefits of methylmercury
    exposure control in Europe: Monetary value of neurotoxicity prevention.
    Environ Health; 2013 [Online 7 January 2013]. Published online at:
    http://www.ncbi.nlm.nih.gov/pubmed/23289875.
        \12\ Anderson GB, et al., Heat-related emergency hospitalizations
    for respiratory diseases in the Medicare population. AJRCCM [In Press]
    Published on 14 March 2013 as doi: 10.1164/rrcm.201211-1969OC.
    ---------------------------------------------------------------------------
                                     ______

    Prepared Statement of Stephen I. Katz, M.D., Ph.D., Director, National
          Institute of Arthritis and Musculoskeletal and Skin Diseases

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Arthritis
    and Musculoskeletal and Skin Diseases (NIAMS) of the National
    Institutes of Health (NIH). The fiscal year 2014 NIAMS budget of
    $540,993,000 includes an increase of $6,202,000 over the comparable
    fiscal year 2012 level of $534,791,000.

                                  INTRODUCTION

        As the primary Federal agency for supporting medical research on
    diseases of the bones, joints, muscles, and skin, NIAMS touches the
    lives of nearly every American. The burden of these diseases is
    substantial. Arthritis limits the activities of nearly 21 million
    adults in the United States each year; medical care and lost wages
    attributable to musculoskeletal conditions cost Americans an estimated
    $950 billion annually; and skin conditions such as eczema and psoriasis
    affect more than 12 percent of people world-wide.\1\ NIAMS is
    accomplishing its mission of improving health by supporting basic and
    translational research that will impact clinical practice, by training
    the next generation of bone, joint, muscle, and skin scientists, and by
    disseminating the findings from its studies, and related health
    information, to all Americans.

                   BASIC SCIENCE: THE FOUNDATION FOR TOMORROW

        Tomorrow's treatments are rooted in the basic research conducted
    today. NIAMS is committed to better understanding the molecular and
    cellular processes that contribute to health and disease. This basic
    research will serve as the foundation for new diagnostic tests,
    therapies, and prevention strategies that will improve the lives of
    those who are affected by arthritis, and musculoskeletal and skin
    conditions.
        NIAMS investigators are leveraging the Nation's investment in
    understanding the human genome and making use of its associated
    technologies. One such project is studying facioscapulohumeral muscular
    dystrophy (FSHD)--a neuromuscular disease of the face, shoulders, and
    upper arms. Building on earlier findings about DNA sequences on
    chromosome 4 that lead to FSHD, researchers discovered that a rare form
    of the disease--called FSHD2--is caused by mutations on both chromosome
    4 and chromosome 18. These results set the stage for new diagnostic
    tests and treatments for patients who have FSHD2. Moreover, the
    recognition that distant genes interact with each other may lead to
    similar discoveries in other conditions.
        NIAMS recognizes industry's important role in conducting basic
    research, developing new technologies, and commercializing federally
    supported discoveries. For this reason, NIAMS is offering grants to
    eligible small businesses for development of biomarkers or therapies
    for rare musculoskeletal, rheumatic, or skin diseases.

               TRANSLATIONAL SCIENCE: BRIDGING BENCH AND BEDSIDE

        NIAMS basic research can only improve public health when the
    understanding it generates is translated into new and improved
    treatments and preventive strategies. Recent insights into the
    molecular mechanisms of cell processes are already suggesting
    treatments. NIAMS researchers at the NIH Clinical Center launched a
    small clinical trial after experiments into the cause of neonatal-onset
    multisystem inflammatory disease (NOMID) revealed that it may be
    corrected with the adult rheumatoid arthritis (RA) drug anakinra. The
    children participating in the trial, who had been ill for years,
    improved within days of receiving the drug. Their rashes disappeared,
    their eye problems resolved, and their hearing improved or stopped
    worsening. The investigators then initiated a 5-year study, which led
    to U.S. Food and Drug Administration (FDA) approval of anakinra for
    pediatric NOMID patients earlier this year.
        NIAMS-funded basic research also contributed to the recent FDA
    approval of a new treatment for RA. The drug, tofacitinib, targets a
    protein discovered at NIH in 1993. Following many years of
    collaboration between NIH and private industry, tofacitinib became the
    first drug approved in more than a decade that can be taken as a pill,
    rather than an injection, to slow or halt RA joint damage. It provides
    an option for adults with moderately to severely active RA who do not
    respond well to the standard therapy for the disease--methotrexate.
        In addition to helping patients by supporting basic research and
    developing new treatments, NIAMS facilitates work that guides
    clinicians in the use of existing therapies. NIAMS funding assisted a
    national consortium of pediatric rheumatologists establish treatment
    recommendations for newly diagnosed juvenile idiopathic arthritis
    patients, and for children who develop kidney inflammation due to
    lupus. These recommendations are guiding patient care today and can be
    integrated into future effectiveness and toxicity studies as therapies
    are developed.
        Other work may help clinicians predict which scleroderma patients
    will respond to the drug mycophenolate mofetile (MMF), one of the
    standard therapies for this disorder. A small clinical trial built on
    findings about the molecular causes of scleroderma revealed a
    connection between gene expression patterns in patients' skin biopsies
    and their responses to MMF. If an ongoing study confirms this genetic
    biomarker's predictive value, countless patients might be spared
    needless exposure to MMF and could begin receiving other drugs before
    their disease progresses.
        NIAMS-supported research also is contributing to knowledge about
    dietary and behavioral changes that can prevent common public health
    challenges. Poor nutritional habits increase older Americans' risk of
    metabolic acidosis, a condition that occurs when the body produces too
    much acid or the kidneys fail to remove excess acid from the blood.
    Because bone is a reservoir for alkaline salts (e.g., calcium
    phosphate), it can lose minerals and weaken in an effort to maintain a
    healthy acid-base balance. Findings from an NIAMS-funded clinical trial
    revealed that the dietary supplement potassium citrate improves the
    acid-base equilibrium of people's blood, their calcium balance, and
    markers of skeletal health. This supports the hypothesis that potassium
    citrate can slow or prevent bone loss that occurs with age. If future
    studies confirm the results, potassium citrate could become a safe and
    easily administered intervention for patients who have, or are at risk
    of, osteoporosis and related fractures.
        NIAMS research findings are assisting healthcare providers and
    patients select among treatment options. Many adults have debilitating
    knee pain due to a tear in the meniscus, a cushion-like tissue that
    absorbs impact. Although meniscal tears can be treated with physical
    therapy or surgery, it was unclear which intervention was best until a
    recent paper showed that most patients benefited equally from either
    option over time. Those in the physical therapy group improved less
    quickly, however, and about one-third resorted to surgery because
    physical therapy did not provide adequate relief.

                    ENSURING A DIVERSE SCIENTIFIC WORKFORCE

        NIAMS is committed to developing and retaining a diverse and
    collaborative scientific workforce. Planning discussions in fiscal year
    2012 that included investigators, health professionals, and patients
    identified the transition from mentored research to full independence
    as a vulnerable period in clinician-scientists' careers. In fiscal year
    2013, NIAMS met with grantees nearing the end of their clinical or
    patient-oriented research career development awards to learn about the
    challenges they and their peers are facing. NIAMS plans for fiscal year
    2014 include a similar effort, with a long-term goal of identifying
    ways to better support early-stage investigators' transition to
    research independence.

                SHARING HEALTH INFORMATION AND RESEARCH PROGRESS

        The Internet and other electronic communication platforms have
    emerged as valuable tools for disseminating health information. An
    increasing number of visitors are accessing the NIAMS Web site from
    mobile devices, and current trends indicate that mobile traffic to Web
    sites may overtake desktop traffic as soon as 2015. In response, NIAMS
    began providing its health information in a mobile device friendly
    format in fiscal year 2013. NIAMS will continue to assess and adapt to
    new technologies and tools to provide research updates and health
    information to the widest possible audience.
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        \1\ Cheng YJ, et al. Prevalence of doctor-diagnosed arthritis and
    arthritis-attributable activity limitation--United States, 2007-2009.
    MMWR 2010;59(39):1261-1265.
        U.S. Department of Health and Human Services, Agency for Healthcare
    Research and Quality, Medical Expenditures Panel Survey, 1996-2006.
    Data analyzed and modeled by Edward H. Yelin, PhD, Institute for Health
    Policy Studies, University of California, San Francisco, San Francisco,
    CA, as cited in www.boneandjointburden.org/highlights/FactsinBrief.pdf,
    accessed March 27, 2013.
        Vos T, et al. Years lived with disability (YLDs) for 1160 sequelae
    of 289 diseases and injuries 1990-2010: a systematic analysis for the
    Global Burden of Disease Study 2010. Lancet. 2012 Dec
    15;380(9859):2163-96. doi: 10.1016/S0140-6736(12)61729-2.
    ---------------------------------------------------------------------------
                                     ______

      Prepared Statement of James F. Battey, Jr., M.D., Ph.D., Director,
        National Institute on Deafness and Other Communication Disorders

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute on Deafness
    and Other Communication Disorders (NIDCD) of the National Institutes of
    Health (NIH). The fiscal year 2014 NIDCD budget of $422,936,000
    includes an increase of $7,436,000 over the comparable fiscal year 2012
    appropriation of $415,500,000.
        NIDCD conducts and supports research, and research training in the
    normal and disordered processes of hearing, balance, smell, taste,
    voice, speech, and language. Our Institute focuses on disorders that
    affect the quality of life of millions of Americans in their homes,
    workplaces, and communities. The physical, emotional, and economic
    impact for individuals living with these disorders is tremendous. NIDCD
    continues to make investments to improve our understanding of the
    underlying causes of communication disorders, as well as their
    treatment and prevention. It is a time of extraordinary promise, and I
    am excited to be able to share with you some of NIDCD's ongoing
    research and planned activities on communication disorders.

               RESEARCHERS RESTORE HEARING IN NOISE-DEAFENED MICE

        Our ability to hear relies on sensory hair cells in the inner ear.
    The hairs on these specialized cells convert sound vibrations into
    electrical signals, which travel to the brain by way of the auditory
    nerve. When hair cells are damaged--by disease, injury, or aging--a
    person experiences hearing loss, and mammals cannot regenerate these
    lost hair cells.
        Researchers supported by NIDCD have shown for the first time that a
    drug can be used to grow sensory hair cells in the inner ear. They
    injected a drug into the cochlea (a spiral shaped organ in the inner
    ear that shelters hair cells) of mice made deaf by exposure to loud
    noise. The drug blocked a cell-signaling system known to keep stem
    cells in the inner ear from turning into hair cells. By blocking that
    particular pathway, the drug encouraged cells supporting and
    surrounding the hair cells to turn into new hair cells, which led to a
    small improvement in the mice's hearing.
        This is the first study to show that scientists can use a drug to
    restore partial hearing in a mouse with noise-induced hearing loss.
    Scientists now hope to develop similar treatments to reverse hearing
    loss in humans, especially among the estimated 36 million adult
    Americans who report hearing loss.

              NOVEL APPROACHES OF INNER EAR REGENERATIVE THERAPIES

        Although research to determine ways to regenerate inner ear hair
    cells is under way, there remains a lack of potential treatments to
    restore lost mammalian hair cell function. Research is needed to
    identify and facilitate important molecular switches and regulators
    that initiate and sustain mammalian hair cell repair.
        NIDCD places a high priority in research that focuses on
    regenerative medicine. For example, the Institute is planning a
    research initiative for fiscal year 2014 with the goal of developing
    hair cell regeneration strategies. NIDCD held a workshop, in September
    2011, to identify opportunities to induce regeneration in the inner
    ear. As a result of this workshop, NIDCD issued a Funding Opportunity
    Announcement to encourage innovative and novel approaches to inner ear
    regenerative therapies research. The ultimate goal of the research is
    to identify and ``turn on'' important molecular switches and regulators
    to enable mammals to regenerate and repair their own inner ear hair
    cells. This research may result in therapies that will provide hope of
    future treatments for those who have lost hearing due to aging, injury,
    or noise exposure, including military veterans returning from active
    duty.
        Another purpose of the initiative is to attract and support NIH-
    defined basic and clinical early-stage investigators (ESIs) to the area
    of biological repair of mammalian inner ear hair cells. NIDCD is
    especially interested in ESIs who bring new, innovative approaches, and
    strategies from scientific fields minimally represented in the NIDCD
    portfolio, such as tissue fabrication, biomaterials, and regenerative
    medicine. By supporting ESIs from other scientific areas, this
    initiative will encourage diversified approaches and an increased
    number of investigators focused on regenerative therapies in the inner
    ear.

    RESEARCHERS IDENTIFY GENE LINKED TO PROGRESSIVE HEARING LOSS FROM NOISE
                                   AND AGING

        An international team of scientists funded by NIDCD has identified
    the first gene in humans and mouse models that is associated with both
    noise-induced and age-related hearing loss. The gene, P2X2, appears to
    be crucial for the preservation of life-long normal hearing and for
    protection from exposure to loud noise. P2X2 is associated with the
    human gene locus DFNA41, a form of hearing loss that typically begins
    early in life (around 12-20 years of age), and progresses with age.
    High-frequency tinnitus (high-pitched ringing in the ears) often
    accompanies hearing loss associated with DFNA41.
        The research team discovered that the P2X2 gene mutation found in
    DFNA41 results in defects in sensory hair cells in the inner ear, which
    eventually lead to ongoing hearing loss. The study establishes, at the
    cellular and molecular levels, that the function of this ion channel,
    previously known to be involved in sensory signaling of pain, has a
    major impact on noise-induced and age-related hearing loss.
        These findings demonstrate the importance of genetic approaches to
    uncover the underlying mechanisms that contribute to hearing loss,
    either as a result of age or chronic exposure to noise. Importantly,
    identifying the P2X2 mutation may provide scientists with a way to
    develop targeted treatments for progressing hearing loss in humans with
    DFNA41, and may be applicable to the treatment of noise-induced and
    age-related hearing loss in the broader population.

       NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
      SUPPORTS RESEARCH TO DEVELOP A VACCINE AGAINST AN EMERGING TYPE OF
                            CHILDHOOD EAR INFECTION

        Ear infections during childhood are of great concern to NIDCD,
    because they not only cause pain and suffering, but they also interfere
    with a child's ability to hear properly during a critical period of
    language development. Since 2000, childhood vaccines have prevented
    many ear infections caused by two strains of bacteria--``Haemophilus
    influenzae and pneumococcus''. However, doctors are now seeing an
    increase in the number of ear infections caused by another strain of
    bacteria, called ``Moraxella catarrhalis (M. catarrhalis)''.
        NIDCD-supported scientists are working to understand how this
    bacterium infects humans and avoids destruction by the immune system.
    They hope to identify a particular structure (called an antigen) that
    is very similar among all strains of ``M. catarrhalis'', so that a
    vaccine based on a single antigen will protect against as many strains
    of the bacterium as possible.
        The research team is using bioinformatics to predict which ``M.
    catarrhalis'' proteins are likely to be found on the surface, to make
    an attractive antigen target. They are using gene chips to identify
    which genes are identical or similar among multiple strains of the
    bacterium, and then testing these in petri dishes and in animal models.
    The scientists are now testing several promising vaccine antigens
    against ``M. catarrhalis'', and hope that a new vaccine could be ready
    for human testing in a few years.
                                     ______

        Prepared Statement of Nora D. Volkow, M.D., Director, National
                            Institute on Drug Abuse

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute on Drug Abuse
    (NIDA) of the National Institutes of Health (NIH). The fiscal year 2014
    budget of $1,071,612,000 includes an increase of $20,202,000 over the
    comparable fiscal year 2012 level of $1,051,410,000.
        The individual and societal impact of both licit and illicit
    substance abuse in America is incalculable, not to mention the
    associated economic cost, estimated at well over half a trillion
    dollars a year in healthcare, crime-related, and productivity losses.
    The current landscape of the problem reveals both new and recurrent
    trends. Prescription drug abuse remains at high levels in all age
    groups, causing thousands of needless overdose deaths each year. New
    synthetic drugs, like ``bath salts'' and synthetic marijuana
    (``spice''), are sending many teens and young adults to emergency
    rooms. And as cultural changes promote greater acceptance of the use of
    marijuana, more teens report using it and fewer perceive its real
    risks. This, despite new research showing that early onset of marijuana
    use can disrupt learning circuitry and lower IQ.
        NIDA supports a broad research agenda that leverages the full
    potential of genetic/epigenetic, psychosocial, neuroimaging,
    pharmacological, health services, and epidemiological studies in order
    to reduce the burden of drug abuse and addiction. In the context of the
    current prescription drug abuse epidemic, for example, NIDA is
    harnessing the translational power of a multidisciplinary addiction
    science to: (1) identify the major factors that modulate risk; (2)
    develop universal, broad-based prevention and treatment models
    involving individuals, their families, schools, and communities; (3)
    develop pain medications with little or no abuse potential (for
    example, a new opioid medication that must pass through the digestive
    system to become active, preventing its abuse via non-oral routes); and
    (4) promoting physician education to both improve pain treatment and
    minimize drug abuse. NIDA also supports research to make the most of
    new opportunities and therapeutics, including healthcare reform
    legislation that stands to extend effective interventions to under-
    served populations, including people with substance use disorders.

                               NOVEL THERAPEUTICS

        To help those already suffering from addiction, we must expand our
    treatment toolkit. NIDA is optimally positioned to parlay research
    findings into new medication targets and promising compounds for
    pharmaceutical company investment or partnerships. Strategies now being
    tested include recruiting the body's immune system to attack and
    destroy drug molecules before they can enter the brain. This is being
    tried against nicotine, heroin, and stimulant drugs such as cocaine and
    methamphetamine, for which no medications are yet available. A related
    strategy involves delivery of an enzyme that has been molecularly
    engineered to rapidly destroy cocaine in the blood, currently in a
    phase II clinical trial. Combining existing medications is another
    promising approach, which has proven successful for a number of
    diseases (e.g., cancer and HIV/AIDS) but has not been exploited for
    treating addictive disorders. NIDA also continues to use its National
    Drug Abuse Treatment Clinical Trials Network (CTN) as a community-based
    platform to test new therapeutic interventions. For example, the CTN is
    testing an FDA-approved anxiety medication, buspirone, for its safety
    and efficacy in preventing relapse to cocaine use.

                           WIDENING THE SCOPE OF CARE

        Even effective interventions are not useful if they fail to reach
    the people who need them. Implementation research and inclusiveness of
    diverse populations in clinical trials are thus vital components of
    NIDA's research agenda to close the vast treatment gap. One example is
    research that pertains to the integration of substance abuse screening,
    brief intervention, and referral to treatment (SBIRT) into routine
    medical care and evaluation of the impact of such an approach in
    clinical outcomes of patients. Importantly, our goals in this context
    dovetail those of the Affordable Care Act, which promises to expand the
    scope of care and treat more patients suffering from substance use
    disorders. Another critical setting is the criminal justice system,
    where NIDA has long supported research to better deliver evidence-based
    treatment. Now, this focus extends to youth in the juvenile justice
    system, virtually all of whom could benefit from prevention or
    treatment interventions for drug abuse.
        Improving drug abuse prevention and treatment services also helps
    ameliorate other health consequences of abuse, including infectious
    diseases like HIV and hepatitis C virus (HCV) that can readily spread
    through the sharing of needles and other injection drug use equipment.
    One of the many translational initiatives spearheaded by NIDA is the
    ``Seek, Test, and Treat'' (and ``Retain'') strategy, aimed at
    evaluating the impact of expanding highly active antiretroviral therapy
    (HAART) coverage in criminal justice and other at-risk populations
    through aggressive outreach, early entry into HIV treatment, and
    follow-up in the community. There is accumulating evidence that early
    treatment with HAART reduces new HIV diagnoses, deaths, and HIV
    prevalence, suggesting that ``Treatment as Prevention'' should be
    implemented as soon and as widely as possible.

                          NEW SCIENTIFIC OPPORTUNITIES

        By taking full advantage of continuous developments in a wide range
    of scientific disciplines, NIDA is positioned to make significant
    advances in averting and treating addictive disorders. For example, we
    can now affordably sequence full individual genomes to identify rare
    genetic variations that influence addiction and responses to treatment,
    increasing not just our basic understanding of addiction but also
    paving the way for personalized treatments. Through the rapidly
    developing field of ``epigenetics'', we can determine the lasting
    impact of environmental variables like early stress or drug exposure on
    gene expression linked to later drug use. Another powerful new tool
    called ``optogenetics'', which allows us to activate (or deactivate)
    specific brain cells and networks, has enabled NIDA researchers to link
    compulsive cocaine-seeking in rats to deficits in the prefrontal cortex
    that were reversed by activating the affected brain regions. Clinical
    trials will soon test whether noninvasive (magnetic) stimulation can
    modify brain activity and reduce compulsive drug-seeking and craving in
    human drug users. Meanwhile, advanced imaging techniques are allowing
    us to ask questions about brain structure and function that were
    unimaginable just a few years back.
        Yet even with these new technologies, the underlying causes of most
    neurological and psychiatric conditions remain poorly understood, due
    to the human brain's incredible complexity. NIDA is one of the key
    participants in an exciting new NIH initiative to conquer this major
    frontier. Brain Research through Advancing Innovative
    Neurotechnologies, or BRAIN, will produce a revolutionary new dynamic
    picture of the brain, showing how individual cells and complex neural
    circuits interact in healthy individuals, and in those with brain
    disorders.
        To better capitalize on synergies in addiction science, NIDA, the
    National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the
    National Cancer Institute (NCI) have formed a consortium, the
    Collaborative Research on Addiction at NIH (CRAN), which will pool
    resources and expertise to address unmet research opportunities and
    public health needs. Among these, the study of ``comorbidities'' is
    poised to benefit. NIDA, NIAAA, and the National Center for
    Complementary and Alternative Medicine, in collaboration with the
    Department of Defense, recently issued a call for research on
    interventions to prevent comorbid alcohol and other drug abuse in U.S.
    military personnel, veterans, and their families. NIAAA and NIDA also
    issued a call for research on mechanisms of alcohol and nicotine co-
    addiction.
        The accelerating pace of science is rapidly outstripping our
    capacity to use what we collect. ``Big Data'' requires a significant
    repositioning in who we train and how we can best identify and exploit
    emerging scientific opportunities. We will need to build a workforce
    that includes people skilled in non-biomedical fields, such as
    informatics, computational science, mathematics, and engineering.
    Training the next generation of scientists to be able to understand the
    possibilities and complexities of what they will be dealing with is a
    daunting but exciting challenge as we go forward.
        In closing, we know much more about the causes and treatment of
    substance use disorders than ever before. Yet obstacles such as the
    lingering stigma attached to diseases of addiction continue to hamper
    our ability to recognize and care for those afflicted. NIDA remains
    committed to tackle these and other challenges, taking advantage of
    unprecedented scientific opportunities to transform how we prevent and
    treat substance abuse and related health consequences in this country.
                                     ______

       Prepared Statement of Kenneth R. Warren, Ph.D., Acting Director,
               National Institute on Alcohol Abuse and Alcoholism

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute on Alcohol
    Abuse and Alcoholism (NIAAA) of the National Institutes of Health
    (NIH). The fiscal year 2014 NIAAA budget request of $463,848,000
    reflects an increase of $5,183,000 over the comparable fiscal year 2012
    level of $458,665,000.

                              SCOPE OF THE PROBLEM

        According to the Centers for Disease Control and Prevention,
    excessive alcohol use cost the U.S. an estimated $223.5 billion in
    2006; it also takes a tremendous toll on individuals and their
    families. Alcohol affects individuals across the lifespan, from the
    developing fetus to the elderly. Each of you likely knows someone
    affected by alcohol problems.

          NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM RESEARCH

        To reduce the considerable burden of illness associated with
    alcohol misuse, NIAAA is working to prevent the onset and escalation of
    drinking during childhood and adolescence and intervene with problem
    alcohol use at all ages. A substantial portion of NIAAA's research
    portfolio focuses on the underlying mechanisms, prevention, and
    treatment of alcohol dependence. The remainder is allocated to studies
    on the consequences of alcohol use, including: health benefits
    associated with moderate drinking; adverse effects resulting from
    alcohol misuse such as fetal alcohol spectrum disorders (FASD), effects
    on the developing adolescent brain, and tissue and organ damage; and
    policy research to reduce harms both to drinkers and those around them.

                             FUNCTIONAL INTEGRATION

        NIAAA has embraced the decision of the NIH Director to pursue a
    functional integration of addictions research, which provides a
    framework for NIAAA, the National Institute on Drug Abuse (NIDA), the
    National Cancer Institute (NCI), as well as other Institutes and
    Centers (ICs), to enhance and expand collaborations and identify
    synergistic research opportunities to advance addictions science. Now
    referred to as the Collaborative Research on Addictions at NIH (CRAN),
    this new venture will support a variety of activities. Importantly,
    while advancing addictions research, a functional integration maintains
    the unique research contributions of each IC.
        Prior to the official launch of CRAN, NIAAA, and NIDA implemented a
    number of changes to improve integration between the two ICs and
    initiated additional joint funding opportunity announcements (FOA). One
    joint FOA focuses on research to prevent alcohol and other drug abuse
    in active military personnel, veterans and their families. Going
    forward, CRAN will explore cross-cutting research opportunities such as
    studies on individuals who suffer from addiction to multiple
    substances--40 percent of individuals who have a past year addiction to
    illicit drugs and/or abuse prescription drugs also have past year
    alcohol abuse or dependence, and 16 percent of individuals with past
    year alcohol abuse or dependence have a past year drug addiction. CRAN
    will also support efforts to identify mechanisms that underlie tobacco,
    alcohol and/or other drug addiction, recognizing that while some
    mechanisms may be common to more than one substance, others will be
    unique. Expanding studies to address multiple substances when feasible
    and appropriate will enhance our ability to treat multi-substance co-
    morbidities in an efficient and cost-effective manner. Funding
    opportunities under CRAN will begin in fiscal year 2014 with two
    initiatives; the first will expand existing projects to be more
    integrative and/or collaborative, the second will focus on mobile
    technologies and social media for interventions for substance abuse.

     NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM'S UNIQUE RESEARCH
                                     FOCUS

        NIAAA also has a robust research program outside of CRAN. Studies
    exploring pharmacological, behavioral and policy interventions to
    reduce acute and chronic consequences of alcohol misuse are a major
    component of NIAAA's portfolio. Medications development is an active
    area of study, both for the treatment of alcohol dependence and for the
    treatment of consequences of chronic alcohol misuse such as alcohol-
    induced liver disease. NIAAA's Clinical Investigations Group (NCIG) has
    streamlined the process for phase 2 clinical testing of potential
    compounds for alcohol dependence and has established an active
    collaboration with pharmaceutical companies. In a recent NCIG-led
    study, the smoking-cessation medication varenicline (Chantix)
    significantly reduced alcohol consumption and craving among people who
    are alcohol-dependent. Varenicline's effects were comparable to those
    seen in studies of naltrexone and acamprosate, two of the medications
    already approved by the U.S. Food and Drug Administration (FDA) for the
    treatment of alcohol dependence. If varenicline receives FDA approval
    for treatment of alcohol dependence, it could significantly expand
    treatment options. Personalizing treatment also continues to be a goal,
    and studies showing links between an individual's genetic make-up and
    treatment efficacy for various medications suggest that goal is within
    reach. Relapse, however, is still common and a focus of NIAAA research.
    A recent study showed that distinct patterns of brain activity are
    linked to a higher rate of relapse among patients in early recovery.
    These patterns may be useful for identifying patients at greatest risk
    for relapse.
        The link between stress and alcohol-related problems is an
    important area of investigation. While a number of studies have focused
    on how stress contributes to the development of alcohol-related
    problems and relapse, a recent line of investigation is exploring how
    chronic alcohol use might increase vulnerability of the brain to the
    development of stress-related disorders. A study in mice suggests that
    chronic alcohol use may increase the risk for post-traumatic stress
    disorder (PTSD) by altering neural circuits that normally enable the
    brain to extinguish fear following a traumatic event.
        NIAAA also continues to support medications development for the
    treatment of alcoholic liver disease (ALD), one of the most serious
    medical consequences of alcohol dependence, and continues to seek
    biomarkers for alcoholic liver damage. Scientists are gaining an
    appreciation for the interconnectedness of systems within the human
    body. NIAAA uses a systems biology approach to investigate how
    pathological changes in one organ as a result of alcohol exposure can
    also result in physiological aberrations in another. Basic research
    using animal models is also important to better understand the
    mechanisms underlying ALD; however, many of the current models do not
    evoke the full range of symptoms or are expensive and technically
    difficult. A new mouse model of alcohol drinking and disease was
    developed which more closely approximates ALD in humans and may also be
    useful to study alcohol damage of other organs.
        The developing embryo/fetus is uniquely vulnerable to the effects
    of alcohol; prenatal alcohol exposure is a significant contributor to
    neurodevelopmental disorders in children. Understanding the mechanisms
    leading to the neurodegeneration that underlies development of FASD is
    a critical step in developing treatments. A recent study provides
    evidence that endocannabinoids and their receptors in the brain play a
    role in the development of FASD.
        Policy research is another important component of NIAAA's
    portfolio. Data from NIAAA-supported studies will help inform local
    decisions such as the implementation of policy measures on college
    campuses to reduce alcohol poisonings. In addition, research findings
    play an important role in national issues such as the debate over the
    legal limit for blood alcohol content for operation of a motor vehicle,
    as policy-makers work to find a balance between increased alcohol
    restrictions and public safety. Screening and brief intervention for
    harmful alcohol use have been a major focus of NIAAA research for
    several decades. Based on this research, the U.S. Preventive Services
    Task Force (USPSTF) recently recommended that clinicians screen adults
    for alcohol misuse and provide persons engaged in risky or hazardous
    drinking with brief interventions. The USPSTF did not endorse screening
    for adolescents citing insufficient evidence. To increase this evidence
    base, NIAAA is supporting six studies to evaluate its youth alcohol
    screening guide in a variety of settings as a predictor of alcohol
    risk, alcohol use, and alcohol problems, and as an initial screen for
    other behavioral health problems such as drug use or smoking.
        In summary, NIAAA is enthusiastic about opportunities to expand
    research to improve the lives of Americans struggling with addiction to
    alcohol and other substances through the newly created CRAN. At the
    same time, NIAAA continues to focus on reducing the significant burden
    of illness associated with alcohol misuse.
                                     ______

      Prepared Statement of Patricia A. Grady, Ph.D., RN, FAAN, Director,
                     National Institute of Nursing Research

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Nursing
    Research (NINR) of the National Institutes of Health (NIH). The fiscal
    year 2014 NINR budget of $146,244,000 includes an increase of
    $1,744,000 over the comparable fiscal year 2012 level of $144,500,000.
        The mission of NINR is to promote and improve the health of
    individuals, families, communities, and populations. The Institute does
    so by supporting and conducting clinical and basic research to build
    the scientific foundation for clinical practice, prevent disease and
    disability, manage and eliminate symptoms of illness, improve
    palliative and end of life care, and train the next generation of nurse
    scientists. NINR-supported investigators contribute to developing the
    evidence base for science-driven practice through innovative treatment
    and behavioral research. Today, I offer a brief overview of NINR's
    investment and progress in six key areas and provide examples of how
    the research we support improves quality of life.

               SYMPTOM MANAGEMENT IN MULTIPLE CHRONIC CONDITIONS

        Due to the large aging population with longer life expectancies,
    and treatment advances for formerly fatal diseases, over one in four
    Americans are living with multiple chronic conditions (MCC) and their
    associated adverse symptoms. To address these symptoms and improve
    quality of life, NINR currently supports five Centers of Excellence in
    symptom science that explore pain, sleep disturbance, and the effects
    of chronic illness on neurocognitive functioning. A recent NINR-
    supported study found an association between an anti-inflammatory
    protein and a symptom cluster, including pain, fatigue, and sleep
    disturbance, opening the door to potential therapeutics development to
    alleviate these symptoms.

                      FAMILY AND COMMUNITY-BASED RESEARCH

        The family and community-based approach to clinical and
    translational research is intrinsic to nursing science and NINR. Child
    behavioral issues can create problems that negatively affect learning
    and peer relationships. NINR-supported studies that developed and
    tested the Chicago Parent Program (CPP), a high-quality, cost-
    effective, early childcare program for low-income communities that
    promotes positive parenting behaviors and reduces risky behaviors in
    children and their families. The CPP was adapted and disseminated to
    Chicago Head Start sites, where it was well-received in the community.
    The researchers reported improvements in parenting skills and child
    behavior. Based on these results, CPP-derived interventions have been
    implemented in diverse settings across the U.S., such as the Mayo
    Clinic, the Harlem Children's Zone, Johns Hopkins Bayview Medical
    Center, and New York City and Chicago Head Start centers. CPP's
    successful adoption into diverse communities underscores the importance
    of partnering with individuals, families, communities, and healthcare
    practitioners to ensure a program's effective translation into real
    world settings.

                    PALLIATIVE CARE AND END OF LIFE RESEARCH

        As the lead NIH Institute for end-of-life research, NINR supports
    evidence-based palliative care research that assists individuals,
    families, and healthcare professionals in managing the symptoms of
    advanced illness and planning for end-of-life decisions. Individuals of
    all ages with advanced illness can face protracted courses of decline,
    requiring that difficult decisions be made to ensure appropriate
    intervention and to maximize quality of life. NINR supports a
    palliative care research cooperative to enhance the evidence base for
    palliative care by carrying out multi-site research studies and
    clinical trials to be used to inform health practice and policy.
        NINR grantees are also evaluating palliative care interventions for
    patients with heart failure. Others are testing the efficacy of an
    integrated model of palliative care early in the cancer diagnosis
    process. The Institute also supports research on family members'
    perceptions and the importance of end-of-life strategies. These
    activities will provide for both optimal care and treatment for
    patients facing life-limiting conditions, and assist patients and
    family members.

                     RESEARCH TO IMPROVE CLINICAL PRACTICE

        As the healthcare providers most frequently interacting with
    patients, nurses are uniquely positioned to develop successful
    interventions to address treatment challenges. As our Nation's aging
    population continues to grow, the demand for critical care services is
    projected to increase. As a result, the number of patients transferred
    to long-term acute care hospitals, and the resulting costs, are
    expected to increase significantly. A recent NINR-funded study compared
    two methods for weaning patients from prolonged mechanical ventilation.
    Researchers found that one method, using a device known as a
    tracheostomy collar, resulted in earlier, successful weaning from
    mechanical ventilation. Implementing standard, best practice guidelines
    based on these findings could lead to shorter length of stays, better
    patient outcomes, and decreased healthcare costs. NINR will continue to
    facilitate the implementation of evidence-based treatment interventions
    into the clinical setting.

                 INNOVATIVE TECHNOLOGIES TO ENHANCE HEALTHCARE

        Innovative technologies are gaining a larger role in healthcare,
    and nursing science can provide the foundation for developing novel
    advances that deliver personalized care and real-time information to
    individuals, families, and communities. For example, subtle changes in
    an individual's health status often indicate the early development of
    acute illness or worsening of chronic conditions, but detecting these
    changes can be difficult. NINR supported the development of an
    unobtrusive, inexpensive proactive disease management system that uses
    infrared sensors to monitor older adults' daily activities and
    automatically alert healthcare providers to changes in the patient's
    health status. This technology identified health conditions 1-2 weeks
    earlier than traditional assessment methods and led to improved
    functional abilities. Based on these successful results, the
    researchers hope to expand its use to other care facilities.
        For example, NINR supports scientists who are using information
    technology (IT) to assist patients in understanding the medications
    they are supposed to take and track whether they are actually taking
    the medications as prescribed. These scientists are developing an
    Electronic Medical Record (EMR)-based tool (the Medtable), which is now
    being evaluated for its effectiveness in provider/patient communication
    and whether it improves medication knowledge, adherence, and health
    outcomes among chronically ill adults with complex medication regimens.

                  LOOKING TOWARD THE FUTURE: NURSE SCIENTISTS

        This Nation is facing complex healthcare challenges, and nurses and
    nurse scientists will play a pivotal role in addressing these issues.
    Since its inception, the training and career development of an
    innovative and diverse scientific workforce have been fundamental to
    NINR's mission. NINR supports nurse scientists and promotes earlier
    entry of nurses into research by providing research fellowships and
    career development awards. A recent initiative, the Scholars Training
    for the Advancement of Research (STAR) program, provides additional
    resources for institutions to support the ``fast-track'' training of
    outstanding undergraduate nursing students who are interested in
    pursuing a Ph.D. NINR training programs produce future nursing school
    faculty to strengthen the nursing workforce.
        In closing, NINR appreciates the opportunity to support science
    that can significantly improve the health of the Nation. The Institute
    provides innovative nursing science that becomes the evidence-based
    practice for clinical care. NINR will continue its mission to improve
    the quality of life by advancing nursing science to shape the future
    direction of healthcare.
                                     ______

     Prepared Statement of Eric D. Green, M.D., Ph.D., Director, National
                        Human Genome Research Institute

        Mr. Chairman and members of the committee: I am pleased to present
    the fiscal year 2014 President's budget request for the National Human
    Genome Research Institute (NHGRI). The fiscal year 2014 budget of
    $517,319,000 includes an increase of $5,061,000 above the comparable
    fiscal year 2012 level of $512,258,000.

           THE LAST DECADE OF GENOMICS HAS CHANGED BIOMEDICAL SCIENCE

        This year, we celebrate the tenth anniversary of the completion of
    the Human Genome Project (HGP). An ambitious scientific endeavor
    likened to biology's ``moon shot,'' HGP catalyzed profound changes for
    many areas of biomedical research and beyond. To provide a perspective
    about these changes, it is illustrative to compare the ``state-of-the-
    art'' at the beginning of HGP in 1990, at its completion in 2003, and
    now. To place these three-time points in a cultural context, in 1990
    Americans communicated by phone and fax; in 2003 it was email; and in
    2013 it is the tweet.
        Just as technology development has transformed routine
    communications (from the phone call to the tweet), it has been the
    cornerstone of the Federal investment in genomics. During the HGP, it
    took 6-8 years of active sequencing and approximately $1 billion to
    generate that first sequence of the human genome. In 2003, that same
    feat would have required 3-4 months and $10-50 million. Today, a human
    genome can be sequenced in approximately 1-2 days for a mere $3-5
    thousand. As the time and cost have plummeted, the power of genomic
    strategies to advance research and the volume of generated genomic data
    have increased profoundly.
        Why is this massive increase in capacity for data generation
    important? This extraordinary increase in data generation allows us to
    understand genome structure and function and through this knowledge to
    learn how genomes contribute to health and disease. For example, in
    1990, we knew of approximately 50 genes that, when mutated, caused a
    human disease; in 2003 that number was almost 1,500; and today, it is
    nearly 3,000. Further, knowledge about the genomic basis for our
    responses to medications--an area of science called pharmacogenomics--
    has also grown steadily. In 1990, only four Food and Drug
    Administration (FDA)-approved drugs required labels that pointed out
    the relevance of a patient's genetic makeup for that medication; by
    2003, this number had increased to 46; and today, it stands at 106. In
    fact, genomic contributions to medical research have been so
    substantial that fully half of the 2012 ``Top 10 Medical
    Breakthroughs'' identified by ``Time Magazine'' \1\ reflected genomics
    accomplishments, and these were in large part supported and/or
    facilitated by NHGRI's research programs.
        Although extraordinary progress has occurred over the past decade,
    much remains to be learned about the genome's role in biology and
    disease, and how to translate that knowledge to improve health
    outcomes. At the conclusion of HGP, we were but at the beginning of an
    exciting, but long journey to learn how to apply genomic information to
    improve health.

                         LEARNING FROM THE DATA DELUGE

        A major challenge for genomics research is the handling, analysis,
    and interpretation of the large volumes of genomic data now routinely
    generated. Solving this will require innovative infrastructure and
    novel methodologies. In fiscal year 2014, NHGRI will support pioneering
    bioinformatics research across its research portfolio, from the use of
    cloud computing for efforts such as the 1000 Genomes Project to the
    development of novel clinical bioinformatics tools by the Clinical
    Sequencing Exploratory Research (CSER) program and the Electronic
    Medical Records and Genomics (eMERGE) Network, two flagship programs
    intended to study how to utilize an individual's genomic information in
    different clinical settings. Additionally, the Institute will provide
    key leadership within NIH for the Big Data to Knowledge (BD2K)
    initiative.
        Consistent with NHGRI's 2011 strategic plan, the Institute's
    portfolio spans a continuum from basic research to study genomic
    structure and function, to translational research to discover the
    genomic basis for disease, through efforts to use genomics to increase
    the effectiveness of healthcare. The ENCyclopedia of DNA Elements
    (ENCODE) project, a key effort to identify the `functional parts'
    within the human genome, published a landmark series of papers in 2012
    reporting a catalog of functional elements within the human genome. The
    ENCODE catalog is like a GPS map for the human genome--just as by
    zooming in on a GPS map of the United States (to find the location of
    points of interests like banks and gas stations), the ENCODE catalog is
    now routinely used by researchers worldwide to zoom in on regions of
    interest in the human genome that are important for their studies. In
    fiscal year 2014, NHGRI will begin to add another layer of knowledge to
    this map with the launch of the Genomics of Gene Regulation (GGR)
    initiative. GGR will fund research to decipher how genes are regulated
    and to understand how gene regulation affects the function of cells and
    tissues, human development, and disease.
        In fiscal year 2014, NHGRI also will continue advancing the
    discovery of the genomic bases of disease. For example, the search for
    genes that play a role in rare diseases will be accelerated through the
    work of NHGRI's Centers for Mendelian Genomics, as well as an
    extramural expansion of the highly successful NIH Undiagnosed Diseases
    Program. Through research programs such as the Large-Scale Genome
    Sequencing and Analysis Centers, the genomic underpinnings of common
    complex diseases, such as cancer, diabetes, autism, and Alzheimer's
    disease, will remain a focus within NHGRI's portfolio as well.

                         IMPLEMENTING GENOMIC MEDICINE

        With the increasing accessibility of genomic technologies, the
    utility of genomics is already being demonstrated in clinical areas
    such as pharmacogenomics, non-invasive prenatal testing, infectious
    disease diagnostics, and cancer. The largest class of drugs now with
    FDA-required pharmacogenomic information to guide use on their labels
    includes those used for the treatment of cancer. Further, genome
    sequencing to identify mutations in a tumor's DNA sequence is now
    commonplace in the research setting and beginning to be seen in the
    clinical setting. Current examples of genomics informing care include
    the widespread use of ``BRCA'' testing in patients with familial risk
    factors for breast and ovarian cancer, the use of testing to predict
    breast cancer recurrence, and the use of genomic diagnostic tests to
    determine the suitability of particular treatments such as trastuzumab
    (Herceptin) use in breast cancer, vemurafenib (Zelboraf) use in
    melanoma, or crizotinib (Xalkori) use in lung cancer.
        In fiscal year 2014, NHGRI also will continue extending its
    portfolio to investigate the methods and evidence needed to integrate
    genomics as a standard component of clinical care. Both existing (e.g.,
    CSER program) and new (e.g., Genomic Medicine Pilot Demonstration
    projects and the Genomic Sequencing and Newborn Screening Disorders
    program) initiatives will be carried out by integrated research teams
    that include clinicians, scientists, and bioethicists. These multi-
    disciplinary groups will examine the medical as well as the ethical,
    social, and legal issues involved with making genomic data an
    essential, broadly accessible and broadly desirable element to inform
    clinical care. In fiscal year 2014, the Institute will continue
    supporting research pertaining to the pursuit of genomic research and
    the realization of genomic medicine, including protecting research
    participant privacy, determining when to return individual results, and
    how to handle unanticipated, but clinically important, ``incidental
    findings''.
        Through these and other programs, NHGRI will continue to lead the
    field of genomics in an effort to benefit the broad biomedical research
    enterprise and to realize the goal of advancing human health through
    genomics research.
    ---------------------------------------------------------------------------
        \1\ http://healthland.time.com/2012/12/04/top-10-health-lists/
    slide/junk-no-more/.
    ---------------------------------------------------------------------------
                                     ______

      Prepared Statement of Roderic I. Pettigrew, M.D., Ph.D., Director,
          National Institute of Biomedical Imaging and Bioengineering

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Institute of Biomedical
    Imaging and Bioengineering (NIBIB) of the National Institutes of Health
    (NIH). The fiscal year 2014 NIBIB budget request of $338,892,000 is
    $1,164,000 more than the comparable fiscal year 2012 level of
    $337,728,000. The mission of NIBIB is to improve human health by
    leading the development and accelerating the application of biomedical
    technologies. The Institute is committed to integrating the engineering
    and physical sciences with the life sciences to advance basic research
    and medical care. As we enter our second decade as an NIH Institute,
    NIBIB is continuing to build on that integration.
        From wound healing to finding ways for the human body to create new
    cartilage for damaged joints, advances in regenerative medicine are
    helping wounded warriors and an aging population. Robotic leg
    prostheses with powered knee and ankle joints and other efforts in
    rehabilitation engineering hold the promise of giving once unimaginable
    independence to people who are severely paralyzed or have lost limbs.
    Advances in the field of nanotechnology, such as the ability to deliver
    drugs directly into tumors while sparing healthy tissue, and using
    imaging technologies for non-invasive treatment as well as diagnostics,
    hold the potential to make healthcare more precise and more effective
    for patients.

                       ADVANCES IN REGENERATIVE MEDICINE

        NIBIB is at the forefront of the developing field of tissue
    engineering and regenerative medicine, and already advances in stem
    cell research are being developed to aid our wounded warriors and the
    general population. Working toward this goal is the Armed Forces
    Institute for Regenerative Medicine (AFIRM), which includes NIBIB-
    funded researchers and more than thirty U.S. universities and
    companies. Research supported by AFIRM has developed advanced treatment
    options and accelerated delivery of regenerative medicine therapies to
    treat the most severely injured U.S. service members. An exciting
    example of just one of the many innovative projects under way is the
    development of bioprinting of skin for battlefield injuries. This
    technology uses a bioprinter that creates and delivers skin cells and
    biomaterials to rapidly cover large wounds, which are a major cause of
    morbidity and mortality in severe burn injuries in civilians and
    military personnel. Other efforts are focusing on the difficult repair
    of segments of bone and nerve that are lost or damaged following
    traumatic injuries.
        In the general population, injury to cartilage can lead to joint
    pain and arthritis. One regenerative medicine project may help patients
    with knee injuries to successfully regenerate new, working cartilage
    through an innovative technique developed by NIBIB-funded researchers.
    The technique uses an engineered `biogel' scaffold (a structure that
    supports and holds cells together) that solidifies when exposed to
    light, combined with a strong biological adhesive that covers the
    injured area and provides an environment that promotes the growth of
    cartilage-producing cells. This successful research led to a small
    clinical trial in patients undergoing microfracture surgery, a first-
    line therapy for cartilage repair where holes are drilled in the
    cartilage to encourage new growth. Patients who received the biogel and
    adhesive, in addition to microfracture surgery, had improved cartilage
    growth, less scarring, and decreased pain at 6 months post-surgery,
    when compared to microfracture without the biogel treatment. The
    technique has the potential to transform the field of knee cartilage
    repair, which affects many people and is difficult to treat
    successfully. A larger clinical trial using this promising technique is
    currently in progress. While the clinical trials are not funded by
    NIBIB, these are examples of public private partnerships of translating
    research to clinical settings.

               REHABILITATION ENGINEERING TO ENABLE INDEPENDENCE

        Overcoming major barriers, researchers have now developed an
    implantable, compact, self-contained device for the sensing and
    transmission of brain activity. The device is an important step toward
    the development and use of brain-computer interfaces that harness the
    power of thought to remotely control computers, prosthetics, and other
    devices. The new wireless device allows the user more freedom of
    movement than the earlier version, which was connected to a computer
    with wires and cables and greatly limited the range of movement. The
    small device is fully implanted beneath the skin much like a cochlear
    implant. It is capable of recording neural activity from 100 different
    sites and converting this neural activity into digital signals. It also
    transmits these digital signals to a wireless receiver located some
    distance outside the body. The device is recharged wirelessly. Initial
    tests in animals were successful at recording data in real-time for
    more than a year. The device may one day be used to control prosthetic
    arms and other devices, motorized wheelchairs, or for diagnostic
    monitoring in disorders such as in epilepsy, where patients currently
    are tethered to the bedside during assessment.

                     ENGINEERING ADVANCED MEDICAL SOLUTIONS

        NIBIB continues to support technologies for more efficient and
    effective drug delivery. Key developments include the creation of
    nanoparticles that can target powerful cancer-killing medications to a
    tumor without inadvertently damaging surrounding healthy tissues. In
    addition to successfully targeting the tumor, a drug that is tethered
    to a nanoparticle can only reach its target if it survives in the
    blood, where the immune system is constantly removing foreign
    particles. To address this technical hurdle, researchers devised a
    stealth coating for nanoparticles that tricks the immune system into
    ignoring the particles. By disguising the nanoparticles to chemically
    look like ``self'', the immune system does not clear the particles, and
    more medication can be delivered to their target tumors. Using this
    method, tumors in mice were reduced by 70 percent compared with tumors
    that were targeted with the cancer drug but without the nanoparticle
    and stealth coating. Based on these encouraging results, human clinical
    trials using stealth-coated nanoparticles to deliver anticancer drugs
    are currently under way. This technology might one day be used to
    deliver genes for gene-therapy treatment or to enhance biocompatibility
    and durability of larger foreign objects such as pacemakers and
    implants, whose function can degrade over time due to attacks by the
    immune system.
        NIBIB also supports research that harnesses the power of magnetic
    resonance imaging (MRI) and the faster metabolic rates of cancer cells
    than normal cells to develop a biomarker for prostate cancer. The goal
    is to use the biomarker to distinguish which prostate cancer disease is
    aggressive from those that are indolent where watchful waiting may be
    the appropriate course of action. Researchers have developed a
    technique using hyperpolarized carbon-13 (C-13) compounds to measure
    the faster metabolism of glucose in prostate cancer. In this method, by
    ``hyperpolarizing'' the carbon isotope, investigators are able to
    increase the target signal by about 10,000-fold, making this carbon
    labeled signal much more readily detectable. The researchers developed
    a system for synthesizing, hyperpolarizing, and rapidly delivering
    carbon-13-labeled pyruvate, a product of glucose metabolism. The
    metabolic changes of pyruvate to lactate serve as a biomarker or
    indication for prostate cancer as the disease progresses and provide
    useful measures of the aggressiveness of the tumor. Preliminary
    clinical results show promise for this approach for cancer biomarkers.

               NEW USES OF ULTRASOUND FOR DIAGNOSIS AND TREATMENT

        The immune system's natural killer (NK) cells are those that find
    and destroy foreign substances in the body. A human NK cell line, NK-92
    can be used to target and destroy tumors. However, this promising
    strategy to use the immune system to fight tumors is not possible for
    use in the brain because NK cells cannot penetrate the blood brain
    barrier (BBB). NIBIB-funded researchers developed an experimental
    system using ultrasound to deliver NK-92 cells to tumors in the brain.
    The movement of the NK cells into the tumor was monitored with and
    without focused ultrasound disruption of the BBB. Using MRI,
    researchers found that approximately 1 NK cell for every 100 tumor
    cells had reached the brain when using focused ultrasound to open the
    BBB, compared to 1 NK cell per 1,000 tumor cells when ultrasound was
    not used. These preclinical results suggest that the tumor-killing
    ability of immune natural killer cells combined with focused ultrasound
    has tremendous potential for targeting and destroying brain tumors.
        Another new ultrasound imaging technique developed by NIBIB-
    supported researchers can noninvasively detect tumors and fibrosis in
    the liver. Typically, liver disease is diagnosed using liver biopsy, a
    surgical procedure that can be painful and cause complications. This
    new ultrasound-based technique, called Acoustic Radiation Force Impulse
    imaging does not produce harmful ionizing radiation and is relatively
    inexpensive compared with other imaging modalities. This means it can
    be used more frequently to track the progression of fibrosis. In
    contrast to a biopsy, which can only examine a small discrete sample of
    the liver, this method examines the entire liver. The technique uses
    focused, high intensity sound waves to produce ``push-pulses'' that
    generate shear within tissue. Ultrasound is then also used to monitor
    the tissue response. The tissue response is related to the stiffness
    properties and structure of the liver, and is displayed as a high
    resolution, qualitative image. This technique can also produce
    quantitative stiffness measurements based on the speed of the shear
    waves. These measurements are used to quantify specific levels of
    fibrosis that can be used to classify different stages of liver
    fibrosis or tumors.
        Yet another advance is the use of the mechanical force of
    ultrasound to breakup thrombi and minimize the damage to heart muscle
    during a heart attack. Researchers first demonstrated in porcine models
    of coronary arteries blocked by blood clots or thrombosis, that
    conventional ultrasound using a high ``mechanical index'' in
    conjunction with micro-bubbles and a conventional clot dissolving agent
    achieved greater restoration of flow in the blocked artery.
    Consequently, there was also greater heart muscle salvaged. In an
    initial human study, this technique was successfully and safely used in
    patients who presented at a hospital with evidence that a heart attack
    had begun. If the promise of these preliminary studies continues, this
    could be implemented at hospitals throughout the country as a first-
    line treatment to minimize damage in evolving heart attacks.
        NIBIB will continue to target the unique scientific opportunities
    of the 21st century in rehabilitation engineering, regenerative
    medicine, and advanced imaging techniques to improve disease diagnosis
    and treatment. This era promises a revolution in employing technology
    to realize innovations that address healthcare challenges, reduce
    disease mortality and morbidity, and enhance quality of life and
    improve the health of the Nation.
                                     ______

     Prepared Statement of Christopher P. Austin, M.D., Director, National
                  Center for Advancing Translational Sciences

        Mr. Chairman and members of the committee: It is a privilege to
    present to you the President's budget request for the newly established
    National Center for Advancing Translational Sciences (NCATS) for fiscal
    year 2014. The fiscal year 2014 budget for NCATS is $665,688,000, which
    represents an increase of $91,391,000 over the fiscal year 2012
    comparable level of $574,297,000. The request includes $50 million for
    the Cures Acceleration Network (CAN), an increase of $40 million over
    fiscal year 2012. CAN will fund initiatives designed to address
    scientific and technical challenges that impede translational research,
    including support for the Tissue Chips for Drug Screening Initiative,
    the Discovering New Therapeutic Uses for Existing Molecules Program,
    and other programs. Common Fund support of these programs will end by
    fiscal year 2014, at which time they will be funded through the NCATS
    direct appropriation.
        NCATS' mission is to catalyze innovations that enhance the
    development, testing, and implementation of diagnostics and
    therapeutics across a wide range of human diseases and conditions. In
    the short time since its founding in December 2011, NCATS has become a
    hub of innovation for translational sciences at NIH and in the broader
    translational ecosystem that includes the pharmaceutical,
    biotechnology, venture capital, regulatory, and patient advocacy
    communities. The Center has launched several major research
    initiatives, cultivated promising strategic partnerships, and
    established a presence at NIH and in the community. For example, NCATS'
    Therapeutics for Rare and Neglected Diseases (TRND) program was
    responsible for the development and first-in-human testing of new
    therapies for four different diseases in a period of 16 months via
    novel partnership structures. Another achievement was the agreement
    with the Defense Advanced Research Project Agency and the Food and Drug
    Administration (FDA) to initiate an innovative grant program to create
    new tools for predicting drug toxicity. The goal is to fund researchers
    who will create 3-D ``chips,'' which are miniature models with the
    structure and function of human organs. These chips will be used to
    test drugs to see if they are safe or toxic to humans, thus saving
    researchers time and money compared to current methods. NCATS also
    developed the New Therapeutics Uses for Existing Molecules initiative,
    a breakthrough partnership program with eight pharmaceutical companies
    to find new uses for existing drugs owned by these companies. The eight
    companies agreed to make many of their molecular compounds available to
    outside researchers for testing for new therapies. These compounds have
    already undergone safety and toxicity testing in humans and so provide
    researchers with valuable data that may help speed the research process
    forward. In addition, NCATS has created template agreements with the
    drug companies ready for use by the investigator, thus saving the time
    the investigator would have spent negotiating an agreement with the
    drug company.
        Collaborations among Government, academia, industry and nonprofit
    patient organizations are crucial for successful translation. For
    example, support from the NCATS' Clinical and Translational Science
    Award (CTSA) program at the University of Pittsburgh contributed to the
    development of a robotic arm that allowed a quadriplegic patient to
    feed herself using just her thoughts. This remarkable achievement was
    the result of NIH, the Department of Defense, the Department of
    Veterans Affairs (VA), the FDA, a private foundation, two academic
    research centers, and a private company working together, which made
    this possible.

                AVOIDING DUPLICATION, REDUNDANCY AND COMPETITION

        A fundamental principle of NCATS is that it addresses the many
    translational problems that are not undertaken by industry because this
    early-stage research hasn't yet proven to be commercially viable. Thus,
    NCATS is explicitly complementary to efforts in industry. Our work is
    in the ``precompetitive'' space where industry and NIH/academia have
    long collaborated to mutual benefit.
        In addition to this general positioning of NCATS as an ``adaptor''
    or ``intermediary'' between academic and industry science, many
    specific initiatives have been put in place to prevent duplication,
    redundancy, and competition with industry. We recently published a
    Notice in the Federal Register that enumerates and seeks comments on
    the procedures and methods NCATS is using to ensure that industry is
    both aware of and able to provide input on our activities and planned
    initiatives. Some of these methods include frequent updates to the
    NCATS Web site, an NCATS Director's newsletter, publication of Requests
    for Information on proposed programs, open public meetings to which
    industry representatives are specifically invited, and meetings
    arranged with industry trade groups and associations.

     PRE-CLINICAL RESEARCH: CONNECTING LABORATORY POTENTIAL WITH CLINICAL
                                    PROMISE

        NCATS is active in the development, demonstration, and
    dissemination of a broad range of technologies, tools, and resources
    that facilitate collaborative pre-clinical testing and first-in-human
    clinical trial implementation. For example, NCATS' Matrix Screening
    ``Platform,'' or testing process that includes specific equipment, is a
    transformative technology that identifies combinations of drugs to
    treat diseases resistant to single drugs, which is particularly
    important for treatment-resistant cancers. Since this testing is done
    in a high-speed fully automated robotic format, thousands of drug
    combinations can be tested in a single day to determine which are best
    able to kill the cancer cells while minimizing toxic side effects.
        Determining toxicity is a major roadblock in the advancement of
    promising discoveries. The Tox21 Program, along with the Environmental
    Protection Agency, the National Institute for Environmental Health
    Sciences, and the FDA, is testing over 10,000 drugs and environmental
    chemicals for hundreds of activities relevant to toxicity, with all
    data being made publicly available.

                CLINICAL RESEARCH: DEMONSTRATING MEDICAL BENEFIT

        Clinical research is conducted to test the safety and effectiveness
    of a new or improved diagnostic or therapeutic intervention, more
    effectively diagnose a disease, demonstrate the utility of biomarkers
    or prognostic risk factors, and discover better ways to implement
    health-improving interventions. The centerpiece of this area at NCATS
    is the CTSA program.
        The purpose of the CTSA program (http://www.ncats.nih.gov/research/
    cts/ctsa/ctsa.html) is to support the entire spectrum of translational
    research in order to accelerate the transition of laboratory
    discoveries into patient studies and into clinical practice. Through
    integrated homes that build on academic institutions' scientific
    strengths, CTSAs provide expertise, resources, and workforce training,
    which improve the quality, validity, generalizability, and efficiency
    of clinical and translational research. For example, a team of
    scientists with support from the University of California, Davis, CTSA
    developed a test to determine the prevalence of a debilitating disease,
    called Fragile X, in the general population. This information will help
    researchers create screening and diagnostic strategies and allow
    planning of clinical trial recruitment strategies for new Fragile X
    therapies.

                             FOCUS ON RARE DISEASES

        Targeting support to accelerate new treatments for rare diseases is
    a major priority for NCATS. About 6,000 rare diseases affect an
    estimated 25 million Americans; and, according to the Office of Orphan
    Products Development, FDA, 450 orphan drugs have been approved, which
    together treat only 250 of the 6,000 diseases. Discoveries about the
    molecular basis of rare diseases based on the Human Genome Project
    offer unprecedented scientific opportunities to change systematically
    this landscape, by approaching rare diseases and their treatment as a
    holistic systems-based problem, and NCATS is capitalizing upon these
    opportunities. For example, the TRND program speeds the development of
    new treatments for rare diseases of very low prevalence and otherwise
    commercially neglected tropical diseases. It forms public-private
    partnerships, which leverage the unique strengths and capabilities of
    each party. Partnerships with disease foundations and/or biotech firms
    helped bring promising therapies to the first-in-human testing stage
    for chronic lymphocytic leukemia, sickle cell disease, hereditary
    inclusion body myopathy, and Niemann-Pick Type C disease.

                                   CONCLUSION

        NCATS has sought to establish new technologies and paradigms that
    can be implemented broadly to improve the efficiency of the
    translational process for all and to broker collaborative development
    of new interventions. We are grateful for the support of this
    subcommittee for this new Center and look forward to sharing progress
    with you each year.
                                     ______

     Prepared Statement of Roger I. Glass, M.D., Ph.D., Director, Fogerty
                              International Center

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the Fogarty International Center
    (FIC) of the National Institutes of Health (NIH). The fiscal year 2014
    FIC budget of $72,864,000 includes an increase of $3,371,000 over the
    comparable fiscal year 2012 appropriation of $69,493,000.
        From leading the call for an AIDS-free generation to developing
    vaccines and therapeutics for diseases that affect populations
    worldwide, the United States is a global leader in health research and
    scientific advances that improve the lives of Americans and people
    across the globe. These discoveries are often made by U.S. and foreign
    scientists working in close collaborations that enable the best and
    brightest minds to tackle complex health challenges together. The
    Fogarty International Center therefore supports innovative training and
    research programs for U.S. and low- and middle-income country (LMIC)
    scientists that strengthen the research capabilities and catalyze the
    international scientific partnerships that lead to research discovery
    and improved health. By investing in current and future leaders in
    global health research and strengthening the long-term capacity of
    research institutions to provide robust and sustainable platforms for
    cutting-edge science, Fogarty advances the goals and extends the
    leadership of the NIH and the U.S. Government in science and research,
    while playing a vital role in building the capacity needed to
    successfully tackle critical health challenges.

       RECRUITING AND RETAINING DIVERSE SCIENTIFIC TALENT AND CREATIVITY

        Fogarty programs have supported long-term research training for
    more than 4,500 scientists worldwide, in collaboration with more than
    230 U.S. and LMIC research institutions. These investments provide
    unique training opportunities for early-career global health
    researchers, and aid in the retention of diverse scientific talent in
    the research enterprise. The vast contribution of FIC programs can be
    seen in the over 5,000 PubMed publications citing FIC awards over the
    last 5 years alone. Today's complex public health challenges benefit
    when investigators from diverse fields work together to produce
    transformative advances in science and technology. Fogarty's unique
    ``Framework Program for Global Health Innovation'' trains multi-
    disciplinary teams of postdoctoral researchers to work together to
    produce fresh insights into global health problems and develop
    effective innovations for implementation in low-resource settings. For
    example, with Fogarty support, a team of medical, engineering, and
    architecture researchers from Boston, South Africa, and Peru is
    designing and validating effective, affordable prototypes for air
    disinfection. This work can not only help prevent airborne infections
    such as tuberculosis and influenza from spreading in the low-resource
    settings where they cause significant illness and death, but can also
    potentially help higher income countries such as the United States
    improve their programmatic approaches to airborne infection.
      --Funded under the U.S. President's Emergency Plan for AIDS Relief
            (PEPFAR) in collaboration with 18 NIH Institutes and Centers,
            Fogarty and the Health Resources and Services Administration
            (HRSA) jointly co-administer an innovative cross-U.S.
            Government initiative funded primarily by the Office of the
            Global AIDS Coordinator (OGAC) that is transforming medical
            education and research training for medical students in 12
            African countries. The 13 direct MEPI awardees and more than 40
            partner institutions use a broad range of state-of-the-art
            teaching and collaboration tools to train the next generation
            of scientific leaders to solve their country's most pressing
            health problems--from HIV/AIDS to maternal and child health,
            and non-communicable conditions such as mental health and
            cardiovascular disease. MEPI is increasing the quality,
            quantity, and retention of medical faculty and physicians with
            research skills, and building relationships with the public
            sector partners that promote sustainable research capacity. For
            example, Zimbabwe's Ministry of Education is now co-funding the
            University of Zimbabwe's MEPI work.

                             TRANSLATIONAL SCIENCE

        Fogarty programs support researchers who are generating the
    critical scientific evidence that can be applied to specific
    interventions, policies, and programs, and make a difference in
    fighting disease and improving health.
      --In recent years, we have seen that infectious diseases from animal
            as well as human hosts can cause outbreaks that pose
            significant health and economic threats to the U.S. and other
            countries, Fogarty's ``Research and Policy in Infectious
            Disease Dynamics (RAPIDD)'' program--co-funded by the
            Department of Homeland Security (DHS)--brings together senior
            infectious disease modelers and postdoctoral fellows to conduct
            the research and develop infectious disease modeling approaches
            that can help the U.S. and other policymakers plan for and
            respond to potential infectious disease threats. ``RAPIDD''
            models have contributed to a greater understanding of how Avian
            Influenza and Hand, Foot, and Mouth disease can develop into
            outbreaks from an initial case, and how these outbreaks can be
            controlled effectively.

               TODAY'S BASIC SCIENCE FOR TOMORROW'S BREAKTHROUGHS

        Fogarty supports catalytic basic biomedical and behavioral research
    that can lead to tomorrow's breakthroughs.
      --Despite recognition of a looming antibiotic resistance crisis in
            the U.S. and around the world, the number of new antibiotics
            reaching the clinic continues to decline sharply, and most
            recent discovery has been confined to minor modifications of
            known antibiotics, with limited new therapeutic potential. The
            Fogarty International Cooperative Biodiversity Groups (ICBG)
            program, is working to change this. Fogarty-funded researchers
            have developed an innovative and cost-effective approach to
            antibiotic discovery, using an ``antibiotic mode of action
            profile'' (BioMAP). BioMAP is a ground-breaking tool that can
            be used to facilitate new natural products antibiotic discovery
            and address the looming antibiotic crisis in the United States
            and around the world.
      --Brain disorders such as epilepsy and Alzheimer's pose significant
            health problems around the globe. Fogarty's ``Brain Disorders''
            program supports cutting-edge basic science research in LMICs
            on the nervous system--research that could lead to new
            diagnostics, prevention, and treatment strategies. In India,
            for example, Fogarty grantees are exploring why Alzheimer's
            affects Indian populations less than populations in developed
            countries, with the goal of discovering useful evidence to
            understand and mitigate Alzheimer's globally. In Uganda,
            Fogarty-supported research is creating a base of knowledge on
            dementia in those with long-term HIV infection, obtaining data
            on prevalence, risk factors, and possible differentiation by
            HIV sub-type that will be useful in understanding the course of
            the disease and developing potential interventions worldwide.

                               FUTURE CHALLENGES

        The need for sustainability poses a significant challenge for
    investments in global health research and research training. Fogarty
    investments continue to evolve with increasing research capabilities in
    LMICs in order to build on successes and support the training of
    individual scientists and strengthen research institutions. Fogarty's
    deep regional expertise will continue to serve as a unique resource for
    NIH and individual foreign scientists, institutions and countries that
    are seeking new models and mechanisms that enable collaboration around
    areas of mutual interest. In addition, Fogarty will increase support
    for institutional networks and hubs for data collection and sharing.
    When such sharing platforms are built around a core of trained
    individuals and strengthened institutions, they can harness effectively
    the different strengths of these institutions, and promote enhanced
    efficiencies and more robust, collaborative science.
      --Fogarty envisions that its U.S.-LMIC ``GEOHealth'' hubs will become
            global leaders in the collection, management, synthesis, and
            interpretation of data on environmental and occupational
            health, serving the larger multi-national regions in which they
            reside as well as supporting research of great relevance to
            both these LMIC regions and the U.S.
      --In sub-Saharan Africa, universities supported by ``MEPI'' are
            emerging as regional training centers and upgrading the
            technology to enable distance learning and resource-sharing
            among institutions. This model is revolutionizing African
            medical education and research training by enabling partner
            institutions across Africa to pool their areas of expertise,
            share teaching tools, and ensure that all students receive the
            highest-quality instruction from the continent's best qualified
            faculty and researchers.
        In an increasingly interconnected world, the U.S. is often called
    upon to play a leading role in addressing the world's most pressing
    challenges. Fogarty programs harness the capabilities of the U.S. as a
    leader of biomedical research, extend the frontiers of science,
    accelerate discovery, improve the health of Americans and people across
    the globe, and help the U.S. continue to compete and lead in science.
                                     ______

     Prepared Statement of Donald A.B. Lindberg, M.D., Director, National
                              Library of Medicine

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for the National Library of Medicine
    (NLM) of the National Institutes of Health (NIH). The fiscal year 2014
    budget of $382,252,000 includes an increase of $17,365,000 over the
    comparable fiscal year 2012 level of $364,887,000. Funds have been
    included to allow the National Center for Biotechnology Information
    (NCBI) to meet the challenges of collecting, organizing, analyzing, and
    disseminating the deluge of data emanating from research in molecular
    biology and genomics.
        As the world's largest biomedical library and the producer of
    internationally trusted electronic information services, NLM delivers
    trillions of bytes of scientific data and health information to
    millions of users every day. Many searches that begin in Google or a
    mobile ``app'' actually retrieve information from an NLM Web site. NLM
    is a key link in the chain that makes biomedical research results--DNA
    sequences, clinical trials data, toxicology and environmental health
    data, published articles, and consumer health information--readily
    available to scientists, health professionals, and the public. A leader
    in biomedical informatics and information technology, NLM also conducts
    and supports leading-edge research and development in electronic health
    records, clinical decision support, natural language processing,
    information retrieval, imaging, computational biology,
    telecommunications, and disaster response.
        NLM's programs and services directly support NIH's key initiatives
    in basic research, translational science, and research training, as
    well as in Big Data. The Library organizes and provides access to the
    published medical literature and massive amounts of scientific data
    from high throughput sequencing; assembles data about small molecules
    to support research and therapeutic discovery; provides the world's
    largest clinical trials registry and results database; and is the
    definitive source of published evidence for healthcare decisions. NLM's
    PubMed Central (PMC) provides essential infrastructure for the NIH
    Public Access Policy, which since 2008 has made published NIH-funded
    research freely and permanently available to the public.
        Research supported or conducted by NLM underpins today's electronic
    health record systems. The Library has been the principal funder of
    university-based informatics research training for 40 years, supporting
    the development of today's leaders in informatics research and health
    information technology. NLM's databases and its partnership with the
    Nation's health sciences libraries deliver research results wherever
    they can fuel discovery and support health decisionmaking.

                         RESEARCH INFORMATION RESOURCES

        NLM's PubMed/MEDLINE database is the world's gateway to research
    results published in the biomedical literature, linking to full-text
    articles in PubMed Central, including those deposited under the NIH
    Public Access Policy, and on publishers' Web sites, as well as
    connecting to vast collections of scientific data. NLM is a primary
    source for results of patient-centered outcomes research, providing
    access to evidence on best practices to improve patient safety and
    healthcare quality. The Library maintains an expanding collection of
    full-text guidelines, evidence summaries, and systematic reviews from
    authoritative agencies and organizations around the world.
        NLM is also a hub for the international exchange and use of data
    utilized in molecular biology, genomics, and clinical and translational
    research. Many NCBI databases, including dbGaP, the Genetic Testing
    Registry (GTR) and ClinVar, are fundamental to the identification of
    important associations between genes and disease, and to the
    translation of new knowledge into better diagnoses and treatments.
    NLM's Lister Hill National Center for Biomedical Communications
    operates ClinicalTrials.gov, the world's most comprehensive clinical
    trials database. It contains registration data for more than 145,000
    clinical studies with sites in 185 countries. ClinicalTrials.gov has
    novel and flexible mechanisms that enable submission of summary results
    data for clinical trials subject to the Food and Drug Administration
    (FDA) Amendments Act of 2007. Summary results are available for nearly
    9,000 completed trials of FDA-approved drugs, biological products, and
    devices--providing a new and growing source of evidence on efficacy and
    comparative effectiveness. NLM will leverage experience with these
    resources and its research in related fields to contribute to NIH
    efforts to improve access to other types of NIH-funded Big Data.

              HEALTH DATA STANDARDS AND ELECTRONIC HEALTH RECORDS

        Electronic health records (EHRs) with advanced decision-support
    capabilities and connections to relevant health information are
    essential to improving healthcare and helping Americans manage their
    own health. For 40 years, NLM has supported seminal research on
    electronic patient records, clinical decision support, and health
    information exchange, including concepts and methods now reflected in
    EHR products and personal health record tools. As the Department of
    Health and Human Services (HHS) coordinating body for clinical
    terminology standards, NLM works closely with the Office of the
    National Coordinator for Health Information Technology and the Centers
    for Medicare and Medicaid Services to facilitate adoption and
    ``meaningful use'' of EHRs. NLM supports, develops, and distributes key
    terminology standards now required for U.S. health information
    exchange. To help EHR developers implement standard terminologies, NLM
    produces related software tools, frequently used subsets, and mappings
    to administrative code sets, and provides the authoritative versions of
    terminology value sets for required clinical quality measures. NLM's
    MedlinePlus Connect also supports meaningful use by providing a way for
    EHR products to link patients to high quality health information
    relevant to a specific health conditions, medications, and tests,
    directly from their EHRs.

                      INFORMATION SERVICES FOR THE PUBLIC

        This EHR connection builds upon NLM's extensive information
    services for patients, families and the public. The Library's
    MedlinePlus Web site provides integrated access to high quality
    consumer health information produced by all NIH components and
    Department of Health and Human Services (DHHS) agencies, other Federal
    departments, and authoritative private organizations. It serves as a
    gateway to specialized NLM information sources for consumers, such as
    the Genetic Home Reference and the Household Products Database.
    Available in English and Spanish, with selected information in 40 other
    languages, MedlinePlus averages well over 750,000 visits per day.
    Mobile MedlinePlus, also in both English and Spanish, reaches the large
    and rapidly growing mobile Internet audience.
        The ``NIH MedlinePlus'' magazine, in English and Spanish, is an
    outreach effort made possible with support from many parts of NIH and
    the Friends of the NLM. Distributed free to the public via physician
    offices, community health centers, libraries and other locations, the
    magazine reaches a readership of up to 5 million nationwide. Each issue
    focuses on the latest research results, clinical trials and guidelines
    from the 27 NIH Institutes and Centers.
        To be of greatest use to the widest audience, NLM's information
    services must be known and readily accessible. The Library's outreach
    program, with a special emphasis on reaching underserved populations,
    relies heavily on the more than 6,000-member National Network of
    Libraries of Medicine (NN/LM). The NN/LM is a network of academic
    health sciences libraries, hospital libraries, public libraries and
    community-based organizations working to bring the message about NLM's
    free, high-quality health information resources to communities across
    the Nation.

                INFORMATION FOR DISASTER AND EMERGENCY RESPONSE

        NLM builds on proven emergency backup and response mechanisms
    within the NN/LM to promote effective use of libraries and information
    specialists in disaster preparedness and response. NLM conducts
    research on new methods for sharing and ensuring continued access to
    health information in emergencies, including as its contribution to the
    Bethesda Hospital Emergency Preparedness Partnership, a model of
    private-public hospital collaboration for coordinated disaster
    planning. NLM works with the Pan American Health Organization (PAHO)
    and the Latin American Network for Disaster and Health Information to
    promote capacity-building in disaster information management. In
    addition, NLM responds to specific disasters worldwide with specialized
    information resources appropriate to the need. Mobile apps and tools
    developed for first responders have been downloaded nearly 500,000
    times worldwide.
        In summary, NLM's information services and research programs serve
    the Nation and the world by supporting scientific discovery, clinical
    research, education, healthcare delivery, public health response, and
    the empowerment of people to improve personal health. The Library is
    committed to the innovative use of computing and communications to
    enhance public access to the results of biomedical research.
                                     ______

    Prepared Statement of Jack E. Whitescarver, Ph.D., Director, Office of
                                 AIDS Research

        Mr. Chairman and members of the committee: I am pleased to present
    the President's budget request for fiscal year 2014 for the trans-NIH
    AIDS research program, which is $3,121,716,000. This amount is
    $46,921,000 above the comparable fiscal year 2012 level of
    $3,074,795,000. It includes the total NIH funding for research on HIV/
    AIDS and the wide spectrum of AIDS-associated malignancies,
    opportunistic infections, co-infections, and clinical complications;
    intramural and extramural research; research management support;
    research centers; and training.

          NATIONAL INSTITUTES OF HEALTH AIDS RESEARCH ACCOMPLISHMENTS

        In the three decades since AIDS was first reported, NIH has been
    the global leader in research to understand, prevent, diagnose, and
    treat HIV and its many related conditions. From the development of the
    first blood test for HIV infection and the discovery and clinical
    testing of the first effective therapies, through today's research to
    determine whether a vaccine, microbicide, or eventual cure for AIDS
    will one day be possible, NIH research has transformed HIV from a
    mysterious and uniformly fatal infection into one that can be
    accurately diagnosed and effectively managed with appropriate
    treatment. A recent study estimated that 14.4 million life years have
    been gained since 1995 by the use of AIDS therapies developed as a
    result of NIH-funded research. Recent discoveries include:
      --Development of new treatments for many HIV-associated co-
            infections, comorbidities, malignancies, and clinical
            manifestations;
      --Development of new strategies for the prevention of mother-to-child
            transmission (MTCT), which have resulted in dramatic decreases
            in perinatal HIV in the U.S., where now fewer than 100 babies a
            year are born with HIV infection;
      --Demonstration of the first proof of concept that a vaccine can
            prevent HIV infection and identification of potential immune
            markers for protection;
      --Discovery of more than 20 potent human antibodies that can stop up
            to 95 percent of known global HIV strains from infecting human
            cells in the laboratory;
      --Demonstration of the first proof of concept that a microbicide gel
            can prevent HIV transmission;
      --Demonstration that the use of antiretroviral therapy by infected
            individuals can reduce HIV transmission to an uninfected
            partner dramatically;
      --Demonstration of the feasibility of pre-exposure prophylaxis
            (PrEP), the use of antiretroviral treatment regimens by
            uninfected individuals to reduce their risk of HIV acquisition;
      --Discovery that genetic variants may play a role in enabling some
            individuals, known as ``elite controllers,'' to control HIV
            infection without therapy;
      --Critical basic science discoveries that continue to provide the
            foundation for novel research; and
      --Advances in basic and treatment research aimed at eliminating viral
            reservoirs in the body that for the first time are leading
            scientists to design and conduct research aimed at a cure for
            HIV/AIDS.

                               THE AIDS PANDEMIC

        In spite of these advances, the HIV/AIDS pandemic remains a global
    scourge. UNAIDS reports that in 2011, more than 34 million people were
    estimated to be living with HIV/AIDS; 2.5 million were newly infected;
    and 1.7 million people died of AIDS-related illnesses. The majority of
    cases worldwide are the result of heterosexual transmission, and women
    represent more than 50 percent of HIV infections worldwide. More than
    25 million men, women, and children worldwide have already died. Around
    330,000 children were newly infected with HIV in 2011, a reduction of
    24 percent in just 2 years--from 2009-2011--a result of the
    distribution of HIV treatment to prevent mother-to-child transmission
    developed by NIH research.
        In the United States, the Centers for Disease Control and
    Prevention estimates that approximately 1.2 million people are HIV-
    infected; approximately 50,300 new infections occur each year; and one
    in four people living with HIV infection in the U.S. is female. HIV/
    AIDS continues to be an unrelenting public health crisis,
    disproportionately affecting racial and ethnic populations, women of
    color, young adults, and men who have sex with men. The number of
    individuals aged 50 years and older living with HIV/AIDS is increasing,
    due in part to antiretroviral therapy, which has made it possible for
    many HIV-infected persons to live longer, but also due to new
    infections in individuals over the age of 50.

                  COORDINATED TRANS-NIH AIDS RESEARCH PROGRAM

        The NIH AIDS research program is coordinated and managed by the
    Office of AIDS Research (OAR), which functions as an ``institute
    without walls'' with responsibility for AIDS-related research supported
    by nearly every NIH Institute and Center (IC). OAR coordinates the
    scientific, budgetary, and policy elements of the trans-NIH AIDS
    research.
        Through its unique trans-NIH planning, budget, and portfolio review
    processes, OAR identifies the highest priority areas of scientific
    opportunity and ensures that precious research dollars are invested
    effectively.
        In collaboration with both Government and non-Government experts,
    OAR develops the trans-NIH AIDS strategic Plan. The priorities of the
    Plan guide the development of the trans-NIH AIDS research budget. OAR
    develops each IC's AIDS research allocation based on the Plan,
    scientific opportunities, and the IC's capacity to absorb and expend
    resources for the most meritorious science--not on a formula. This
    process reduces redundancy, promotes harmonization, and ensures cross-
    Institute collaboration. OAR has the authority to shift resources
    across ICs and areas of science to meet the needs of the changing
    epidemic and scientific opportunities.

                   NEW SCIENTIFIC ADVANCES AND OPPORTUNITIES

        The advances made by NIH investigators have opened doors for new
    and exciting research opportunities to answer key scientific questions
    that remain in the search for strategies to prevent and treat HIV
    infection both in the U.S. and around the world. These advances
    represent the building blocks for the development of this trans-NIH
    AIDS research budget request. These include:
      --Basic research that will underpin further development of critically
            needed ``vaccines and microbicides''.
      --Innovative multi-disciplinary research and international
            collaborations to develop novel approaches and strategies to
            eliminate viral reservoirs that could lead toward ``a cure for
            HIV''.
      --Critical studies in the area of ``therapeutics as a method to
            prevent infection'', including treatment to prevent HIV
            transmission; Pre-Exposure Prophylaxis; a potential prevention
            strategy, known as ``test and treat,'' to determine whether a
            community-wide testing program with treatment can decrease the
            overall rate of new HIV infections; and improved strategies to
            prevent mother-to-child transmission. A key priority is to
            evaluate prevention interventions that can be used in
            combination in different populations, including adolescents and
            older individuals.
      --Research to develop better, less toxic treatments and to
            investigate how genetic determinants, sex, gender, race, age,
            nutritional status, treatment during pregnancy, and other
            factors interact to affect treatment success or failure and/or
            disease progression.
      --Studies to address the increased incidence of malignancies;
            cardiovascular, neurological and metabolic complications; and
            premature aging associated with long-term HIV disease and
            antiretroviral treatment (ART).
      --Research on the feasibility, effectiveness, and sustainability
            required to scale-up interventions from a structured behavioral
            or clinical study to a broader ``real world'' setting.

                               FUNDING PRIORITIES

        OAR has utilized its authorities to shift AIDS research resources
    across ICs to meet the new and exciting scientific opportunities in
    AIDS research. These shifts reflect the scientific priorities
    identified in the annual trans-NIH strategic planning and budget
    process and address the evolving clinical profile of the epidemic,
    changing demographics, and most recent scientific advances. In this
    budget request, OAR has provided increases to high-priority basic
    research (etiology and pathogenesis) that provides the underlying
    foundation for all HIV research. An important area will focus on
    research related to the potential for a cure or lifelong remission of
    HIV infection, including studies on viral persistence, latency, and
    reactivation. Increases are also provided for the development of
    vaccines and microbicides to prevent HIV infection. In order to provide
    those increases, OAR has reduced and redirected funds from natural
    history and epidemiology, therapeutic clinical trials, and training and
    infrastructure support.

                                    SUMMARY

        The NIH investment in AIDS research has produced groundbreaking
    scientific advances. AIDS research also is helping to unravel the
    mysteries surrounding many other cardiovascular, malignant, neurologic,
    autoimmune, metabolic, and infectious diseases, as well as the complex
    issues of aging and dementia. Despite these advances, however, AIDS is
    not over, and serious challenges lie ahead. The HIV/AIDS pandemic will
    remain the most serious public health crisis of our time until better,
    more effective, and affordable prevention and treatment regimens are
    developed and universally available. NIH will continue to search for
    solutions to prevent, treat, and eventually cure AIDS.

        Senator Harkin. Thank you, again, Dr. Collins, for your
    statement, and for bringing us up-to-date.
        We'll begin a round of 5-minute questions.
        Who is running the time here? There we go.
        So we'll begin a round of 5-minute questions. I'm sure
    we'll have more than one round.

            FAVORING SAFER VERSUS INNOVATIVE RESEARCH PROJECT GRANTS

        So, Dr. Collins, as I said in my opening statement, I think
    you repeated it, that the reviewed NIH grants will drop to
    about 16 percent this fiscal year. I'm concerned that when
    money gets that tight, there's a tendency to shy away from
    awarding ideas that are thinking outside the box, and we've
    talked about that many times here with you over the last many
    years.
        I'm concerned that, consciously or unconsciously, your peer
    reviewers might tend to favor safer incremental advances and to
    avoid ideas that are bolder but may carry more risk. Any
    validity to that?
        Dr. Collins. Mr. Chairman, that's certainly an area of
    considerable concern for all of us, because imagine yourself on
    a study section where you have a big pile of exciting science
    in front of you and you know you're going to only be able to
    fund a very small number of those. You have in front of you a
    really powerful strong proposal that builds on previous work
    from an established investigator that you know is going to be
    successful, and then you got something over here that's a bit
    risky from an investigator who doesn't have the same track
    record.
        If it works, it could be groundbreaking, but you're not
    sure it's going to work. And in that setting where you would
    love to fund both, but you may not be able to, there can be a
    tendency then to go with what you know is going to produce
    results. But that could be just the wrong thing to do.
        We in NIH have a number of programs that aim to try to
    encourage innovation in this climate by setting up programs
    like the Pioneer Awards, the Transformative RO1s, the New
    Innovator awards. You can't apply to those programs unless you
    have an out-of-the-box idea.
        So, there's this common fund effort to do that, and many of
    the institutes have initiated efforts of that sort as well.
        But there's no question about it. There's no magic here in
    terms of loss of innovation potential. Just the fact that we're
    only funding 15, 16 percent or less of the applications that
    come in, there's a lot of innovation at the 18th percentile and
    the 22nd percentile. Most of us have a very hard time telling
    the difference between a grant that scores at the 11th
    percentile and the 17th. Yet, one is going to get funded and
    one may not.
        So, the real anxiety we all feel is how much talent is
    being wasted and how many ideas are not getting followed up on
    that could be.

              EFFECTS OF SEQUESTRATION ON RESEARCH PROJECT GRANTS

        Senator Harkin. So sequestration has an effect on that
    also?
        Dr. Collins. Absolutely, because sequestration drops the--
    as we've all just mentioned, 700 grants that we hoped we would
    fund this year are not going to be. I'm sure in those 700 there
    were some great, innovative, out-of-the-box ideas.

                     NCI'S PROVOCATIVE QUESTION INITIATIVE

        Senator Harkin. Okay. I'm going to go to Dr. Varmus,
    talking about thinking out-of-the-box and everything. Tell us
    more about your Provocative Questions program, and what's the
    purpose, and how is it proceeding?
        Dr. Varmus. We did two things to try to ensure that we do
    the best we can, imperfect though that is, to address the
    concerns you and many others have raised about risk-taking
    under these adverse fiscal circumstances.
        The first thing we do is to look at a large number of our
    grant applications, and award grants even when the score is a
    little less than you might think is required for success by
    saying this is really innovative and addresses a very important
    issue.
        Number two, we set up some special programs, one of which
    is called Provocative Questions. These questions come from
    groups that we assemble around the country, interdisciplinary
    groups, people who haven't been in cancer research before, to
    raise some difficult questions that we think technology now may
    be prepared to address. We have these questions debated on our
    Web site. We then invite applications for answering about 24
    each year, and we're funding--last year, over 50; this year we
    hope more than that--to try to address the 24 questions that
    we've been selecting as particularly important and difficult
    questions.
        Too early to say how well we're going to do with this, but
    it's a way to try to guarantee some answer to the question
    you're appropriately raising.

                         BRAIN INITIATIVE: WHAT IS IT?

        Senator Harkin. I'll have a follow-up question on that
    later, but I wanted to ask Dr. Landis, in the short time I have
    left, about the new BRAIN Initiative.
        The President talked about mapping the brain, what does it
    mean? Someone compared it to, again, the Human Genome Project.
    But even at the beginning, some of us were there at the
    beginning, we knew what the end result was going to be, and we
    knew when it was going to end. We didn't know exactly when, but
    we knew what the end result was.
        What do we know about what is the end result? Is there
    something that we're looking to reach at a certain point in
    time?
        Dr. Landis. So, what we would really like to be able to do
    with the BRAIN Initiative is to understand how information is
    processed in circuits. As Dr. Collins told you, we're beginning
    to have better maps of connections between nerve cells in
    different regions of the brain. And, we can lay them out in
    circuits that control particular movements, vision, or hearing.
        But what we don't understand is how information is
    processed through those pathways. And in order to understand a
    number of psychiatric diseases and even neurodegenerative
    diseases, we have to understand how circuits work. We simply do
    not have the tools to do that now. So, that would be one of the
    major goals for the first 5 years of the BRAIN Initiative, to
    get better tools and technologies that will be able to help us
    track activity in circuits, and understand how information
    changes as it goes from one nerve cell in a circuit to another.
        Much more, as I've already said to Dr. Collins, much more
    complicated than just lining up the As and Cs and Ts and Gs,
    but could have as much, or even greater, impact. And he did
    agree with me on that.
        Senator Harkin. Yes, but 3 billion base pairs, we thought
    that was a lot. Now we're talking about a trillion or something
    like that. I don't know. We'll get back to that.
        Senator Moran.
        Senator Moran. Mr. Chairman, thank you very much.
        Dr. Collins, thank you very much for your compelling
    testimony.
        Dr. Varmus, thank you for coming to Kansas City and
    visiting a couple of facilities, a research facility and a
    hospital. But thank you especially for riding your bike to
    raise money for cancer research.
        Dr. Varmus. Along with the barbeque.
        Senator Moran. Along with the barbeque. That's right. That
    was the real inducement. Thank you very much for highlighting
    Kansas City barbeque.

                        BRAIN INITIATIVE: 10-YEAR BUDGET

        Dr. Collins, and this may be this is for Dr. Landis,
    because it's a follow-up to what the chairman was asking about.
    On the BRAIN Initiative, the budget documents are not very
    specific in regard to what we should expect as far as budget
    requests in the next 10 years.
        I was interested in what the goals are in the short term of
    this project. You outlined already what, at least in the first
    5 years, is the significant goal. But what would we as a
    committee, what would we as members of the Senate, expect the
    request to be in regard to the budget into the future?
        Dr. Collins. So, a very appropriate question. This is sort
    of like the genome project in 1988 where it was clear there was
    an opportunity, and it wouldn't happen without a coordinated
    effort, particularly the focus on technology. But nobody was
    quite sure at that point what the trajectory could look like as
    far as accomplishing that goal.
        We're in the process right now of trying to define that,
    Senator, in the long term, over the next 10 or 15 years. What
    could be accomplished? What would the steps be? What kind of
    technologies do we need? And what would the cost be?
        So, we brought together a really remarkable group of
    visionary neuroscientists in a group--co-chaired by Cori
    Bargmann from Rockefeller and Bill Newsome from Stanford along
    with 13 other remarkable folks--and we've asked them, in the
    course of the next few months, and they're hard at work at
    this, to lay out some initial milestones of what this project
    needs to accomplish. And by the summer of 2014, to have a much
    more detailed roadmap of where the BRAIN Initiative needs to go
    and how quickly it can get there.
        So, frankly, I don't have a clear answer to your question
    at the moment, in terms of what the budget trajectory of this
    might be over the next 10 or 15 years. We have to be sure we
    have the science plan laid out.
        Senator Moran. And there's no justifiable reason that we
    should expect that plan at this point? That's just not
    accomplishable, at this point? Before we start down this path,
    we're not going to know what to expect?
        Dr. Collins. I think at this point, it would be premature
    to try to attach budget numbers to a scientific plan that
    hasn't quite formed in a coalesced way and been embraced and
    endorsed by all of the scientific experts that we want to
    participate and to take part in this.
        So, it has always been our view that if you're going to try
    to start something really bold, the first step is to map out
    the science, and then you figure out, okay, what does that mean
    in terms of the timetables and the costs? Of course, you have
    to set priorities within the realistic envelope of what costs
    might be available to you.
        We recognize this may be a tough time to be starting a very
    ambitious project, but we just don't think it would be right to
    wait, given the opportunity.

         STATUS OF NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

        Senator Moran. Dr. Collins, this might be for you, as I
    don't think the National Center for Advancing Translational
    Sciences (NCATS) director is here.
        Dr. Collins. He is not.
        Senator Moran. Let me ask about the status of NCATS. I was
    supportive of its establishment. I think that is now about a
    year and a half ago. And I'd be interested in having you bring
    me up-to-date on its developments.
        One of the environments in which NCATS now works is that
    with the economic conditions we face, private drug companies
    can no longer make a financially sound business case to invest
    in new drug development projects. There's this gap, what has
    been described as a valley of death between scientific
    discovery on the one side and patient benefit and commercial
    success on the other.
        The goal of NCATS has been to fill that valley. What kind
    of success is NCATS having in doing that?
        Dr. Collins. Well, thank you for the question.
        Let me say right upfront how wonderful it's been for Chris
    Austin, the Director of NCATS, to work with folks in Kansas at
    the university and with the Leukemia and Lymphoma Society on a
    few groundbreaking projects. Particularly one on chronic
    lymphocytic leukemia (CLL), which is actually a good example of
    one of the things I want to mention that NCATS is catalyzed,
    and that is this whole idea of repurposing drugs that were
    developed for something but turned out to have a use for
    something else.
        The project they're working on with Kansas is a drug
    developed for rheumatoid arthritis, Auranofin, which turns out
    to have activity against leukemia, and more recently to the
    delight of all of us, also against a very resistant kind of
    cancer called mantle cell lymphoma.
        The CLL protocol is already well along in a clinical trial.
    This is an amazing quick turnaround, because if you had to
    start from scratch, it would take years and tens of millions of
    dollars to get to a clinical trial. But, if you can identify a
    compound and try it for a new purpose, you already have all
    that background data and you shave off years and many, many
    tens of millions of dollars in cost.
        So, NCATS is in fact catalyzing that kind of repurposing
    both for drugs that have already been approved but also in
    working with companies, eight of them, they have agreed to make
    58 compounds available for new uses that actually turned out
    not to be effective for the original use but the drugs are
    known to be safe.
        This is crowdsourcing, if you will, the opportunity to find
    a new use for a really heavily invested compound that may turn
    out to have failed for disease A but might be just the thing
    for disease B.
        NCATS is also working with the Food and Drug Administration
    (FDA) and with Defense Advanced Research Projects Agency
    (DARPA) on developing a new and very high-tech way of
    identifying whether or not a drug is going to be safe before
    you ever give it to that first human patient, using a biochip
    depending upon the stem cell, iPS cell technology.
        NCATS also serves now as the home for the largest
    investment in clinical and translational science, namely our
    Clinical and Translational Science Award (CTSA), of which they
    are 60 across the country in many of your States, and basically
    then bringing that network together in a way that makes the
    whole really much greater than the sum of the parts, sort of
    CTSA 2.0, as we are starting to call it.
        So, I think even though NCATS has only been around for, you
    know, a year and maybe 5 months, the evidence is very clear
    that this is an opportunity that we have grabbed on to. The
    private sector is enthusiastic about the way in which this
    serves as a complementary set of contributions to what they are
    doing. Academics are fired up about it. I think this has turned
    out to be a really good thing for NIH, too.
        Senator Moran. Very good.
        I assume you're the one who coined the phrase ``valley of
    death'' and now ``crowdsourcing.'' I will use it in my comments
    next.
        Dr. Collins. I don't think I can take credit, but you are
    welcome to use the terms.
        Senator Harkin. Senator Mikulski, Senator Shelby, Senator
    Cochran.
        Senator Mikulski.
        Chairwoman Mikulski. Thank you very much, Mr. Chairman.
        And, Dr. Collins, I want to welcome you and your entire
    team, and also other heads of institutes who are not at the
    blue table but are certainly always at the head of the line at
    the head table.
        I just wanted to just tell you in the warmest way, and to
    my colleagues, what a sense of joy and pride that I have
    representing NIH. The fact that it is located in my home State
    of Maryland, Senator Cardin and I both know that every day, to
    have such a premier institution is one of the reasons we want
    to be in the Senate, really to be an advocate for the kinds of
    resources, policy, and framework, so you get to be you and you
    get to be what the American people want you to do, which is to
    find cures to disease, to find containments of disease, to look
    for those things to even prevent them from happening or prevent
    them from escalating.
        So it's not only a source of pride, but I can tell you, as
    the chair of this full committee, I'm going to work with
    Senator Harkin and Senator Moran across party lines, to make
    sure they get the kind of allocation they need to do their job.
        Much has been said here about sequester. I'm not going to
    go into it in detail, but I'm concerned about the negative
    impact that it has, first of all on the people who work at NIH
    and those who participate in the extramural programs, like the
    University of Maryland, like Hopkins, like the great land-grant
    universities that, again, are out there working every day.
    That's the genius of what we do.
        It's not Government-owned and operated. It's also out there
    extramurally and also functioning around the world, because who
    you are, you talk to the others around the world.
        And, therefore, we need to look at the impact of sequester
    on jobs, on the economy, and not only on our reducing public
    debt today, but the impact on growth.
        I am just struck by what you've done. Deaths from heart
    attacks and strokes have fallen more than 60 percent--60
    percent. A wonderful colleague like Mark Kirk could make it up
    the steps of the Capitol when he was sworn in for his comeback
    into the United States Senate because of his grit, his verve,
    and the medical science behind him.
        This is not only for a member of the United States Senate;
    it's for all Americans.
        HIV/AIDS--we remember, Dr. Fauci, when the crisis came. We
    were here when a little boy named Ryan White testified. He was
    kept isolated in his own class in school because nobody would
    talk to him. HIV/AIDS, thanks to your work and the brilliant
    scientists, are no longer a death sentence.
        And for the children of the world in our own country,
    children with the most common childhood leukemia have a 90
    percent chance of surviving.
        What a phenomenal story.
        Dr. Varmus, you were the Director of NIH. You go to Sloan-
    Kettering. You have one of those cushy, full professorships
    that most people dream about. You come back to head up an
    institute. You announce that cancer rates are down 12 to 15
    percent across the board.
        This is just stunning. And yesterday we saw a brilliant
    actress, an esteemed actress take the bold step, announcing the
    bold step where she had a prophylactic mastectomy in order to
    ensure her own survival rate. But she knew her genetic
    situation. She could have decisions, informed consent. This is
    who we are, and this is what we're fighting for.
        I didn't mean to give a speech, but I'm so excited about
    you.
        And I want to say to my colleagues, this is why we have to
    not only--this sequester I think has a very deleterious,
    eroding, and corrosive effect. So I want to do all I can to
    cancel sequester this year, and also cancel sequester for the
    next 9 years, for which you would then fall behind to the tune
    of $19 billion.
        We hope that the other side--we've got support here on the
    other side of the aisle. I worry about the other side of the
    dome.
        Mr. Ryan, in his budget, is sending it to us to work with
    at $966 billion. That's bad enough, but he took all of it out
    of domestic discretionary spending.
        I'm not going to turn this into politics. We want to be
    above politics. But we're going to have to deal with politics.
        I want my subcommittee chairman and the vice chairman of
    this subcommittee to know, I want to work with them, because
    what I see my job as doing is to do all we can to help you be
    you and help you do the mission that the United States of
    America and its people gave you.
        So I'm going to work my earrings off to make that happen.
    And with that, I just wish we could even get more done.
        I'm not going to ask questions. I've taken a lot of the
    time here. I will be interested in the further discussion that
    we're having.
        Senator Harkin. Madam Chairman, thank you very, very much
    for your leadership of this full committee, and not only your
    leadership of the full committee, but your great leadership on
    this particular subcommittee. For all of the input and
    leadership you've given us through all these years, we thank
    you very much.
        Now, we'll turn to Senator Shelby.
        Senator Shelby. Thank you.
        First of all, I want to associate myself with the remarks
    of Senator Mikulski. She said it so well.
        I believe that the top investment we can make in America to
    save lives, to improve lives, for the American people is to
    invest in the NIH. I believe this.
        I'd like to see us double NIH's funding. I know that's hard
    to do, but to at least get on the upward funding trend, not the
    downward trend, of biomedical research in this country is a
    critical first step.
        And I'm saying that because I see the results of NIH
    research, as Senator Mikulski has pointed out, Senator Harkin
    has, and others, Senator Moran.

                RESEARCH AND ITS IMPACT ON THE STANDARD OF CARE

        Having said that, Dr. Collins, I want to get a little
    parochial, if I can.
        Researchers at the University of Alabama in Birmingham, as
    you well know, conducted an important study on very premature
    babies, a study called ``SUPPORT'' from 2004 to 2009 that was
    funded by the National Institutes of Health. Researchers at
    more than 20 sites were trying to determine, as I understand
    it, the proper oxygen levels for these vulnerable premature
    babies by comparing two ranges of oxygen saturation within the
    standard of care at that time.
        It's my understanding that the SUPPORT study has had an
    important effect on clinical care. Dr. Collins, how important
    is research like this that study and ultimately improve the
    standard of care?
        Dr. Collins. Senator Shelby, thank you for the question.
        Very important, indeed. Standard of care reflects what we
    know at the time, and oftentimes, we don't know enough, and so
    it may be a rather broad range of options and physicians and
    other caregivers who are trying to do the best job of taking
    care of patients. And patients who are seeking the best care
    may not be well-served by all, the entire range, of
    opportunities that are called standard of care.
        That was certainly the case for the study of the optimum
    oxygen levels to give to premature babies.
        Senator Shelby. But you learn by investigating and by
    studying. That's the bottom-line.
        Dr. Collins. You're exactly right.
        So, for us at NIH, we invest heavily in these kinds of
    studies. Let me give you another couple of examples.
        Individuals who are going through hemodialysis, and there
    are a lot, sad to say, many of them because of diabetes. There
    has never really been a clear understanding of what the right
    schedule is for hemodialysis, how many times a week, how many
    hours. That's a huge impact on somebody's quality of life, in
    terms of how much time they're spending there. But also,
    quality of life is dependent on how effective the dialysis is.
    So, a study called the Frequent Hemodialysis Network (FHN):
    Daily Trial, that we have been funding, aimed to try to get an
    answer to that. All in the standard of care, everybody in that
    study, is getting the kind of treatment that you would consider
    standard, but we're trying to find the sweet spot, to do a
    refinement of that.
        I could cite you two or three others. This is very
    important and yet we depend upon patient----
        Senator Shelby. It goes to the basis of your research, does
    it not?
        Dr. Collins. Yes, it does. That's what our goal is, is to
    try to be sure that people get the best possible information in
    order to guide their medical care.

           UNIVERSITY OF ALABAMA AT BIRMINGHAM INFANCY CLINICAL STUDY

        Senator Shelby. As you well know, the University of Alabama
    at Birmingham (UAB) received a letter from the Office of Human
    Research Protection (OHRP) about the SUPPORT clinical trial
    that we're carrying out under the auspices of NIH. And the OHRP
    determined that UAB should have informed parents of an
    increased risk of death of their infant by participating in the
    study. But it was my understanding that the risks were unknown
    at the time of the study's commencement in 2004, and there was
    no specific scientific data that existed at the start of the
    study that showed an increased risk.
        Were babies in that study at any greater risk than babies
    not in the study? Do you know?
        Dr. Collins. No, Senator. I don't believe they were.
        Senator Shelby. Okay.

         INSTITUTIONAL DEVELOPMENT AWARDS PROGRAM ELIGIBILITY CRITERIA

        We've talked about the sequester, I'll move on, on that.
    I'm committed to working with Senator Mikulski to see if we can
    plus-up NIH, though.
        Institutional Development Awards (IDeA), we discussed this
    topic a little bit before. I think it's important to recognize
    that the next scientific discovery may come from anywhere. You
    don't really know where. And I believe that institutions that
    do not historically have high NIH grant rates can still
    substantially contribute to biomedical research. And I believe
    we need to give these institutions an opportunity.
        As we discussed before, Dr. Collins, the eligibility
    criteria for the IDeA program is outdated. Both the fiscal
    years 2012 and 2013 Senate Labor-HHS bills included report
    language regarding this issue.
        However, it's my understanding that no significant
    information on the subject has ever been provided to the
    subcommittee.
        Dr. Collins, could you work with us to develop a better
    criteria, eligibility criteria, for some of these institutions
    that really could contribute, if given a chance?
        Dr. Collins. So, Senator, I know time is short, but I'll
    answer quickly. I do agree that it's a wonderful opportunity
    for capacity-building in this competitive program that is known
    by the name of IDeA.
        The Institute of Medicine has been undertaking a study of
    whether the criteria for IDeA and Experimental Program to
    Stimulate Competitive Research (EPSCOR) are in fact in need of
    revision, and we expect that report to be released fairly soon.
    It would be a good time then to have a conversation with you
    and others about this issue.

                        BREAKTHROUGHS IN CYSTIC FIBROSIS

        Senator Shelby. Let's talk about, if we could, the
    breakthroughs in the research that has been done in cystic
    fibrosis over the years. We've talked about this before, and
    there's been some breakthroughs there.
        Would you highlight some of them, and how we're doing in
    that area?
        Dr. Collins. It's an area of enormous excitement. My own
    research lab back in 1989 played a role in collaborating with
    another group in Toronto in discovering the gene for cystic
    fibrosis. And now, just in the last couple of years, the really
    exciting fruits of that in terms of drug therapy have emerged
    with one drug called Kalydeco now approved in record time by
    the FDA, which shows dramatic responses from individuals who
    have a particular misspelling of that cystic fibrosis gene.
        Unfortunately, only about 4 or 5 percent of cystic fibrosis
    patients are in that category. But there's great excitement
    because of phase II and phase III trials now being conducted by
    Vertex on two new compounds, which should be actually quite
    useful for 90 percent or more of people with cystic fibrosis.
        This all builds upon NIH research that's been done over the
    decades. It's a wonderful collaboration with the Cystic
    Fibrosis Foundation in interaction with the company called
    Vertex. The National Heart, Lung, and Blood Institute, which
    Dr. Gibbons directs, has funded a lot of this effort through
    the years. It is a great success story, and one that we hope to
    replicate for lots of other diseases.
        Senator Shelby. Thank you for sharing it with us.
        Thank you, Mr. Chairman.
        Senator Harkin. Senator Cochran.
        Senator Cochran. Mr. Chairman, I'm pleased to join you in
    welcoming our distinguished panel of witnesses today.
        Dr. Collins, we appreciate your being here again and also
    coming out into the countryside where we live and work.
        Dr. Collins. I enjoy that very much, Senator.
        Senator Cochran. We appreciated the honor of your visit to
    Mississippi.
        And it might interest you to know that just recently, there
    was an announcement from the Blair Batson Hospital for Children
    in Jackson, Mississippi, where you were, by a Dr. Hannah Gay,
    who reported a functional cure of a child who was born HIV
    positive. And this is news that's getting around the world now
    and is attracting attention again to the distinction that
    Mississippi has for people like Dr. Arthur Guyton, who wrote
    many of your textbooks, and others who have pioneered in
    research in different areas.
        So we look forward to supporting the work that you do, and
    we hope we'll be able to provide some seed money or incentive
    grants, funding to ensure that we continue to embark upon
    daring and innovative approaches to dealing with our health
    problems in America.
        Thank you.
        Senator Harkin. Senator Boozman.
        Senator Boozman. Thank you all, and thank you for being
    here. I really do want to compliment you all as a group. Your
    efforts, your work, your advocacy really has changed the world,
    and we appreciate your efforts very, very much.
        There's a lot of things that the Government possibly, we
    could argue, doesn't need to be doing. I think what you all
    represent is something the State of Arkansas, our communities,
    can't do individually, and so we do appreciate the work that
    you do.

                         PUBLIC ACCESS TO NIH RESEARCH

        One thing I'd like to ask about, we have to make some
    significant decisions here. The agencies have to make some
    significant decisions. As we have research that is publicly
    funded, generally, we allow that research to be made available;
    is that correct?
        Dr. Collins. Yes, we strongly support the need for that. If
    the public has paid for the research, the public should have
    access to it. I think NIH, it's fair to say, has taken the lead
    in trying to make sure that that kind of access to information
    happens in a timely fashion.
        The recent suggestion, by the Obama administration, is that
    this kind of policy should be applied broadly across all of the
    agencies, and I think many are looking at NIH's model as
    something to replicate in other parts of the Government as
    well.

                          DUAL-USE RESEARCH SAFEGUARDS

        Senator Boozman. And again, I appreciate that and agree
    wholeheartedly. And I'm glad that that is the policy.
        Can you envision a reason not to do that in some cases?
        Dr. Collins. Perhaps you're talking about circumstances
    where the data that's being generated might in fact create some
    risk to the public if it fell into the wrong hands.
        I'm going to ask Dr. Fauci to comment on this, because this
    often falls in the category of areas that might be amenable to
    bioterrorist misuse, and we've certainly been engaged in those
    conversations. And Dr. Fauci has had the lead in many of them.
        Tony?
        Dr. Fauci. Yes, thank you for that question.
        It is a delicate balance, particularly when you do what is
    called dual-use research of concern, where the public health
    imperative for understanding whatever process you're looking at
    is quite important. Yet you're concerned with two things.
        One is the deliberate misuse of things that have to do, for
    example, with potentially pathogenic microbes that could be
    used in a bioterror situation or the inappropriate and careless
    use of that information by people who are not qualified. It
    transcends all areas of research, but it's particularly acute
    when you're dealing with the study and perhaps even creation of
    a microbe that might, in fact, be an issue.
        Having said that, we tend, unless there's a really very
    good reason, to be as open and transparent as possible, because
    the default rule--and we're careful about that and not
    careless--is that not allowing knowledge to be generally spread
    throughout the scientific community has more deleterious
    effects than the risk of having something being used in a
    deleterious way accidentally or deliberately by others.
        So, it goes along with the concept that Dr. Collins
    mentioned, that we have been the leaders and we continue to
    stress the open nature of scientific information.

                 CLINICAL TRIALS AND VOLUNTEER CONFIDENTIALITY

        Senator Boozman. Okay. And as far as we can always put
    safeguards and a lot of research sometimes involves people and
    things like that. I mean, we can always put the safeguards in
    to protect, so that we are able to release the data without
    jeopardizing people. Is that----
        Dr. Collins. So, I think there, you're getting at the issue
    about privacy and confidentiality for people who are part of
    clinical trials that NIH supports who have been willing to
    volunteer to take part in a study and who are happy to be part
    of that, but don't want all of their medical records to be
    accessible by everybody on the planet.
        Yes, we take that with great seriousness and make every
    effort, and I think we've been quite successful, to keep that
    information only in the hands of those who have a need to know
    as part of the research project.
        Senator Boozman. Again, thank you all for being here. I
    really do appreciate your efforts and, as a new member on the
    panel, I look forward to working with you in the future and
    supporting your efforts. Thank you.
        Dr. Collins. We look forward to that, too. Thank you.

            IMPACT OF THE BRAIN INITIATIVE ON NEUROLOGICAL DISORDERS

        Senator Harkin. Thank you, Senator.
        We'll start a second round here. I wanted to follow-up a
    little bit on the BRAIN Initiative, Dr. Landis and Dr. Hodes,
    because when I first heard about this bump-up in this new
    initiative, we were talking about it and someone said, well,
    how is this going to affect all the research on Alzheimer's? I
    don't know.
        There's a report that came out that said that the total
    cost of care for individuals with Alzheimer's disease will soar
    from $172 billion in 2010 to more than $1 trillion by 2050;
    that Medicare costs are increasing more than 600 percent from
    $88 billion today to $627 billion in 2050, if we keep on the
    same trajectory.
        So, tell me about this BRAIN Initiative. What's it going to
    do in terms of the research we're doing on Alzheimer's, or is
    this something separate and apart?
        Dr. Landis. So, let me talk about the BRAIN Initiative and
    the promise of the BRAIN Initiative, and then I'll turn it over
    to Dr. Hodes to address the issue of Alzheimer's.
        The long-term goal of the BRAIN Initiative is to be able to
    develop treatments for patients across the broad range of
    psychiatric and neurological disorders, and I'll give you a
    very specific example.
        In the case of Parkinson's disease, one of the major
    advances has been the development of deep brain stimulation
    where electrodes are planted in particular regions bilaterally
    of Parkinson's patient's brains in the midcourse of the
    disease.
        This stimulation, kind of like a brain pacemaker, can
    transform the quality of life of those patients. They can move
    freely. They're much more active. They would, in some cases,
    not even appear to have Parkinson's.
        That effect wears off with time. This stimulation is very
    crude. It's an electrode that is influencing the circuit
    behavior. If we understood more about how the circuits work
    that control movement, that control compulsions, that control
    speech, we would be able to design much better interventions,
    electroceutical interventions--not pharmaceutical, but
    electroceutical--that would rebuild those circuits in a much
    more effective way.
        Deep brain stimulation is now being used for obsessive-
    compulsive disorder. It's being used for intractable
    depression. And in each case, the electrode is going in a
    different part of the brain, but it's the same crude
    stimulation.
        So, just by analogy to Parkinson's, if we understood the
    circuits for obsessive-compulsive disorder or intractable
    depression, we would be able to come up with much more
    effective ways to change the circuitry to ameliorate those
    diseases.

             IMPACT OF THE BRAIN INITIATIVE ON ALZHEIMER'S DISEASE

        Senator Harkin. That's all well and good, but we have a
    crisis on our hands with Alzheimer's, a real crisis. And I'm
    wondering--this is well and good. I'm all for that. But I'm
    concerned that we're not doing enough to really focus more
    research on, if you can just put off the onset of Alzheimer's
    for 5 years, that would save so much money.
        So tell me how this affects Alzheimer's research?
        Dr. Hodes. Thank you for the opportunity to comment on
    this.
        As noted, the cost, the public health and human suffering
    cost of Alzheimer's, is huge. In addition to the public health
    demand, of course, what is important is for us to assess
    scientific opportunity and quality of science. It's one thing
    to recognize a problem. Now we have a responsibility to address
    it in the best possible way.
        And the most responsible way to do this at this point, when
    we don't know what ultimately would be the successful approach,
    is to invest across a spectrum from those basic discovery on
    through translation.
        So, we have some enormously important and innovative
    clinical trials happening. In the last year, for the first
    time, we're able to identify people at enormously high genetic
    risk, in whom we can find, by bio-imaging, signs of disease
    years, even decades, before onset and begin for the first time
    to treat them.
        So, we have new opportunities we didn't have before.
        But having said all this, we still have an opportunity,
    and, in fact, an obligation to better understand the cellular
    and molecular underpinnings, so that we can continue the effort
    to generate new generations of investment. That is where this
    BRAIN Initiative happens.
        It's clear that Alzheimer's disease is not a disease of
    just a single cell or even a single cell type. It involves
    defects in the communications between cells, and the more we
    understand, in the sense of what the brain will tell us, the
    better we can intervene to the specific things that are going
    wrong in Alzheimer's disease.
        Senator Harkin. So, again, you're both telling me that this
    BRAIN Initiative does have an impact on Alzheimer's research.
        Dr. Landis. Yes. So, one very surprising finding of the
    last couple of years has been that there is abnormal electrical
    activity, almost like mini seizures in the brains of
    Alzheimer's patients. It's not clear the extent to which that
    abnormal activity influences the course of the disease.
        But if we knew better how to modulate activity in circuits,
    and which were the right circuits, we could potentially
    intervene in those electroform activities in Alzheimer's
    patients and potentially have a very positive effect on their
    quality of life.
        Dr. Hodes. It's well-described, and in fact, it comes back
    to another point made, the concern we have about not being
    overly conservative, that we don't fail to take advantage of
    truly bold and innovative new approaches. This is an example,
    at the same time we're doing the best we can to translate what
    we think is the best information about cause and potential
    interventions for Alzheimer's, we still have an obligation to
    make sure we examine broadly the kinds of information which
    will tell us about whole new approaches that may be, in the
    end, the best or most definitive solution.
        Senator Harkin. Thank you all very much.
        Senator Moran.

                             CARDIOVASCULAR DISEASE

        Senator Moran. Mr. Chairman, thank you.
        Dr. Gibbons, cardiovascular disease is the leading cause of
    death in the United States. It's certainly a driver of
    healthcare expenditures. I'm told it costs the U.S. consumer,
    the patient, $312.6 billion a year.
        Sunday's New York Times had an article on an NIH study that
    is using genetic sequencing to find factors that increase the
    risk of heart disease beyond the usual suspects of high
    cholesterol, high blood pressure, smoking, and diabetes.
        Would you tell us more about that study?
        Dr. Gibbons. Well, thank you for that question. This is one
    of the great success stories, I think, in biomedical research,
    where discovery science related to the pathways that determine
    low density lipoprotein (LDL) cholesterol, the bad cholesterol
    metabolism, led to Nobel Prizes for Brown and Goldstein.
        There was a great public-private partnership that led to
    the identification of a target that would lower LDL
    cholesterol. That led to a drug, Statins. I suspect, for those
    of us over 50, a lot of us in this room may even be on one.
        That was a breakthrough drug that's transformed medicine.
    Indeed, that public-private partnership is one that is critical
    to advancing medicine.
        The question now is that although we have studies that show
    the remarkable improvements of having patients on statins,
    unfortunately, there are still patients on statins who have a
    heart attack every few moments in this country. So, that tells
    us there's still unfinished business. There's still some
    unsolved mysteries.
        That article related to us continuing to try to figure out
    those patients where we don't really understand all the risk
    factors, all the predictors of who's going to have a heart
    attack. And as you saw in that article, a devastating impact on
    a whole family that we really couldn't explain, but that's
    where we have these unprecedented opportunities.
        With new technologies, we're able to sequence parts of the
    genome and probe into why is this family so different and
    distinctive in a way that's really devastating to it? We're
    hopeful that that will identify new pathways that will tell us
    more about the risk of heart attacks. That may recapitulate
    that story we just had with LDL cholesterol.
        That's the promise of the future. Those are the investments
    we need to make now for those breakthroughs tomorrow.
        Senator Moran. Is there enough research to give us a clue
    as to what those other factors may be?
        Dr. Gibbons. Well, there's a lot of promise. Perhaps one
    example, a sort of a harbinger of that, relates to a molecule
    called proprotein convertase subtilisin/kexin type 9 (PCSK9),
    in which a similar sort of strategy delved into the molecular
    determinants of, again, a group of families, a group of
    patients that had an abnormal level of LDL cholesterol. The
    probing use of modern genomic technologies unveiled this new
    gene in this other pathway that told us another potential
    target.
        And indeed, as part of the recapitulation of that public-
    private partnership in which discovery science translated into
    drug development, a new drug has been developed that targets
    that same sort of pathway. That's now in the midst of clinical
    trials, to see if on top of statins or in a complementary way
    going after this new target can actually give us more bang for
    the buck.
        Similarly, one of the things that we're learning is that
    although you have that bad cholesterol, what we're also
    appreciating is not just that clogging of the arteries but it's
    also the activation of the body's immune system that sort of
    turns against the blood vessel and inflames it just like your
    allergies flare up your sinuses.
        In that sense, the blood vessels were inflamed.
        So, what we're now looking at is new targets that may not
    only target the cholesterol level but that inflammatory
    response that also promotes heart attacks. That's where some of
    the great breakthroughs, I believe, are coming. And indeed,
    we're funding a study that's looking at tackling that
    inflammation part of the story, to see if we can make the next
    breakthrough.
        Senator Moran. I wish you great success.
        Dr. Gibbons. Thank you.

                           ACCESS TO CLINICAL TRIALS

        Senator Moran. Dr. Collins, I have very little time left,
    but as people know, Kansas is a very rural State. I have
    concerns about clinical trials.
        And in order, I assume, for a clinical trial to have
    validity, it takes a wide range of demographics and
    characteristics. And it seems to me there are barriers toward
    some people joining clinical trials based upon geography, age,
    other demographic and personal characteristics, perhaps fear of
    Government research, lack of awareness of clinical trial
    availability.
        What can I do--what is NIH doing--but what can I do as a
    Senator in caring for Kansans to make certain they are aware of
    the opportunity to participate in clinical trials and
    potentially improve their health and save their lives?
        Dr. Collins. It's a great question. NIH is by law, in our
    clinical trials, required to be sure we are reaching out to a
    diverse population. We track that carefully, and all the
    individuals who review clinical trial grant proposals and the
    program staff who follow those, make sure that we have a
    diversity of population involvement in the studies, whether
    it's heart disease, diabetes, cancer, whatever.
        But of course, we are dependent upon public knowledge about
    the ability to be part of such trials, and I appreciate your
    question very much in that regard.
        There is a Web site called clinicaltrials.gov, which is
    heavily utilized in every clinical trial that we support. And
    most of the ones supported by industry are also listed on that
    site. You can search it very readily to identify a particular
    condition, in some particular part of the country, where a
    trial is currently enrolling patients and what's the nature of
    that trial. And people can decide if they want to take part.
        Getting the word out about that would be a wonderful thing
    to do, and I appreciate very much your suggestion of helping
    with that. We would welcome that.
        Dr. Landis. If I could just add something. The National
    Institute of Neurological Disorders and Stroke (NINDS) recently
    set up a phase II clinical trials network called NeuroNEXT,
    with 25 sites across the country. One of them is at the
    University of Kansas Medical Center, and we are hoping to
    incorporate into the clinical trials undertaken by that network
    telemedicine, which would enable, for example, for stroke where
    patients at a distance to be seen by and treatment recommended
    or randomization recommended through the main NeuroNEXT site.
        So we're very interested in engaging in this with you.
        Senator Moran. I like that answer. Thank you very much.
        Senator Harkin. I'm sure you do.
        Senator Shelby.

                PROGRESS OF THE PROVOCATIVE QUESTIONS INITIATIVE

        Senator Shelby. Thank you, Mr. Chairman.
        Dr. Varmus, last year, we discussed a new initiative that
    you started to answer what we call provocative questions in
    cancer research.
        When budgets are constrained, we need, I believe, out-of-
    the-box ideas to answer some of the big research questions that
    could lead to the next breakthrough. You're in the forefront
    and I think your project is an innovative approach to define
    some of the unanswered questions in cancer research.
        Would you share with the committee this afternoon some of
    the progress you've made on this initiative, and what
    provocative questions have been awarded grants, or where are
    you?
        Dr. Varmus. Thank you, Senator.
        Obviously, this program is only a little over a year old,
    so we don't have results yet, but we do have results of
    advertising for applications.
        The first year, we chose 24 questions, the kinds of
    questions that were raised vary dramatically from questions
    about why people with profound obesity have increased risk of
    dying of certain kinds of cancer. There were questions about
    why drugs that are not all that effective in many
    circumstances, like chemotherapy for certain kinds of cancer,
    are remarkably effective for testicular cancer and certain
    other rare cancers.
        We've asked questions about behavior. Why do people still
    smoke when they know how bad smoking is?
        There were 24 questions of those similar dimensions chosen.
    We've received 750 applications to try to answer those
    questions. All 24 questions were addressed by at least several
    of the applications.
        Funding is short. We were able to fund slightly over 50
    applications. The funded grants address most, but not all, the
    questions.
        We then revised the questions, included some new ones that
    had come from recent workshops. We reconfigured some questions
    that we thought, perhaps, could be addressed more effectively
    if we rephrase them. And we received, this year, so far,
    several hundred applications.
        So, there is obviously a pent-up need. How good the
    applications are? It's hard to say. Many received very high
    marks from the reviewers. How well they'll do, that's always a
    crapshoot, frankly. And we won't know for a few years how well
    this works.
        We have gotten, of course, a lot of feedback from our
    community. They like the idea that we're not dictating the
    questions. The questions are coming from a community effort.
        We're trying to support the community at a period when
    morale is poor because of the low success rate. We're trying to
    say, we are partners in trying to develop the kinds of
    questions we think this community should answer, the kinds of
    risk we should be taking. We see this as one of the ways, not
    the only way, by any means, in which we try to cope with
    sequestration, with reduced opportunity to get grants.
        Thank you for the question.

                          AUTOIMMUNE DISEASE RESEARCH

        Senator Shelby. Dr. Collins, I'd like to talk about
    autoimmune and the research there.
        The NIH and various investigators have come a long way in
    dealing with autoimmune research, because it goes to the basis
    of so many things. In particular, where are you today in trying
    to deal with lupus? We've talked about this before and there
    have been some breakthroughs there. And where do you think you
    might go?
        Dr. Varmus, do you want to get into that?
        Dr. Varmus. No, thank you.
        Senator Shelby. Okay, okay. Any of you could. Dr. Collins.
        Dr. Collins. Actually, I'm going to ask Dr. Fauci to get in
    on this, because he's a card-carrying immunologist, and he can
    really talk about this.
        Senator Shelby. Doctor, thank you very much.
        Dr. Fauci. It's a pleasure. Thank you for the question. One
    of the approaches that we and other institutes are taking with
    regard to autoimmune diseases is making some significant
    advances in the field of what we call immune tolerance.
        Immune tolerance is to train the body's immune system not
    to respond inappropriately against certain antigens. In the
    case of lupus, those are self-antigens, and that's the reason
    why they call it autoimmunity.
        Several years ago, we established an immune tolerance
    network that was originally established to look at ways that we
    could prevent the rejection of transplants. We've expanded that
    now into the study of a number of other diseases that are
    clearly characterized by autoimmune phenomenon, including type
    1 diabetes, certain allergies, as well as very important
    rheumatologic diseases like systemic lupus erythematosus.
        So, it really is, again, another, I think, beautiful
    example of studying the fundamental, basic research on the
    immune system that is now being translated into therapies to
    suppress inappropriate immune responses.

                          COLLABORATION WITH INDUSTRY

        Senator Shelby. Dr. Collins, do you want to talk about any
    therapies that are coming along?
        Dr. Collins. I appreciate the chance to respond. I just
    want to mention one collaboration that's underway right now,
    which is actually quite groundbreaking and, I think,
    innovative. And that is something called the target validation
    consortium, which is a group that has come together between
    industry and NIH to try to identify amongst a wealth of new
    potential drug targets that have emerged from basic science
    studies, things like genomics and immunology, which are the
    ones that are actually going to work, because the industry
    wants to put their bets on something that's actually going to
    lead to a drug that's safe and effective.
        So, working with industry, we've identified four areas of
    great opportunity. One of them is autoimmune diseases--
    rheumatoid arthritis, lupus, Crohn's disease. The others are
    type 2 diabetes, Alzheimer's disease, and schizophrenia.
        And right now, we're in the midst of the design phase of
    this effort with 10 companies that have agreed to sign up. This
    is at the very high level with the companies in the design
    phase. And, if it looks promising in the next couple of months,
    we're likely to see a major new kind of collaborative effort
    where industry and NIH agree that this is actually open access,
    precompetitive information, we can all work on this together.
    Let's find the most appropriate targets and then turn industry
    loose to find that next generation of drugs.
        Senator Shelby. Thank you very much.
        Thank you, Mr. Chairman.
        Senator Harkin. Thank you, Senator.
        Senator Mikulski.
        Chairwoman Mikulski. Thank you.
        You know, if we just stuck with the A words, it would keep
    us all very busy for three lifetimes, from arthritis to
    Alzheimer's to allergies and so on.
        So it's great to hear both sides of the aisle talking about
    the same thing.
        I want to come back to Dr. Fauci.
        Senator Shelby, I was also going to raise the question of
    autoimmune. I'm glad that you did.

                        MULTIPLE DRUG-RESISTANT BACTERIA

        But I want to raise, Dr. Fauci, with you the superbug
    problem, because this is a significant issue. And I'd like to
    know where are we heading with our research? What are your
    thoughts and recommendations? Is it also recommendations that
    should be implemented in more quality initiatives in hospitals,
    like the Pronovost checklist?
        Could you share with us, because this is a really
    significant issue that we're hearing from both constituents and
    hospitals?
        Dr. Fauci. You're very correct, Madam Chairwoman, that the
    issue of multiple drug-resistant bacteria, and we'll just
    concentrate on them now as opposed to other types of resistant
    microbes, are a very important problem in the United States and
    worldwide, and a growing problem.
        If you look at the number, up to a million hospital-
    acquired infections, of which a rather substantial proportion
    of them are resistant to the standard drugs leading to the
    unnecessary deaths of people in the hospital. This is a major
    public health issue.
        There are two approaches to that. One is a public health
    approach, which really relates to some of the recommendations
    of our own Centers for Disease Control and Prevention, and the
    other is the basic research approach, which we at the NIH are
    taking.
        The public health approach is on things like isolation,
    identification of people when you transfer from one hospital to
    another to make sure you let people know that you're
    transferring somebody with a resistant microbe. You know, we
    had a problem at the NIH a-year-and-a-half ago that we luckily
    solved. One of the things we learned is that you have to make
    people aware of when you're dealing with a drug-resistant
    microbe in a patient. Washing hands, all kinds of isolation
    procedures.
        But the real core problem, that we've been intensively
    addressing over the last couple of years, is the lack of a
    really robust pipeline of new drugs that could take the place
    of the drugs that are now--to which the microbes are resistant.
        So, if you look at how things work with the NIH and how we
    interdigitate with industry, we generally do the fundamental
    basic concepts. We make the initial discovery, proof of
    principle, then maybe go into a phase I or maybe even a phase
    II trial. Whereas industry, which is responsible for making the
    product, generally meets us halfway or so.
        The risk, economically, for a company to invest a lot of
    money into the development of new antibiotics is such that we
    have to help what we call de-risk them. In other words, pushing
    the envelope closer to getting better understanding of
    mechanisms of drug resistance, how you can target on a microbe,
    new targets for drugs to make it easy for the company to get
    involved in providing us with this robust pipeline.
        I think that's going to be a very good approach, because
    we've actually just recently established a new clinical trial
    network for multiple drug resistant bacteria in our hospitals.
        So again, to reiterate, it's a very serious problem, and at
    the NIH, we're taking it very seriously.
        Chairwoman Mikulski. Well, first of all, that's promising
    to hear. And we also have to look at the role of the Centers
    for Disease Control and Prevention (CDC) here.
        I know, Mr. Chairman, you'll be holding a hearing on that
    in a matter of days.
        But, Dr. Collins, is that, I know it's not the--but is this
    the methodology you're talking about where you work with the
    industry on what, I used the term precompetitive, or whatever
    is the right legal term. But, really because there was so much
    risk in some of these areas, the private sector is not going to
    get into it, and we do create our own valley of death, because
    we don't go far enough. Is this one of those endeavors?
        Dr. Collins. You're quite right. The valley of death in
    this situation, that Tony was just describing, can be broad and
    yawning because the far side of it is even further away,
    because of companies' lack of really commercial motivation to
    get engaged.
        You develop a drug for highly resistant organism. People
    will say, you shouldn't use that drug, except in very specific
    circumstances. Otherwise, you'll use it up and it won't be any
    good anymore. So the market is very small.
        Chairwoman Mikulski. And people want cheap antibiotics,
    too.
        Let me get to another thing before my absolute time is up.
    I know you've talked about Alzheimer's and many issues.

                                     AUTISM

        I want to talk about autism, another A word. This is really
    another epidemic that has hit our family, our family of fellow
    Americans.
        Just about in every school, almost now in every extended
    family, there is a child facing one of the aspects of the
    spectrum of autism.
        Could you share with us where we're heading with research
    on this? Is this something we should also look at beefing up?
    Could you share with us where we are on this? Whoever is
    appropriate, for anyone.
        Dr. Collins. I'll say one sentence, and then ask Dr. Landis
    to say more.
        One area that is making progress is to understand genetic
    contributions to autism. We now think maybe 15 to 20 percent of
    cases are the result of new misspellings in DNA that were not
    present in either parent but appear in that child.
        Almost always that seems to be in a pathway that involves
    synapses in the brain. That seems to be the common thread here
    about what's wrong in autism. The connections between nerve
    cells aren't forming in the way that they normally should.
        But there's much more to say here.
        Dr. Landis. So, I think that is in fact one of the most
    promising avenues, and there are a number of genetic studies,
    which are looking at trios where the parents are normal and the
    child has autism, and using advanced genetic techniques,
    identifying the genes that affect the gene or genes
    responsible.
        What's particularly interesting is, as the number of genes
    go, just as Dr. Collins said, these are genes which act on the
    development of connections and the development of the synapses.
    Of most interest is the fact that the same genes are being
    identified in epilepsy and schizophrenia and a number of other
    neurodevelopmental disorders.
        It will be very important to figure out, first of all, what
    those mutations do to development, but also why the phenotype
    of patients, each of which has the same mutation, is so
    different. So, very interesting, very interesting clues.
        Dr. Collins. Just to quickly point out also that despite
    the advances in genetics, we know that's not at all the whole
    story. There must be profound influences that are based upon
    other environmental events, some of them probably happening
    during pregnancy. There's a great deal of intense effort to try
    to understand that as well.
        Chairwoman Mikulski. Thank you very much, and just thank
    you for what you do every day. Thank all the 18,000 people at
    NIH and the extramural people.
        Senator Harkin. Thank you, Senator.
        Senator Boozman.

                           INTER-AGENCY COLLABORATION

        Senator Boozman. Thank you, Mr. Chairman.
        Dr. Collins, I'd like to ask about, and really use two very
    different examples, about the ability of NIH to perhaps work
    with the other agencies.
        I'm on the Veterans Affairs Committee. Everybody at the
    panel here is very, very concerned about veteran suicide.
    They're working really hard to try and do something under a lot
    of pressure to perform.
        One of my concerns is the easiest thing to do, if you have
    a caseload that is bigger than you can handle, there is a
    tendency to overmedicate. I think that is a problem.
        But aside from that, again, the ability of your agency to
    come in, recognizing there is a problem. They're spending a lot
    of money in trying to solve the problem.
        If there's an effort that we could collaborate, and you all
    use the unique expertise that you have to help with that
    problem.
        The other thing is I was at the toxicological lab in Pine
    Bluff of the FDA. And another very differing example is the
    nanotechnology, which the FDA is concerned about, we're all
    concerned about. What really helped me grasp it was the fact,
    when you look up, you can think of infinite upness. With
    nanotechnology, you're really dealing with infinite smallness,
    which is amazing.
        And as you guys know better than anyone, as you get very
    small, then everything changes.
        But it is something that offers tremendous potential. One
    of these things that truly can change the world by helping us
    not use as much resources by better lubrication, things like
    that where things don't wear out, these conflict minerals and
    things.
        So is there the ability for you all to step in and help FDA
    deal with those kinds of problems and support the work at the
    toxicological lab?
        Dr. Collins. Senator, those are two terrific questions.
        With regard to suicide, I think all of us are deeply
    concerned to see what the rates are of suicide, especially in
    returning servicemen. We've been working, actually, closely
    with the Department of Defense in a program called Study To
    Access Risk and Resilience in Servicemembers (Army STARRS),
    which has enrolled more than 100,000 recruits, trying to
    identify what, if any, kind of warning signs have been missed
    in the past that could give us a better chance to intervene
    before suicide occurs.
        This is a close collaboration between our National
    Institute on Mental Health (NIMH) and the Department of
    Defense. And there is an interaction there also with the
    Department of Veterans Affairs (VA) because of their very
    strong interest in the same issue.
        With regard to your question about toxicology----
        Senator Boozman. I'm sorry, the next step again would be
    dealing with people that are actually at that point.
        Dr. Collins. Yes.
        Senator Boozman. That might be helpful also.
        Dr. Collins. Indeed. And of course, suicides are more
    common than homicides in this country, and there is a great
    deal of effort to try to understand ways to identify risks.
        Obviously, for people who have not been in the military, if
    you look at what are the risk factors for suicide, bipolar
    illness is a very major correlate, because when people with
    that condition go into a deep depression, that is often where
    the risk is highest.
        Senator Boozman. And heavily medicating in some cases makes
    it worse or better?
        Dr. Collins. I think the experience has been that proper
    medication, with Lithium and other efforts, can be lifesaving.
    Reading books by Kay Jamison, for instance, would emphasize
    that, as someone who has written about it and who has
    experienced it herself.
        But there are challenges in terms of getting it just right,
    and we are still working on new interventions that will be more
    effective than what's currently available, because most of the
    drugs have been around quite a long time, and it's time to see
    if we could find some new answers. This notion of working with
    industry to find new targets comes to mind.
        With regard to your question about toxicology and
    nanotechnology, Peggy Hamburg, who's the commissioner of the
    FDA and I jointly run a leadership council that tries to
    identify ways that our agencies can work closely together,
    particularly helping FDA with identifying new regulatory
    science opportunities, and FDA helping NIH identify areas where
    more science is needed and where our investigators can be
    better prepared to conduct trials that FDA can then review.
        Nanotechnology is a very interesting example, because there
    is a question about the safety of nanotechnology applications
    for human health. Given that this isn't exactly a simple area,
    all different particle sizes, all different kinds of compound
    constitution, NIEHS, the National Institute of Environmental
    Health Sciences, has a research program on this. And we are
    part of the National Nanotechnology Initiative.
        We mentioned earlier the BRAIN Initiative, trying to come
    up with ways that could sample these 86 billion neurons. If
    we're going to get anywhere near that, we're going to need
    nanotechnology tools to do so. So, it is very much an
    appropriate question. To be sure, we're working together.
        Senator Boozman. Thank you, and again, thanks for all you
    do.

                 NIH/CDC/FDA COLLABORATION ON H7N9 (AVIAN FLU)

        Senator Harkin. The last question Senator Mikulski asked, I
    think Dr. Fauci, the question about the superbugs. One last
    thing was that in meeting with Dr. Frieden of the Centers for
    Disease Control and Prevention a few days ago, talking about
    this new avian flu.
        You've been down that road before, Dr. Fauci.
        So, a new one has popped up. This one is known as H7N9, and
    there have been 131 confirmed cases by the World Health
    Organization (WHO), 32 deaths. There has been no evidence of
    sustained human-to-human transmission.
        But the problem is, as I understand it, that there is
    obviously a very high death rate, but the birds that are
    infected have no symptoms. And so again, how are you
    correlating research on this along with the CDC?
        Dr. Fauci. Thank you for that question. It's a very good
    example of very nice collaboration and coordination between the
    different agencies of HHS, not only CDC and NIH, but also FDA.
        So, where we are right now, there are actually 35 deaths.
    There were three deaths that were reported yesterday and today.
    So it's 131 cases and 35 deaths.
        We are approaching this exactly the same way as we
    approached the H5N1 that started in 2003 that we discussed
    before this committee many times that's still smoldering, as
    well as the 2009 H1N1 real pandemic that we had. That is
    virtually within days of noticing this, the virus was isolated,
    sequenced, sent to the CDC with the sequence, who are then, by
    reverse genetics, created what we call seed viruses for the
    development of a vaccine.
        A seed virus is a virus that we make that we can then
    distribute to the different pharmaceutical companies that we
    have contractual relationships with for our regular seasonal
    flu. They are already starting to make what we called pilot
    lots to determine whether or not we're going to be able to test
    these.
        The NIH, which is our main responsibility, has already
    developed and designed clinical protocols to test what is the
    right dose, do you need an adjuvant or not, do the doses differ
    between children, adults, elderly, and pregnant women. I've
    seen the trial designs and they are ready to go. As soon as the
    pilot lots are up, which will likely be by the end of June, the
    beginning of July, we'll start clinical trials.
        Now, we may not ever have to use the vaccine. But the
    important thing is, we'll get those lots, we'll know how to use
    it. So, if it does begin to have what you mentioned correctly,
    sustained human-to-human transmissibility, which it does not
    have right now, if it does, then we can scale up and have a
    vaccine available.
        We've also done many of the sequencing to look for genes
    that might predict whether it's sensitive or resistant to the
    neuraminidase inhibitors, the ones we commonly use, Tamiflu and
    Relenza. Fortunately, they appear to still be sensitive to
    those antivirals.

                          UNIVERSAL INFLUENZA VACCINE

        Dr. Collins. So, Tony, wouldn't it be great if you didn't
    have to do this every time a new strain appeared? Do you want
    to say something about progress to get a universal influenza
    vaccine, because that's quite exciting? We might not have to
    have this conversation in 10 or 15 years.
        Senator Harkin. How close are we to that?
        Dr. Fauci. Well, you know, I can't give you a time, but I
    can tell you we're clearly closer than we were a year or two
    ago, and let me explain why. Because, what Francis is alluding
    to, for people who didn't hear it, is the universal flu vaccine
    that you could actually give to someone and then it would be
    inducing protection against a wide range of influenza strains,
    from season to season, and even from pandemic to pandemic.
        What was discovered a few years ago by NIH grantees, that
    there's a part of the protein that's the main protein of
    influenza called hemagglutinin that is shielded from the immune
    system recognizing it.
        So, when you get infected, Mr. Chairman, or you get a
    vaccine every year, your body's immune system doesn't recognize
    a part of that protein that doesn't change from strain to
    strain. The part that changes is called, well it looks like a
    mushroom, it's got a head and it's got a stalk. The part that's
    the protective part is the head, and it changes from season to
    season. And when you have a pandemic, it changes a lot.
        So, if you make an immune response, you're good for that
    season, but you're not good for the next season when it
    changes. Whereas on the stalk of the hemagglutinin, there is a
    sequence, a particular protein, that doesn't change from flu to
    flu. So, we've now figured out a way, how to show the immune
    system that particular protein, so that it makes an immune
    response against it. We've now shown it in animals, mice,
    ferrets, and monkeys, that when you show them this protein,
    they make antibodies against the wide array of influenzas.
        We started phase I trials, showing that it's safe, and it
    induces a response. We're getting ready to go into a phase II
    trial.
        So, I can't give you a year when we're going to have it,
    but we're a heck of a lot closer than the last time you asked
    me that question.
        Senator Harkin. I had no idea of that. That's pretty
    encouraging. I mean, just think of the health implications.
        Dr. Fauci. That would be enormous.
        Senator Harkin. It would be huge.
        Dr. Fauci. Right.
        Senator Harkin. And the savings in illnesses, the
    hospitalizations, loss of work, my goodness, plus just knowing
    that you're safe against some of these pandemic flus.
        Dr. Fauci. And you could stockpile. See, that's the thing
    that we can't do. We're always in a yearly race. We find out
    what's going to be circulating, and we race to make a vaccine
    to be ready in the fall to give to people, so they can have it
    for the winter.
        If you have a universal flu vaccine that essentially covers
    it all, you can start making it right now for 2 years from now.
        Senator Harkin. Of course. Keep us informed.
        Dr. Fauci. I will.
        Senator Harkin. That's very encouraging. Especially if
    you've got something that you know dosage-wise you can do for
    children, adults, pregnant women, all the different types of
    people that need this type of a vaccine.
        Dr. Fauci. So, when you come to the NIH, we'll show you
    where it's done.
        Senator Harkin. I will, thank you. That's very encouraging.
        Senator Moran.

                    EXPERIENCED AND NEW INVESTIGATOR FUNDING

        Senator Moran. Mr. Chairman, thank you.
        Just a brief question, Dr. Collins. I'd like to have you
    assure me that there are actions in place that make certain
    that both well-established investigators are funded as well as
    incubator-type environments where young investigators can
    thrive and provide great breakthroughs.
        Dr. Collins. Of course, that's very important. It could
    hardly be more important.
        I think the most important resource we have is the talented
    scientists who do the work, and some of them are in mid-career
    and just incredibly at the top of their game, and others just
    getting started with vision and drive and energy.
        The sad story is that all of those groups are taking a hit
    right now. There's nobody getting protected.
        We do what we can, particularly with early stage
    investigators to be sure they have a chance to get started. So,
    we have them, in the way we do our peer review, compete against
    each other. The early stage investigators, they don't have to
    compete in the same pool as far as funding decisions with
    somebody who already has an established lab and a lot of
    preliminary data and a lot of publications, because we want to
    be sure that we're not disadvantaging our future, which are
    these folks that are just getting started.
        But there is no magic here when success rates have fallen
    for everybody to 15, 16 percent. I know we are losing
    significant talent all through the career range of the people
    that we support, from the young to the middle, to those who are
    basically in the cap of their career.

                   DECLINE IN THE NUMBER OF NEW INVESTIGATORS

        Senator Moran. You have the statistics--I've never seen you
    not be able to answer a question, so I know you have the
    statistics. Are the numbers of new applicants, individuals who
    have never applied, or organizations that have never applied
    for a grant, is that number changing?
        Dr. Collins. You know, I'm a little concerned to see that
    this year, the numbers seem to be dropping back a bit, and
    that's actually quite troubling. That begins to suggest that
    people are beginning to lose hope. And you can sort of see why.
        When investigators, with this success rate of 15 or 16
    percent, spend most of their time just writing a grant only to
    have it rejected, but then they'd better be writing another
    one, otherwise, their lab is going to close.
        They don't get to do science that much anymore. It's all
    about trying to find the funding from the Government, from
    foundations. I think, after a while, as people begin to burn
    out with that, perhaps we are seeing a fall off in the
    willingness to go through that experience over and over again
    only to see rejection.
        So, I am concerned, as one of the warning signs that the
    community is beginning to be sufficiently disheartened as we're
    going to lose people.
        We have lots of anecdotes about that. It's hard to collect
    precise data about exactly how many investigators have given
    up. We're in the process of trying to do that, but the
    anecdotes are sufficiently numerous that I'm deeply worried.
        Senator Moran. Well, Doctor, I would never contradict you,
    but I find this hearing always a place of hope. And it is one
    of the places within the halls of Congress in which, when you
    leave the hearing, you have a better outlook for what the
    future holds.
        And so I appreciate very much what you and your team, what
    the folks at NIH and those that you fund and support, provide
    something that America desperately needs, something called
    hope.
        And I just would encourage you to let Dina Faddah know that
    there is hope, and tell her that we all encourage her to pursue
    that career in research and science and medicine. And that
    while there's always challenges, the opportunity to provide
    hope to Americans, to provide hope to the world, it's worth the
    battle. And we look forward to being allies with her in that
    effort to see that hope continues.
        Dr. Collins. Senator, that's wonderful, and I will
    personally pass that word of encouragement to her.
        Senator Moran. Thank you.
        Senator Harkin. Thank you, Senator.
        Senator Shelby.

                                VETERAN SUICIDE

        Senator Shelby. I want to follow up on the troubling
    information we have about so many veterans committing suicide
    when they come back from Iraq or Afghanistan, and the
    devastation it does to the families, to the society and so
    forth.
        My question is this, I don't know if you have it, I don't
    know if the VA has it or DOD, but are there statistics, say,
    going back to the end of the Second World War, about the number
    of veterans coming back, the number of suicides per thousand,
    the Korean war, the Vietnam war, the conflict in Iraq and so
    forth. Because that would be very troubling, yes, but maybe
    informative, too, to a point.
        Do you know if they have those statistics, Doctor?
        Dr. Collins. I'm sure there are such statistics. I don't
    have them at my fingertips. And of course, one would have to
    look at the statistics with some caution in the fact that in
    the past, anyway, oftentimes suicides were not reported as
    suicide, because of the stigma attached to that. So, it could
    well be that one looks at those and it looks as if----
        Senator Shelby. That could be skewed.
        Dr. Collins. Yes, they would be skewed, particularly in the
    past and probably still in the present, where suicides, because
    they do carry for families----
        Senator Shelby. Soldiers go through this awful stress in
    combat.
        But as a society, we need to figure out how to prevent it,
    don't we?
        Dr. Collins. I totally agree with you. And again, I think
    if Dr. Tom Insel were on this panel, who is the director of the
    National Institute of Mental Health (NIMH), he would
    immediately put forward to you a number of things that our
    Mental Health Institute is trying to do in terms of identifying
    risk factors and interventions, figuring out how this fits
    together with things like traumatic brain injury and post-
    traumatic stress disorder (PTSD).
        Senator Shelby. Thank you very much.
        Thank you, Mr. Chairman.
        Dr. Landis. I think one of the differences between Iraq,
    Afghanistan, or in earlier wars are the improvised explosive
    devices with significant repeated mild traumatic brain injury.
    There's evidence that it's an invisible wound, and soldiers
    often don't recognize that this has been an issue and don't
    seek appropriate help.
        So, I think that the statistics for these wars might be
    different than previous wars.
        Senator Shelby. One added dimension, I just thought of it,
    because so many of our soldiers have had multiple tours--some
    volunteered, some didn't, in all this--which puts a lot of
    stress on them and their families.
        Maybe there are studies into that, too, say one tour, two
    tours, three tours, and dramatic effects.
        Dr. Collins. Yes, I'm quite sure that data has been looked
    at by the Department of Defense and is part of the effort as
    we're identifying risk factors in this STARRS study that ought
    to be looked at very carefully. And if there is some indication
    that the number of tours is a factor, obviously one would want
    to intervene in a prospective way to try to provide that kind
    of support that apparently is not currently sufficient.

                           FUNDING THE FUTURE OF NIH

        Senator Harkin. Thank you, Senator Shelby.
        Well, again I want to thank you all for your dedicated
    public service, your leadership in health.
        It's been my privilege and pleasure to have either chaired
    or been the ranking member of this subcommittee since 1989. So
    I worked with some of you for a long time.
        And every time we have you all up here for NIH, again, it's
    just again a reminder, I think to all of us, that there's just
    certain things we can't back down from. We made so many great
    strides in health research, keeping people healthy, their
    cancer rates. Everything else has been phenomenal, especially
    in childhood leukemia. It's been remarkable.
        And with the Human Genome Project, we now have some keys
    that we've never had before, the new technologies that we have
    that we can use now. It just seems that this is the time to
    redouble our efforts to increase significantly the funding for
    NIH.
        How do you do that? Well, there seems to be an attitude,
    I'm not saying anybody in particular, that we want something
    for nothing. If you want the best, it costs something, in terms
    of the best scientists, the best brains, the best technologies,
    the best equipment. We've always been the best in biomedical
    research in this country.
        I'm afraid that we are falling way behind, so we've got to
    find sources of funding.
        Back in the early 1990s, Senator Mark Hatfield was the
    chair of this committee. And I was ranking member at that time,
    and he was on this subcommittee. This was one of his devotions
    as it is Senator Mikulski's now.
        And we came up with a proposal. I don't know if it was his
    idea or my idea.
        But the basis of it was this, that when you buy a drug,
    when you go out to your pharmacy and you buy a drug today, some
    of that money goes for research. But when you buy a health
    insurance policy, none of that goes for health research.
        So our idea then, and this was about the time, I think,
    when we're working on the Clinton proposed health bill and
    stuff like that, we came up with a proposal, Hatfield and
    Harkin, and that was to have every health insurance policy that
    you would have a certain amount, percentage of each one that
    would then go to the NIH.
        It would come through this committee. And it was only just
    a few cents, a couple, 2 or 3 cents, I think, on the dollar.
        And then someone pointed out, well, but if you do that,
    then that would just supplant what you're doing on the
    discretionary money. So, okay, what we'll do is we'll say,
    okay, it will go into like a trust fund for NIH, but it can
    only be accessed as long as the Congress appropriates at a
    minimum what they did last year, plus an inflation factor.
        Dr. Fauci. That's a good idea.
        Senator Harkin. Well, yes, thank you.
        Well, we tried. We kind of pushed that along for a while.
    We got some pushback, obviously, from the health insurance
    industry, I understand that, and others.
        But then that whole thing sort of faded out and nothing was
    done on it.
        Now with this new healthcare system, Obamacare, coming
    along, there's going to be 35 million more people having health
    insurance policies in this country. Some of them subsidized by
    the Government, others not.
        I just wonder if it's not time. I ask my friends here to
    revisit this and to think about some new source of funding like
    that.
        Yes, the ultimate payer will always be that individual
    person out there, because their health insurance payment will
    go up a little, 2 or 3 cents on the dollar. But they'll have
    the satisfaction of knowing that little increase is going to go
    for only one thing. That's NIH research.
        It can't go anywhere else, and it can only go as long as
    Congress appropriates what we did last year plus an inflation
    factor.
        Somehow, we've got to come up with this funding. Anybody
    else got a better idea, the door is open. I am willing to look
    at anything. If anybody's got a better idea, let me know about
    it.
        Senator Shelby. Mr. Chairman?
        Senator Harkin. Yes.
        Senator Shelby. Did you do some work as to how much money
    that would raise?
        Senator Harkin. Oh, yes. It was quite significant.
        Senator Shelby. It would help a lot?
        Senator Harkin. Oh, big time. And it was just a couple of
    cents on the dollar, was all, when you think about it. And now
    we're going to have a lot more heath insurance policies out
    there.
        And I talked to some of my health insurance carriers, and
    we have a lot of health insurance carriers out there.
        Well, you know, I suppose they could live with it, but it
    wasn't high on their agenda. But again, it's just something I
    think we ought to roll around.
        And like I said, anybody else here in the audience or
    anybody else listening got any better ideas, let me know.
        But we've got to get more funding for NIH. We can't
    continue to go down this road. I got 20 months left here, 19
    months left here. I'd like to see this turned around.

                         ADDITIONAL COMMITTEE QUESTIONS

        Obviously, I'd like to see us start the doubling process
    again, but that won't happen. I understand that. But finding a
    new source of dedicated revenue that will be there and that we
    know will be there year after year after year, that's got to
    happen so that these young researchers, the one you're talking
    about, it's nice to give her a pat on the back and say follow
    your dreams. Yes, I back up what Jerry said on that.
        But there's got to be something there to make sure that
    those dreams are realizable, and that funding has to be there.
        So, yes. Then we need to go on, but I just think this is
    something we've just got to address.
        So the record will remain open for 7 days for additional
    statements or questions for the record.
        [The following questions were not asked at the hearing, but
    were submitted to the Department for response subsequent to the
    hearing:]
                 Questions Submitted to Dr. Francis S. Collins
                   Questions Submitted by Senator Tom Harkin

        Question. Dr. Collins, last month was the 10th anniversary of the
    completion of the Human Genome Project, which you led and, I'm happy to
    say, came in ahead of schedule and under budget. What have we learned
    from this effort and where are we going?
        Answer. To gain perspective about how the field of genomics has
    advanced since the Human Genome Project (HGP), it is illustrative to
    compare the ``state-of-the-art'' at the beginning of the HGP in 1990,
    at its completion in 2003, and now, in 2013. For instance, during the
    HGP, it took 6-8 years of active sequencing and approximately $1
    billion to generate that first reference sequence of the human genome.
    In 2003, that same feat would have still required 3-4 months and $10-50
    million. But today, a human genome can be sequenced in approximately 1-
    2 days for a mere $3-5 thousand. As the time and cost of human genome
    sequencing have plummeted, the power of genomic strategies and the
    volume of generated genomic data have increased profoundly.
        This capacity to generate more data through improved and less
    expensive technologies has enabled researchers to interrogate genome
    structure and function and learn how the genome contributes to health
    and disease. For example, in 1990, we knew of approximately 50 genes
    that, when mutated, caused a human disease; in 2003 that number was
    almost 1,500; and today, it is nearly 3,000. Further, knowledge about
    the genomic bases for our different responses to medications--an area
    of science called pharmacogenomics--also has grown steadily. In 1990,
    only four Food and Drug Administration (FDA)-approved drugs required
    labels that pointed out the relevance of a patient's genomic makeup for
    that medication; by 2003, that number had increased to 46; and today,
    it stands at 106. In fact, genomic contributions to medical research
    have been so substantial that fully half of ``Time'' magazine's ``Top
    10 Medical Breakthroughs in 2012'' reflected genomics accomplishments,
    and these were in large part supported and/or facilitated by National
    Human Genome Research Institute (NHGRI) research programs.
        During the last decade, building on the discoveries of the HGP, we
    have learned much more about how the genome functions and how genomes
    differ from person to person. For instance, in 2012, the ENCyclopedia
    of DNA Elements (ENCODE) project funded by NHGRI published a landmark
    series of papers reporting a catalog of functional elements within the
    human genome. The ENCODE catalog is like a GPS map for the human
    genome--just as by zooming in on a GPS map of the United States (to
    find the location of points of interests like banks and gas stations),
    the ENCODE catalog is now routinely used by researchers worldwide to
    zoom in on regions of interest in the human genome that are important
    for their studies.
        Meanwhile, the 1000 Genomes Project, funded in part by NHGRI, has
    led to a much greater understanding of the variation among human
    genomes. By sequencing the genomes of more than 2600 individuals from
    different populations across the world, the project is identifying
    patterns of variation between individuals and populations that will
    help advance understanding of the genetic factors contributing to many
    common diseases. To date, the 1000 Genomes Project data have been used
    in published research studies focused on autism, Alzheimer's disease,
    cancer, cardiovascular disease, and cirrhosis.
        The field of genomics is now focusing increasingly on the links
    between genomic variation and disease--and how that knowledge can be
    applied clinically. Genomic medicine is being used to advance certain
    medical specialties such as oncology, where genomics-based diagnostic
    methods are increasingly being used for cancer screening and for
    guiding treatment strategies. Examples include the widespread use of
    ``BRCA'' testing in patients with familial risk factors for breast and
    ovarian cancer, the use of testing to predict breast cancer recurrence,
    and the use of genomic diagnostic tests to determine the suitability of
    particular therapeutic treatments. Findings being generated through the
    work of The Cancer Genome Atlas--a research program co-funded by NHGRI
    and the National Cancer Institute--are confirming that cancers that
    appear to be morphologically similar can be separated into distinct
    subtypes based on genomic information, thereby informing the choice of
    therapies. Establishing the specific mutations that drive the growth of
    a patient's tumor can prevent the needless and costly use of harsh
    chemotherapeutic drugs that are ineffective for that tumor subtype.
    From less complex diagnostic tests that predict the effect of
    trastuzumab (Herceptin) use in breast cancer, vemurafenib (Zelboraf)
    use in melanoma, or crizotinib (Xalkori) use in lung cancer, to more
    advanced strategies of sequencing a tumor's mutated genome as a means
    to guide treatment, genomic medicine is becoming a powerful tool for
    guiding clinical care.
        Beyond cancer, genomics is also fueling major strides in other
    clinical areas. For instance, National Institutes of Health's (NIH)
    Intramural Undiagnosed Diseases Program applies genomic analyses to
    cases where a diagnosis has proven elusive to medical experts. To date,
    through the program, two new diseases have been discovered, and 50
    patients have received long-sought diagnoses. Similar approaches using
    genome sequencing to diagnose rare diseases have been used in Wisconsin
    (Nic Volker) \1\ and California (Noah and Alexis Beery),\2\ resulting
    in life-altering treatments for the affected patients. Beyond
    applications for disease identification or categorization, a promising
    study at Stanford University showed that DNA sequencing could be used
    to monitor organ transplant recipients non-invasively to detect early
    signs of rejection. Another study, also conducted at Stanford
    University, used genomics to screen a library of existing FDA-approved
    drugs to determine whether they might be repurposed for use in other
    diseases. Through this work, the possibility of repurposing an epilepsy
    drug for use in ulcerative colitis and Crohn's disease, and using an
    anti-ulcer drug to treat certain forms of lung cancer, has been
    highlighted.
        It is worth noting that although the primary aim of the HGP was to
    improve health, the project's effects have not, and will not, be
    confined to the clinic. A report by Battelle Technology Partnership
    Practice (Battelle) published in 2011 showed that the HGP has had a
    very positive impact on the United States economy.\3\ Specifically, the
    report estimates that between 1988 and 2010, Federal investment in
    genomic research generated an economic impact of $796 billion,
    particularly impressive considering that HGP spending between 1990 and
    2003 was only $3.8 billion. The report further found that in 2010, the
    genomic sector directly supported more than 51,000 jobs, indirectly
    supported more than 310,000 jobs, created $20 billion in personal
    income, added $67 billion to the United States economy, generated more
    than $3.7 billion in Federal taxes, and generated more than $2.3
    billion in State and local taxes. An updated report is being published
    by Battelle on June 12th.
    ---------------------------------------------------------------------------
        \1\ See: http://www.jsonline.com/features/health/111224104.html.
        \2\ Bainbridge MN et al. ``Sci. Trans. Med'', June 15, 2011 Whole-
    Genome Sequencing for Optimized Patient Management. http://
    www.ncbi.nlm.nih.gov/pubmed/21677200.
        \3\ Tripp, S. ``Economic Impact of the Human Genome Project''
    (Battelle Technology Partnership Practice: 2011).
    ---------------------------------------------------------------------------
        Question. Dr. Collins, a Council of Councils working group recently
    recommended that NIH retire all but 50 chimpanzees to a sanctuary, in
    response to an Institute of Medicine report on research involving
    chimpanzees. Are you likely to accept that recommendation? If not, why
    not? Are there any issues or road blocks to moving the chimpanzees?
        Answer. On January 22, 2013, a working group of the Council of
    Councils presented its report to the Council on the Use of Chimpanzees
    in NIH-Supported Research. The report recommended that, among other
    things, ``The majority of NIH-owned chimpanzees should be designated
    for retirement and transferred to the Federal sanctuary system'' and
    that ``A small population of chimpanzees [approximately 50] should be
    maintained for future potential research. . . .'' The same day, the
    Council of Councils accepted these and 26 additional Working Group
    recommendations, and transmitted them to NIH for consideration. NIH
    subsequently issued a request for comments and, after considering the
    public comments, accepted most of the Council recommendations on June
    26, 2013.
        With respect to the recommendation that advises that NIH retire the
    majority of NIH-owned chimpanzees, a vast majority of the commenters
    agreed with this recommendation. However, a number of commenters noted
    that the funding limits of the Chimpanzee Health Improvement
    Maintenance and Protection (CHIMP) Act of 2000 may affect the agency's
    decisions about retiring chimpanzees no longer needed for research. The
    CHIMP Act amended the Public Health Service Act to establish and
    maintain a system of sanctuaries for the lifetime care of chimpanzees
    that were used in research that the Health and Human Services (HHS)
    Secretary (through NIH) designates as no longer needed for research.
    Prior to accepting the Council recommendation, there were already 219
    chimpanzees living in, or were scheduled to be relocated to, the
    Federal sanctuary system. Three-hundred sixty (360) additional NIH-
    owned chimpanzees are not retired and reside outside the sanctuary
    system.
        Despite overwhelming public support to retire most NIH-owned
    chimpanzees, three issues need to be addressed before NIH could fully
    implement the recommendation to retire the majority of NIH-owned
    chimpanzees: (1) restrictions on funding levels in the CHIMP Act (often
    referred to as the cap), (2) lack of capacity in the Federal sanctuary
    system, and (3) limits in authority to manage the sanctuary system.

     FUNDING RESTRICTIONS IN THE CHIMPANZEE HEALTH IMPROVEMENT MAINTENANCE
                               AND PROTECTION ACT

        The CHIMP Act authorized HHS to establish the sanctuary system but
    includes a technical provision that currently limits the amount of its
    financial resources that HHS (through NIH) can provide for: (1) care
    and maintenance of the chimpanzees within the Federal sanctuary system;
    and (2) construction to establish the system. NIH believes that its
    authority to use appropriated monies to fund the Federal sanctuary
    system expires once the funds spent for the operation and establishment
    of the sanctuary system reach $30 million. As of February 2013, NIH had
    spent over $29 million in Federal funding on the sanctuary system and
    expects to reach $30 million early in fiscal year 2014. After that, HHS
    may lack the authority under the CHIMP Act to obligate additional
    funding to the Federal sanctuary system for care and maintenance of the
    chimpanzees within the Federal sanctuary system as well as future
    construction to expand the system. General Provision language has been
    proposed in the fiscal year 2014 President's budget request to remove
    this restriction.

                                    CAPACITY

        The agency agrees that the majority of chimpanzees that NIH owns
    could be eligible for retirement but additional capacity in the Federal
    sanctuary system is needed. Although the contractor (Chimp Haven, Inc.)
    that maintains the Federal sanctuary system plans to use private
    funding to construct additional space to house 110 chimpanzees from the
    New Iberia Research Center, these new areas will not be sufficient to
    accommodate the majority of NIH-owned chimpanzees that the Council
    recommended retiring. NIH is currently unable to support construction
    at the sanctuary due to funding restrictions in the CHIMP Act. Without
    additional construction or the authority to support such work
    financially, NIH understands that the Federal sanctuary system will be
    unable to accept additional chimpanzees until the current sanctuary
    population declines.

           LIMITS IN AUTHORITY TO MANAGE THE FEDERAL SANCTUARY SYSTEM

        NIH believes the CHIMP Act also limits the HHS Secretary's
    authority to expand the Federal sanctuary system by adding additional
    compliant retirement facilities. Currently, the system is composed of
    only one sanctuary that is now at capacity, but several facilities have
    approached the agency with an interest in accommodating retired
    chimpanzees. NIH would like to consider additional facilities to add to
    the system so long as they conform to CHIMP Act requirements and the
    implementing of sanctuary regulations.
        To add additional sanctuaries to the Federal system, the CHIMP Act
    requires the HHS Secretary to seek approval from the Board of Directors
    that oversees the nonprofit entity that runs the Federal sanctuary
    system. This provision, consequently, could limit the Secretary's
    ability to retire chimpanzees to other potentially compliant retirement
    facilities that could provide a cost savings or less expensive option.
    HHS believes it should be able to retire chimpanzees directly to other
    facilities if the Secretary determines the criteria in the law are met.
    We would like to point out that it would not incur additional costs to
    retire chimpanzees into an expanded sanctuary system. Funds to support
    their care in the research facilities could be transferred for their
    care in the sanctuary system. Alternatively research facilities could
    be modified to qualify for participation in the Federal sanctuary
    system. Although NIH agrees that the majority of its chimpanzees could
    be designated for retirement and transferred to the Federal sanctuary
    system, NIH is not in a position at this time to implement the
    recommendation.
                                     ______

                Questions Submitted by Senator Mary L. Landrieu

        Question. A year ago, our Nation adopted a National Plan that set
    as goal one treating and effectively preventing Alzheimer's disease by
    2025. This plan was required under the National Alzheimer's Project
    Act, bipartisan legislation approved unanimously by Congress in 2010.
    Achieving this goal will not be easy. In the past several months, at
    least three industry trials testing potential therapies for Alzheimer's
    have reported disappointing phase 3 study results.
        Based on what you know today, how confident are you that the Nation
    will achieve the 2025 goal of preventing and treating Alzheimer's
    disease?
        Answer. The identification and development of interventions that
    will prevent or treat Alzheimer's disease have proven to be extremely
    challenging, and it is still not possible to predict with certainty
    when an effective treatment or preventive intervention will be
    available. However, we have greater reason than ever before to be
    optimistic.
        Our efforts have been significantly advanced by recent
    breakthroughs in biomedical imaging that are enabling us to identify
    and track the earliest pathological stages of the disease process, long
    before clinical symptoms are apparent. These discoveries, in addition
    to discovery of other early biomarkers of the Alzheimer's disease
    process, have opened a ``window of opportunity'' for us to target and
    potentially reverse the disease's underlying pathology before
    cognitive, behavioral, and emotional symptoms appear. National
    Institutes of Health (NIH) has begun to launch its first such clinical
    trials in presymptomatic individuals. For example, in one high-profile
    study, investigators are studying whether an antibody treatment,
    crenezumab, which is designed to bind to and possibly clear away
    abnormal amounts of amyloid protein in the brains of people with
    Alzheimer's, can prevent decline in cognitive function. Crenezumab is
    being tested among members of a unique and large family population in
    Colombia sharing a genetic mutation known to cause observable signs of
    Alzheimer's disease at around age 45, along with a smaller number of
    U.S. participants ages 30 and older. We anticipate initial results from
    this groundbreaking study by 2017.
        NIH also supports more than 35 Alzheimer's disease clinical trials,
    including a number of studies of interventions to slow disease
    progression among individuals who are already showing symptoms. More
    than 40 compounds are currently under study to stimulate and advance
    research on the discovery and development of new preventive and
    therapeutic interventions for Alzheimer's disease (AD), mild cognitive
    impairment, and age-related cognitive decline.
        Question. What level of funding for Alzheimer's research at the NIH
    do you think is needed to maximize our chances of achieving this goal,
    and what other measures can our Nation take, recognizing these fiscally
    challenging times, to stop this disease?
        Answer. NIH has made one-time internal re-allocations to the
    Alzheimer's disease budget in fiscal year 2012 ($50 million) and fiscal
    year 2013 ($40 million) that have made it possible to develop new
    opportunities in critical priority areas. Sustained availability of
    funds, as indicated in the fiscal year 2014 President's budget request,
    would further facilitate targeted initiatives in high-priority research
    areas. Under the fiscal year 2014 President's budget request, NIH
    currently estimates it would spend a total of $562 million on
    Alzheimer's disease research.
        In the current challenging budget climate, we are continuing to
    take a number of steps to leverage our resources to the maximum extent
    possible. For example:
      --We have developed a rigorous and inclusive process for soliciting
            expert advice on research priorities, most notably through the
            May 2012 Alzheimer's Disease Research Summit, at which
            internationally recognized experts in the field met to
            formulate an integrated multidisciplinary research agenda that
            will accelerate the development of successful therapies for AD
            across the disease continuum. Summit participants also
            identified the types of resources/infrastructure and new public
            private partnerships that will be necessary to successfully
            implement this research agenda.
      --We have created the International Alzheimer's Disease Research
            Portfolio, a unique database of nationally/internationally
            funded AD research, which will enable organizations around the
            world to coordinate funding strategies and leverage resources
            in order to maximize the impact on public health and avoid
            duplication of effort and inefficiency.
      --We have conducted an in-depth analysis of the NIH Alzheimer's
            disease research portfolio and tied specific milestones to the
            goals of the National Plan to Address Alzheimer's Disease.
      --Where appropriate, we are coordinating efforts with private funders
            and advocacy organizations and actively pursuing public-private
            and international partnerships.
        Question. With respect to the level of funding at the NIH for
    Alzheimer's disease, I would like for you to address what appears to be
    an unacceptable gap between the growing costs of this disease to the
    Nation and the amount of our Federal investment. More than 5 million
    Americans are estimated to be suffering from Alzheimer's disease, a
    number that is expected to more than triple by 2050. If the prevalence
    and trajectory of the disease remains unchanged, the total costs
    associated with Alzheimer's disease will near or exceed $1 trillion
    annually by mid-century.
        Answer. In fiscal year 2012, the total NIH expenditure for
    Alzheimer's disease research was approximately $503 million, an
    increase of approximately $55 million, or 12 percent over fiscal year
    2011. This reflected a one-time $50 million increase allocated to NIH
    Alzheimer's research for fiscal year 2012. In fiscal year 2013, NIH is
    also allocating $40 million of funds within the Office of the
    Director's budget to Alzheimer's research. For the fiscal year 2014
    President's budget, NIH estimates it will spend a total of $562 million
    on research related to this disease.
        It is important to recognize that while Alzheimer's research
    continues to be of tremendous importance to NIH, it is one of a number
    of highly compelling priorities that include research on diabetes,
    heart disease, cancer, mental illness, as well as cross-cutting
    research affecting discovery in multiple disease areas. NIH maintains a
    careful, rigorous, and ongoing planning and priority-setting processes
    to ensure an appropriate balance of resources in basic, clinical, and
    translational research, with the ultimate goal of safeguarding the
    health and well-being of all Americans.
        Question. A recent RAND Corporation study published in the New
    England Journal of Medicine estimates that the direct healthcare costs
    associated with Alzheimer's disease are $109 billion annually,
    exceeding the direct care costs associated with cancer and heart
    disease. When costs of informal caregiving are factored in, annual
    costs of Alzheimer's and dementia skyrocket and are estimated today to
    be as high as $215 billion annually. Alzheimer's is the most expensive
    disease to American families and taxpayers--more expensive than HIV
    AIDS, Heart Disease and Cancer. Despite the recognized scope of this
    crisis, NIH is spending approximately $480 Million on Alzheimer's
    research
        How do you explain this disparity between the growing societal
    burden and economic threat posed by Alzheimer's and the very small
    investment we are making at the NIH in Alzheimer's research?
        Answer. In fiscal year 2012, the total NIH expenditure for
    Alzheimer's disease research was approximately $503 million, an
    increase of approximately $55 million over fiscal year 2011. This
    reflected a one-time $50 million increase allocated to NIH Alzheimer's
    research for fiscal year 2012. The National Institute on Aging (NIA)
    funded over $335 million in Alzheimer's disease research--approximately
    one third of the Institute's research budget. For the fiscal year 2014
    President's budget, NIH estimates it will spend a total of $562 million
    on research related to this disease.
        Alzheimer's research continues to be of tremendous importance to
    the NIH and the NIA. The number of individuals with Alzheimer's disease
    continues to increase, and our efforts to identify an intervention that
    will prevent or treat the disease have borne disappointing results.
    However, Alzheimer's disease is one of a number of highly compelling
    NIH priorities that include research on heart disease, cancer, mental
    illness, and diabetes, as well as cross-cutting research that informs
    discovery in multiple disease areas. Both NIH and NIA maintain careful,
    rigorous, and ongoing planning and priority-setting processes to ensure
    an appropriate balance of resources in basic, clinical, and
    translational research, with the ultimate goal of safeguarding the
    health and well-being of all Americans.
        Question.  Do you agree that Alzheimer's research deserves funding
    that begins to approach the scope of the problem it poses? If you agree
    that there is a problem here, please provide specifics on how you
    intend to address this vast disparity in funding within the authorities
    you have available to you today.
        Answer. In this challenging budget climate, we are continuing to
    take a number of steps to leverage our resources to the maximum extent
    possible. For example:
      --We have developed a rigorous and inclusive process for soliciting
            expert advice on research priorities, most notably through the
            May 2012 Alzheimer's Disease Research Summit, at which
            internationally recognized experts in the field met to
            formulate an integrated multidisciplinary research agenda that
            will accelerate the development of successful therapies for AD
            across the disease continuum. Summit participants also
            identified the types of resources/infrastructure and new public
            private partnerships that will be necessary to successfully
            implement this research agenda.
      --We have created the International Alzheimer's Disease Research
            Portfolio, a unique database of nationally/internationally
            funded AD research, which will enable organizations around the
            world to coordinate funding strategies and leverage resources
            in order to maximize the impact on public health and avoid
            duplication of effort and inefficiency.
      --We have conducted an in-depth analysis of the NIH Alzheimer's
            disease research portfolio and tied specific milestones to the
            goals of the National Plan to Address Alzheimer's Disease.
      --Where appropriate, we are coordinating efforts with private funders
            and advocacy organizations and actively pursuing public-private
            and international partnerships.
        Question. I have a longstanding interest in and commitment to
    improving the health of all Americans. The research activities at NIH
    play a critical role in this issue. The National Institute on Minority
    Health and Health Disparities (NIMHD) at NIH only has a budget of
    approximately $200 million, paling in comparison to other NIH
    Institutes and Centers (ICs) like Human Genome Institute with $500
    million or the National Cancer Institute at $5 billion. I stand for
    elimination of health disparities to be a national priority--and for it
    to be funded like one. The NIMHD's budget should be increased to
    fulfill this mission.
        As you know, the RCMI program within the NIMHD is responsible for
    developing and enhancing the research infrastructure of minority
    institutions and directly fosters the development of new generations of
    minority scientists. I am disappointed to see the nearly $6.5 million
    decrease from fiscal year 2012 funds being requested for the Research
    Centers in Minority Institutions program.
        Can you please tell me the rationale in the decreased funding for
    this important program?
        Answer. The Research Centers in Minority Institutions (RCMI)
    program provides resources for several critical areas of support for
    biomedical, clinical, behavioral, and social sciences research.
    Infrastructure development creates a foundation for the research
    enterprise through renovation/alteration of new research facilities and
    the development of specialized research support capabilities such as
    biomedical informatics and research design/biostatistics expertise.
    Activities under the RCMI program broaden the opportunities to conduct
    clinical and translational research through collaborative projects with
    an emphasis on improving minority health and reducing health
    disparities. In addition, instructive training and mentored research
    training experiences for early-stage investigators interested in health
    disparities research facilitate career advancement for junior faculty
    members.
        The RCMI program was transferred to NIMHD in fiscal year 2012 with
    the dissolution of the National Center for Research Resources (NCRR).
    At the NCRR, the RCMI program was one of the Center's main programs
    aimed at addressing minority health and health disparities. Consistent
    with its mission, the NIMHD's program portfolio is exclusively focused
    on improving minority health and eliminating health disparities.
    Integrating the RCMI program into the NIMHD has been a priority for the
    Institute over the past year. This integration means taking a strategic
    look at the Institute's priorities, plans, and the overall portfolio,
    with the goal of balancing our scientific research investments,
    particularly since the RCMI program is programmatically similar to
    other NIMHD congressionally mandated programs. In so doing, the NIMHD
    seeks to ensure that priorities, programs, and resources are
    appropriately aligned consistent with its mission, as well as the
    mission of the NIH; the changing pace of science and the health
    disparities environment; and that duplication in efforts are identified
    and reduced; therefore, a reduction in funding for the RCMI program and
    other NIMHD programs was proposed for fiscal year 2014. NIMHD is
    committed to the goals and objectives of the RCMI program, and to fully
    integrating the program into the Institute in a manner that fosters
    collaboration and partnership between RCMI and other NIMHD/NIH
    programs, and provide opportunities to enhance the program's
    contribution to the Institute's mission, as well as the health and
    well-being of the Nation.
        Question. The National Center for Advancing Translational Sciences
    (NCATS) mission includes a commitment to the behavioral sciences but I
    am concerned that the Center has not taken sufficient action to bring
    basic behavioral and psychological science discovery into new applied
    behavioral interventions. A stronger effort is critical to accelerate
    the translation of basic behavioral research discoveries into broadly
    disseminated new therapeutics and clinical care products and protocols,
    particularly in addressing substance abuse, suicide, depression, and
    similarly urgent public health issues confronting the Nation
        Answer. To bring the benefits of science more quickly into patient
    care, NCATS was formed with the mission to catalyze the generation of
    innovative methods and technologies that will enhance the development,
    testing, and implementation of diagnostics and therapeutics across a
    wide range of human diseases and conditions. NCATS' mission includes
    strengthening the entire spectrum of translational research--defined
    broadly to include the early steps necessary to develop new
    therapeutics, devices and diagnostics from basic discoveries, the steps
    necessary to establish real world efficacy, and the research needed to
    improve the practical implementation and dissemination of improved
    approaches to care.
        NCATS is committed to translating basic behavioral and
    psychological discovery into interventions that have a discernible
    impact on human health. These interventions can span the translational
    space of development of a therapeutic, preventive, or diagnostic or
    addressing the critical areas of implementation, dissemination, or
    adherence. New methods and technologies are needed in addressing
    behavioral and psychological interventions as well as greater
    integration of these approaches in all portions of the translational
    spectrum.
        Many Clinical and Translational Science Awards are already
    supporting investigators working in these areas through their study
    design and biostatistical, regulatory, and community engagement
    resources, as well as with pilot project funds for innovative
    approaches. For example, the National Institute on Drug Abuse (NIDA)
    Clinical Trials Network (CTN) provides an enterprise in which NIDA
    treatment researchers, and community-based service providers
    cooperatively develop, validate, refine, and deliver new treatment
    options to patients in Community Treatment Programs (CTPs). The NIDA
    CTN utilizes the resources of the CTSA program at many of its sites for
    their studies of new interventions for substance abuse and addiction.
                                     ______

                Questions Submitted by Senator Richard J. Durbin

        Question. Congenital heart disease (CHD) is one of the most
    prevalent birth defects in the United States and a leading cause of
    birth defect-associated infant mortality. Due to medical advancements
    more individuals with congenital heart defects are living into
    adulthood.
        The healthcare reform law included a provision, which I authored,
    that authorizes the Centers for Disease Control and Prevention (CDC) to
    expand surveillance and track the epidemiology of CHD across the life-
    course, with an emphasis on adults. The Consolidated Appropriations Act
    of 2012 provided the CDC with $2 million in new funding for enhanced
    CHD surveillance.
        Premature deaths across the life-span related to CHD are
    unacceptable, however recent data suggest that the number of infant
    deaths related to CHD is decreasing. Successful interventions in
    infancy and childhood are resulting in an aging population of
    congenital heart disease survivors. How is the National Institutes of
    Health (NIH) systematically responding to this new population of
    survivors reaching adolescence, adulthood, and advanced age? How are
    you utilizing adult congenital heart disease research experts in these
    efforts? How are you supporting adult CHD experts to grow the field? Is
    the NIH offering training grants to grow the field? Is the Pediatric
    Heart Network inclusive to adult CHD experts? Is your agency formally
    engaging adult populations in CHD research?
        Answer. The National Heart, Lung, and Blood Institute (NHLBI) is
    keenly aware of the medical and research needs of adults with
    congenital heart disease and is supporting a number of activities to
    meet these needs.
        The Pediatric Heart Network (PHN) is following a cohort of
    patients, now aged 13-27, who underwent a Fontan procedure, to correct
    a CHD, earlier in life. Assessments include family functioning, quality
    of life, neurodevelopment, and access to healthcare as children
    transition into adulthood.
        The Pediatric Cardiac Genomics Consortium (PCGC), whose goal is to
    understand the genetic basis of congenital heart disease and the
    contributions of genetics to individual patient outcomes, has enrolled
    more than 5000 patients with congenital heart disease, 20 percent of
    whom are adults.
        The Health, Education and Access Research Trial (HEART-ACHD),
    conducted with NHLBI support in partnership with the Adult Congenital
    Heart Association (ACHA) and the Alliance of Adult Research in
    Congenital Cardiology (AARCC), found that more than 40 percent of
    adults with congenital heart disease have a gap in cardiac care of over
    3 years, usually during the critical ``transition'' time from the
    teenage years into the early 20s. The study investigators also found
    that these patients responded well to educational interventions,
    resulting in improved knowledge about their conditions and also about
    research.
        The Research Empowerment for Adult Congenital Hearts (REACH)
    project, another ACHA-AARCC collaboration, received NHLBI American
    Recovery and Reinvestment Act (ARRA) funding to demonstrate the
    feasibility of a patient-centered research model for adults with
    congenital heart disease and employ electronic health record technology
    to create a national infrastructure for research.
        NHLBI has been exploring the use of global unique identifiers
    (GUIDs) to link information already collected in a number of different
    databases on persons with congenital heart disease. PCGC investigators,
    in collaboration with colleagues at the National Institute of Mental
    Health (NIMH) who developed the GUID software, have begun a pilot to
    assign GUIDs to enrolled patients. If successful, GUIDs will be rolled
    out to PHN studies and registries that enroll patients with congenital
    heart disease such as the Society for Thoracic Surgery Registry.
        NHLBI staff responsible for adult and pediatric cardiovascular
    disease research meet regularly with adult congenital heart disease
    experts and ACHA representatives to advise them about NIH research
    opportunities generally, discuss relevant NHLBI activities, and provide
    input into specific research proposals from the community.
        NHLBI supports several research training and career development
    programs that focus on various aspects of congenital heart disease in
    adults, including adherence to treatment and medical outcomes. The
    Institute recently developed a PHN Scholars award to fund small pilot
    studies and encourage young investigators to conduct research in
    congenital heart disease. One of the awards, titled ``The Clinical
    Significance of Abnormal Spirometry after the Fontan Procedure,'' will
    enroll adult participants in the PHN cohort study mentioned above. The
    young investigator's primary mentor directs the Boston Adult Congenital
    Heart Service.
        Question. In May of 2010, the National Cancer Institute (NCI)
    reported that the likelihood of being diagnosed with gastric cancer at
    age 25-39 years had increased by almost 70 percent since 1977. There
    are minimal symptoms of gastric cancer and it is most often diagnosed
    at a late stage when curative treatment is impossible. The American
    Cancer Society (ACS) estimates 21,600 new cases of gastric cancer will
    be diagnosed in 2013 and 10,990 people will die from the disease.
    According to the NCI, about 80 percent of people with stomach cancer
    are diagnosed with advanced metastatic cancer. At stage 4, the 5-year
    survival rate for gastric cancer is four percent.
        Please describe what investments are being made by the NCI to
    improve biomedical discoveries pertaining to gastric cancer. The Cancer
    Genome Atlas (TCGA) provides a rewarding opportunity to enhance our
    understanding of gastric cancer through genomic data. What steps is the
    NCI taking to ensure TCGA data are utilized for gastric research?
    Further, what steps is the NCI taking to assist gastric cancer
    researchers in utilizing the TCGA data to translate promising data from
    the research bench to patient bedsides?
        Answer. Most gastric cancers arise from the gastric epithelium and
    are classified as adenocarcinomas. These are divided into two types,
    the intestinal type, which develops in the antrum and is usually well-
    differentiated, and the diffuse type, which develops in the body of the
    stomach, is poorly differentiated, and usually has a poorer prognosis
    than the intestinal type. Gastric cancer does not appear to be
    hereditary in most patients. However, a few with the diffuse type have
    a hereditary form, arising from an inherited mutation in the E cadherin
    gene, which encodes a protein that helps the epithelial cells stick
    together. Most cases of gastric cancer are attributable to infection
    with the bacterium ``Helicobacter pylori (H. pylori)'', and
    progressively stronger evidence suggests that early antibiotic
    treatment of this common infection in high-risk patients can reduce the
    risk of developing this cancer.
        The expected frequency of gastric cancer in 2013 actually
    represents a substantial decrease compared to 80 years ago. Since 1930,
    the incidence and mortality from this cancer have decreased by more
    than 80 percent. The rates continued to decline during the first decade
    of the 21st century, according to the 2013 Annual Report to the Nation
    on the status of cancer, a joint effort of the American Cancer Society,
    the Centers for Disease Control and Prevention, and the NCI. The report
    also notes that during this decade, the incidence of gastric cancer
    decreased about 15 percent for men (who account for about 60percent of
    cases) and a little under 10 percent for women, while its mortality
    rate decreased even faster, by more than 30 percent for men and more
    than 25 percent for women. Nevertheless, gastric cancer remains a
    formidable disease, with most advanced cases having a poor prognosis.
    The NCI has more than 80 research projects devoted at least in part to
    gastric cancer. Several other NIH Institutes, especially the National
    Institute of Allergy and Infectious Disease (NIAID) and the National
    Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), also
    support research in this area, with emphasis on ``H. pylori''.
        Gastric cancer is one of the cancers being studied by The Cancer
    Genome Atlas (TCGA), which is a joint research effort of the NCI and
    the National Human Genome Research Institute. TCGA is expected to have
    a major impact on our understanding of the genetic and epigenetic
    changes associated with more than 30 cancer types being studied in
    unprecedented detail in this initiative. Tumor tissues from
    approximately 325 cases have been collected to date and are being
    analyzed. Data is expected to be available next year.
        In general, TCGA data is being used to refine the diagnosis of
    cancer, to define and delineate both the heterogeneity and the common
    features of various cancer types, and to elucidate the molecular
    pathways that control the malignant behavior of cancer cells, with the
    long-term goal of improving the outlook for cancer patients. These data
    are available to qualified researchers through public databases
    designed to protect patient privacy. The TCGA team provides extensive
    support to researchers accessing TCGA data, including step-by-step
    protocols for how to apply and locate TCGA data, as well as preliminary
    data analysis to those not able to manipulate the raw data. The
    availability and broad utilization of the TCGA data are demonstrated by
    the number of publications using TCGA data (to date, already close to
    400) and the number of grant applications that include TCGA data (to
    date, more than 800). TCGA works with investigators and other
    components of NCI to help apply findings from TCGA to the development
    of new diagnostics and therapeutics.
        The era of targeted treatment of gastric cancer, with research
    support from the NCI, has begun even before the TCGA data on this
    cancer become available. One recurring therapeutically relevant theme
    in cancer is that abnormalities in one tumor type may also be found in
    other tumor types. In this context, the protein encoded by the ErbB2
    gene, which was found initially to be effectively targeted in breast
    cancer by a specific monoclonal antibody, trastuzumab, has also been
    found to be overexpressed in some gastric cancers; treatment of these
    patients with trastuzumab, in conjunction with standard chemotherapy,
    can increase their overall survival, which has led to its approval by
    the FDA for the treatment of gastric cancer. Encouraging preliminary
    results in gastric cancer have also been seen with therapy directed
    against other molecular targets, such as epidermal growth factor
    receptor (EGFR) and vascular endothelial growth factor (VEGF).
        Prevention is another important NCI-supported area. Research on
    ``H. pylori'' has provided insight into the observed differences in
    oncogenicity among different strains of the bacterium. These basic
    research findings have clinical implications, as they can identify
    those patients most likely to benefit from eradication of their ``H.
    pylori'' with antibiotics.
        We anticipate that the detailed information from TCGA and other
    research from NCI-sponsored grants will bring new information about the
    causes of gastric cancer and its pathogenesis, and will identify new
    molecular targets, leading to continued progress in our efforts to
    fight this cancer.
        Question. In fiscal year 2013 alone, sequestration threatens to cut
    the NIH's $30.7 billion budget by almost $1.6 billion. This reduction
    in funding jeopardizes NIH's ability to invest in biomedical research
    and slows the pace of discoveries. Please summarize the impact of
    sequestration on NIH's ability to award grants and support the training
    and education of scientists. Please describe the impact of
    sequestration on biomedical innovation and how the cuts in funding may
    impact patients currently enrolled in clinical trials. Are you aware of
    reports quantifying the ripple effect sequestration has on biomedical
    research, biotechnology industries, and economic development in the
    United States?
        Answer. Sequestration requires NIH to cut 5 percent or $1.55
    billion of its fiscal year 2013 budget. NIH must apply the cut evenly
    across all programs, projects, and activities (PPAs), which are
    primarily NIH institutes and centers. This means every area of medical
    research will be affected. Compared to fiscal year 2012, NIH expects to
    issue approximately 700 fewer competitive research project grants and
    admit approximately 750 fewer new patients to the NIH Clinical Center.
    In addition, NIH will not increase training stipends for National
    Research Service Award recipients in fiscal year 2013. While much of
    these decreases are due to sequester, NIH funding is always a dynamic
    situation with multiple drivers.
        The reductions imposed under sequestration have, and will continue
    to have a negative impact on biomedical innovation and the training and
    education of young scientists. Medical breakthroughs do not happen
    overnight. In almost all instances, breakthrough discoveries result
    from years of incremental research to understand how disease starts and
    progresses. Even after the cause and potential drug target of a disease
    is discovered, it takes on average 13 years and $1 billion to develop a
    treatment for that target. NIH is aware that its research funding
    directly supports hundreds of thousands of American jobs and serves as
    a foundation for the medical innovation sector, which employs 1 million
    U.S. citizens. Cuts to NIH funding will have an economic impact in
    communities throughout the U.S.
        For additional details on the impact of sequestration see: http://
    www.nih.gov/news/health/jun2013/nih-03.htm
                                     ______

                    Questions Submitted by Senator Jack Reed

        Question. The Congressional Budget Justification for the National
    Institute of Child Health and Human Development highlights the National
    Children's Study as an ``unprecedented opportunity'' to examine factors
    that affect child health and development. However, the research
    community continues to raise concerns with the major changes to the
    design of this landmark study proposed by the National Institutes of
    Health (NIH).
        The NIH is supposed to have a contract in place with the IOM to
    review the Vanguard Study and new proposals by the end of May. Has that
    contract been signed?
        Answer. The fully executed Task Order for the contract with the
    Institute of Medicine (IOM) to review the study design for the National
    Children's Study (NCS) Main Study was signed on May 28, 2013. The
    period of performance for the contract began June 3, 2013.
        Question. What process are you developing in anticipation of the
    final report next year in order to incorporate the recommendations from
    the IOM into the methodology for carrying out the Main Study?
        Answer. All procurements related to data collection for the Main
    Study are delayed until after the IOM report is released. The content
    of those solicitations will be based on the recommendations of the IOM
    panel, and guided by ongoing public discussions with the NCS Federal
    Advisory Committee, the Independent Study Monitoring and Oversight
    Committee, and the Federal Consortium. These groups will meet within
    the month following the projected public posting of the IOM report in
    June 2014. The NIH will integrate the IOM recommendations with input
    from the advisory committees to construct the NCS Main Study, including
    the Study's methodologies and implementation plan. New solicitations
    based on the updated design, methodologies, and implementation plan
    will be published at least 60 days following the release of the IOM
    report.
        Question. Presuming the data already collected could be useful,
    will researchers have access to the data already collected while the
    IOM conducts its study? Could NIH provide grants through other programs
    to use the data that the Federal government already spent $1 billion to
    collect?
        Answer. Qualified researchers, whether or not they are directly
    associated with the NCS, already have access to the Study data, and
    will throughout the course of the Study. While we anticipate that many
    NIH Institutes and Centers may choose to support grants that utilize
    NCS data and samples, access to NCS data and samples will not require
    such grants.
        Question. I understand that NIH is currently engaged in an internal
    process to evaluate how it tracks research data on age, gender, race,
    and other patient identifiers. What is the timeline for completing this
    process?
        Answer. In 2010, the NIH Principal Deputy Director convened an
    internal task force to evaluate the policies and procedures related to
    the inclusion of women, minorities, and children. Among the outcomes of
    the task force was the formation of a new Subcommittee on Inclusion
    Governance (SIG) in November 2011, co-chaired by Dr. Janine Austin
    Clayton, Associate Director for Women's Health, and Dr. Alan
    Guttmacher, Director, ``Eunice Kennedy Shriver'' National Institute of
    Child Health and Human Development.
        With input from the task force, the SIG is taking a comprehensive
    look at the NIH policies regarding the inclusion of women, minorities,
    children, and other population groups in clinical research and clinical
    trials. The SIG has reaffirmed that the primary goal of NIH inclusion
    policies is not enumeration, but rather to ensure that the distribution
    of participants in clinical research reflects the population(s) needed
    to accomplish the scientific goals of the study. Investigators,
    reviewers, and NIH staff all have key roles to play in implementing and
    monitoring the policies.
        Data collection on the basis of sex/gender, race, and ethnicity is
    currently being re-engineered to streamline and simplify the processes
    and align better with the electronic grant application procedure. We
    anticipate the new system will be deployed in mid-late 2014. With
    respect to age, the governance committee is examining how information
    about age is provided by grant applicants, reviewed during the peer
    review process, monitored during the period that the study is carried
    out, and captured by internal NIH systems. In addition, the
    subcommittee is analyzing the NIH pediatric portfolio to determine
    what, if any, modifications may be needed to ensure the inclusion of
    women, minorities, and children in NIH clinical research.
        Question. The National Institute of Child Health and Human
    Development (NICHD) conducts the majority of pediatric research among
    all of the Institutes, but a substantial portion of the research
    relevant to children occurs in the Institutes across NIH. For research
    projects that are not designed specifically for children--but could
    possibly be relevant to children--how does NIH work with investigators
    to determine the appropriate participation of children?
        Answer. While the NICHD does support a plurality of the pediatric
    research funded by the NIH, nearly every NIH Institute and Center (IC)
    reports annual support for pediatric research. This support comprises
    new and continuing investigator-initiated pediatric research projects,
    and projects funded under Funding Opportunity Announcements. These
    projects are coded using NIH's Research, Condition, and Disease
    Categorization process, a computerized tool that allows the NIH to
    provide consistent and transparent information to the public, providing
    a list for each fiscal year of all NIH-funded projects related to a
    specific research category:
    http://report.nih.gov/rcdc/. If a given project is sufficiently related
    to an area of pediatric research, it will be included in the Pediatric
    Research category.
        NIH also supports a range of mechanisms to foster pediatric
    research training and career development, and an active pediatric
    research loan repayment program, which enables qualified health
    professionals who commit to conducting pediatric research for at least
    2 years to receive a substantial repayment of their educational loans.
    These programs signal to the research community the importance of
    pediatric research and the commitment of the NIH to fostering this area
    of science.
        On a more individual basis, the NIH peer review process helps
    researchers to refine and clarify the goals of their research
    applications or proposals. Reviewers can be helpful in providing
    guidance to applicants who wish to conduct clinical research, including
    whether their proposed research includes adequate numbers of
    individuals from affected populations. Researchers whose projects
    receive funding then work with NIH program officials during the entire
    course of the grant or contract, reporting on their progress annually
    and receiving input from those officials about whether their aims are
    being successfully met.
        Question. What more could NIH be doing to support investigators in
    pediatric enrollment in their research studies and clinical trials?
        Answer. NIH is committed to ensuring that children participate in
    the full range of NIH research. In fiscal year 2012, NIH pediatric
    research funding totaled approximately $3.6 billion, including studies
    in pediatric patients conducted in NIH's intramural research program at
    the Clinical Center in Bethesda, MD. NIH supports nearly 100
    multidisciplinary center and network programs focused on children's
    health needs. These include the Autism Centers of Excellence, the Paul
    D. Wellstone Muscular Dystrophy Cooperative Research Centers, and the
    Children's Oncology Group. NIH's Office of Rare Diseases Research and
    several NIH Institutes and Centers fund the Rare Diseases Clinical
    Research Network to facilitate collaboration among experts in many
    different types of rare diseases. NIH works with the FDA to administer
    the Best Pharmaceuticals for Children Act to support and coordinate
    pediatric pharmacology research, with the goal of increasing the dosage
    and efficacy information available about therapeutics used by children.
    The 60 centers that comprise NIH's Clinical and Translational Sciences
    Awards include substantial pediatric expertise.
        NIH reviews and awards these and other networks and centers
    programs on a regular basis, usually at about 5-year intervals,
    ensuring that they are productive and continue to produce the best
    science. For example, during the coming year, the NIH will post a
    funding opportunity announcement seeking applications for sites to
    participate in the ongoing Collaborative Pediatric Critical Care
    Research Network, which provides the infrastructure to pursue rigorous
    clinical trials and other studies in pediatric critical care medicine.
    The eight currently funded sites include pediatric expertise in
    pulmonology, cardiology, nursing, and other disciplines essential to
    children's health.
                                     ______

                   Questions Submitted by Senator Jon Tester

        Question. Most of the research programs that receive NIH research
    grants are affiliated with an institution of higher education. I
    encourage you to support non-University and non-hospital affiliated
    research institutions throughout the country, and in particular to
    focus on those located in rural America. Academic and non-profit
    institutions based in rural States consistently receive less funding
    from the NIH. This oversight is compounded when their work is
    overlooked by other researchers, regardless of the quality of their
    science.
        Due to a lack of higher education or medical facility affiliation,
    outstanding research institutions in rural areas often struggle to
    obtain research support and funding. I am concerned that the bias
    towards researchers with affiliations is short-sighted and overlooks
    quality research being done by nimble, independent institutes.
        In 2012, the NIH received 63,524 research grant applications. How
    many of those grant applications were from facilities and researchers
    not affiliated with an institution of higher education? How many of the
    grants ultimately awarded went to independent small research
    institutions?
        Answer. In fiscal year 2012, more than 18,500 applications were
    submitted by organizations that were not institutions of higher
    learning. Approximately 4,600 of these applications were submitted by
    nonprofit independent research organizations, and approximately 800 of
    the applications submitted by nonprofit independent research
    organizations were awarded grants. Independent research organizations
    have a success rate that is comparable to those of research hospitals
    and institutions of higher learning.
        Question. How do the sequestration cuts further impact the ability
    of small research institutions' access to grants? What steps is the NIH
    taking to mitigate this issue and ensure that smaller institutions can
    compete with larger institutions?
        Answer. NIH's post-sequestration fiscal policy applies similar
    reductions in funding to all organizations regardless of institution
    size or type. Investigators from all types of organizations, including
    small academic institutions and research organizations, often develop
    collaborations with research personnel at large institutions to gain
    access to resources that would not otherwise be available to them. NIH
    encourages these collaborations and works to ensure access to research
    resources and technologies among its grantees through its sharing
    policies (http://grants.nih.gov/grants/sharing.htm)
        In addition, the Academic Research Enhancement Award (AREA) grant
    program supports small-scale research projects in the biomedical and
    behavioral sciences conducted by faculty and students at educational
    institutions that have not been major recipients of NIH research grant
    funds. Eligible institutions are institutions of higher education that
    do not receive more than $6 million per year in NIH support in each of
    four of the last 7 years. NIH remains committed to the AREA grant
    program in the face of budget restrictions.
                                     ______

                 Questions Submitted by Senator Jeanne Shaheen

        Question. Diabetes and its complications significantly impacts our
    Nation's health and economy. In fact, new estimates show that the
    disease costs our Nation $245 billion annually, a 41-percent increase
    from 2007. It is the number one cause of end-stage renal disease
    (ESRD), which is the largest driver of Medicare costs at $29 billion in
    Medicare in 2009.
        I understand that tight blood sugar control can cut in half the
    incidence of ESRD and could save Medicare over $126 billion in 25
    years. Given this personal and economic toll on our Nation, how is
    National Institutes of Health (NIH) prioritizing diabetic kidney
    disease? What, if any, are some new insights into the prevention and
    treatment in the area of kidney disease?
        Answer. There is no known way to restore kidney function once it is
    lost, but treatment can usually slow or prevent degradation of kidney
    function if diabetic kidney disease is detected early. Therefore,
    prevention and early detection of kidney disease are important research
    priorities. At the NIH, the Institute with the primary responsibility
    for supporting research related to diabetes and kidney disease is the
    National Institute of Diabetes and Digestive and Kidney Diseases
    (NIDDK), and many of the research efforts included below have been
    supported by this Institute.
        The NIDDK's Diabetes Control and Complications Trial showed that
    intensive blood glucose control reduces risk of complications of the
    kidneys, eyes, and nerves of people with relatively recent onset type 1
    diabetes; the U.K. Prospective Diabetes Trial established that careful
    blood glucose control provides similar benefit to people with recent
    onset type 2 diabetes. The NIDDK's Diabetes Prevention Program clinical
    trial moved that prevention effort one step earlier, even before the
    onset of diabetes. It found that people at risk of developing type 2
    diabetes can prevent or delay disease onset and improve their blood
    sugar through an intensive diet and exercise intervention, or, to a
    lesser degree, with the diabetes drug metformin. In cases where people
    receiving the lifestyle intervention actually progressed to develop
    type 2 diabetes anyway, their diabetes was found to be easier to
    control, and to confer a lower risk for complications.
        Despite these efforts to proactively and aggressively manage
    diabetes, the risk for end-stage renal disease (ESRD) in patients with
    chronic kidney disease (CKD) associated with diabetes remains high.
    Moreover, among the larger population of people with CKD who have not
    progressed to ESRD, cardiovascular disease poses a significant burden.
    The NIDDK's Chronic Renal Insufficiency Cohort (CRIC) Study, which
    started in 2001, is a prospective observational cohort study of
    approximately 4,000 men and women and is the largest cohort study of
    CKD yet undertaken. The objectives of the Chronic Renal Insufficiency
    Cohort (CRIC) Study are to improve understanding of the relationship
    between CKD disease and cardiovascular disease and to examine
    traditional and non-traditional risk factors for progression of these
    diseases. An emphasis was placed on recruiting participants at high
    risk for ESRD, including persons with diabetes (about one-half of the
    study participants), African Americans (also about one-half of the
    study participants) and Hispanic Americans. Important scientific
    findings are emerging from this study. For example, fibroblast growth
    factor 23 (FGF-23) is a growth factor that regulates phosphate
    metabolism. Elevated FGF-23 was shown to be an independent predictor of
    risk for ESRD in patients with relatively well-preserved kidney
    function. FGF-23 may turn out to be a useful biomarker to predict risk
    of adverse outcomes in patients with CKD. In a separate study,
    increased levels of FGF-23 were associated with an indicator of
    cardiovascular disease. CRIC Study investigators have also found a
    strong association between eye disease and levels of kidney function,
    suggesting that eye disease may reflect underlying CKD. In addition,
    the increased burden of cardiovascular disease in Hispanic Americans
    with CKD has been documented. These and other findings from the CRIC
    Study in the coming years are expected to inform clinical trials and
    clinical management practices to reduce the burden of ESRD in the U.S.
        The NIH is also seeking to improve the translation and
    implementation of treatment approaches to kidney disease and diabetes
    in a real-world setting. This research seeks to identify factors that
    lead to the adoption, maintenance, and sustainability of science-based
    interventions at the practice level, where they can have an immediate
    impact on patients' lives, such as improving blood pressure control,
    improving laboratory measures of metabolic control or nutritional
    status, and/or changes in kidney function. Looking forward, the NIH
    recently asked the community to identify research objectives that would
    improve our understanding of basic kidney function and aid in the
    prevention and treatment of impaired kidney function and prevention of
    progression to ESRD, welcoming interested parties to submit, discuss,
    and prioritize ideas via an interactive Web site. The approaches
    identified may aid in the discovery of new therapies, the
    identification of regulatory pathways, the generation of animal models
    for preclinical work, and the development biomarkers with clinical
    utility so that diabetic kidney disease patient outcomes can be
    improved.
        Question. Over the past few years, I have been concerned that the
    level of funding for NIDDK in the President's budget proposals has not
    kept pace with the rate of biomedical inflation and the growing
    diabetes epidemic, threatening the ability of NIDDK to continue to make
    progress on promising diabetes research.
        Would you please share the percentage of grants that NIDDK has been
    able to fund over the past 2 years and how this will affect grants/
    research going forward?
        Answer. In fiscal year 2011 and fiscal year 2012, the National
    Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) used 81
    and 80 percent of its regular appropriations, respectively, to fund new
    and continuing grants supporting the biomedical research enterprise at
    sites around the country. This support includes research project
    grants, research centers, careers, other types of research support, and
    research training awards for individuals and institutions. In those two
    fiscal years, the NIDDK sustained a success rate for funding research
    project grants--which receive the majority share of grant funding--of
    21 and 20 percent, respectively. These data reflect a combined success
    rate for funding research project grants supported by the NIDDK's
    regular appropriation and the Special Statutory Funding Program for
    Type 1 Diabetes Research. The success rate is defined as the percentage
    of reviewed grant applications that receive funding, and is calculated
    for the fiscal year. In fiscal year 2013, we expect that the success
    rate will decline somewhat due to the loss of funds through
    sequestration. At the President's budget request level for fiscal year
    2014, the NIDDK anticipates a success rate for funding research project
    grants of 22 percent. These relatively stable success rates for
    research funding are enabling NIDDK to continue to foster progress and
    new advances in diabetes.
        Question. Would you also please share how the Administration plans
    to ensure that there is a strong investment in the NIDDK in fiscal year
    2014 that will lead to breakthrough discoveries and ultimately a cure
    of diabetes?
        Answer. The President's fiscal year 2014 budget request reflects a
    strong commitment of the NIDDK to support research tackling diabetes
    and its devastating health and economic consequences. For example, the
    funds requested for fiscal year 2014 will enable the NIDDK to continue
    major diabetes clinical trials, such as a recently launched multicenter
    study of the comparative effectiveness of four common drugs used for
    treating type 2 diabetes, and a new trial testing vitamin D for type 2
    diabetes prevention. The fiscal year 2014 budget request will also
    enable NIDDK to pursue emerging opportunities in the study of diabetes
    risk genes in minority populations, which could lead to new therapeutic
    approaches. These resources will also support NIDDK's plans for
    research that can lead us to personalized medicine for diabetes--for
    example, the Institute plans to support research to elucidate how an
    individual's genetic makeup affects his or her response to anti-
    diabetic medications, such as metformin. Under the President's budget
    request, the NIDDK will continue to fund translational research in
    fiscal year 2014 and support health information dissemination
    activities to bring scientific discoveries in diabetes to real-world
    medical practice and other community settings. NIDDK plans for fiscal
    year 2014 also include advancing research on brown fat--an exciting new
    area of study with therapeutic potential--and moving forward with major
    studies of gestational diabetes. Moreover, the NIDDK investment in
    diabetes research is augmented by the research activities of the many
    NIH Institutes, Centers, and Offices with an interest in diabetes and
    its complications, which will also continue in fiscal year 2014. All
    these efforts will be further enhanced by fiscal year 2014 mandatory
    funds from the Special Statutory Funding Program for Type 1 Diabetes
    Research, and the NIDDK will convene an expert panel on June 6-7, 2013,
    to obtain external scientific and lay input on future research
    directions to be pursued with these funds.
        Our plans for fiscal year 2014 are contingent upon Congressional
    action, but we are hopeful that the fiscal year 2014 investment in
    diabetes research, spearheaded by NIDDK, will continue to lead us
    toward new discoveries, new therapies, and possibly cures for diabetes.
                                     ______

                   Questions Submitted by Senator Jerry Moran

        Question. As a follow-up to my questions at the hearing on the
    Brain Research through Advancing Innovative Neurotechnologies (BRAIN)
    Initiative, I understand that the National Institutes of Health (NIH)
    is currently working on a scientific plan for this program. However, I
    remain concerned that we have no details on how much funding would need
    to be provided in the coming years. Could you please provide the
    subcommittee a 10-year budget estimation, both for the overall mapping
    project and NIH's share in particular.
        Answer. It will be imperative that cost estimates be strongly
    informed by a rigorous scientific planning process. NIH has charged a
    high-level advisory group with developing a plan for the NIH BRAIN
    Initiative, which is to include timetables, milestones, and cost
    estimates. As part of this process, members will consult the scientific
    community, patient advocates, and the general public to ensure that
    this plan is informed by stakeholder input. Interim recommendations are
    expected late this summer and final recommendations are anticipated in
    the summer of 2014. This plan will be publicly available and widely
    shared with both the public and with BRAIN Initiative partners.
        Question. As the lead institution, do you foresee NIH's funding
    role being increased in future years?
        Answer. It is anticipated that as the BRAIN Initiative gains
    momentum, additional funds may be needed to support promising areas of
    research. The pace at which NIH's role might grow in future years will
    depend on the relative competing priorities and the overall
    availability of funds at that time.
        Question. Will NIH be expected to be the primary funding agency in
    future years?
        Answer. At this time, each funding agency is undertaking an
    extensive scientific planning process to identify their specific areas
    of focus and to define their potential investments in the BRAIN
    Initiative. Given that NIH has such a substantial investment in
    neuroscience research, it is certain that we will remain a leader in
    advancing the goals of the BRAIN Initiative.
        Question. Can you specify the role you see each Federal agency
    taking in this initiative?
        Answer. In general, NIH will develop new tools, training
    opportunities, and other resources. The Defense Advanced Research
    Projects Agency (DARPA) intends to explore applications--such as a new
    generation of information processing systems and restoration
    mechanisms--that dramatically improve the way we diagnose and treat
    soldiers suffering from post-traumatic stress, brain injury, and memory
    loss. The National Science Foundation (NSF) has expressed a commitment
    to supporting research that spans physical, biological, social, and
    behavioral sciences. Moving forward the agencies will work in close
    collaboration to ensure that their efforts are complementary and
    leverage the unique missions of each; ultimately catalyzing an
    interdisciplinary effort of unprecedented scope.
        Question. What role do you expect private research institutions to
    play in the project?
        Answer. Currently there are four private partners involved in the
    BRAIN Initiative: the Allen Institute for Brain Science, the Howard
    Hughes Medical Institute, the Salk Institute for Biological Studies,
    and the Kavli Foundation. Each partner will support areas of research
    in which they are best positioned to advance the overarching goals of
    the BRAIN Initiative. The Allen Institute for Brain Science, a
    nonprofit biomedical research organization, is a leader in large-scale
    data generation, for example, mapping gene expression in mouse, monkey
    and human brains and public sharing of data and tools. The Howard
    Hughes Medical Institute, the Nation's largest nongovernmental funder
    of basic biomedical research, has a focused investment in developing
    and disseminating new imaging technologies for use in model organisms.
    The Kavli Foundation will encourage the application of nanotechnology
    to neuroscience.
        Question. Is it your goal to expand the public-private partnership
    for this initiative in the future?
        Answer. NIH's first goal is to develop a rigorous scientific plan
    for the BRAIN Initiative that is sufficiently informed by a broad and
    inclusive process. After the scientific plan is established, NIH will
    continue to seek ways to leverage public-private partnerships.
        Question. What would happen if each of the proposed agencies does
    not provide the requested amount in fiscal year 2014?
        Answer. The NIH Director recognizes the tremendous opportunity of
    the BRAIN Initiative and is committed to ensuring its success. In the
    event that funds are not provided for this Initiative, NIH will
    continue to support smaller aspects of this project that continue to
    advance neuroscience research. However, the scale of this project might
    be minimized in comparison to the President's bold vision of truly
    ``revolutionizing'' our understanding of the human brain.
        Question. The goal of the Institutional Development Award (IDeA) is
    to broaden the geographic distribution of NIH funding for biomedical
    and behavioral research. This is the second year in a row that NIH has
    proposed reducing funding for the IDeA program after Congress restored
    funding in the prior year. I question why the budget would reduce
    funding for the IDeA program whose purpose is to diversify biomedical
    research to all regions of the country when the budget requests new
    funding for new proposals to diversify the biomedical workforce. Why is
    NIH not supporting level funding for the IDeA program which is already
    a critical component of diversifying the biomedical research capacity?
        Answer. At a time of difficult economic environment when many
    investigators throughout the Nation are struggling to compete for NIH
    funding, the allocation of funding for selected States to increase
    their competitiveness must be balanced with other NIH initiatives for
    promoting a more diverse biomedical workforce nationwide.
        Question. The IDeA program is operating under a budget of $262.5
    million for the remainder of fiscal year 2013. Dr. Collins, if your
    budget request of $226 million were agreed to, the IDeA program would
    issue no new Centers of Biomedical Research Excellence (COBRE) awards
    in fiscal year 2014 and cut the COBRE grants currently funded. Why
    would you propose funding reductions that require reducing existing
    awards to a current program whose goal is to increase diversity, while
    then proposing a new diversity initiative within the Common Fund?
        Answer. The IDeA Program is a funding set-aside designed to build
    research capacity in selected States to the point where investigators
    in these States can compete for NIH funding. We have proposed returning
    the IDeA program appropriation to the level where it had been before
    the one-time spike in fiscal year 2012. The IDeA program is a
    congressionally mandated program envisioned as a long-term initiative
    for building biomedical research competitiveness of selected States
    while the Common Fund initiative is a limited term program designed to
    support student development from underrepresented groups.
        Question. Given today's Federal budget constraints and drug
    companies' hesitation to pursue costly development of drugs that may
    have a low success rate, I believe programs like NCATS' Learning
    Collaborative is an innovative model to help address these issues. As
    we discussed in this hearing last year, the University of Kansas Cancer
    Center has engaged in a partnership with the National Center for
    Advancing Translational Sciences (NCATS) and the Leukemia & Lymphoma
    Society to repurpose auranofin, an arthritis drug, for use on a rare
    form of blood cancer. The Learning Collaborative has repurposed a drug
    from the shelf into a clinical trial in less than 2 years, and at one-
    sixth the cost of developing a new drug. Dr. Collins, could you talk
    about the progress the Learning Collaborative has made?
        The success of this project appears clear--within 2 years, The
    Learning Collaborative has moved a compound to treat arthritis into a
    Phase IIa Clinical Trial to treat Chronic Lymphocytic Leukemia (CLL), a
    rare blood cancer. This project has not only shown promising results
    for those suffering from CLL, but the research studying auranofin has
    also helped broaden our understanding of how the drug may work to fight
    other forms of cancer. As a result of this initiative, the University
    of Kansas was able to submit two additional investigational new drug
    applications to study auranofin's effects on other forms of cancer. Dr.
    Collins, do you expect this model to be replicated with other
    repurposing initiatives?
        Answer. Parallel, independent studies conducted at The University
    of Kansas (KU) and University of Rochester demonstrated positive
    results when using auranofin to treat a rare, difficult to treat
    lymphoma called Mantle Cell Lymphoma. Investigators at both NCI cancer
    centers believe that auranofin acts synergistically with a class of
    anticancer agents called proteosome inhibitors (e.g., Velcade or
    bortezomib) to treat this cancer. Velcade is not very effective when
    given alone to treat this lymphoma. In a series of collaborative
    experiments with University of Kansas, NCATS obtained results
    supporting the use of Velcade with auranofin to treat this cancer. As a
    result, on March 15, 2013, KU investigators filed a second
    Investigational New Drug (IND) application with the Food and Drug
    Administration (FDA). In late April, FDA cleared researchers to proceed
    with a clinical proof-of-concept trial, studying auranofin alone and in
    combination with Velcade, in lymphoma patients. This trial will be
    conducted at the University of Rochester, University of Iowa, and
    University of Kansas NCI cancer centers.
        Investigators at KU submitted a third IND on March 28, 2013,
    seeking clearance to study auranofin for the treatment of
    gastrointestinal stromal tumors (GIST). The cancer, GIST, afflicts
    approximately 4,000 U.S. patients. Auranofin is active, in the test
    tube, in treating GIST that is both sensitive and resistant to Gleevec.
    Very recently, investigators received clearance from the Food and Drug
    Administration (FDA) to proceed with this trial. The trial will be
    conducted at the University of Kansas Cancer Center and Children's
    Mercy Hospital in Kansas City, MO.
        Auranofin was discovered as active against these cancer cells in
    screens of the NCATS Pharmaceutical Collection (NPC), a comprehensive
    collection and database of approved and investigational drugs. NCATS
    collaborates with investigators worldwide to identify other drugs in
    the NPC that can be repurposed for unmet medical needs.
        Question. How will NCATS share the lessons learned in these types
    of collaborations so others in the field of translational research can
    benefit?
        Answer. Sharing the lessons learned is the best way for NCATS to
    increase the impact of its programs. When the Center develops a
    strategy and demonstrates the value of that strategy, the dissemination
    and adoption of the strategy by other organizations in both the public
    and private sectors is how NCATS will amplify the impact of its
    investment. Such dissemination is accomplished via sharing of data and
    template agreements in public Web sites, peer-reviewed publications,
    and presentations to stakeholders. NCATS uses all of these strategies
    to disseminate lessons learned and communicate the value of our
    strategies. For example, NCATS collaborated with FasterCures, a center
    of the Milken Institute, to disseminate the collaborative lessons from
    The Learning Collaborative with KU and the Leukemia & Lymphoma Society
    (LLS) via webinars, and made the Research Collaboration
    Agreement (http://train.fastercures.org/pdf/tools/
    CollaborationAgreementNCATS
    012412.pdf) and Memorandum of Understanding (http://
    train.fastercures.org/pdf/tools/RedactedMOU5June2012.pdf) public for
    others to use.
        Question. Through Federal investment, the NIH has advanced our
    understanding of health for the last century. But the NIH provides more
    than medical discoveries, it creates and sustains jobs and produces
    measurable benefits to the American economy. Dr. Collins, at a time
    when global competitiveness in biomedical research is intensifying, and
    our global competitors are spending more funding to advance their own
    biomedical research efforts, can you discuss the ramifications of
    reducing the Federal investment in NIH?
        Answer. Reducing the Federal investment in medical research has
    many ramifications. NIH is currently the largest funder of biomedical
    research in the world, and the work it supports and conducts leads to
    advances in the diagnosis, treatment, and prevention of disease. As you
    note, NIH research also has significant economic benefits and creates
    and sustains jobs in research and development. In ``NIH's Role in
    Sustaining the U.S. Economy'', United for Medical Research, an advocacy
    organization, calculated that the $23.7 billion spent by NIH
    extramurally in the U.S. in 2011 directly and indirectly supported
    432,094 jobs. NIH funding also affects the size of the bioscience
    industry, according to the Milken Institute's 2012 report, ``Estimating
    Long-Term Economic Returns of NIH Funding on Output in the
    Biosciences''. The authors, representing an advocacy organization,
    argue that a $1 increase in NIH funding will increase the size (output)
    of the bioscience industry by at least $1.70 in that year.
        NIH's current operating budget, post sequestration, of $29.15
    billion is about 5 percent below last year's budget. In addition, in
    inflation-adjusted terms, the NIH budget has declined almost every year
    since 2003. Other countries are increasing their investment and
    threatening the U.S.'s leadership in the global life sciences industry.
    Between 1999 and 2009, Asia's share (including China, India, Japan,
    Malaysia, Singapore, South Korea, Taiwan, and Thailand) of worldwide
    R&D expenditures grew from 24 percent to 32 percent, while U.S. R&D
    expenditures declined from 38 percent to 31 percent. In addition, the
    European Commission has recently urged its member nations to increase
    substantially their investment in research, recommending budgets of 80
    billion euros ($108 billion) in 2014-2020, a 40-percent increase over
    the previous seven year period.
        As other countries continue to devote a larger share of their
    annual budgets to R&D, it will be essential for the U.S. to continue to
    invest in biomedical research, training, and infrastructure. These
    investments--critical components in the ``engine of innovation''--will
    be needed to keep the U.S. in the position of worldwide leader. A
    sustained commitment to biomedical research, will allow NIH to keep up
    the pace of advancements in the treatment, diagnosis, and prevention of
    disease and in the improvement of the public health and for the U.S. to
    maintain its global lead in biomedical innovation.
        Question. Dr. Collins, diseases such as Alzheimer's, cancer,
    diabetes, and heart disease affect millions of Americans and cost
    hundreds of billions of dollars to treat each year. We all know people
    who have been impacted by each of these diseases and how important the
    development of preventive measures, diagnostic tools, and new
    treatments are. Yet recent estimates for this year project that the NIH
    will fund the fewest number of new and competing research projects
    since 1998--the first year of the doubling of the NIH. What steps are
    being taken to ensure that we continue to make progress against these
    and other diseases?
        Answer. NIH is operating at a program level of $29.15 billion in
    fiscal year 2013, a decrease of about 5 percent from fiscal year 2012.
    Despite this reduction, NIH remains committed to funding outstanding
    science and will continue to strive to find new, more effective ways to
    prevent, treat, and cure human diseases. NIH also remains committed to
    supporting the other critical elements of our mission, namely training
    and development of talented researchers and maintaining a
    technologically advanced scientific infrastructure.
        The sequester is having real effects on our ability to support both
    new and competing research projects as well as non-competing
    continuation awards. Although NIH is likely to make fewer competing
    awards in fiscal year 2013, we will be trying to keep the average size
    of competing awards constant at fiscal year 2012 levels. Most non-
    competing continuation awards that have already been made in fiscal
    year 2013 were funded up to 10 percent less than the previously
    committed level. Although we may be able to make some adjustments
    during the year depending on the final level of each NIH Institutes and
    Centers' (ICs) appropriation, we will not be able to restore them to
    the previous level. Finally, new research infrastructure and core
    facilities are now ready for use, but without support for researchers
    who can take advantage of these resources, their productivity will not
    be fully realized.
        NIH will be strategic in deploying its resources in fiscal year
    2013 to achieve continued success in addressing the public health
    challenges of today and tomorrow including those you reference in your
    question. For example, to advance the progress of research on
    Alzheimer's disease, NIH will enable rapid sharing of data, disease
    models, and biological specimens, and it will promote the building of
    new multidisciplinary translational teams and create both physical and
    virtual sites where these teams can operate. NIH will also establish
    new public-private partnerships to speed drug development by
    repurposing abandoned compounds. NIH's Cancer Genome Atlas (TCGA), a
    joint effort of the National Cancer Institute (NCI) and the National
    Human Genome Research Institute (NHGRI), is a publicly accessible
    database that is opening new avenues for the identification of useful
    biomarkers and the development of targeted therapies. Among efforts in
    diabetes research, NIH will work to translate the important findings of
    controlled clinical trials for diabetes prevention or treatment into
    approaches that are effective, affordable, safe, and sustainable in
    real world settings. For heart disease, NIH is funding studies of the
    cellular and molecular mechanisms underlying large conduit-artery
    stiffening in hypertension and the examination of the temporal
    relationship between arterial stiffening and the development of
    hypertension in animal models.
        Using a priority setting process that strikes a dynamic balance
    between multiple factors, including ongoing and newly emerging public
    health needs, scientific opportunities, responses to unexpected
    scientific findings, and the need to sustain longer-range workforce and
    infrastructure development, NIH is able to support all of our mission
    areas. This process and the continuous monitoring and evaluation of
    research portfolios help ensure an ever-increasing understanding of
    basic biological functioning and the application of that understanding
    to the amelioration of disease burden. Nevertheless, decreased funding
    will limit NIH's ability to fund all of the most promising scientific
    ideas and affect the pace of the advances we generate in the treatment,
    diagnosis, and prevention of disease and in the improvement of the
    public health.
        Question. The fiscal year 2014 budget request proposes a multi-
    agency reorganization of science, technology, engineering, and
    mathematics (STEM) education, which includes nine consolidations of
    NIH-related STEM programs to other agencies. What is NIH's plan with
    respect to the STEM education proposal?
        Answer. The fiscal year 2014 President's budget proposes to
    consolidate a number of science education programs under the Department
    of Education, the National Science Foundation, and the Smithsonian
    Institution. NIH staff have participated in preliminary transition
    planning discussions with representatives in those three agencies, and
    we are preparing for phase out of those programs. While K-12 science
    education is important, it is not a core NIH function given our focus
    on training the scientific workforce at the undergraduate, graduate,
    and doctoral levels.
        Question. NCATS' Learning Collaborative has incorporated resources
    from the NIH, a State university, and a nonprofit advocacy organization
    to develop new therapeutics for blood cancers. It is my understanding
    that this public-private collaboration was made easier by using a
    Collaboration Research and Development Agreement (CRADA). Do you expect
    NCATS to continue to use CRADAs in future collaborations?
        Answer. A Collaboration Research and Development Agreement (CRADA)
    is a useful tool for formalizing collaborations between intramural NIH
    scientists and university and industry scientists, and NCATS is
    utilizing this agreement type for many of its collaborations with for-
    profit and non-profit organizations. NCATS anticipates continued usage
    of the CRADA mechanism, due to the collaborative nature of many of
    NCATS programs.
        Question. Do any changes need to be made to allow for the NIH to
    better leverage the benefits of CRADAs?
        Answer. While there are various mechanisms that support
    collaborations between companies and NIH intramural scientists, the
    CRADA is the only mechanism that permits the NIH to offer an upfront
    option to companies to license inventions that may be made within the
    scope of the collaboration agreement, and it also permits the
    collaborating company to provide funds to the NIH in support of the
    research. Over the last few years, the number of CRADA collaborations
    has steadily increased with new inventions being developed as a result
    of these critical scientific relationships. Currently, NIH is
    developing an online system that will tailor the CRADA terms to the
    specific needs of the collaboration and streamline the negotiation and
    implementation processes. As NCATS and other ICs explore innovative
    collaborative relationships with the private sector, NIH is flexible in
    adapting CRADAs to meet those programmatic needs.
                                     ______

                Questions Submitted by Senator Richard C. Shelby

        Question. The budget proposes a government-wide realignment of
    Federal science, technology, engineering, and mathematics (STEM)
    education programs. Dr. Collins, do you support the Office of
    Management and Budget's proposal to move nine of the National
    Institutes of Health's (NIH) STEM education programs to other agencies?
        Answer. The NIH supports the proposal in the fiscal year 2014
    President's budget to consolidate K-12 science education programs under
    the Department of Education, the National Science Foundation, and the
    Smithsonian Institutions. NIH staff are participating in initial
    transition planning discussions with representatives in those three
    agencies, and we are considering phase out of those programs. While K-
    12 science education is important, it is not a core NIH function given
    our focus on training the scientific workforce at the graduate and
    doctoral levels.
        Question. Without Congressional approval, NIH could still move
    forward to consolidate STEM education programs within NIH. Do you think
    you will move in that direction should Congress not act on the
    government-wide realignment?
        Answer. The NIH is supportive of efforts to improve coordination of
    Federal science education programs consistent with the President's
    desire to take action to improve student outcomes. The NIH is reviewing
    its K-12 science education programs in light of reorganization and
    consolidation of STEM education proposed in the fiscal year 2014
    President's budget, but cannot speculate on a scenario where Congress
    does not act on the government-wide proposal.
        Question. Dr. Collins, the budget request proposes a new diversity
    program in the Common Fund called NIH Building Infrastructure Leading
    to Diversity (BUILD). The budget justification states that the program
    would support initiatives to strengthen the infrastructure of
    ``comparatively under-resourced institutions.''
        What are the eligibility criteria for this proposal?
        Answer. NIH intends for BUILD awards to involve partnerships from
    multiple types of institutions, but only those that are referred to as
    Primary Institutions would submit applications. Primary Institutions,
    the applicant organization, are intended to be those that have the
    primary responsibility for implementation of the project and for
    management of the award. NIH intends for Primary Institutions to be
    baccalaureate-granting colleges/universities that receive less than
    $7.5 million (total costs) in NIH research project grants (RPG)
    (average of fiscal years 2010-2012) and have a pool of undergraduate
    students, at least 25 percent of whom are supported by Pell grants. The
    BUILD Primary Institution eligibility criteria are intended to target
    funds to relatively under-resourced institutions (less than $7.5
    million in NIH RPG funding) with a demonstrated commitment to students
    from diverse backgrounds that have been historically underrepresented
    in the biomedical research workforce. The intended requirement that
    BUILD institutions have a substantial pool of students from
    disadvantaged backgrounds (at least 25 percent must be Pell grant
    recipients) is based on the recognition that (1) many students from
    economically disadvantaged backgrounds are underrepresented in the NIH
    workforce in the fields of biomedical, behavioral, and clinical
    research, and (2) institutional commitment to these students often
    comes at the expense of investments in research infrastructure.
        Primary Institutions will be encouraged, but not required, to
    develop appropriate partnerships in order to optimally position
    themselves to provide a rigorous environment for research training.
    Partnerships involving a Primary Institution and one or more of the
    following institution types are encouraged:
        Pipeline Partner Institutions are intended to be 2- or 4-year
    undergraduate institutions with students that will enrich and expand
    the pool of students eligible for BUILD scholarships. Research Partner
    Institutions are intended to be research intensive institutions with
    committed investigators able to serve as effective research mentors for
    BUILD scholars. Research partnerships are intended to expand education
    and research opportunities available to BUILD scholars, work with
    Primary Institutions to develop innovative curricula, and provide
    sabbatical opportunities to faculty from Primary Institutions. Academic
    institutions, government institutions, industry, and nonprofit research
    institutions may all be considered as potential Research Partners.
    Graduate/Medical Partner Institutions are intended to be medical,
    dental, or graduate research institutions with no undergraduate program
    but with a pool of doctoral-level students engaged in research and/or
    planning a research career, and less than $7.5 million (total costs)
    through research project grants (average of fiscal years 2010-2012).
    Primary Institutions and Graduate/Medical Partner Institutions are
    intended to work collaboratively to provide joint programs for both
    undergraduate and graduate students.
        In addition to the BUILD initiative, the NIH Common Fund's
    ``Increasing the Diversity of the NIH-Funded Workforce'' program
    includes two other initiatives: the National Research Mentoring Network
    (NRMN) and the Coordination and Evaluation Center (CEC). The NRMN is
    intended to facilitate the development of robust mentoring
    relationships by coordinating nationwide pairings of scientific leaders
    and early career scientists (undergraduate students through junior
    faculty members) who may benefit from additional mentoring, including
    but not limited to individuals from underrepresented backgrounds. The
    CEC is intended to serve as a centralized hub to enable the integration
    of BUILD and NRMN with existing programs, assessing the impact of the
    BUILD and NRMN initiatives from the earliest stages of implementation
    to provide early indications whether the novel approaches implemented
    by BUILD and NRMN awardees are having a meaningful effect. NIH intends
    for both the NRMN and CEC to be open to any institution within the
    United States, including academic institutions, nonprofits, and
    professional organizations.
        Question. How many institutions do you propose funding with fiscal
    year 2014 funds?
        Answer. In fiscal year 2014, we expect to support approximately ten
    Primary Institutions within BUILD, each of which will be encouraged to
    form partnerships with other institutions as appropriate. In addition,
    we expect to support one institution within NRMN, and one institution
    within CEC. The number of institutions supported will be contingent
    upon availability of funds and receipt of a sufficient number of
    meritorious applications.
        Question. How much do you expect the awards to be?
        Answer. Details of the anticipated budgets for BUILD, NRMN, and CEC
    will be provided in the Funding Opportunity Announcements for these
    initiatives, which are expected to be released in the fall of 2013. As
    described in a presentation to the NIH Advisory Committee to the
    Director (http://acd.od.nih.gov/Diversity-in-the-
    Biomedical-Workforce-Implementation-Plan.pdf), the entire ``Increasing
    Diversity of the NIH-Funded Workforce Program'' budget is planned to
    average approximately $50 million per year. The majority of these funds
    are intended to go towards the BUILD initiative.
        All anticipated award budgets are contingent upon the availability
    of funds and the receipt of a sufficient number of meritorious
    applications.
        Question. Could you please provide additional details beyond those
    provided in the Funding Opportunity Announcement, related to the
    expected collaboration between the Primary, Pipeline, Research and
    Graduate/Medical Partner institutions? (OD/Common Fund)
        Answer. NIH intends for BUILD Primary Institutions to be
    encouraged, but not required, to partner with Pipeline Partners,
    Research Partners, and/or Graduate/Medical Partner Institutions. The
    intent of encouraging these partnerships is to provide the best
    research training environment for students involved in the BUILD
    program. Partnerships with Research Partners would allow students from
    under-resourced institutions to participate in robust research
    experiences that are unavailable at their home institutions.
    Participation in mentored research experiences is a critical factor in
    determining whether undergraduate students choose to pursue a research
    career; therefore, engaging students from underrepresented backgrounds
    in meaningful research experiences is anticipated to have a major
    impact on the diversity of the biomedical research workforce. Primary
    Institutions and Research Partners are intended to also work together
    to develop novel curricula, and faculty from Primary Institutions are
    intended to have the opportunity to pursue sabbatical activities at
    Research Partner Institutions. Partnering with Pipeline Partner
    Institutions will enrich the pool of students eligible to participate
    in the BUILD programs, so that students at 2- or 4-year colleges (such
    as community colleges) can benefit from research training experiences
    not available at their home institutions. Similarly, partnerships with
    Graduate/Medical Partner Institutions are intended to also expand the
    pool of BUILD-eligible scholars by providing additional research
    experiences to doctoral-level students at these institutions. NIH
    intends for Graduate/Medical Partner Institutions to include
    Historically Black Medical/Graduate Schools, which have a rich history
    of training students from underrepresented backgrounds and have a
    robust pool of students who may benefit from BUILD activities.
        Question. Dr. Collins, you stated at the hearing that while the
    Administration has proposed an overall goal of mapping the human brain,
    there are no specific scientific details or timeline you can put
    forward at this time. While I understand that you expect fiscal year
    2014 to be a scientific planning year, it is critical that the
    Appropriations Committee has a full understanding of the goals and
    timeframe of this project before funding is appropriated. Therefore,
    can you please provide the subcommittee with the following information:
        The BRAIN Initiative has no clearly defined goals or endpoint. When
    do you expect to have a scientific framework in place to answer these
    critical questions?
        Answer. NIH is undertaking a rigorous scientific planning process
    to determine the scientific aims of the NIH component of the Brain
    Research Through Advancing Innovative Neurotechnologies (BRAIN)
    Initiative, which is anticipated to include a plan for timetables and
    milestones. As part of this process, members will consult the
    scientific community, patient advocates, and the general public to
    ensure that this plan is informed by a broad and inclusive input. Final
    recommendations are anticipated in the summer of 2014, at which time
    the NIH will be able to comment on the scientific framework.
        Question. How long do you estimate mapping the human brain will
    take?
        Answer. The goal of the BRAIN Initiative is not actually to map the
    brain, per se, but rather to accelerate the development and application
    of new technologies that will enable researchers to produce dynamic
    pictures of the brain that show how individual brain cells and complex
    neural circuits interact at the speed of thought. These technologies
    will open new doors to explore how the brain records, processes, uses,
    stores, and retrieves vast quantities of information, and shed light on
    the complex links between brain function and behavior. The group
    advising the NIH on the scientific framework for the BRAIN Initiative
    has been asked to articulate the short, mid, and long term objectives
    required for achieving these aims.
        Question. What goals do you expect to accomplish in 1, 3, and 5
    years?
        Answer. It is premature to speculate on the accomplishments in the
    absence of a strategic plan outlining the scientific goals of the
    Initiative.
        Question. Do you expect the Department of Defense and the National
    Science Foundation to continue to financially support this project for
    the duration?
        Answer. NIH cannot comment on the financial commitments of the
    other agencies. However, given the different perspectives and strengths
    of each agency, NIH sees much benefit in having other agencies
    involved.
        Question. What specific role will each Federal agency contribute to
    this project?
        Answer. In general, NIH will develop new tools, training
    opportunities, and other resources. The Defense Advanced Research
    Projects Agency (DARPA) intends to explore applications--such as a new
    generation of information processing systems and restoration
    mechanisms--that dramatically improve the way we diagnose and treat
    soldiers suffering from post-traumatic stress, brain injury, and memory
    loss. The National Science Foundation (NSF) has expressed a commitment
    to supporting research that spans physical, biological, social, and
    behavioral sciences. Moving forward the agencies will work in close
    collaboration to ensure that their efforts are complementary and
    leverage the unique missions of each; ultimately catalyzing an
    interdisciplinary effort of unprecedented scope.
        Question. It has been reported that the first several years of the
    program will emphasize the development of technologies. However, this
    approach has been criticized and some neuroscientists have said that
    money would be better spent by first figuring out what needs to be
    measured and then determining the best means to measure them. How do
    you respond to this critique?
        Answer. The group advising the NIH on the scientific framework for
    the BRAIN Initiative has been asked to review the neuroscience
    landscape in order to determine the opportunities, challenges, and
    impediments in neuroscience research. It is precisely through this
    analysis that they will indeed assess what needs to be measured or what
    is missing in order to focus the investment in promising areas of
    research.
        Question. The European Union (EU) has a similar initiative called
    the Human Brain Project. How is the BRAIN Initiative different than the
    EU program?
        Answer. The EU's Human Brain Project and the BRAIN Initiative share
    the broad goal of advancing the understanding of the brain and its
    diseases. They also both recognize that technological opportunities are
    emerging to accelerate progress toward that goal. However, the two
    initiatives differ in their emphasis. The European Project emphasizes
    the development of informatics and computer infrastructure to
    systematically integrate all available data into unifying models of the
    brain. The BRAIN Initiative will focus on the development of tools that
    will transform our ability to gather new data, heretofore impossible to
    acquire, that will advance understanding of how millions of brain cells
    work together in circuits that enable us to think, act, and sense the
    world. That said, it is important to emphasize that the EU Project is
    new, multi-faceted, and will develop over time, and the BRAIN
    Initiative is in its early formative stages. As the BRAIN Initiative
    Working Group develops plans for the BRAIN Initiative, including how to
    analyze and disseminate the data it generates, the group is building
    bridges to the EU Project and to other projects outside of the U.S.
    government to take advantage of all possible opportunities for synergy.
        Question. Do you expect collaboration with the EU on the ultimate
    goal of mapping the brain in its entirety?
        Answer. As part of the working group's charge, they have been asked
    to identify areas in which collaboration with others (i.e. foundations,
    industry, other agencies) would result in either complementary
    activities or the leveraging of efforts. EU efforts will be considered
    in this analysis.
                                     ______

                 Questions Submitted by Senator Lamar Alexander

        Question. You testified that sequestration caused the National
    Institutes of Health (NIH) to cut 700 extramural grants. Was intramural
    grant funding similarly affected? If so, are extramural and intramural
    on the same ``playing field?'' It is my understanding that extramural
    grants must go through a competitive peer-review process, which might
    not be the case for intramural grants.
        Answer. The NIH Intramural Research Program has been subjected to
    similar cuts due to sequestration as extramural grants. The cuts in
    intramural and extramural research similarly affect hiring, purchase of
    equipment and supplies, scientific travel, etc. In addition, some
    clinical trials conducted through extramural research are being
    delayed, and reductions in intramural research will cause approximately
    750 fewer new patients to be admitted to study protocols at the NIH
    Clinical Center. All NIH intramural principal investigators undergo
    rigorous peer review at least once every 4 years by outside scientific
    experts whose advice affects the resources allocated to them. These
    experts are members of the scientific community who receive extramural
    grants, and they are thus in a position to compare the intramural
    research with research that is funded by extramural grants. Intramural
    scientists do not, however, receive actual grants but rather compete
    for and receive internal funding and resources for scientific programs
    and projects, thus making direct comparisons in numbers of grants
    difficult.
        Question. According to your testimony, an average of 15-16 percent
    of grant applications to NIH submitted actually receive funding.
        Are all grant applications submitted included as part of this
    statistic or do are only those grants that pass a minimal standard
    initial screening process included?
        Answer. The National Institutes of Health (NIH) reports success
    rate statistics http://report.nih.gov/NIHDatabook/Charts/
    Default.aspx?showm=Y&chartId=124&cat
    Id=13 on the RePORT Web sites for various grant application types. The
    success rate in fiscal year 2012 for research project grants was 18
    percent, and it is projected that the success rate for fiscal year 2013
    will decline. Decreases in the Success rates are tied to availability
    of funding and the number of applications received, thus the overall
    growth in the number of applications reduces the success rate.
        The success rate describes the percentage of grant applications
    accepted for peer-review that were subsequently funded. A small
    fraction of applications submitted to NIH are not accepted for review
    for various reasons, and thus, are not included in the success rate
    calculation. Examples would include if the applicant institution is
    ineligible for the funding program for which it has applied, or does
    not have active registrations in the United States System for Award
    Management and/or NIH's Electronic Research Administration (eRA)
    Commons. Some applications are not accepted because they are missing
    required information or violate application formatting requirements.
    Finally, a small number of applications are submitted that describe
    research projects that are virtually identical to applications
    previously reviewed, or do not fall within NIH's mission, and are not
    accepted for review.
        Question. Of the total number of grant application submitted, what
    percentage are such that, even with unlimited funding, would not be
    worthy of funding? For what reasons would they be excluded?
        Answer. Most grant applications submitted to the NIH are from
    recognized scientific experts and many are worthy of funding.
    Nevertheless, it is desirable to maintain a highly competitive process
    to identify the best science to support with the resources available.
    As part of the initial peer review process, reviewers have the ability
    to identify a particular application as Not Recommended for Further
    Consideration, if it lacks significant and substantial merit; presents
    serious ethical problems in the protection of human subjects from
    research risks; or presents serious ethical problems in the use of
    vertebrate animals, biohazards, and/or select agents. Applications
    designated as NRFC do not proceed to the second level of peer review
    (National Advisory Council/Board) because they cannot be funded. This
    is a very rare event, and all other applications are considered to have
    been recommended by the initial review group as eligible for funding.
    The Institutes and Centers typically regard applications that have been
    assigned Overall Impact Scores better than the 33 percentile to be
    worthy of consideration for funding. However, each NIH Institute and
    Center (IC) may fund applications that do not meet this threshold, if
    they can establish high program relevance. Indeed, the success rate for
    Research Project grants reached 32 percent during 1999 to 2001;
    however, the high success rate is tied to the relatively low number of
    applications received. For example, in 1999, NIH received about 26,000
    applications, compared to the over 50,000 received in 2012.
        Question. How is NIH working with private foundations regarding
    young investigator awards? What percent of young investigator awards
    are being funded by NIH?
        Answer. NIH identifies New Investigators as those who have not
    previously competed successfully as the Project Director or Principal
    Investigator for a substantial NIH independent research award, e.g., an
    investigator-initiated R01 Equivalent Grant (R01, DP2 or R37). It is
    the goal of NIH to support New Investigators on new, R01 equivalent
    awards at success rates comparable to those of established
    investigators submitting new or Type 1 applications. In fiscal year
    2012, NIH awarded 1,286 competing R01 equivalent grants to New
    Investigators, for a success rate of 13 percent. There were 2,429
    comparable awards made to established investigators, for a success rate
    of 15 percent.
        NIH has a novel program for intramural scientists that is
    coordinated collaboratively with the Lasker Foundation. The Lasker
    Clinical Research Scholars Program supports a small number of
    exceptional clinical researchers in the early stages of their careers
    to promote their development as independent investigators. Scholars
    receive 5 to 7 years of support as an independent principal
    investigator in the NIH Intramural Research Program, followed by the
    competitive opportunity for additional years of financial support,
    either at the NIH or at an extramural research institution.
        Question. The National Cancer Institute (NCI) assembled a list of
    24 questions that should engage scientific community in debate and
    further advancements in cancer research. What is the timeline for
    measurable outcomes for the NCI Provocative Questions program?
        Answer. The Provocative Questions Initiative (PQI) has lofty goals
    but it is less than 2 years old, so the outcomes that can be measured
    now are largely procedural and subjective. The PQI was designed to
    engage the scientific community in efforts to identify important and
    often long-standing questions in cancer research--e.g., how obesity
    contributes to the development of cancers or why some cancers respond
    to specific drugs when others do not--and to address them
    experimentally, using new methods and new information. Part of the
    motivation was to encourage the research community to take risks and
    address important problems, even in this time of limited funding and
    low success rates. The ultimately desired outcomes of the PQI will be
    answers to at least some of the questions and applications of the
    answers to the ways in which cancers are prevented, diagnosed, and
    treated. But such outcomes cannot be expected for at least 5 to 10
    years.
        Other aspects of the PQI--its attractions for the cancer research
    community and its capacity to generate interest and exciting ideas--can
    be measured, however, even at this early stage. For instance, the PQI
    was designed to stir imaginative, inter-disciplinary thinking by asking
    working scientists, rather than NCI program directors, to develop the
    Provocative Questions. As measures of the enthusiasm generated by this
    project, we have kept track of the many PQI workshops that the NCI has
    conducted throughout the country, bringing scientists from different
    disciplines together to propose and discuss questions; and we have
    observed the heavy traffic on our PQI Web site, where questions are
    posted and debated. When we selected twenty-four questions to be
    addressed in the first round of competition for grants, we received
    over 750 applications, indicating a high level of interest and we
    funded slightly more than fifty of the best applications. The NCI is
    currently evaluating a second set of applications received in response
    to Provocative Questions.
        Question. Please address any overlap between the NIH Common Fund
    and the NIH National Center for Advancing Translational Sciences. How
    are these two areas coordinating efforts?
        Answer. By design, the Common Fund is not separate from the ICs.
    Scientific oversight for each Common Fund Program is provided by two or
    three IC Directors who serve as co-chairs. Requests for applications
    (RFAs) are issued from the IC of one of the co-chairs and day-to-day
    and long-term program oversight is provided by staff from the co-
    chairs' ICs. In addition, each program has a trans-IC Working Group
    composed of program staff from as many ICs as are interested in
    participating. Successful coordination of this distributed management
    model is the responsibility of the Office of Strategic Coordination in
    the Division of Program Coordination, Planning, and Strategic
    Initiatives (DPCPSI), NIH Office of the Director (OD). There are
    several programs within the National Center for Advancing Translational
    Sciences (NCATS) that originated from, and are currently being funded,
    either fully or partially, by the Common Fund. These include the
    Bridging Interventional Development Gaps (BrIDGs) program; the NIH
    Chemical Genomics Center (NCGC), which is part of the Common Fund's
    Molecular Libraries and Imaging program; the Tissue Chips for Drug
    Screening program and the Discovering New Therapeutic Uses for Existing
    Molecules program, which are both part of the Common Fund's Regulatory
    Science program; and the Extracellular RNA Communication program. For
    all of these initiatives, there is ongoing coordination between NCATS
    and Common Fund staff, with guidance from trans-NIH working groups.
    Complementarity between the Common Fund and NCATS in how these programs
    are currently conceptualized, managed, and led on behalf of the trans-
    NIH community.
        The fiscal year 2014 President's budget requests additional funding
    for NCATS so that support for several of these programs can be shifted
    from the Common Fund to NCATS.
        Question. One of the newest entities within the NIH is the NCATS.
    Could you provide the committee with an update on some of NCATS'
    current activities and planned expenditures in fiscal year 2014? I am
    especially interested in the Clinical Translational Science Awards
    (CTSAs) program, which I believe the Institutes of Medicine is
    currently reviewing at NIH's request. Vanderbilt University in
    Nashville is the coordinating center for the 60 research institutions
    linked by this program, which supports local and national research
    communities to improve the quality and efficiency of all phases of
    translational research. Going forward, how do you envision building on
    the work of CTSA recipients to complement other NIH initiatives in
    translational science? How do you see the CTSA program working with
    Foundations, patient advocacy groups and industry?
        Answer. To bring the benefits of science more quickly into patient
    care, the NCATS was formed with the mission to catalyze the generation
    of innovative methods and technologies that will enhance the
    development, testing, and implementation of diagnostics and
    therapeutics across a wide range of human diseases and conditions.
    NCATS' mission includes strengthening the entire spectrum of
    translational research--defined broadly to include the early steps
    necessary to develop new therapeutics, devices and diagnostics from
    basic discoveries, the steps necessary to establish real world
    efficacy, and the research needed to improve the practical
    implementation and dissemination of improved approaches to care.
        NCATS will utilize a number of programs to accomplish its mission
    across this translational spectrum. Extending the success of the CTSA
    program in transforming the local and regional environment for
    translational research to, in turn, transform the national environment
    for translation will be a central component. In order to accomplish
    this transformation across a broad spectrum of diseases and conditions,
    NCATS will focus on collaboration in and across all of its programs.
    Key partners will include, but are not limited to, other NIH
    Institutes, Federal agencies, patient advocacy groups, professional
    societies, foundations, healthcare systems, and a wide range of
    commercial entities. NCATS will leverage and build on existing
    relationships with many foundations, patient advocacy groups and
    industry, as collaborators, advisors, committee members and program
    partners.
        NCATS engaged the Institute of Medicine (IOM) to review the CTSA
    program and provide recommendations for any changes needed in the
    program. The report was released at the end of June and NCATS is
    reviewing the recommendations of this group as we work to evolve the
    CTSA program within NCATS.
                                     ______

                    Questions Submitted by Senator Mark Kirk

        Question. BrainGate is a promising technology. How does the
    National Institutes of Health (NIH) plan to integrate promising
    technologies like BrainGate--and other existing stroke research
    priorities--with the proposed Brain Research through Advancing
    Innovative Neurotechnologies (BRAIN) Initiative?
        Answer. The BrainGate neural interface system is a promising type
    of brain-computer interface intended to put prosthetic arms and other
    assistive technologies under the control of people who are disabled
    because of a stroke or other neurological disorder. Using BrainGate in
    a controlled laboratory setting, a paralyzed woman was able to move a
    robotic arm and take a sip of coffee on her own for the first time
    since she had been paralyzed more than 14 years earlier. BrainGate
    consists of sensors implanted in the brain that monitor signals from
    nerve cells in a brain area that controls movement, and computer
    software and hardware that translate these signals into digital
    commands for assistive devices. A clinical trial, funded in part by the
    NIH, is evaluating the safety and feasibility of this device.
        The BRAIN initiative will advance the prospects for more effective
    brain computer interface devices in two ways. First, BRAIN will develop
    tools that will transform researchers' capabilities to monitor larger
    numbers of brain cells, in a less invasive manner, more stably over
    time. This addresses major limitations of the current generation of
    brain computer interfaces, which monitor relatively few cells and rely
    upon invasive electrodes that often do not maintain a stable signal
    over time. Second, with the tools from BRAIN in hand, researchers will
    learn to better understand the ``neural code'' by which brain circuits
    control movement and perceive the environment. This will enable the
    design of devices that interface with brain circuits more effectively
    to provide precise and natural movement control and sensory feedback.
        The potential for extraordinary long-term benefits of the BRAIN
    Initiative is tantalizing, with transformative technologies for
    recording nerve cells now in use or on the horizon, including those
    that rely on optical signals. However, these technologies are currently
    not suitable for use in humans, and laboratory research in animals,
    including those with much simpler brains, will initially be a focus of
    BRAIN. NIH is continuing to support the near-term development of brain
    computer interfaces, such as BrainGate, as we also invest through the
    BRAIN Initiative in research that will revolutionize the understanding
    of the brain and its disorders in the future.
        Question. Rehabilitation research is cross-cutting within NIH. What
    is NIH doing to prevent duplication in research?
        Answer. NIH's rehabilitation research efforts include a range of
    studies from developing next generation prostheses and assistive
    devices, to optimizing physical, cognitive, and combination drug
    therapies. A number of NIH Institutes and Centers (ICs) support
    extensive research related to medical rehabilitation.
        Although multiple ICs are involved, they proactively work to
    coordinate their activities and prevent duplication of efforts. For
    example, the Eunice Kennedy Shriver National Institute of Child Health
    and Human Development's National Center for Medical Rehabilitation
    Research (NCMRR) supports research needed to enhance the health,
    productivity, independence, and quality-of-life of people with
    disabilities. The Center's role includes coordination of medical
    rehabilitation research, and promoting research specific to the health
    related problems of people with disabilities in order to capitalize on
    advances occurring in the biological, behavioral, and engineering
    sciences. The Center's work has been aided by a blue ribbon panel
    formed in 2011 to focus on medical rehabilitation research at NIH. The
    panel conducted an analysis of rehabilitation science activities within
    the NCMRR and across the NIH to identify the most promising research
    opportunities which was reported to the National Advisory Child Health
    and Human Development Council.
        In addition, NIH has an established record of identifying
    scientific areas of potential overlap and developing trans-NIH
    programs, activities, and policies to optimize the strengths and
    expertise within each of the ICs and to ensure the complementarity of
    their programs and activities. The Division of Program Coordination,
    Planning, and Strategic Initiatives (DPCPSI) in the Office of the
    Director works closely with the NIH Institutes and Centers (ICs) to
    plan and coordinate trans-NIH research cross-cutting activities. As
    part of this process, DPCPSI will work with all relevant ICs to conduct
    a portfolio analysis designed to identify scientific gaps and areas of
    sufficient investment.
        DPCPSI's Office of Portfolio Analysis provides consultation and
    training to NIH program staff in the use of portfolio analysis tools
    that allow IC staff to identify gaps in specific research portfolios
    and areas that are adequately funded across ICs. Such evaluation tools
    provide data to enhance prioritization efforts of current and emerging
    areas of research, and also prevent unnecessary overlaps and
    duplication of effort.
        Administrative processes are also in place to monitor for
    scientific overlaps in funding opportunity announcements (FOAs) and in
    grant applications. At the FOA stage, the new Guide Publishing System
    allows ICs to review of funding opportunity announcements prior to
    publication. When grant applications are received, duplicative
    proposals can be identified at the receipt and referral stage and at
    the peer review stage. After review, meritorious applications are
    checked for other sources of support, including all existing and
    pending financial resources, whether Federal, non-Federal, commercial
    or organizational, to determine whether there may be budgetary,
    scientific, or commitment overlap. This step is key to identifying and
    eliminating duplicative proposals.
                                     ______

                   Questions Submitted to Dr. Story C. Landis
                    Question Submitted by Senator Tom Harkin

        Question. Dr. Landis, when you add up the contributions from your
    private sector partners--the Allen Institute for Brain Science (at
    least $60 million/year), the Howard Hughes Medical Institute (at least
    $30 million/year), and others--they're planning to contribute
    approximately the same amount or more as the President is requesting.
    Do you expect the same situation in future years of the initiative?
        Answer. Each partner has a long-standing commitment to neuroscience
    research and we do not anticipate that their contributions to the Brain
    Research through Advancing Innovative Neurotechnologies (BRAIN)
    Initiative will be a one-time event. However, details of the initiative
    are still under development as part of a rigorous scientific planning
    process, for which final recommendations are anticipated in the summer
    of 2014. This plan will be widely shared with both the public and with
    our BRAIN Initiative partners.
                                     ______

                  Questions Submitted to Dr. Richard J. Hodes
                   Questions Submitted by Senator Jerry Moran

        Question. Dr. Hodes, the RAND Corporation recently released a
    report that found that the cost of caring for all Americans with
    dementia in 2010 was between $157 billion and $215 billion. By 2030,
    the number of Americans with dementia is expected to more than double.
    A few statistics:
      --Medicaid payments alone are 9 times higher for those with
            Alzheimer's compared to those without the disease.
      --64 percent of Medicare beneficiaries in nursing homes over 65 years
            old have Alzheimer's disease or other dementia and Medicare
            pays approximately $11 billion a year for their care.
      --Each dementia case costs between $41,000-$56,000 a year.
        We know that these numbers will only increase as our population
    ages. I support the National Institutes of Health (NIH) for many
    reasons--the impact to health being paramount. But another key
    component of my support is that I believe if we can find effective
    treatments for diseases like Alzheimer's and dementia, we can not only
    extend quality of life for patients, but reduce the cost of caring for
    these patients in years to come. Could you discuss some of the research
    projects the National Institute on Aging will fund if this proposal is
    approved and the impact these projects could have on our Nation's
    healthcare costs?
        Answer. Pending availability of funds, the ongoing Alzheimer's
    disease (AD) research supported by the National Institute on Aging
    (NIA) will continue in 2014, along with several recently launched
    efforts made possible with increased funding. These include:
      --Whole genome sequencing to identify new genetic variants that
            either increase risk (risk factors) or reduce risk (protective
            factors) for AD (in collaboration with the National Human
            Genome Research Institute).
      --A treatment trial to test the effectiveness of intranasal insulin
            in individuals with mild cognitive impairment or mild
            Alzheimer's dementia on cognition and daily functioning.
      --A 5-year prevention trial to test the ability of an antibody called
            crenezumab to bind to and clear away abnormal amounts of
            amyloid protein in the brain and prevent cognitive decline in
            people with early-onset AD.
      --Research to be funded in fiscal year 2013 and fiscal year 2014
            under four 2012 Funding Opportunity Announcements supporting
            drug discovery, development, and preclinical and clinical
            testing for the treatment and prevention of Alzheimer's disease
            and dementia.
        In addition, recent scientific advancement suggests that some new
    activities may be feasible. If so, we anticipate new activities in the
    following areas in fiscal year 2014:
      --Additional Drug Development and Testing.--This will include support
            for drug repurposing and combination therapy, phase 2 (proof of
            concept) drug trials for agents against currently known
            therapeutic targets, and studies of possible agents against
            not-yet-known therapeutic targets for AD.
      --Non-Pharmacological Intervention Development.--We will focus on
            advancing non-pharmacological interventions for the cognitive
            and behavioral symptoms of AD and the design of approaches that
            combine pharmacological and non-pharmacological treatments.
      --Biomarkers of Disease Progression to Measure the Effects of
            Potential Treatments.--We will test imaging and fluid
            biomarkers for the assessment of disease-related pathology,
            work to develop and validate sensitive measures to detect and
            track the earliest clinical changes of AD, and develop and test
            methods for the standardization of neuroimaging procedures and
            data collection.
        The issue of the impact of this research on healthcare costs is
    highly complex. Alzheimer's disease treatment and care place an
    enormous financial and economic burden on patients, their families, and
    the healthcare system, as illustrated by the NIA-supported study from
    the Rand Foundation noting that the costs of caring for people with
    dementia in the United States in 2010 were between $159 billion and
    $215 billion, and could double by 2040. Estimates of cost savings
    resulting from an effective therapy need to account for a number of
    factors, including the cost of the therapy itself, which could be
    significant, or savings offset by other costs of providing care to
    those surviving patients.
        Question. Many diseases are increasingly common with older age.
    What efforts is NIH making to understand the aging process and its
    relationship to these diseases?
        Answer. Age is a primary risk factor for many disabling diseases
    and conditions, and NIH supports a robust program of research aimed at
    understanding the relationship between aging and disease and
    disability. Ongoing initiatives include:
      --NIH Geroscience Interest Group.--The NIH Geroscience Interest Group
            (GSIG) was established in 2012 to accelerate and coordinate
            efforts to promote further discoveries on the common risks and
            mechanisms behind age-related diseases and conditions by
            developing a framework that includes multiple NIH Institutes.
            By pooling resources and expertise, the GSIG identifies major
            cross-cutting areas of research and proposes coordinated
            approaches to identify hurdles and envision solutions. In
            September 2012, the GSIG sponsored a workshop on inflammation
            and age-related diseases, and this activity has led to a
            Funding Opportunity Announcement on the subject, co-sponsored
            by several NIH Institutes. As a way of gaining further input
            from the research community, a larger-scale workshop titled
            ``Geroscience: Foundations for Delaying Chronic Disease and
            Increasing Healthspan'' is planned for fall 2013. This two and
            a half day forum will bring together 53 leaders from the fields
            of aging and major chronic diseases.
      --Nathan Shock Centers on the Basic Biology of Aging.--NIH supports
            five Nathan Shock Centers on the Basic Biology of Aging. These
            Centers provide leadership in the pursuit of basic research
            into the biology of aging through a Research Development Core
            which administers small start-up funds locally, and organizes
            national annual meetings to highlight specific areas of
            research. In addition, each Nathan Shock Center has several
            specialized cores that provide services to other investigators.
            The cores are different in each Center, depending on the
            strengths of each Institution. Funding for the Nathan Shock
            Centers is slated for renewal in fiscal year 2015.
      --Interventions Testing Program (ITP).--This ongoing program, which
            began in 2003, supports the testing of compounds with the
            potential to extend the lifespan and delay disease and
            dysfunction in a mouse model of aging. A number of
            interventions, including foods, diets, drugs, and hormones, are
            tested through the ITP, and some compounds, such as rapamycin,
            have been found to increase not only lifespan, but health as
            well. Further research is ongoing, and a parallel program has
            been established to test interventions in the worm model
            ``Caenorhabditis elegans''.
        Question. How might this understanding allow better treatment or
    prevention?
        Answer. A better understanding of the basic biochemical, genetic,
    and physiological mechanisms underlying the process of aging and age-
    related changes will provide insight as to how these changes become
    risk factors for (or accompany) age-related disease and disability.
    This, in turn, will suggest interventions that may increase both
    lifespan and health span in older adults.
        An example of basic discovery that may suggest pathways for
    prevention of disease and disability is the exciting research being
    conducted around cellular senescence and aging. Senescent cells no
    longer divide but still function within the organism and until recently
    scientists believed that they were very rare in living organisms and
    would not play an active role in aging. However, NIH-supported
    investigators recently found that high levels of senescent cells
    actually do accumulate in many tissues in aged mice, and may be an
    early marker of cancer--in fact, the earliest marker of cancer
    described to date. In a separate study, removal of senescent cells in
    mice delayed the onset of disease-related changes in skeletal muscle,
    fat, and eye tissues. In addition, removing senescent cells later in
    the life of the mice slowed the progression of already established age-
    related disorders. While research on cell cultures has long suggested
    that senescent cells have a role in aging, the nature of this
    connection in live animals was less clear. The new finding suggests
    that cell senescence may be a fundamental mechanism that drives aging,
    and provides a clear target for interventions to prevent age-related
    damage to cells and tissues.
        Question. Dr. Hodes, as a nation, we invest a significant amount of
    funding towards healthcare. What is the NIA doing--and what should the
    NIA do--to expand and translate research on prevention and wellness for
    our rapidly aging population?
        Answer. Recent NIA-supported studies conducted by the National
    Academy of Sciences have shown that although the United States spends
    more on healthcare than any other nation, Americans are in poorer
    health and live shorter lives than people in many other high-income
    countries. This health disadvantage exists across the lifespan, from
    birth to age 75. Many of the reasons behind these disparities appear to
    be behavioral and social--for example, Americans are more likely to
    engage in certain unhealthy behaviors, such as heavy caloric intake and
    behaviors that increase the risk of fatal injuries. However, even
    Americans who have health insurance, college educations, and higher
    incomes who adopt healthy behaviors appear to be sicker than their
    peers in other wealthy nations. The reasons for these disparities
    remain unclear. NIA continues to support research to determine the
    factors that contribute to premature mortality and lower disability
    adjusted life years in the United States, as well as the prospects for
    modifying such risk factors.
        In addition, NIA supports a number of studies of interventions to
    prevent disease and disability. For example, the ongoing Lifestyle
    Interventions and Independence for Elders (LIFE) Study, a major
    clinical trial comparing the effects of a moderate-intensity physical
    activity program to a health education program on prevention of
    mobility loss disability in older Americans, began in 2010. In
    addition, NIA supports a number of studies exploring the effects of
    exercise and physical activity on everything from mobility to mood and
    cognition. NIA also supports studies of a variety of interventions for
    health conditions common to old age. Ongoing studies include: the
    ASPirin in Reducing Events in the Elderly (ASPREE) trial, designed to
    determine whether the benefits of aspirin outweigh the risks in people
    over age 70; testosterone supplementation to delay or prevent frailty
    in older men; and an array of interventions for menopausal symptoms.
        Translation of research findings related to healthy aging is an
    important priority for the NIA. For example, we support 13 Edward R.
    Roybal Centers for Translational Research in the Behavioral and Social
    Sciences of Aging, which stimulate broadly based multidisciplinary
    research that improves the health, wellbeing, and productivity of older
    adults. The Roybal Centers focus on diverse topics including health and
    mobility, disease and pain management, and decisionmaking and behavior
    change.
        NIA also supports a successful program of communication and health
    education for older adults, their caregivers, and healthcare providers.
    For example, recognizing the value of exercise, the NIA partnered with
    the U.S. Surgeon General to launch its nationwide ``Go4Life'' campaign.
    This program is designed to motivate older Americans to engage in
    physical activity and exercise by becoming active for the first time,
    returning to exercise after a break in their routines, or building
    activity into daily routines. Go4Life offers exercises, motivational
    tips, and free resources to help participants get ready, start
    exercising, and keep going. The Go4Life campaign centers on an
    interactive Web site (www.nia.nih.gov/go4life), which features an
    evidence-based exercise guide in English and Spanish, exercise videos,
    and more. The initial partners include a diverse group of public and
    private Go4Life Team Members from major health and aging organizations
    and agencies, and the Institute intensified program activities in 2012.
        Further, NIA produces informative, evidence-based educational
    materials for older adults, including ``Age Pages'' in English and
    Spanish on a wide variety of topics of interest, as well as more in-
    depth documents providing information and advice on an array of topics,
    including healthy nutrition, planning for retirement, and end-of-life
    care. Finally, NIA and the National Library of Medicine have created
    NIHSeniorHealth.gov, a health information Web site tailored to the
    specific cognitive and information needs of older Americans.
                                     ______

                  Questions Submitted to Dr. Harold E. Varmus
                   Questions Submitted by Senator Jerry Moran

        Question. Dr. Varmus, I have read several news articles about the
    impressive results being generated by the Cancer Genome Atlas project.
        What is being done to ensure that the new information being
    discovered about cancer genomes will have direct benefits for patients?
        Answer. The unprecedented wealth of data generated by the Cancer
    Genome Atlas (TCGA) is dramatically increasing our knowledge of the
    range and combination of abnormalities that may be found in cancer and
    refining our understanding of molecular pathways that control its
    malignant behavior. With the long-term goal of improving diagnostic
    precision and treatment outcomes for cancer patients, TCGA data are
    being applied to an array of projects and programs in the U.S. and
    abroad. For example, the National Cancer Institute (NCI) Cancer Target
    Discovery and Development (CTD2) Network, which is a consortium of
    investigators from many research institutions in the U.S., is
    elucidating new targets for therapeutic attack in cancer and developing
    means to inhibit these targets. TCGA data are also being used to
    explore the relationship between germline genetic variation and the
    molecular features of tumors that arise in various tissues.
        TCGA data are widely available to qualified researchers through
    public databases designed to protect patient privacy, and we are
    continually striving to improve our management of these extremely large
    datasets through enhanced computational methods. The TCGA team provides
    extensive support to researchers who access TCGA data, including step-
    by-step protocols for how to locate and apply TCGA data, as well as
    preliminary data analysis to those who need assistance with
    manipulating the raw data, in an effort to maximize the efficient and
    effective use of the data. The large number of publications that use
    TCGA data (almost 400 since 2008) and the number of grant applications
    that include TCGA data (to date, more than 800) reflect the widespread
    availability and broad utilization of TCGA data by the cancer research
    community. In addition, the NCI is expanding its computational power in
    various ways to cope more effectively with the rapidly growing data
    sets from TCGA and other endeavors in cancer genomics.
        Pursuing the genetic foundations of many cancers is a vital element
    of NCI's current research, comprising a substantial proportion of the
    institute's research portfolio. A principal task in the years ahead,
    for NCI and for the entire cancer research enterprise, will be to
    capitalize on the information developed through TCGA by supporting
    additional studies that validate and extend our understanding of--and
    ability to use to diagnostic, prognostic, and therapeutic advantage--
    the critical roles for specific genomic changes in tumors. Ultimately,
    these efforts can be expected to lead to more precise classification of
    cancers and more effective interventions that improve outcomes for
    patients.
        Question. For example, are the data and the methods being
    incorporated into the design of NCI's clinical trials?
        Answer. NCI has recently consolidated a number of its genomics
    initiatives--including TCGA and several pediatric cancer initiatives,
    most notably TARGET (Therapeutically Applicable Research to Generate
    Effective Treatments), as well as CTD2--into a single Center for Cancer
    Genomics. The new Center is working with other components of NCI and
    with other investigators in addition to those directly involved in TCGA
    to ensure that research findings are applied to developing new
    diagnostics and therapeutics that can be integrated into medical
    practice. For example, new therapeutic studies are now being designed
    by our clinical trials groups in conjunction with TCGA staff to match
    the genotypes of advancing cancers with targeted drugs and to seek
    genomic explanations for unexpectedly good responses to existing drugs
    or to not yet approved agents used in clinical trials; these studies
    will use methodology developed in conjunction with TCGA projects. In
    addition, several clinical trials have already been established based
    directly on TCGA data, and we expect additional trials to be initiated
    as TCGA continues to generate new information about potential targets
    for cancer treatment strategies.
        We anticipate that our growing understanding of the molecular
    events that drive cancer development and distinguish one cancer type
    from another will have a marked effect on the way future clinical
    trials are designed. The new knowledge should enable the NCI
    cooperative groups that do most of our clinical trials to run smaller,
    more precise clinical trials with greater likelihood of therapeutic
    success. In addition, we can expect an increasing number of clinical
    trials that are somewhat tumor site-agnostic: directed at molecular
    vulnerabilities that are common to cancers that may arise in different
    tissues.
                                     ______

                Questions Submitted by Senator Richard C. Shelby

        Question. Dr. Varmus, last year you expressed concerns about
    legislation that originally would have required the National Cancer
    Institute to spend $887.8 million of its budget on pancreatic cancer
    research. I share the concern about earmarking disease specific
    research. I believe science should dictate funding and a legislative
    mandate on disease specific research would lead to a slippery slope of
    Congress moving into the driver seat of determining how the National
    Institutes of Health (NIH) research funding is spent. That said, the
    current Administration has attempted to earmark NIH funding in the past
    for both cancer and Alzheimer's disease research.
        How can it be wrong for Congress to direct funding, but not for the
    Administration to do so?
        Answer. NIH is comprised of 27 institutes and centers (IC) mostly
    organized by specific diseases, organs, and stages of life. These
    entities come together to seek the fundamental knowledge about the
    nature and behavior of living systems and the application of that
    knowledge to enhance health, lengthen life, and reduce illness and
    disability.
        Historically, Congress has given NIH the flexibility to drive
    research and this flexibility has nurtured scientific advances and
    development of means to prevent and treat diseases more effectively. A
    baby born today can look forward to an average lifespan of nearly 79
    years, nearly three decades longer than a baby born in 1900. For
    example, U.S. cancer death rates are falling more than 1 percent each
    year. and age-adjusted death rates from heart disease and stroke have
    fallen more than 60 percent in the last half-century. Thanks to anti-
    viral therapies developed by NIH funded researchers, HIV-infected
    people in their 20s can expect to live to age 70 and beyond.
        NIH will continue invest research funds based on scientific
    opportunities and public health needs. As part of the Executive Branch,
    the NIH works closely with the Administration to plan future research
    efforts. The Administration's past interest in increased spending on
    cancer research and more recent interest in Alzheimer's disease (AD)
    research both came at a time of enhanced scientific opportunity and
    public health need for progress against these devastating and common
    diseases. About half of men and a third of women in the U.S. will have
    a cancer diagnosis in their lifetimes, and cancer is the second most
    common cause of death. Moreover, research over the past three decades
    has transformed our conception of the disease, creating opportunities
    for rapid advances Thus we have learned that cancer is a disease of the
    genome, that it's not just one but many diseases, and that investments
    to use the new tools of genomics are likely to lead to rapid progress
    in the diagnosis and treatment of those several diseases. For example,
    as drugs are developed that target certain mutations, doctors will be
    able to use information about the molecular profile of a patient's
    tumor to assess whether a given drug is likely to be effective. Genomic
    knowledge can also be used to decide against a particular treatment, if
    the appropriate target mutations are not in play, thus sparing a
    patient the costs, waste of time, and side effects of a drug that is
    not likely to help them.
        The number of individuals with AD is expected to increase
    dramatically as the population ages. The U.S. Census Bureau estimates
    that the people 65 years and older will double to about 72 million
    during the next 20 years. As the population ages, the medical and
    treatment expenses associated with AD will continue to increase and
    impose a significant economic burden to society and the government. At
    the time the Administration announced the additional funding for AD,
    NIH seized the opportunities to expand on several AD advances. NIH
    supported researchers discovered that higher amounts of the brain
    amyloid deposits in dementia-free individuals were associated with an
    increased risk of developing dementia over time, making it a possible
    preclinical sign of disease even among individuals who appear mentally
    normal. In addition, NIH supported researchers developed a method of
    testing for the known biomarkers for AD in the cerebrospinal fluid.
    With these discoveries, NIH hopes to help diagnosis individuals with AD
    in order to initiate treatment efforts early and delay the progression
    of AD.
        Question. It is my understanding that you had numerous concerns
    about authorizing legislation proposed last year that would have
    specified an amount of funding for pancreatic cancer. Can you discuss
    some of those concerns?
        Answer. The National Cancer Institute (NCI) raised serious
    objections last year to a legislative proposal (a version of H.R. 733,
    filed originally on February 16, 2011, ``to provide for a Pancreatic
    Cancer Initiative''). However, our objections were directed largely
    against a new methodology that would have altered how NCI funds grant
    applications.
        In this instance, the legislation would have required that the
    Secretary of Health and Human Services convene a group, composed almost
    entirely of pancreatic cancer researchers, to recommend which grant
    applications should be funded. This would have created an unfortunate
    precedent for many groups to ask for similar privileges, a situation
    that would have been unworkable and damaging. Fortunately, this and
    several other objectionable elements were removed from H.R. 733 before
    its eventual approval as the Recalcitrant Cancers Act.
        Although we objected to the bill in question largely on other
    grounds, the NCI generally disapproves of mandates to spend specific
    amounts of money on individual cancers. This is so for several reasons.
    First, it is difficult to determine an exact number for disease-
    specific spending: some studies address multiple cancers; many are
    aimed at fundamental cell processes that are relevant to most or all
    cancers; and some grants support training, technology development, and
    other infrastructural issues that cannot be classified. More
    importantly, history has supported the argument for supporting the best
    science, rather than meeting a fiscal quota for each disease type. It
    is common for studies of one type of cancer to provide unanticipated
    insights into another type or for studies of the basic features of
    cancer to illuminate our understanding of a variety of cancers. For
    example, investment in a rare disease, retinoblastoma, was critical for
    the discovery of tumor suppressor genes, a class of genes that is
    affected in essentially every cancer type. Similarly, work on an animal
    model of neuroblastoma led to the discovery of an oncogene, HER2, which
    is targeted by antibodies now widely used in the treatment of breast
    cancer. What has worked best is the support of experiments that pursue
    the most inviting scientific opportunities. Of course, the NCI is
    attentive to its patterns of spending on many types of cancer,
    especially with regard to clinical research; but rigid prescriptions
    for funding levels limit the Institute's capacity to support the most
    productive work and respond quickly to new developments in cancer
    science.

                              SUBCOMMITTEE RECESS

        Senator Harkin. The hearing of the Labor, Health and Human
    Services Subcommittee is adjourned. Thank you again all very
    much.
        [Whereupon, at 4:20 p.m., Wednesday, May 15, the
    subcommittee was recessed, to reconvene subject to the call of
    the Chair.]