[Senate Hearing 115-663]
[From the U.S. Government Publishing Office]


                                                        S. Hrg. 115-663

                  GENE EDITING TECHNOLOGY: INNOVATION 
                               AND IMPACT

=======================================================================

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                     ONE HUNDRED FIFTEENTH CONGRESS

                             FIRST SESSION

                                   ON

  EXAMINING GENE EDITING TECHNOLOGY, FOCUSING ON INNOVATION AND IMPACT
                               __________

                           NOVEMBER 14, 2017
                               __________

 Printed for the use of the Committee on Health, Education, Labor, and 
                                Pensions
                                
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                              ___________

                    U.S. GOVERNMENT PUBLISHING OFFICE
                    
27-682 PDF                WASHINGTON : 2019    



        
          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                  LAMAR ALEXANDER, Tennessee, Chairman
MICHAEL B. ENZI, Wyoming		PATTY MURRAY, Washington
RICHARD BURR, North Carolina		BERNARD SANDERS (I), Vermont
JOHNNY ISAKSON, Georgia			ROBERT P. CASEY, JR., Pennsylvania
RAND PAUL, Kentucky			AL FRANKEN, Minnesota
SUSAN M. COLLINS, Maine			MICHAEL F. BENNET, Colorado
BILL CASSIDY, M.D., Louisiana		SHELDON WHITEHOUSE, Rhode Island
TODD YOUNG, Indiana			TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah			CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas			ELIZABETH WARREN, Massachusetts
LISA MURKOWSKI, Alaska			TIM KAINE, Virginia
TIM SCOTT, South Carolina		MAGGIE WOOD HASSAN, New Hampshire

               David P. Cleary, Republican Staff Director
         Lindsey Ward Seidman, Republican Deputy Staff Director
                 Evan Schatz, Democratic Staff Director
             John Righter, Democratic Deputy Staff Director
                            C O N T E N T S

                              ----------                              

                               STATEMENTS

                       TUESDAY, NOVEMBER 14, 2017

                                                                   Page

                           Committee Members

Alexander, Hon. Lamar, Chairman, Committee on Health, Education, 
  Labor, and Pensions, opening statement.........................     1
Murray, Hon. Patty, a U.S. Senator from the State of Washington, 
  opening statement..............................................     3
Warren, Hon. Elizabeth, a U.S. Senator from the State of 
  Massachusetts..................................................     5
Collins, Hon. Susan M., a U.S. Senator from the State of Maine...    26
Scott, Hon. Tim, a U.S. Senator from the State of South Carolina.    29
Hassan, Hon. Maggie Wood, a U.S. Senator from the State of New 
  Hampshire......................................................    31
Kaine, Hon. Tim, a U.S. Senator from the State of Virginia.......    37

                               Witnesses

Statement of Matthew Porteus, M.D., Ph.D., Associate Professor of 
  Pediatrics, Stanford University, Palo Alto, CA.................     5
    Prepared statement...........................................     7
Statement of Katrine Bosley, Chief Executive Officer and 
  President, Editas Medicine, Cambridge, MA......................    14
    Prepared statement...........................................    16
    Summary Statement............................................    20
Statement of Jeffrey Kahn, M.D., Ph.D., Director, Johns Hopkins 
  Berman Institute of Bioethics, Johns Hopkins School of Public 
  Health, Baltimore, MD..........................................    21
    Prepared statement...........................................    23
    Summary Statement............................................    25

                          ADDITIONAL MATERIAL

    Response by Matthew Porteus to questions of:
        Senator Collins..........................................    43
        Senator Murray...........................................    44
        Senator Bennet...........................................    45
        Senator Whitehouse.......................................    48
    Response by Katrine Bosley to questions of:
        Senator Murray...........................................    50
        Senator Casey............................................    51
        Senator Bennet...........................................    52
        Senator Whitehouse.......................................    53

 
             GENE EDITING TECHNOLOGY: INNOVATION AND IMPACT

                              ----------                              


                       Tuesday, November 14, 2017

                               U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The Committee met, pursuant to notice, at 10 a.m. in room 
SD-430, Dirksen Senate Office Building, Hon. Lamar Alexander, 
Chairman of the Committee, presiding.
    Present: Senators Alexander [presiding], Murray, Collins, 
Young, Scott, Casey, Warren, Kaine, and Hassan.

                 Opening Statement of Senator Alexander

    The Chairman. Good morning.
    The Senate Committee on Health, Education, Labor, and 
Pensions will please come to order.
    Senator Corker is chairing a Foreign Relations Committee 
hearing down the hall about when the President of the United 
States can use nuclear weapons.
    We are taking a different tack today.
    We are looking at something quite different and extremely 
interesting to me. It is about gene editing and a new 
technology with amazing potential that raises important ethical 
questions as well.
    Senator Murray and I will each have an opening statement, 
then we will introduce the witnesses. After the witnesses' 
testimony, Senators will each have 5 minutes of questions.
    Eric Lander, a leading geneticist and mathematician, who 
was integral to the Human Genome Project said, ``It is hard to 
recall a revolution that has swept biology more swiftly than 
CRISPR.''
    Today, we are looking at this remarkable technology to edit 
genes that has the potential to treat devastating diseases, 
including those that currently have limited treatments or 
cures.
    While CRISPR is not the only way to edit the human genome, 
it is one of the most exciting and talked about ways in the 
medical research community. It is a relatively new technology. 
It essentially uses molecules that can be targeted to act as 
scissors to cut and edit genes.
    While CRISPR acts as the search function, it goes and finds 
the mutated gene--Cas9 is the tool that deletes the disease-
causing gene--inserts new genes or repairs mutated genes. In a 
way, it is like cutting and pasting in a computer document.
    That may be an oversimplification, but CRISPR technology is 
less expensive, more precise, and more readily available to 
scientists all over the world than other gene editing 
technologies.
    A ``New York Times'' story in August reported that CRISPR 
can be used to do something as frivolous as making yeast glow 
like jellyfish to something as serious as making real strides 
against diseases, such as correcting the gene that causes 
sickle cell anemia.
    While CRISPR was developed in 1993, its use was perfected 
for humans in 2013, only 4 years ago. Its most widespread use 
until now has been in agriculture. Disease resistant wheat and 
rice has been created using CRISPR, and CRISPR has been used to 
modify tomatoes and soybeans to improve yields and create 
healthier soybean oil.
    There is the potential to create crops that can produce 
higher yields, are able to live through a drought, and have 
increased nutritional value. Some researchers are even looking 
at ways to make better tasting crops.
    CRISPR's use in humans is more recent, but the possibility 
of the diseases it could treat, and the lives that could be 
improved, is remarkable.
    According to the Centers for Disease Control and 
Prevention, sickle cell disease occurs in about 1 out of every 
365 African-American births. One of our witnesses today will be 
able to speak to research on how CRISPR can help with this 
devastating disease.
    Editas Medicine, who is represented by one of our other 
witnesses today, sees the potential to treat blood disease that 
today are currently only treatable through blood transfusions 
and bone marrow transplants. Using CRISPR, the genes causing 
blood disease could be edited and re-administered to treat the 
disease more safely and effectively.
    For cancer patients, CRISPR could improve the amount of 
time immune cells are active in fighting tumors. The 
possibilities could go on further.
    If we could eventually identify the gene mutation that, for 
example, shows a predisposition to Alzheimer's, could we edit 
that gene and prevent the suffering and heartache that 
Alzheimer's causes?
    While CRISPR, and other gene editing technologies, could 
transform human health, it is not hard to see how we can 
quickly get into societal and ethical issues.
    The technology could lead to permanent changes in the human 
genome. There is even the possibility of making changes in 
embryos to create so-called ``designer babies.''
    In the hands of our adversaries, CRISPR poses national 
security concerns through the potential to produce new 
biological weapons. In February 2016, former Director of 
National Intelligence, James Clapper, added gene editing to a 
list of ``weapons of mass destruction and proliferation.''
    I know the leaders at Oak Ridge National Laboratory, and 
other places in the intelligence community, are having 
classified discussions similar to the one we are having today.
    Part of our job on this Committee is to learn about new 
technologies, to lead the discussions with experts about the 
implications of these scientific advancements, and to ensure 
that the National Institutes of Health and others have the 
proper authority to oversee and conduct research.
    Our Committee has a long history of working in a bipartisan 
way to pass legislation that helps advance biomedical research 
to improve the health of Americans, through the 21st Century 
Cures Act last year and the reauthorization of the Food and 
Drug Administration user fees this year.
    Senator Murray has had a special role in that. Over the 
last 3 years, the Appropriations Committee--on which others of 
us serve--has added $2 billion a year to the National 
Institutes of Health and then another $4.8 billion through the 
21st Century Cures Act, and I thank her for that.
    I am also a member of that Appropriations Committee. I am a 
strong proponent of what we just described and CRISPR is just 
one of the amazing discoveries that have come from basic 
research funded, in part, by the Federal Government.
    Today's hearing is truly a hearing. I intend to do more 
listening than talking, and I appreciate our panel taking the 
time to discuss this promising technology today.
    Senator Murray.

                  Opening Statement of Senator Murray

    Senator Murray. Well, thank you very much, Chairman 
Alexander.
    Thanks to all of our witnesses, and our colleagues, for 
joining us today.
    About a year ago, Congress passed the 21st Century Cures 
Act after 2 years of work from this Committee, boosting funding 
for lifesaving research that will help drive the next 
generation of innovative treatments.
    Nearly $5 billion more will be invested to tackle our most 
challenging scientific and medical puzzles. I am really pleased 
today that we have an opportunity to talk about one piece of 
this puzzle that is truly exciting and promising.
    Gene editing technology has the potential to be used as a 
tool to tackle difficult research questions. A treatment for 
serious genetic diseases like sickle cell and Huntington's, an 
approach to engineering our own cells to fight cancer and 
infections, and a new way to help stop the spread of 
infections, vector-borne diseases like Zika and Malaria.
    I am proud that my home State of Washington is leading the 
way in advancing this technology. At Seattle Children's Ben 
Towne Center for Childhood Cancer Research, scientists are 
harnessing patients' own immune system to cure cancers that 
were not responsive to other types of therapies.
    I have had the opportunity to meet with researchers from 
Juno Therapeutics, which is working to develop T-cell therapies 
for a number of cancers.
    Though we still have much to learn about harnessing the 
power of T-cells, researchers like Dr. Porteus and companies 
like yours, Ms. Bosley, have already begun to apply gene 
editing technology to T-cells. I will be interested in hearing 
from both of you about how CRISPR technology is supporting that 
work.
    As we all know, mosquito transmitted viruses like Zika have 
had a devastating impact on patients and families across the 
United States and throughout the globe. The Bill and Melinda 
Gates Foundation is doing promising work on strategies to 
combat the spread of those viruses, which includes harnessing 
CRISPR gene editing technology to change the genetic material 
of particular mosquitoes, for example, causing mosquitoes to 
only have male offspring, which could eventually eradicate this 
particular species that serves as vectors for the viruses.
    Those are just a couple of examples, and I have no doubt 
there are ways CRISPR technology could help patients and 
families that we have not even begun to think of yet.
    I am glad that bipartisan work on this Committee has 
enabled us to enact policies in 21st Century Cures and the FDA 
user fee reauthorization that will help continue to spur 
innovation.
    In addition to investing more in research at the NIH, we 
ensured federally funded research includes diverse populations 
who have historically been underrepresented in clinical 
research. We put in place new protections to keep research 
subjects' genetic information private and given the FDA new 
hiring authority to make sure we have the best minds at the 
agency to help foster the development of this exciting new 
technology.
    There is certainly more to do and I am interested in your 
perspectives on how Congress can continue to best support 
progress while protecting patients' health and safety.
    It is absolutely critical that in continuing to make 
medical advancements, our country upholds the highest standards 
of ethics and consumer safety, and helps to ensure those 
standards are being followed around the globe.
    Dr. Kahn, you have done extensive work on the ethical 
questions surrounding biomedical research. I am glad you are 
here today to help share your expertise with the Committee 
today because in order for congressional oversight to be 
valuable, scientific consensus and standards must drive our 
decision making and approach.
    I will close by saying I continue to be inspired and 
heartened by the bipartisan commitment to investing and 
supporting biomedical research. I hope, as new opportunities 
and technologies like CRISPR emerge, we can build on the 
foundation we have established and work together to support 
those efforts and prioritize patient safety and health.
    Thank you very much, Chairman Alexander, for holding this 
hearing and I look forward to it.
    The Chairman. Well, thank you, Senator Murray.
    I would say, just for the record, this is one more 
bipartisan hearing which, for the uninitiated, means that 
Senator Murray and I agree on the subject. We agree on the 
witnesses, and that is the way we do most of our hearings, and 
that is the way we usually do our best work.
    We welcome our witnesses. Each will have up to 5 minutes. 
If you could compress your thoughts into 5 minutes, that will 
leave Senators more opportunity to ask questions.
    I am pleased to welcome the three of you.
    The first witness is Dr. Matthew Porteus, Associate 
Professor at Stanford University. His lab is using gene editing 
technology to develop potential cures for genetic diseases such 
as sickle cell, cystic fibrosis, HIV, and Huntington's disease. 
He is a member of the National Academy's Committee on Human 
Gene Editing, which published a report earlier this year.
    Senator Warren, would you like to introduce the second 
witness?

                      Statement of Senator Warren

    Senator Warren. I would. Thank you very much, Mr. Chairman.
    Massachusetts researchers and companies are at the 
forefront of the development and application of gene editing 
technology. So I am very pleased that Katrine Bosley is joining 
us here today to share her perspective.
    Ms. Bosley is the President and CEO of Editas Medicine, a 
company based in Cambridge, Massachusetts that is developing 
therapies based on the CRISPR gene editing technology.
    Editas' work tackles a wide range of genetic diseases 
including Duchenne muscular dystrophy, sickle cell disease, 
cystic fibrosis, and Usher syndrome.
    Ms. Bosley also serves as a board member of the 
Biotechnology Innovation Organization. She has been working in 
the biotech industry for more than 25 years.
    We are fortunate to have her here today to discuss the use 
of gene editing technology in drug development.
    Thank you, Katrine, and welcome.
    The Chairman. Thank you, Senator Warren, and welcome, Ms. 
Bosley.
    Our third witness will be Dr. Jeffrey Kahn. Dr. Kahn is the 
Director of Johns Hopkins Berman Institute of Bioethics and he 
is Professor in the Johns Hopkins University School of Public 
Health.
    His research interests include ethics and emergency 
biomedical technologies, a topic that is important for our 
hearing today.
    He is an elected member of the National Academy of Medicine 
and was also a member of the National Academy Committee on 
Human Gene Editing.
    Welcome to all of our witnesses.
    Dr. Porteus, let us begin with you.

                  STATEMENT OF MATTHEW PORTEUS

    Dr. Porteus. Chairman Alexander, Ranking Member Murray, 
Senate Committee Members, and the staff.
    Thank you very much for this very great honor to come and 
speak to you regarding these exciting new technologies of 
genome editing, the CRISPR/Cas9 tool, and the potential to cure 
what is now currently incurable.
    Let me briefly introduce myself. I am a physician scientist 
who is trained as a pediatric hematologist/oncologist, which 
means I take care of children who have blood diseases and 
cancer. When I wear my M.D. hat, I actually work on the bone 
marrow transplant unit at the Children's Hospital at Stanford.
    Bone marrow transplants are an intense and complicated 
procedure in which we take the blood stem cells from one person 
and give them to the patient. By using this procedure, we can 
cure children with cancer, bone marrow failure syndromes, and 
other inherited genetic diseases.
    But when I put my scientist hat on, I run a research lab 
within the Department of Pediatrics in the Stem Cell Biology 
Institute at Stanford focusing on developing genome editing to 
cure genetic diseases. It is on that I am excited to speak to 
you about today.
    I have several affiliations with groups that are interested 
in this topic, but everything that I will say today represents 
my viewpoint alone. There is a reasonable chance that at some 
point, I will put my foot in my mouth, and I apologize for that 
in advance.
    Unfortunately, there remain tens of millions of people in 
the United States, and hundreds of millions of people around 
the world, who are born with genetic diseases; most of these 
patients are actually children.
    These are diseases that are caused by single mutations in 
single genes that lead to devastating consequences. Almost all 
of these diseases have no good treatment, much less no good 
curative therapy. As has been mentioned by the Senators, 
diseases such as sickle cell disease, cystic fibrosis, 
hemophilia, and Huntington's disease are all such diseases.
    Genome editing, which is simply a more precise form of gene 
therapy, is a potentially ideal cure for these monogenic 
diseases because it gives us the ability of converting disease 
causing mutations in DNA back into non-disease causing 
sequences. It is a method to correct typographical errors in 
the DNA of cells.
    The current most efficient method of doing genome editing 
is to design a nuclease, a protein, that will bind to a 
specific site in the DNA and break the DNA at that site. This 
activates the cell to try to fix the break, and the cell can 
try to fix this break in one of two ways.
    One of the ways is to simply glue and stitch the ends back 
together. Now, this gluing process is mostly accurate, but 
occasionally it will create insertions and deletions at the 
site of the break, and this is a way of inactivating a harmful 
genetic element.
    The other way that a cell can fix a double stranded break 
is what we call homology-directed repair, which is essentially, 
as has been described, a copy and paste mechanism in which a 
copy of an undamaged piece of DNA is made and then swapped in 
for the damaged piece of DNA. In this way, we can precisely 
change single letters of the DNA; we can change multiple 
letters of the DNA. Again, it is through homology-directed 
repair that we can correct typographical errors.
    There are multiple different ways to create that initiating 
double stranded break, but the CRISPR/Cas9 technology has 
really revolutionized this field because, as has been 
mentioned, it is simple to use, it is highly active, and when 
used in a controlled fashion is highly specific.
    While there are no clinical trials in the U.S. or Europe 
right now using the CRISPR/Cas9 technology for genome editing, 
I expect that in the next 12 to 18 months, there are going to 
be multiple such trials.
    I want to discuss one example of how my lab is using the 
CRISPR/Cas9 technology, and that is to treat sickle cell 
anemia, which we estimate affects about 100,000 people in the 
U.S. They all have mutations in the globin gene.
    What we are able to do in the lab now is to use the CRISPR/
Cas9 homology direct to repair pathways to correct around 50 to 
70 percent of the cells, the blood stem cells, from patients 
who have this disease. It is estimated that if we can keep 
above 20 percent, that this would cure the disease.
    In addition, the specificity is very high and we are about 
hundred to a thousandfold more specific than just cells living 
on their own without being exposed to genome editing.
    We have now had very great conversations with the FDA about 
what our path from the lab to the clinic is, and we are hoping 
that we are able to bring this to clinical trails in 2019.
    In the last few seconds, I want to just point out that we 
believe that the current regulatory structure with the FDA, the 
Recombinant DNA Advisory Committee, and the IRB is completely 
adequate in handling the assessment of the size and ethics of 
doing genome editing of somatic cells.
    I hope that the controversial issues that surround genome 
editing do not distract us from being able to stay focused and 
committed to developing curative therapies for devastating 
genetic diseases like sickle cell anemia.
    With that, I want to thank you and thank you for the 
invitation.
    [The prepared statement of Dr. Porteus follows:]
                                ------                                

                 prepared statement of matthew porteus
    The world is still troubled by diseases for which we have no cure. 
Some of the most devastating diseases for which we have no cure are 
monogenic diseases-disease's in which a child is born with an inherited 
mutation in a single gene causing a disease. Sickle cell disease, beta-
thalassemia, cystic fibrosis, hemophilia, and Huntington's Disease are 
just a few of the most common and well known genetic diseases. It is 
estimated that there may be 10,000 such diseases affecting a total of 
35 million people in the United States and >350 million people 
worldwide although the true health burden is unknown and could be much 
greater. These diseases not only have devastating impact on the 
patient, but incur great costs on families, communities, and societies. 
Most of these have no cures and finding such cures would have broad 
health and economic benefits. Gene therapy is one approach to finding 
cures and after 40 years of hard and focused work, gene therapy is 
beginning to pay off with hundreds of patients now having better lives 
because of it.
    Genome editing is a more precise form of gene therapy and allows 
researchers to change the sequence of the DNA in a cell with single 
letter precision. It has generated tremendous excitement because it 
offers a conceptual approach to providing an ideal cure for thousands 
of diseases. While genome editing has been studied for >15 years, the 
pace of discovery has accelerated in the last 5 years with the 
development of new tools, most notably the CRISPR/Cas9 nuclease system. 
The CRISPR/Cas9 system allows scientists to correct disease-causing 
mutations in human cells with unprecedented efficiencies. In my lab, 
for example, we can correct the mutation that causes sickle cell 
disease in patient derived blood stem cells at a frequency of 50-80 
percent. For severe combined immunodeficiency (``bubble boy disease'') 
our correction frequency is 40-50 percent. For both the correction is 
highly specific and exceeds the level of correction by 5-10 fold over 
the efficiency that is predicted to be needed to cure a patient. We 
have been working closely with the FDA to bring these therapies to 
patients in the next 12-18 months.
    We believe that the current regulatory structure has been 
appropriate as researchers begin to bring somatic cell editing for the 
treatment of disease to clinical trials and ultimately to market as an 
approved drug. The FDA has shown flexibility in working with 
researchers to expedite these therapies in a safe fashion to patients. 
Moving forward, as the research and medical community, private sector, 
and regulatory agencies, become more familiar with genome editing based 
therapeutics, we hope that the FDA will be flexible in its thinking 
such that cures can be brought to market not just for diseases for 
which there is a solid commercial incentive but also for diseases that 
are not commercially profitable.
    While the application of genome editing of somatic cells to cure 
disease is accelerating, there are a number of other applications of 
genome editing that have generated headlines and controversy. These 
other issues, should not distract from what is needed to bring curative 
somatic cell based therapies to patients----including sustained, 
substantial financial support, excellent public/private partnerships, 
and an active, scientifically based and flexible regulatory structure.
    The other issues surrounding genome editing, which notably are not 
new and have been discussed and debated for decades in the scientific, 
medical, bio-ethical community, not to mention in movies and stories. 
These issues include the use of genome editing to: 1) Better understand 
early human development as a research tool; 2) Create genetic changes 
that would be passed along the germline; 3) Create so called genetic 
enhancements in humans. Broad, inclusive and continued discussions are 
needed in each of these areas. The use of genome editing as a research 
tool for understanding early human development will likely yield 
discoveries about what it means to be human and improve the current 
practice of in vitro fertilization. The potential use of germline/
heritable editing to treat disease is likely to be quite limited; would 
be obviated by improvements in somatic cell genome editing or gene 
therapy; and reasonable and restrictive criteria by which it might 
explored have been outlined by the recent National Academy of Sciences/
National Academy of Medicine International Study Committee entitled 
``Human Genome Editing: Science, Ethics and Governance.'' Finally, the 
use of genome editing or any other genetic means for ``enhancement'' 
violates multiple fundamental core beliefs of our society and other 
societies. The FDA currently has the authority to regulate such 
potential applications in the United States. Ongoing international 
conversations and meetings will be important to gain agreement trans-
nationally on the issue of enhancement.
     the relationship of genetics to human disease and human traits
    The instructions or code for the actions of a cell are embedded in 
the DNA sequence of the cell's genome. DNA consists of a series of 
nucleotides (letters (A, C, G, T)) and it is the order of these four 
letters that the cell decodes. The primary unit of the genome is a gene 
which consists of two major parts: 1) The coding part of the gene gives 
instructions to the cell about how to make a protein (proteins are the 
machines that carry out the work of the cell) and 2) The non-coding 
part of the gene gives instructions as to when and where the cell 
should make the protein. A basic example of how a gene works is the 
human beta-globin gene (named HBB). The coding part of the HBB gene 
instructs the cell to make the beta-globin protein in a certain way. 
The beta-globin protein is an essential part of a complex that carries 
oxygen from the lungs to the tissues (such as brain, heart, muscles, 
intestines.). The non-coding part of the HBB gene instructs the cell 
when and where to make beta-globin protein. For the HBB gene, the 
instructions tell the cell to only make beta-globin protein in red 
blood cells but not in any other cell types, such as brain cells or 
even other blood cell types.
    Every cell in a person has a DNA sequence that is nearly identical 
but not exactly identical to the sequence created when the sperm 
fertilized the egg and the sperm DNA combined with egg DNA to make the 
full DNA complement needed for a human cell to function. The sequencing 
of the human genome revealed that each cell has 6 billion total 
nucleotides in the DNA (3 billion from the egg and ?3 billion from the 
sperm). Except for the X chromosome and Y chromosome in males, every 
person has two copies of each gene.
    Since DNA is a chemical, the nucleotides (letters) can be changed 
by exposure to other chemicals creating DNA variants (or 
``mutations''). This mutation process is ongoing and each day it is 
estimated that a cell acquires between 1-100 new mutations per day. 
Thus, every cell in the body has its own unique sequence of DNA. 
Moreover, cells often intentionally create changes in their DNA. In the 
development of the immune system, for example, the cells rearrange 
their genes (``VDJ recombination'') that help fight infection in order 
to create a strong and robust immune system to deal with the world we 
face. In the development of sperm and egg (our germ cells), there is 
the regulated rearrangement of the DNA (``meiotic recombination'') to 
intentionally create genetic diversity in the next generation.
    There is tremendous variation between the DNA sequence of one 
individual and another, thus providing the basis for the rich variation 
and diversity that has been an important contributor to human success 
and robustness. Almost all of the key features that we ascribe to being 
human, however, are not encoded by a single gene but are shaped by a 
large network of genes interacting with the environment. We have only 
rudimentary knowledge of these gene networks and environmental 
interactions and ongoing sustained and substantial funding for research 
is needed.
    An inherited genetic disease (``monogenic disease'') is caused when 
a person is born with a sequence in a gene (a mutation) such that the 
gene does not perform in a healthy way-either the gene is instructing 
the cell to make a protein that does not work properly or the gene 
instructions for telling the cell where and when to make the protein 
are off. Most monogenic diseases are caused by mutations that cause the 
gene to instruct the cell to make a disease-causing protein, rather 
than having the cell to make a functional protein in the wrong time and 
place. There are estimated to be 6,000-10,000 different genetic 
diseases. Sickle cell disease, cystic fibrosis, hemophilia, and 
Huntington's disease are all examples of monogenic diseases. All 
genetic diseases are classified as rare in the United States because 
they affect less than 300,000 people in the country it is estimated, 
for example, that 100,000 people in the U.S. have sickle cell disease, 
30,000 have cystic fibrosis, and 30,000 have Huntington's Disease. Most 
genetic diseases are classified as ultra-orphan diseases because they 
might affect tens or less people in the U.S. at any one time point. 
While each genetic disease might not affect a lot of individuals, 
however, to the patients, families and communities they are devastating 
diseases that often have no cure or even good treatment to lessen the 
severity.
    There are other diseases, such as cancer, that are acquired genetic 
diseases. In acquired genetic diseases, the DNA sequence of a cell 
changes after a birth and that cell now receives instructions that can 
cause disease. In cancer, a cell may acquire mutations that instruct 
the cell to make a variant of a normal protein or it may acquire 
mutations that instruct the cell to make a protein that it normally 
would not. Both types of mutations are usually present in cancer cells.
    Finally, there is a fascinating interaction between the environment 
and our genes. Our DNA sequence may influence our health and who we are 
but it is not deterministic. Even in the most severe genetic diseases, 
such as sickle cell disease and Huntington's disease, there is 
tremendous variation in how the disease affects patients determined by 
the environment and not determined by the DNA sequence. An example is 
sickle cell disease, where every patient carries the same mutation. In 
the United States the average life span for sickle cell disease 
patients is the mid-40's whereas the average life span in Africa's 5-8 
years of age. In this case, living in an environment where there is a 
sophisticated health care system dramatically alters the life of a 
patient.
    While the sequence of the gene shapes when and how a gene will be 
expressed, so does the environment we live in. That is, signals from 
the environment also control when and where a gene is expressed, so 
again the DNA sequence of a genome is not deterministic.
    The relationship of the environment with the genome also shows how 
there is no such thing as one ``best'' genome. Instead different DNA 
sequences may be better in one environmental situation but worse in 
others. One important example is the CCR5 gene, a gene that helps 
regulate how our immune system responds to infection. A small number of 
people have mutations in the CCR5 gene that make them resistant to 
infection by HIV. But these same people are more susceptible having 
severe infections when they get West Nile Virus or other infections. 
Thus, in an environment with high prevalence of HIV, it might be 
beneficial to have a CCR5 mutation. In an environment with a high 
prevalence of West Nile Virus, however, it would be a disadvantage. We 
usually do not know into what environment we are going to be born into 
or what environments we will end up in as we live our lives. I never 
expected in my lifetime to be testifying in front of the Senate HELP 
Committee, for example.
    We are just beginning to understand the complex ways that the 
environment and genome interact and any predictions about how changing 
the DNA sequence of a healthy individual would impact the life of that 
individual should be taken with a large spoonful of humility.
    In sum, for most people the DNA sequence of a person shapes but 
does not determine their health. For certain individuals with monogenic 
diseases, however, they had the unfortunate luck, through no fault of 
their own, to be born with a sequence in a gene that causes them to 
have a severe disease, usually a disease for which we currently have no 
cure or even treatment to lessen its severity. Finding transformative 
therapies, such as by using genome editing, is of tremendous 
importance.
genome editing is a precise form of gene therapy to treat human disease
    Gene therapy is based on the idea that changing the DNA of a cell 
can be a way to cure diseases. Genome editing is a more precise form of 
gene therapy. Genome editing is the ability to change the sequence of 
the DNA of a cell with both spatial and nucleotide precision. A list of 
changes that can be done using genome editing include, but are not 
limited to the following: 1) making precise mutations in genes in order 
to inactivate them; 2) deleting specific segments of DNA, 3) simply 
changing one letter/nucleotide of DNA to another or; 4) inserting large 
DNA segments into precise locations in the genome. Each of these uses 
of genome editing has potential applications in the treatment of human 
disease.
    While there are ways of performing genome editing without making a 
specific DNA break, the current most efficient method of performing 
genome editing is to use a DNA double-strand break. In this method, a 
nuclease is designed to bind to a specific DNA sequence in the genome 
and after binding to cut both strands (thus creating a DNA double-
strand break). The double-strand break then activates the cell's own 
machinery (a complex of proteins) to repair the break. It can repair 
the break in two primary ways.

    1) In non-homologous end-joining (NHEJ) the cell glues/stitches the 
two-ends back together. Usually this stitching is accurate but 
sometimes there is a loss or gain of extra letters during the joining 
which then results in an INDEL (for insertion/deletion) mutation at a 
specific location in the genome. This NHEJ mediated genome editing 
usually results in a mutation-thereby inactivating or breaking the 
gene.
      For example:
    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
    

    2) In homology directed repair (HDR) the cell finds a piece of DNA 
that is nearly identical to broken DNA, makes a copy of the undamaged 
DNA and then uses the new DNA to paste into the damaged site (cut, copy 
and paste).
      For example:
    [GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
    

    Using HDR mediated genome editing, therefore, one can create 
precise changes in the letters for the genomic DNA.

    There are multiple different tools to design an engineered nuclease 
to make a specific DNA doublestrand break. These include homing 
endonucleases, zinc finger nucleases (ZFNs), TAL effector nucleases 
(TALENs), and RNA guided based nucleases including variations such as 
the CRISPR/Cas9 nuclease (please see briefing from ASGCT on November 
21, 2016 for more details). There are likely going to be even more 
tools developed in the future. In the U.S. and Europe, all currently 
approved genome editing clinical trials use either ZFNs or TALENs-
CRISPR/Cas9 based trials will likely begin in 2018 and 2019. 
Nonetheless, the CRISPR/Cas9 system is currently the best tool to 
perform genome editing because of its simplicity of design, its high 
activity, and when used carefully, its high specificity. The CRISPR/
Cas9 tool has opened the field of genome editing to a much broader 
swath of investigator both in the US and around the world and as a 
consequence has transformed the field. With prior nuclease tools there 
was a substantial barrier to scientists entering the field because of a 
small number of gatekeepers who had the necessary expertise for that 
nuclease. With the simplicity of the CRISPR/Cas9 tool, the role of 
gatekeepers to using genome editing has essentially disappeared. While 
the use of CRISPR/Cas9 is not as simple as it is sometimes described 
(that it can be easily used to genetically engineer cells in a garage), 
it is a simple enough that a reasonably staffed and equipped lab can 
use the tool quite easily. The thousands of publications in the last 4 
years from small and large institutions in the United States and across 
the world are an objective marker of the broad utility of CRISPR/Cas9 
based genome editing. While CRISPR/Cas9 Therapeutic Applications of 
Genome Editing to Humans based genome editing can be easily used for 
research in the lab, translating its use to treat human disease remains 
a complex and sophisticated process that goes far beyond simply having 
expertise in the editing process itself.
    For human therapeutic applications, the CRISPR/Cas9 tool does not 
enable theoretically applications that could not be done using other 
nuclease platforms. Practically, however, it makes such applications 
more feasible. My research program has used all of the above nuclease 
platforms over the last 15 years and currently uses the CRISPR/Cas9 
tool because we have identified it as having the features that make 
translating genome editing to the cure or treatment of serious human 
diseases most feasible.
                   genome editing as a research tool
    The CRISPR/Cas9 tool has enabled a broad range of researchers to 
use the powerful approach of genome editing as a research tool to gain 
better understanding of biomedical processes. This development has 
already resulted in important discoveries in all aspects of biomedical 
research including, but not limited to, cancer, infectious diseases, 
autoimmunity, neurodegenerative diseases, developmental diseases and 
monogenic disease. These applications are uncontroversial and with 
significant and sustained support from the Federal government will 
likely transform our understanding and treatment of disease both in the 
short term (next five years), medium-term (next 5-20 years) and long-
term (over the next 20 years).
    There are applications of genome editing, however, that require 
ongoing and further broad discussion. These applications of genome 
editing were possible using prior genome editing tools, but have become 
substantially more feasible with the discovery of the CRISPR/Cas9 tool.
    One such application is the use of genome editing to better 
understand early human development. It is clear that early human 
development cannot be fully understood by studying the early 
development of other species, particularly mice. The precision of 
genome editing provides a powerful tool to better understand this 
critical stage in human development. From a research perspective, using 
genome editing of human zygotes (whether at the blastocyst stage from 
unused embryos derived from in vitro fertilization procedures or 
created directly for research purposes) will lead to important 
discoveries. There is a discrepancy across countries and across states 
within the United States about the legality and permissibility of such 
studies. It is possible that scientists who are interested in this 
stage in early human development will take their research programs to 
places where such research is more permissive. It is also important 
through public discussion and debate that shared beliefs are explored 
such that potential appropriate agreed upon limits and guidelines are 
generated.
    A second area for further discussion is the use of genome editing 
to create large animal models of human disease. Using the new tools of 
genome editing it is now possible to create specific models of 
devastating human diseases in animal models other than mice. This will 
result in the intentional creation of suffering in these animals. There 
should be a forum that allows all interested parties to participate in 
adjudication of the moral, scientific and cultural risk/benefit of 
intentionally creating and propagating such non-rodent models. Whether 
that adjudication should be for non-human primates only or also include 
the creation of models in other species, such as dogs and pigs, needs 
to be broadly discussed.
      genome editing of somatic cells to treat or prevent disease
    One of the areas that generates the most excitement for genome 
editing is its application to treat or prevent human disease. While 
exciting clinical successes have now been reported for the treatment of 
monogenic inherited diseases (severe combined immunodeficiency, Wiskot-
Aldrich syndrome, metachromatic leukodystrophy, cerebral 
adrenoleukodystrophy, spinal muscular atrophy, hemophilia, beta-
thalassemia, congenital blinding diseases.) and cancer (engineered 
Chimeric Antigen Receptor T-cells) using gene therapy, there remains 
tremendous excitement and potential for genome editing.
    Genome editing can be roughly divided into ex vivo and in vivo 
approaches (nicely described in the November 21, 2016 briefing 
documents provided by the American Society of Gene and Cell Therapy to 
the HELP Committee). In ex vivo approaches, cells from a patient are 
removed from the body, genetically modified outside the body, and then 
transplanted back into the patient. In ex vivo gene therapy, the 
therapeutic product is a therapy that combines genome editing (using 
genome editing to modify the genomic DNA sequence of the cell) with 
cell therapy (transplanting the cells back into the patient). In in 
vivo genome editing, the genome editing machinery is packaged into a 
vector. The vector is then delivered directly to the patient with the 
intent of modifying the appropriate somatic cells of the body to 
achieve a therapeutic effect without unintentionally modifying the 
germline cells of the patient.
    There are a broad number of diseases for which genome editing is 
being developed to treat. Some of these, such as sickle cell disease, 
severe combined immunodeficiency, beta-thalassemia, are best approached 
using an ex vivo strategy, while others, such as congenital blinding 
diseases and muscular dystrophies, are probably best approached using 
an in vivo strategy. For many diseases, more research needs to be done 
in order to determine whether an ex vivo or in vivo approach will give 
the best safety and efficacy.
    In these approaches, genome editing is used to fundamentally 
correct a missing function. Another use of genome editing is to enhance 
the disease treating function of the cell. The enhancement of cell 
activity to treat disease should not be confounded with enhancement of 
traits in humans. An example of such an application is using genome 
editing to increase the safety and efficacy of CAR-T cells against not 
only leukemia but also against solid tumors, which so far have been 
recalcitrant to the activity of first generation CAR-T cells.
    CRISPR/Cas9 based genome editing strategies to treat human disease, 
both genetic diseases and cancer, are likely to enter clinical trials 
in the United States in the next 1-2 years.
    The current regulatory structure in the United States, which has 
been developed around the development of gene therapy, is well suited 
to assess which trials and products should be approved in the United 
States. While the field of therapeutic genome editing is relatively 
new, the FDA has the authority and expertise to make the appropriate 
judgments. For issues that may have broader issues, the Recombinant DNA 
Advisory Committee (RAC) has the authority to evaluate genome editing 
based clinical trials of somatic cells with public input and then 
providing advice on such trials. Finally, institutional IRBs have the 
authority and ability to engage relevant scientific and medical 
expertise as needed to evaluate risk/benefit and give ultimate approval 
to deliver the therapy as part of a clinical trial. This safety first, 
patient-centric regulatory structure does not need any major structural 
changes to handle the therapeutic application of genome editing of 
somatic cells.
    There are areas of regulation of somatic cell editing for disease 
that should be considered in order to enhance the distribution of this 
potentially transformative technology.
        1) For first in human uses of genome editing, the current 
        regulatory structure is appropriate. But if genome editing 
        strategies are shown to be safe and are based on a shared 
        platform, the regulatory agencies should have the flexibility 
        to standardize a core set of experiments to allow investigators 
        to bring transformative therapies in a more streamlined fashion 
        to patients. In this way the financial resources of large 
        pharmaceutical companies or well-funded biotechnology 
        companies, whose fiduciary interests might not always align 
        with a developing a therapy for a disease that affects only a 
        small number of patients, would not be necessary. This 
        regulatory flexibility would not preclude such companies from 
        becoming involved in developing such therapies if they chose 
        to, however.
        2) The United States should consider developing a more flexible 
        approval structure for cell and gene therapy products based on 
        data from well-designed early clinical proof-of-concept 
        clinical studies that show both safety and efficacy. This new 
        flexible structure might be similar to what has been put in 
        place in Japan or the pilot program at the European Medical 
        Agency. In this structure, a conditional, time-limited approval 
        for a product is given such that the company can generate 
        revenues while definitive safety and efficacy data is 
        generated. This flexibility would also facilitate the 
        development of therapies for ultra-orphan diseases.
        3) There may be certain devastating childhood diseases for 
        which gene therapy and genome editing needs to be administered 
        before birth to be effective. Depending on the situation and 
        stage at which the therapy might be administered, there is a 
        chance of the unintentional modification of cells that give 
        rise to germ cells. The regulatory agencies should be given the 
        flexibility to evaluate the risk/benefit of such a proposed 
        therapy. They may need to be given the authority to evaluate 
        the ethical risk/benefit in addition to the medical risk/
        benefit in certain circumstances.
    In sum, the application of genome editing in somatic cells shows 
tremendous promise to provide cures for patients with diseases who 
currently often have no disease-modifying, much less curative, therapy 
available. While there is excellent support currently from a large 
variety of funding sources, the long-term success of the clinical 
applications of genome editing will still require the sustained and 
substantial financial support of basic science research-not only of the 
research itself but also of talented, creative, and motivated junior 
researchers who will discover therapies that we might not even be able 
to currently imagine. It should be noted for example, that the best 
genome editing tools we now have, were discovered from basic research 
that at the time was seemingly unrelated to gene therapy, genome 
editing or developing transformative therapies for patients.
        heritable (germline) editing to treat or prevent disease
    As therapeutic cell gene therapy and genome editing becomes better 
and more efficient, the number of diseases for which it might not work, 
becomes smaller and smaller. The consequence of such improvements in 
somatic cell genome editing and gene therapy, is that the need for 
having to make genetic modifications in cells that would then be passed 
along to future generations will decrease.
    Nonetheless, there still could be certain diseases for which 
somatic cell editing may not be possible or effective-such as for 
diseases in which the pathologic manifestations occur prior to birth 
and are not reversible.
    In this situation, the only way to prevent or cure the disease may 
be to intervene at such a stage that genetic modification of cells to 
treat or prevent the disease will result in the genetic modification 
being passed along to future generations (heritable editing).
    The recent International Committee on Human Gene Editing: 
Scientific Medical and Ethical Considerations sponsored by the National 
Academy of Sciences and National Academy of Medicine, released a report 
``Human Genome Editing: Science, Ethics and Governance'' (hereafter 
called the ``NAP Report'' and accessible at: https://www.nap.edu/
catalog/24623/human-genome-editing-science-ethics-and-governance). This 
Committee considered this possibility and outlined some very specific 
and relatively restrictive criteria by which one might consider such an 
approach (listed here):
         Absence of reasonable alternatives
         Restriction to preventing a serious disease or 
        condition
         Restriction to editing genes that have been 
        convincingly demonstrated to cause or to strongly predispose to 
        the disease or condition
         Restriction to converting such genes to versions that 
        are prevalent in the population and are known to be associated 
        with ordinary health with little or no evidence of adverse 
        effects
         Availability of credible pre-clinical and/or clinical 
        data on risks and potential health benefits of the procedures
         Ongoing, rigorous oversight during clinical trials of 
        the effects of the procedure on the health and safety of the 
        research participants
         Comprehensive plans for long-term, multigenerational 
        follow-up while still respecting personal autonomy
         Maximum transparency consistent with patient privacy
         Continued reassessment of both health and societal 
        benefits and risks, with broad on-going participation and input 
        by the public
         Reliable oversight mechanisms to prevent extension to 
        uses other than preventing a serious disease or condition
    All of these criteria are important and need continued and ongoing 
discussion. I will emphasize that the first criteria, ``Absence of 
reasonable alternatives,'' is quite restrictive because In Vitro 
Fertilization followed by Pr Implantation Genetic Diagnosis (IVF-PGD) 
serves as an alternative to almost every situation that a couple might 
encounter if they desired to have a genetically related child without 
disease. The rare situations of both parents carrying an autosomal 
recessive disease, one parent having both copies of an autosomal 
dominant gene (such the child would have a 100 percent chance of 
inheriting one the disease causing dominant genes), or specific types 
of genetically based infertility are the few examples where IVF-PGD 
would not be an approach to having a genetically related child without 
disease. While the process of IVG-PGD remains quite inefficient, it is 
likely to improve with time (particularly as genome editing is used to 
further understand this stage of human development). There are strong 
arguments that IVF-PGD would reduce economic and healthy suffering 
costs for patients, parents, families, communities, and societies. In 
the United States the cost of IVF-GD is not covered by insurance, 
however, and thus is only available to people who have the resources to 
pay for it directly.
              gene therapy/genome editing for enhancement
    A long discussed potential application of genetic engineering, gene 
therapy, and now genome editing is for enhancement--the application of 
the procedure to genetically engineer humans who have characteristics 
beyond what they could achieve by hard work and careful living. I 
believe that such applications violate many of the key ethical and 
moral beliefs of our country and society. While we should endeavor to 
create a society in which everyone has the opportunity to achieve their 
goals, I do not believe genetic tools should be used to do so. I 
believe that the goal of the biomedical research establishment is to 
create healthy babies/humans, not designer babies/humans. Using genetic 
methods to treat a patient to remove suffering and so that they can 
live in the normal range of humans is different than using genetic 
enhancement to give one person an advantage over another. The following 
are reasons for this assessment. For purposes of this document, I will 
use the term ``genome editing'' to encompass all such genetically based 
activities for the purpose of enhancement.
         Genome editing for enhancement involves treating 
        people as objects, not as humans.
         Genome editing for enhancement reduces personal 
        autonomy.
         Genome editing for enhancement violates the principle 
        of humility.
         Genome editing for enhancement violates the principle 
        that the human traits we consider most important are the result 
        of the interaction of multiple gene variants and an environment 
        and cannot be defined by a single gene or gene variant.
         Genome editing for enhancement increases the risk of 
        structural inequality.
         Genome editing for enhancement increases the risk that 
        we increase structural stratification with the belief that one 
        human being is better than another.
         Genome editing for enhancement does not respect that 
        engineering for one trait may result in compromising the long-
        term health of the individual.
         Genome editing for enhancement increases the risk that 
        we make evaluations under the rubric that there is one best 
        thing. There is no such thing as one best trait, human 
        characteristic or feature.
    The concerns listed are magnified if applied to heritable/germline 
genome editing.
                                ------                                

    The Chairman. Thank you, Dr. Porteus.
    Ms. Bosley, welcome.

                  STATEMENT OF KATRINE BOSLEY

    Ms. Bosley. Thank you.
    Chairman Alexander, Ranking Member Murray, and Members of 
the Committee.
    Thank you for the opportunity to testify today about genome 
editing technology.
    I am Katrine Bosley, President and CEO of Editas Medicine 
and at Editas, we are committed to harnessing the power and 
potential of CRISPR genome editing to develop medicines for 
patients with serious diseases where other technologies have 
not been able to help.
    Our company was founded 4 years ago in Cambridge, 
Massachusetts and we built a team of over 100 people to tackle 
these deep scientific challenges of turning this exciting 
science into medicines.
    There are a few times in our lives when science astonishes 
us. When something was science fiction yesterday, but now is 
reality. This is one of those moments.
    Our DNA is at the root of each one of us, that unique 
combination of genes that make you who you are. Sometimes, 
though, there are mistakes in DNA, mutations in genes that can 
cause many different kinds of serious diseases.
    There are over 6,000 different genetically defined diseases 
and the National Organization for Rare Disorders says that 95 
percent of them have no approved therapies.
    What if you could address the root cause of these diseases 
driven by mutations in our DNA? What if you could repair the 
broken genes? How many patients could we help? This is the 
promise of genome editing.
    We bear a great responsibility to patients, to their 
families, and to society broadly, and we take that 
responsibility very seriously.
    CRISPR, which is an acronym for Clustered Regularly 
Interspaced Short Palindromic Repeats, refers to a recently 
developed genome editing technology that can revise, remove, or 
replace DNA. It is the latest in a series of genome editing 
technologies which includes zinc finger nucleases, TALEN's, and 
meganucleases.
    At Editas Medicine, our most advanced CRISPR program is 
focused on a rare disease called Leber's Congenital Amaurosis 
type 10 or LCA 10. Children with LCA 10 go blind and they live 
with that condition the rest of their lives. There are no 
treatments today.
    Our goal is to file an investigational new drug application 
with the FDA for this program by mid 2018. Our broader pipeline 
focuses on a range of other diseases including other eye 
diseases, inherited blood disorders such as sickle cell 
disease, and producing new cell therapies to treat cancer along 
with our partner Juno Therapeutics.
    Editas Medicine and, to my knowledge, all the other 
companies working in this field are exclusively developing 
medicines that work by making non-heritable gene edits to 
somatic cells. This means that these non-heritable gene edits 
cannot be passed onto future generations.
    In the United States, genome editing clinical trials are 
conducted under the current robust regulatory Federal 
framework. This framework has guided clinical research and drug 
development involving genetic technologies over the past 40 
years.
    Genomic medicines developed with novel genome editing 
technologies like CRISPR have and will be subject not only to 
FDA review, but also to public review by the NIH's Recombinant 
DNA Advisory Committee, or the RAC.
    In conjunction with the RAC, the FDA is overseeing gene 
therapy development since the 1990's and these two agencies, 
working in tandem with other oversight mechanisms, will use the 
same framework to oversee clinical applications of CRISPR 
genome editing technology.
    The United States has a rigorous, transparent, and flexible 
regulatory system that is pro-patient, pro-innovation, and has 
served as a model for the rest of the world.
    Today's hearing is another hallmark in this Committee's 
long and distinguished history of overseeing biomedical 
research and promoting a tremendous American ecosystem of 
biomedical innovation and service of patients.
    At Editas Medicine, we are fully aware that genome editing 
in general, and CRISPR in particular, is a fast moving, 
potentially disruptive technology. That is why we believe it is 
our responsibility to engage with major stakeholders in a 
highly transparent and respectful manner.
    I know that the leading organizations in this area 
including BIO, ARM, and the American Society for Gene and Cell 
Therapy are also deeply committed to engaging with others on 
the science and policy implications of genome editing.
    I have been in the biotech industry for more than 25 years 
and it is hard to compare genome editing with any other 
technology that I know. The pace of innovation, the profound 
potential to help patients, the revolutionary impact on 
healthcare, all of this makes the field of genome editing truly 
exceptional.
    Thank you for the opportunity to testify today and I look 
forward to your questions.
    [The prepared statement of Ms. Bosley follows:]

                  prepared statement of katrine bosley
    Chairman Alexander, Ranking Member Murray, and Members of the 
Committee, thank you for the opportunity to testify today about genome 
editing technology.
    I am Katrine Bosley, CEO and President of Editas Medicine. At 
Editas Medicine, we are committed to harnessing the power and potential 
of CRISPR genome editing to develop medicines for patients with serious 
diseases where other technologies have not been able to help. We are 
only focused on applying our CRISPR genome editing platform to cells 
that cannot pass on changes to future generations. Our company was 
founded 4 years ago in Cambridge, Massachusetts, and we have built a 
team of over 100 people to tackle the deep scientific challenges of 
turning this exciting--but young--technology into medicines. We are one 
of a small number of companies in this field of genome editing, and we 
believe we are on the brink of a truly exciting new era of medicine, 
powered by genome editing technologies.
    There are a few times in our lives when science astonishes us, when 
we are suddenly able to do something that seemed like science fiction 
just the day before. This is one of those moments. Our DNA is at the 
root of who each of us is--that unique combination of genes that makes 
you who you are. But sometimes there are mistakes in DNA--mutations in 
genes that can cause many different kinds of serious diseases. There 
are over 6,000 genetically defined diseases, and, according to the 
National Organization for Rare Disorders (NORD), 95 percent of them 
have no approved medicines. What if you could repair broken genes? What 
if you could address the root of diseases caused by mutations in DNA? 
How many patients could we help in the years ahead? This is the promise 
and possibility of gene editing.
    My testimony today will focus on how innovative American 
researchers, universities, and companies are advancing new genome 
editing tools like CRISPR to translate the value of the Human Genome 
Project and its insights into a new class of transformative medicines 
that work at the level of the gene to treat serious diseases that 
afflict millions of Americans. The field of gene therapy and genomic 
medicine has been working toward this moment for decades, and this year 
marks the first time that some of these patients will have access to 
gene therapy products approved by the U.S. Food and Drug Administration 
(FDA). These gene therapy product approvals promise to be the first of 
many new genomic medicines that can address previously untreatable 
diseases and help patients move from chronic to durable treatments. 
Continued success in this field will depend in part upon Congress 
maintaining the robust, but flexible regulatory system over novel 
genetic technologies that has operated effectively since the first 
recombinant genetic research began over 40 years ago. Maintaining 
regulation that is both rigorous and science-driven not only protects 
patients, it also helps the American biotechnology industry flourish. 
Our industry leads the world by a very long measure, and sophisticated, 
highly engaged regulators are a key and valued partner in this 
continuing success story.
    At the outset, I want to remark that at Editas Medicine 1 we are 
fully aware that genome editing in general, and CRISPR in particular, 
represents a fast-moving, potentially disruptive technology that often 
evokes great hopes and, at times, legitimate concerns. That is why we 
believe it is part of our mission and responsibility to engage with 
major stakeholders in a highly transparent and respectful manner. Our 
company, and many of our partners and collaborators in medicine and 
industry, applaud the Committee for convening this hearing and 
judiciously engaging in the science and policy implications of genome 
editing.
    I understand that the Committee also convened a bipartisan staff 
briefing approximately a year ago with the American Society of Gene & 
Cell Therapy (ASGCT), and, therefore, has already benefited from the 
insights of some of the world's leading genome editing experts. Today's 
hearing is another hallmark in this Committee's long and distinguished 
history of overseeing biomedical research and promoting the now-
flourishing American biotechnology industry. From balanced oversight 
hearings of recombinant DNA technology in the 1970's to funding of the 
National Institutes of Health (NIH), overseeing and strengthening the 
FDA to last year's enactment of the 21st Century Cures Act, on a 
bipartisan basis you have thoughtfully helped develop a tremendous 
American ecosystem of innovation in service of patients. These forward-
looking, bipartisan policies are now bringing forth unprecedented 
medicines that can transform, and often save, countless lives. For 
these reasons, I would like to thank the Committee for its historic and 
ongoing support.
    This continued support will also be critically important for the 
United States to remain the global biotechnology leader and a beacon of 
hope for patients around the world. As the Committee is aware, 
developing medicines is a long, complex process that is riddled with 
setbacks and failure. At Editas Medicine, for example, we are a 4-year 
old company with no approved products to generate operating revenue. To 
date, we have raised approximately $500 million from investors and 
partners to fund our scientific discovery and clinical development of 
new medicines. We will need to raise significantly more capital before 
our first product is approved in the U.S. or Europe. This is a 
necessary and important undertaking for us to be successful in our 
ambitious goal to create these unprecedented medicines. We know how 
important this is--every week we receive letters and emails from 
patients and their families asking about our progress, and letting us 
know that they are paying close attention to everything we do. Patients 
are our motivation every day for discovering and developing CRISPR 
medicines.
I. What is Genome Editing?
    In the world of medicine, the idea and the promise of genome 
editing is straightforward: What if we could repair broken genes? Our 
bodies depend on many intricate biological systems that follow 
instructions embedded within our genes. Even one mutation, which is a 
naturally occurring change in our DNA that disrupts the function of a 
gene, can result in serious or life threatening diseases. Most diseases 
caused by genetic mutations have no approved therapeutic options. Some 
of these diseases are well known: rare forms of blindness, sickle cell 
disease, cystic fibrosis, Huntington's disease, and hemophilia. Our 
goal in advancing genome editing is to repair these broken genes at the 
level of DNA.
    CRISPR (pronounced ``crisper'') is an acronym for ``Clustered, 
Regularly Interspaced, Short Palindromic Repeats,'' and refers to a 
recently developed genome editing technology that can revise, remove, 
and replace DNA. It is the latest in a series of genome editing 
technologies that can engineer molecules to cut DNA in a highly 
targeted manner, including zinc finger nucleases (ZFNs), transcription 
activator-like effector nucleases (TALENs), and meganucleases.
    Beyond human health, genome editing can be applied to animal and 
plant DNA, as well as many organisms that are used in basic biological 
research. Applications in agriculture and animal health have the 
potential to deliver major advances to help feed the world. In basic 
research laboratories, the use of CRISPR technology is nearly 
ubiquitous. It is opening up a wide range of new ways to ask and answer 
essential biological questions. Researchers are using it to probe the 
internal workings of cells, to identify the actions of genes with 
unknown function, and to rapidly create new animal models of disease to 
enable testing and advancements of medicines of all kinds. Creative new 
applications of the technology keep emerging, and we are just at the 
beginning of seeing what can be achieved.
II. Innovative Researchers, Clinicians, and Companies Are Applying 
        Genome Editing in Drug Development Programs to Meet Unmet 
        Medical Needs of American Patients with Serious and Life-
        Threatening Diseases.
    Mr. Chairman, it is simply impossible to overstate the needs of 
millions of American patients and their families who urgently need 
medical progress, treatments, and, wherever possible, cures. As we 
continue working to develop gene editing medicines to address this 
need, we are often asked what these medicines might look like. Genome 
editing medicines can take different forms, depending on what tissue in 
the body needs to be treated for a given disease. In some instances, 
the genome editing product could be administered directly to a patient. 
In these cases it could be a biological preparation (such as a viral or 
nanoparticle preparation to deliver the genome editing molecules) or 
edited cells (such as induced pluripotent stem cells, or iPSCs). The 
patient would receive the biological preparation or the cells as an 
injection, either systemically or to a specific tissue. In other 
instances, gene editing can be performed outside the body on a 
patient's cells--for example, cells from the blood like T cells. In 
these cases, a patient's cells would be removed, then edited, and then 
given back to the patient via an infusion.
    Editas Medicine is working to deliver new genomic medicines that 
realize the potential of CRISPR genome editing. Our most advanced 
program is focused on a rare disease called Leber's Congenital 
Amaurosis Type 10 (LCA10). This disease afflicts children with 
significant vision loss and blindness. We have initiated a natural 
history study in LCA10 to better understand the disease's progression 
and intend to use the insights learned from this study to inform 
clinical trials for our first product candidate in development, which 
is called EDIT-101. We aim to file an Investigational New Drug 
application with the FDA for this program by mid----Our broader 
pipeline focuses on genetically defined eye diseases, inherited blood 
disorders, and producing new cell therapies in immuno-oncology, along 
with our partner, Juno Therapeutics.
    In addition to Editas Medicine, there are several leading 
biotechnology companies working to translate the promise of genome 
editing into medicines to help patients in need. These include CRISPR 
Therapeutics and Intellia Therapeutics, both of whom work on CRISPR 
technology, as well as bluebird bio, Cellectis, and Sangamo 
Therapeutics, who are pursuing drug development using other genome 
editing platforms. Editas Medicine and, to my knowledge, all of these 
companies are only focused on applying their technologies to cells that 
cannot pass on genetic information or any edits to future generations. 
As such, the editing is non-heritable, and only applied to somatic 
cells or cells that are derived from somatic cells.
    Around the world, clinical trials with genome editing technologies 
are already underway in patients. Sangamo Therapeutics and Cellectis 
are two examples of companies whose ZFNs and TALENs-based genome 
editing products are currently in clinical trials. Last October, 
Chinese researchers were the first to inject a patient with CRISPR-
edited cells in a clinical trial for lung cancer treatment. The CRISPR 
genome editing platform has yet to be used in a clinical trial in the 
United States or Europe, but U.S. companies are expected to initiate 
clinical trials soon.
III. Genome Editing to Treat Disease Falls Under a Robust and 
        Comprehensive Regulatory System.
    Those clinical trials are carefully regulated by Federal 
authorities. In September, FDA Commissioner Scott Gottlieb spoke to our 
common goals for intelligent oversight of the promising field of genome 
editing. He said, ``.our principles for regulation allow and facilitate 
beneficial new innovation while making sure that FDA continues to meet 
its gold standard for safety and effectiveness.''
    Mr. Chairman, I believe this is an accurate description of the 
current, robust Federal regulatory framework that has guided clinical 
research and drug development involving recombinant genetic technology 
over the past 40 years. Genomic medicines developed with novel genome 
editing platforms like CRISPR have and will be subject not only to FDA 
review, but also public review by the NIH's Recombinant DNA Advisory 
Committee (RAC). The NIH's RAC dates back to the 1970's, and has 
afforded the American public with unique opportunities to review and 
comment on clinical trials and other information that would otherwise 
be deemed confidential by the FDA in its own, parallel review. This is 
appropriate for such novel technologies, and it has proven to be a 
strength of our existing regulatory framework. In conjunction with the 
NIH RAC, the FDA has overseen gene therapy development since the 
1990's, and together, the two agencies will use this same framework to 
oversee potential clinical applications of genome editing technology, 
including CRISPR, to treat human disease. With these agencies working 
in tandem with Public Advisory Committees, local Institutional Review 
Boards (IRBs), and other oversight mechanisms, the United States 
possesses a rigorous, transparent, and flexible regulatory system that 
is pro-patient, pro-innovation, and has served as a model for the rest 
of the world.
    As you know, the FDA has broad authority to uphold high standards 
of safety and effectiveness for any novel biological product, including 
genomic medicines. They have also had extraordinary success 
implementing a range of programs for collaboration with sponsors and 
expedited reviews, including the orphan drug, fast track, breakthrough 
therapy, priority review, accelerated approval, and the recently 
enacted Regenerative Medicine Advanced Therapy (RMAT) programs--all of 
which could expedite the availability of genomic medicines. Perhaps 
most importantly, in our experience, the Agency's leaders and 
scientific reviewers have also demonstrated a strong commitment to 
understanding the latest breakthroughs and to improving their 
regulatory science. I commend the FDA in particular for their outreach 
to leading academic and industry experts in genome editing. To date, 
the Agency has been forward-looking and thoughtful in starting early 
conversations about how they plan to integrate oversight of genome 
editing into their existing regulatory framework. As the field of 
genome editing continues to advance in the years ahead, these kinds of 
early, constructive, and collaborative engagements will be invaluable 
in keeping all parties aligned and focused on delivering important 
medicines to patients.
    The European Union has also sought to understand and appropriately 
regulate this work. On October 18, the European Medicines Agency (EMA) 
gathered leading academics and companies together for an initial 
discussion around the oversight of clinical uses of genome editing. I 
attended this meeting, and the discussion focused used on their 
regulatory framework for gene therapies, how their Committee on 
Advanced Therapies (CAT) should think of genome editing medicines and 
setting standards under such a framework, and their appreciation of the 
importance of the EMA's regulatory science co-evolving with emerging 
technologies. While the EMA has demonstrated foresight on genome 
editing, it was my impression that the early engagement efforts of the 
FDA have brought the Agency to a closer familiarity with the leading 
edge of the field's rapid innovation. Like the FDA, the EMA is 
committed to learning and engaging with leading companies and 
researchers.
    Our expectations for how genome editing medicines will be regulated 
are informed by the experience in the United States and Europe with 
genomic medicines technologies overall, including many years overseeing 
gene therapy clinical trials. In recent years, companies developing 
other genome editing technologies have initiated early clinical trials 
in the U.S. following reviews by the NIH RAC and the FDA.
IV. Recent NAS/NAM Report Endorses Existing Comprehensive Regulatory 
        System.
    We are fortunate to have authoritative, independent confirmation 
that genome editing will be carefully regulated under current law. In 
December 2015, the National Academies of Science and Medicine (NAS/NAM 
or Academies) co-hosted an international summit on human genome editing 
with the British Royal Society and the Chinese Academies of Science. 
The Academies spent 3 days exploring the scientific, social, and legal 
implications of genome editing, and offered a preliminary conclusion 
that clinical use of genome editing in somatic cells ``can be 
appropriately and rigorously evaluated within existing and evolving 
regulatory frameworks. . .''
    In February 2017, the Academies issued a comprehensive report 
titled ``Human Genome Editing: Science, Ethics, and Governance.'' Mr. 
Chairman, I encourage the Members and Staff of this Committee to review 
its analyses and its specific, actionable recommendations to rely on 
current regulations to facilitate progress. Critically, the report 
reaffirms that ``clinical trials of genome editing in somatic cells for 
the treatment or prevention of disease or disability should continue, 
subject to the ethical norms and regulatory frameworks that have been 
developed for existing somatic gene therapy research and clinical use 
to treat or prevent disease and disability.''
    We agree strongly with this conclusion and the finding that the 
Federal Government should continue to ``use existing regulatory 
processes for human gene therapy to oversee somatic human genome 
editing research and uses.'' In short, the Academies' report confirms 
that current, multilateral Federal safeguards, standards, and oversight 
mechanisms, as well as long standing guidelines in the research 
community, preclude the need for additional, potentially disruptive 
restrictions of genome editing research.
V. U.S. Companies Are Developing Non-Heritable, Somatic Cell Medicines, 
        and Not Germline Modifications.
    As I mentioned, U.S. companies are exclusively developing non-
heritable gene edits to somatic cells, which cannot pass on their 
genetic information to future generations. Editas Medicine is not 
working on editing germline cells, and we have no plans to do so. 
Nevertheless, the NAS February 2017 report raised the prospects of 1 
day permitting germline editing for clinical application if select 
criteria could be met. Though this topic is beyond my scope and 
expertise, I would like to share two thoughts. The first is that edited 
human cells of all kinds are under the FDA's jurisdiction, and 
provisions in the Consolidated Appropriations Act of 2017 and the 
Consolidated Appropriations Act of 2016 effectively bar the Agency from 
allowing clinical trials of products that cause germline modifications.
    Second, that the Biotechnology Innovation Organization (BIO) 
recently issued a position statement that reflects its member company 
consensus on germline editing for clinical application:
        BIO views the science of germline genome editing as having not 
        advanced sufficiently for clinical applications to be 
        appropriate at this time. As scientific developments progress, 
        BIO urges continued discussion and engagement on this topic 
        with important stakeholders, including Members of the patient, 
        caregiver, regulatory, legal, academic, ethical, and faith 
        communities, to determine if and under which conditions this 
        status quo should be changed.
VI. Conclusion
    Mr. Chairman, we are discussing this revolutionary translation of 
fundamental breakthroughs in the understanding of human genetics into 
innovative medicines thanks in great measure to the bipartisan 
commitment of Congress, including this Committee, and of successive 
administrations to fully fund the Human Genome Project. That historic 
achievement, in turn, would have been impossible without our country's 
extraordinary, decades-long commitment to basic research--a commitment 
that built a system of higher education that leads the world and is the 
envy of other nations; that secured a lion's share of Nobel Prizes and 
patents in the sciences and medicine; and that has created 
breakthroughs in high technology, computation, the Internet, and 
medicine.
    To sustain this extraordinary success, I urge the Committee to 
continue its support of robust research funding through NIH; to 
maintain its oversight of the FDA and support the Agency in its embrace 
of fast-moving scientific developments, including advances in genome 
editing; and, critically, to continue to support public dialog about 
the tremendous promise and important challenges in the field of genome 
editing. I am greatly encouraged that this hearing exemplifies the 
National Academies' recommendation that ``[p]ublic participation. . . 
be incorporated into the policymaking process for human genome 
editing.''
    Dr. Gottlieb recently said that this field holds ``the promise of 
changing the contours of human illness and altering the trajectory of 
medicine and science''--what the late Chairman of this Committee, 
Senator Kennedy, once called ``the century of life sciences.'' I have 
been in this industry for more than 25 years. I can say without 
equivocation that it is hard to compare genome editing to any other 
field that I know. The implications for medicine and for patients who 
have as yet untreatable diseases; the scientific intensity as we work 
to overcome challenges translating the science into medicines; and the 
intensity of the public spotlight, given the profound implications of 
this technology, all make this field exceptional. We bear great 
responsibility to patients, to their families, and to society broadly. 
We take that very seriously. We are here for the long term, and want to 
listen and respectfully engage with all major stakeholders.
    Thank you for the opportunity to testify today. I look forward to 
answering your questions.
                                 ______
                                 
                                Summary
    Chairman Alexander, Ranking Member Murray, and Members of the 
Committee, thank you for the opportunity to testify today about genome 
editing technology.
    At Editas Medicine, we are committed to harnessing the power and 
potential of genome editing to develop medicines for patients with 
serious or life-threatening diseases. Our company was founded four 
years ago in Cambridge, Massachusetts, and we have built a team of over 
100 people to tackle the deep scientific challenges of turning this 
exciting technology into medicines.
    There are a few times in our lives when science astonishes us, when 
we are suddenly able to do something that seemed like science fiction 
just the day before. This is one of those moments. Our DNA is at the 
root of who each of us is--that unique combination of genes that makes 
you who you are. But sometimes there are mistakes in DNA--mutations in 
genes that can cause many different kinds of serious diseases. There 
are over 6,000 genetically defined diseases, and, according to the 
National Organization for Rare Disorders (NORD), 95 percent of them 
have no approved medicines.
    CRISPR is an acronym for ``Clustered, Regularly Interspaced, Short 
Palindromic Repeats,'' and refers to a recently developed genome 
editing technology that can revise, remove, and replace DNA. It is the 
latest in a series of genome editing technologies that can engineer 
molecules to cut DNA in a highly targeted manner, including zinc finger 
nucleases (ZFNs), transcription activator-like effector nucleases 
(TALENs), and meganucleases.
    Editas Medicine is working to deliver new genomic medicines that 
realize the potential of CRISPR genome editing. Our most advanced 
program is focused on a rare disease called Leber's Congenital 
Amaurosis Type 10 (LCA10). This disease afflicts children with 
significant vision loss and blindness. We aim to file an 
Investigational New Drug application for this program by mid-2018. Our 
broader pipeline focuses on genetically defined eye diseases, inherited 
blood disorders, and producing new cell therapies in immuno-oncology, 
along with our partner, Juno Therapeutics. Editas Medicine is 
exclusively developing non-heritable gene edits to somatic cells, which 
cannot pass on their genetic information to future generations.
    Genomic medicines have and will be subject not only to FDA review, 
but also public review by the NIH's Recombinant DNA Advisory Committee 
(RAC). In conjunction with the NIH RAC, the FDA has overseen gene 
therapy development since the 1990's, and together, the two agencies 
will use this same framework to oversee potential clinical applications 
of genome editing technology, including CRISPR, to treat human disease. 
With Federal agencies working in tandem with Public Advisory 
Committees, local Institutional Review Boards (IRBs), and other 
oversight mechanisms, the United States possesses a rigorous, 
transparent, and flexible regulatory system that is pro-patient, pro-
innovation, and has served as a model for the rest of the world. While 
clinical trials with CRISPR editing have not yet entered clinical 
trials in the U.S., ZFN and TALEN-based genome editing technologies 
have already entered the clinic.
    Many things make the field of genome editing exceptional: its 
scientific promise and intensity, its implications for medicine, and 
its potential to change the lives of patients living with serious or 
life-threatening diseases. We bear great responsibility to patients, 
their families, and to society as a whole. We take this seriously, and 
are committed to listening and engaging with all major stakeholders in 
a thoughtful and responsible manner.
    Thank you for the opportunity to testify today. I look forward to 
answering your questions.
                                 ______
                                 
    The Chairman. Thank you, Ms. Bosley.
    Dr. Kahn, welcome.

                   STATEMENT OF JEFFREY KAHN

    Dr. Kahn. Thank you.
    Thank you, Chairman Alexander, Ranking Member Murray, 
Committee Members, and staff for the opportunity to offer 
testimony on this timely and vitally important subject today.
    I am Director of the Johns Hopkins Berman Institute of 
Bioethics in Baltimore, where I also hold an endowed 
professorship in bioethics and public policy. As you heard in 
Senator Alexander's introduction, I was also a member of the 
National Academy of Sciences International Consensus Committee 
on Human Genome Editing.
    I will focus my comments today on three topic areas, 
policy, history, and related areas of science and biomedical 
research to the topic today; existing ethical frameworks and 
oversight that apply; and ethical issues raised by the use of 
gene editing technologies in humans and considerations for 
future oversight of them.
    The relevant policy history started in 1975 with the 
Asilomar Conference on Recombinant DNA Molecules. The summary 
statement focused on containment of the risks of creating and 
working with genetically modified organisms, and with the 
admonition to avoid experiments that pose, and here is a quote, 
``Such serious dangers that their performance should not be 
undertaken at this time,'' along with a call for continuing 
reassessment of issues arising in light of new knowledge gained 
with experience with the then-new genetic technology.
    These voluntary suggestions gave way to more robust 
oversight as use of genetic technologies became more refined 
and with initial attempts to treat diseases in humans, with the 
now longstanding body that you have heard about three times 
now, the NIH Recombinant DNA Advisory Committee or RAC, which 
is charged with the review of proposed gene transfer research 
involving humans.
    Ethical concerns in genetic modification in humans have 
been addressed through a range of policy and oversight 
approaches in order to limit certain types of research or to 
provide prospective oversight prior to particular proposals 
being undertaken.
    There are a number of institution-level oversight 
mechanisms that will apply to gene editing research. While 
there is no single Institution-Level Committee that is 
currently responsible for gene editing research, there is 
robust oversight with some combination of Committees 
responsible for oversight depending on the specifics of the 
research proposed. They include Institutional Bio-safety 
Committees; Institutional Stem Cell Research Oversight 
Committees, and institutional review boards which, of course, 
are charged with prospective review of all research involving 
humans.
    In addition to institutional oversight requirements, there 
are regulatory bodies with roles that are relevant to gene 
editing research. The aforementioned RAC is charged with making 
recommendations to the NIH Director, here is a quote again, 
``On matters related to the conduct and oversight of research 
involving recombinant DNA.''
    I think it is clear that there is every indication that 
applications of gene editing tools, when they are applied to 
humans, will be subject to such oversight and review as well.
    FDA review and approval would also be required prior to the 
administration of gene editing techniques in humans, a process 
that, in the case of gene transfer, takes place in parallel 
with, and informed by, the review process of the RAC.
    There is a range of ethical issues posed by gene editing 
and related technologies for modifying human DNA, and today I 
will focus on just three.
    First, the expanded use of therapies beyond indications on 
which any approvals might be based.
    Second, interventions that might result in heritable 
genetic modification, sometimes called germline modification.
    Third, some challenges that genome editing poses for 
regulatory oversight.
    The first concern is related to the use of somatic gene 
editing approaches that have clear therapeutic application 
being used for other indications, including moving beyond 
therapies or preventive uses, and instead enhancement beyond 
what we might think of as normal abilities, a challenge long 
known within the gene therapy oversight process and effectively 
blunted through very limited clinical trials and strict 
processes of who should be included.
    But as applications begin to make their way into the 
market, we will need to figure out how to prevent indication 
creep, as it is called, for uses that are unintended in terms 
of indications of approval.
    The second concern has been the focus of much ethical 
analysis in the application of manipulation of genetic 
information in humans, and that is the potential to introduce 
changes that affect the germline.
    The basis of this concern relates to the uncertainty of the 
effects of genetic modification, the ability to undo unintended 
changes, and the risks of passing on such unintended changes to 
future generations.
    The NAS Committee that has been mentioned now noted that 
improvements in genome editing techniques are driving increases 
in the efficiency and accuracy of genome editing while also 
decreasing the risk of off-target events.
    Because germline genome edits would be heritable, however, 
their effects could be multigenerational. As a result, both the 
potential benefits and the potential harms could be multiplied. 
We will need very strict oversight if that is ever to go 
forward.
    Third, while oversight existing is robust and has proven to 
be effective at governing areas like gene therapy, there are 
ethical issues described thus far, along with others, must be 
addressed in policy as gene editing tools become more widely 
used.
    I will say, at the same time, prohibitions should not be 
the logical conclusion of addressing areas that require 
attention. We need only to look at two of our closest allies 
for a real world comparison of two policy approaches and how 
different approaches will have very different effects. I can 
speak more in questions, if you like. There are examples in 
Canada and in the U.K., which have taken very different 
approaches.
    Let me just conclude by saying the U.S. has long played a 
leadership role in both science and in the responsible uses of 
the advances created by scientific discovery. We must be very 
careful to reflect the input and create pathways with 
appropriate oversight and appropriate public input. Only then, 
will we achieve a robust and credible policy framework that 
will assure the promise of responsible use of these 
technologies, while achieving their benefits for advancing 
scientific knowledge and human health.
    Thank you.
    [The prepared statement of Dr. Kahn follows:]
                   prepared statement of jeffrey kahn
    Chairman Alexander and Ranking Member Murray, thank you for the 
opportunity to submit testimony on this timely and vitally important 
subject.
    I am Director of the Johns Hopkins Berman Institute of Bioethics in 
Baltimore, where I also hold an endowed professorship in bioethics and 
public policy. Relevant to my comments today I was a member of the 
National Academy of Sciences International Consensus Committee on Human 
Genome Editing.
    I will focus my comments today on three topics: (1) policy history 
in related areas of science and biomedical research; (2) existing 
ethical frameworks and oversight; and (3) ethical issues raised by the 
use of gene editing technologies in humans and considerations for 
future oversight.

    Related policy history

    The relevant policy history started in 1975 with the Asilomar 
Conference on Recombinant DNA Molecules, whose summary statement 
focused on containment of the risks of creating and working with 
genetically modified organisms, and with the admonition to avoid 
experiments that pose ``such serious dangers that their performance 
should not be undertaken at this time'' along with a call for 
continuing reassessment of issues arising in light of new knowledge 
gained with experience with the then-new genetic technology. These 
voluntary suggestions gave way to more robust oversight as use of 
genetic technologies became more refined and with initial attempts to 
treat diseases in humans, with a now longstanding body called the NIH 
Recombinant DNA Advisory Committee or RAC charged with review of 
proposed gene transfer research involving humans.

    Existing ethical frameworks and oversight

    Ethical concerns in genetic modification in humans have been 
addressed through a range of policy and oversight approaches, in order 
to limit certain types of research or to provide prospective oversight 
prior to particular proposals being undertaken.
Institutional Oversight
    There are a number of institution-level oversight mechanisms that 
will apply to gene editing research. While there is no single 
Institution-level Committee that is currently responsible for gene 
editing research, there is robust oversight with some combination of 
Committees responsible for oversight depending on the specifics of the 
research proposed. Those include:
    Institutional Biosafety Committees (IBCs), charged oversight of 
research with recombinant or synthetic nucleic acid molecules;
    Institutional Stem Cell Research Oversight Committees (SCROs), 
charged with institutional and ethical oversight of research on human 
embryonic stem cells and related areas of research.
    While specifics of gene editing research will determine which if 
any of these existing institutional oversight mechanisms will apply, 
any research involving human participants must be also be reviewed and 
approved by Institutional Review Boards, charged with prospective 
review of all research involving humans, requiring appropriate risk-
benefit balancing, informed consent of subjects, and monitoring adverse 
events that occur, in order to protect the rights and interests of 
those participating in research.
Regulatory Oversight
    In addition to institutional oversight requirements there are 
regulatory bodies with roles that are relevant to gene editing 
research. The aforementioned NIH Recombinant DNA Advisory Committee 
(RAC) is charged with making recommendations to the NIH Director ``on 
matters related to the conduct and oversight of research involving 
recombinant DNA.''\1\ In addition, the NIH Guidelines currently State 
that ``RAC will not at present entertain proposals for germ line 
alterations.''\2\ This indicates a current effective prohibition on the 
use of germline modifying technologies for areas of research within the 
purview of the RAC, with every indication that applications of gene 
editing tools to humans will be subject to such oversight and review.
---------------------------------------------------------------------------
    \1\ Charter, NIH Recombinant DNA Advisory Committee, June 30, 2013.
    \2\ NIH Guidelines, Nov. 2012, Appendix M.
---------------------------------------------------------------------------
    FDA review and approval would also be required prior to the 
administration of gene editing techniques in humans, a process that in 
the case of gene transfer takes place in parallel with and informed by 
the review process of the RAC.

    Ethical Issues Raised by the Use of Gene Editing Technologies in 
Humans and Considerations for Future Oversight

    There are a range of ethical issues posed by gene editing and 
related technologies for modifying human DNA, and I will focus on just 
three in my testimony today: (1) the expanded use of therapies beyond 
indications on which any approvals might be based; (2) interventions 
that result in heritable genetic modification; and (3) some challenges 
that genome-editing poses for regulatory oversight.
    The first concern is related to the use of somatic gene-editing 
approaches that have clear therapeutic applications being used for 
other indications, including moving beyond therapies or preventive 
uses, and instead for enhancement beyond ``normal'' abilities, a 
challenge long known within the gene therapy oversight process and 
effectively blunted through very limited clinical trials with inclusion 
criteria for research participants. But as applications begin to make 
their way into the market, FDA will need to evaluate and apply its 
regulatory tools to assure that what has been termed ``indication 
creep'' or uses for what are unintended indications can be prevented or 
at least limited.
    The second concern has been the focus of much ethical analysis in 
the application of manipulation of genetic information in humans, and 
that is the potential to introduce changes that affect the germline. 
The basis of this concern relates to the uncertainty of the effects of 
genetic modification, the inability to ``undo'' unintended genetic 
changes, and the risks of passing on such unintended changes to future 
generations. As the NAS International Consensus Committee noted, 
``improvements in genome-editing techniques are driving increases in 
the efficiency and accuracy of genome editing while also decreasing the 
risk of off-target events. Because germline genome edits would be 
heritable, however, their effects could be multigenerational. As a 
result, both the potential benefits and the potential harms could be 
multiplied.''\3\
---------------------------------------------------------------------------
    \3\ Human Genome Editing: Science, Ethics, and Governance, National 
Academies Press, 2017, pp. 111-112.
---------------------------------------------------------------------------
    While acknowledging these concerns, if and when such technologies 
have developed sufficiently, policy decisions must be made that balance 
the individual-level benefits of using gene editing against societal-
level risks. The NAS Committee recognized and analyzed this balancing 
and made recommendations about when if ever a clinical trial employing 
heritable genome editing could be acceptable, setting a very high bar-
some have said with criteria that would be impossible to meet. I think 
the criteria are appropriately restrictive, and if they cannot be met, 
then such applications of gene editing tools would and should not be 
permissible.
    Third, while existing oversight is robust and has proven effective 
at governing areas like gene therapy, the two ethical issues I've 
described thus far, along with others, must be addressed in policy as 
gene editing tools become more widely used. At the same time, 
prohibitions should not be the logical conclusion of addressing areas 
that require attention. We need only look to two of our closest allies 
for real-world comparison of two policy approaches and how differences 
in regulatory approach will have very different effects. Just last week 
in Canada, a major group of researchers called for change to their 
Federal law that makes it a criminal offense with penalties of up to 10 
years in prison for using gene-editing tools on cells that could lead 
to heritable genetic change in humans. The concern expressed by the 
group is that research has been stopped in ways that mean Canadian 
scientists are falling behind their international colleagues.
    The counterexample is the United Kingdom, where scientists are 
taking the lead internationally in research involving potential human 
applications of these technologies. This owes not to lax oversight but 
rather the contrary--strict oversight with clear pathways for licensure 
by the responsible regulatory agency, allowing careful and controlled 
progress with clear reporting and evaluation of results before 
proceeding, creating a clear path forward.
    There is no comprehensive regulatory approach, however, the absence 
of which creates an opportunity for some jurisdictions to craft lenient 
or nonexistent regulation, leading to the emergence of so-called 
``regulatory havens,'' the encouragement of both scientific flight and 
medical tourism, and more near-term concerns around scientific 
leadership and competitiveness, and a loss of ability to control 
research that is outside of U.S. jurisdiction.
    In conclusion, the United States has long played a leadership role 
in both science and in the responsible use of the advances created by 
scientific discovery. This was certainly the case with the introduction 
of recombinant DNA technologies in the 1970's and it is critical that 
we continue to do so as the new and powerful genetic technologies 
become both more precise and more widely available. Existing oversight 
approaches are appropriate for providing part of a framework for 
addressing many of the issues raised by gene editing technologies. 
However, some areas require additional clarification or refinement, and 
my caution is that they not be addressed through additional bans or 
prohibitions. Instead work must be done to (1) identify gaps or areas 
requiring updated approaches to oversight in both in the near and 
longer terms, and (2) craft appropriate guidelines to address the areas 
identified, in order to create pathways to allow innovative science to 
go forward carefully and responsibly, and with appropriate oversight. 
This work must reflect input and contributions from the scientific 
community, ethics experts, policymakers, and a range of public 
stakeholders. Only then will we achieve a robust and credible policy 
framework that will assure the responsible use of these technologies 
while achieving their promise for advancing scientific knowledge and 
human health.
    Thank you.
                                 ______
                                 
                                Summary
    I will focus my comments today on three topics: (1) policy history 
in related areas of science and biomedical research; (2) existing 
ethical frameworks and oversight; and (3) ethical issues raised by the 
use of gene editing technologies in humans and considerations for 
future oversight.
    The relevant policy history started in 1975 with the Asilomar 
Conference on Recombinant DNA Molecules. These voluntary suggestions 
gave way to more robust oversight as use of genetic technologies became 
more refined and with initial attempts to treat diseases in humans, 
with a now longstanding body called the NIH Recombinant DNA Advisory 
Committee or RAC charged with review of proposed gene transfer research 
involving humans.
    Ethical concerns in genetic modification in humans have been 
addressed through a range of policy and oversight approaches, in order 
to limit certain types of research or to provide prospective oversight 
prior to particular proposals being undertaken.
    In addition to institutional oversight requirements there are 
regulatory bodies with roles that are relevant to gene editing 
research. The aforementioned NIH Recombinant DNA Advisory Committee 
(RAC), along with FDA review and approval would also be required prior 
to the administration of gene editing techniques in humans.
    There is no comprehensive regulatory approach, however, the absence 
of which creates an opportunity for some jurisdictions to craft lenient 
or nonexistent regulation, leading to the emergence of so-called 
``regulatory havens,'' the encouragement of medical tourism, and more 
near-term concerns around scientific leadership and competitiveness.
    Existing oversight approaches are appropriate for providing part of 
a framework for addressing many of the issues raised by gene editing 
technologies. However, some areas require additional clarification or 
refinement, and my caution is that they not be addressed through 
additional bans or prohibitions.

                                 ______
                                 
    The Chairman. Thank you, Dr. Kahn.
    We will now go to a round of 5 minute questions. We will 
begin with Senator Collins.

                      Statement of Senator Collins

    Senator Collins. Thank you very much, Mr. Chairman.
    Dr. Kahn, the panel today has described gene editing 
technology that is so exciting as we think about conditions 
such as Duchenne muscular dystrophy, sickle cell disease, 
cystic fibrosis, Huntington's disease; the list goes on and on.
    It is clear, however, that as you point out, that there are 
also ethical issues. Rather than being used to combat disease, 
it would be possible for genes to be edited in a way that 
affects, perhaps, intelligence, or athletic ability, or some 
other so-called desirable traits.
    We live in a global world and it seems that the scientific 
advancements have outpaced the policy in this area.
    How do we ensure that this exciting breakthrough in gene 
editing is used for good by scientists in countries like China 
or Russia, as well as in our own country?
    Dr. Kahn. Thank you, Senator Collins, for that insightful 
question and comment.
    It is the case that scientific advancement outpaces policy 
in most arenas and, in some respects, that is to be expected. 
We ought not be making policy before we understand the science 
as it advances. That is just a feature of areas of biomedical 
advance.
    That said, we do have robust structures for oversight for 
making sure that the approved technologies are used for the 
purposes that we intend and not for those that we want to 
avoid. It is easier to do within our domestic borders, of 
course, than when we start talking internationally.
    I think there is evidence that there, at least, is 
discussion and an international dialog happening. The National 
Academies Consensus Committee, that you have heard us mention, 
is an example of that. That was a partnership, actually. The 
National Academies of Science in the U.S. was the host, but in 
partnership with the Royal Academy in the U.K. and the Chinese 
Academy of Sciences; so to invoke one of the Nations that you 
mentioned.
    The Consensus Committee was actually a year long or a year-
plus long process that followed onto an international summit 
that took place in December 2015. The expectation is that there 
will be ongoing discussions at a series of additional 
international summits.
    The last I heard about this, there was a proposed summit to 
be held in China, probably Shanghai, sometime in 2018 as a 
follow on to the Consensus Report that you have heard us 
mention. Then maybe in 18 months time, another would be held 
somewhere in Europe. There is discussion happening 
internationally as a sort of a long way to say that short 
point.
    Then the last thing I would say is it is the case in our 
history that prohibitions and bans have led not to control, but 
rather, quite the opposite. When technologies are banned in 
this country, scientists find places where there are either lax 
or no oversight to go and perform them.
    A much smarter approach to policy is strict control to 
allow careful, responsible science to go forward in ways that 
are controlled and within our borders, not to push them out.
    Senator Collins. Thank you.
    Ms. Bosley, what questions should parents be asking about 
the potential opportunities and limitations that are available 
as a result of this new technology?
    Ms. Bosley. We actually get outreach from parents on a 
nearly weekly basis at Editas Medicine because the promise of 
this technology is so much in the public eye.
    I think that a critical factor is the robust nature of the 
FDA's oversight. Any of these experimental medicines, that come 
into clinical development in the United States, will go through 
that process. They have not only the right regulatory 
authority, but our experience has been very much they are at 
the leading edge of understanding this science. They are 
staying current.
    It is a fast moving field and they are keeping pace with 
it, which is, as we would hope and is excellent, they are 
really understanding of this field and accustomed to rapidly 
emerging science like this.
    I certainly have a great deal of confidence in that 
oversight mechanism, and I would hope that parents would as 
well.
    Senator Collins. Thank you.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Collins.
    Senator Murray.
    Senator Murray. Thank you.
    As I mentioned, Washington State has a really strong life 
sciences sector and is home to several pioneers in immuno-
therapy.
    Seattle Children's Research Institute has spent the past 
few years engineering T-cells to fight leukemia and children 
for whom other treatments had failed. They are collaborating 
with the biotech firm Casebia on applying CRISPR gene editing 
technology to alter T-cells to prevent and treat autoimmune 
disease.
    Dr. Porteus, I understand part of your work has involved 
engineering T-cells to treat and prevent a host of conditions 
like HIV. Ms. Bosley, I understand Editas has been making 
progress with the Washington State firm Juno Therapeutics that 
you mentioned in this area as well.
    I wanted to ask both of you, what are the advantages of 
using CRISPR to engineering the function of T-cells over 
previous methods? What are the current challenges to advancing 
T-cell therapies?
    Ms. Bosley, maybe if you could start.
    Ms. Bosley. Yes, thank you for the question.
    Immuno-oncology, as you point out, is one of the most 
exciting, emerging areas of new therapies to treat a wide 
variety of cancers.
    The earliest versions of these therapies--which have been 
referred to as CAR-T therapies or engineered T-cell therapies--
are promising particularly in treating blood cancers and we 
have seen the first two of these actually achieve FDA approval 
just recently. We are really on the verge of an entire new 
horizon of these therapies.
    But there is much more we would like to be able to do, more 
cancers to treat and improving upon these first steps in 
immuno-therapy that can be enabled by CRISPR genome editing.
    Being able to make additional changes to these T-cells so 
these T-cells have a wider potential to treat cancer is what is 
possible with CRISPR. As compared to earlier genome editing 
technologies, there is a greater flexibility with what you can 
do with CRISPR.
    We do think there is great promise in applying CRISPR to 
these engineered T-cell therapies to be able to extend the life 
of the cells that can fight the cancer to be able to treat 
other kinds of cancers, such as solid tumors not just blood 
cancers.
    Further advancements as we put more edits into the cell, 
perhaps to be able to have off-the-shelf treatments. Not just 
ones that are treating the patients with their own cells, but 
off-the-shelf therapies that can be available to a wider range 
of patients.
    Senator Murray. What are the current challenges?
    Ms. Bosley. There are always challenges of the biology and 
understanding exactly which genes to edit, but that is also 
something where the understanding of the T-cell and its role in 
cancer is moving at a great pace as well.
    I think that the active work of Juno and many others in 
this field is really starting to uncover that biology quite 
rapidly.
    Senator Murray. Dr. Porteus.
    Dr. Porteus. Again, a great question and I will echo Ms. 
Bosley's comments about the excitement about T-cell therapy to 
fight cancer.
    To get to your question about what does genome editing add 
that prior ways of genetically engineering T-cells could not 
give is in two specific areas.
    One is the prior ways of engineering a T-cell is that you 
would introduce a new gene and that new gene would go somewhere 
in the genome, but you did not know exactly where.
    With genome editing, we can actually now take that gene and 
put it precisely in one location. Now, the entire population of 
T-cells has the same property, the same potency. It makes for a 
more homogeneous product, which also means we control the level 
of that gene much more precisely.
    The other thing that you can do with genome editing that 
you cannot do with a gene addition type approach is you can 
knockout or inactivate certain genes.
    One of the thoughts--and again, I echo what Ms. Bosley 
said, that we need to understand more of the biology--but one 
of the thoughts is that when T-cells get activated or tumors 
grow, they put out molecules that suppress the T-cells from 
forming or from being active.
    What we can do with genome editing is inactivate the 
inactivators, a double negative, so to speak. Now, release that 
T-cell to kill the tumor cell whereas prior, it had been 
inhibited.
    Those are the two fundamental things we can do with genome 
editing that prior technologies did not allow us to do.
    Senator Murray. Okay. Any challenges to advancing it?
    Dr. Porteus. Again, I would say we have to understand more 
of the biology.
    I think we have to release the hounds, so to speak, and 
allow lots of people to explore lots of different variations 
here so we find what is the best combination? I think if we 
said, ``One company or one investigator is going to find it,'' 
we would be limiting ourselves. What we want is a thousand 
trees to grow because one of them is going to turn out to be 
the secret.
    Senator Murray. Okay. Thank you very much.
    The Chairman. Thank you, Senator Murray.
    Senator Scott.

                       Statement of Senator Scott

    Senator Scott. Thank you, Mr. Chairman.
    Thank you to the panel for being here this morning.
    This is really an exciting topic that I have done some 
research on for the last year or so, and the more I learn, the 
more I want to learn to about this topic. It is really one of 
the miracles that we could see happen for so many patients in 
the future.
    I have had the good pleasure, Dr. Porteus, to work with the 
Medical University of South Carolina. One of their patients, 
who is their sickle cell champion, is a little kid named Zion 
Thomas who has missed a number of days of school because of the 
pain and the challenges that so many of these youngsters suffer 
through.
    His doctor, Dr. Kanter at the Medical University of South 
Carolina, has been trying to find new ways and new 
opportunities to help him go back to school and to live the 
highest quality of life possible.
    I will say that it has been a tragic disease in so many 
ways, and one of the reasons why is for the last 20 years, 
there has been really no approved new medicines until this past 
summer. This is good news.
    But to me the CRISPR research and your research, 
specifically, seem to provide real opportunities, not just to 
manage the disease, but to eliminate the disease.
    I know that you have been approved with a $5.2 million 
grant to lay the foundation for a clinical trial on potential 
treatments that use CRISPR technology to, hopefully, eradicate 
the sickle cell defect in patients' blood. I want to clarify 
that your research does not alter human embryos.
    Can you elaborate on exactly how this treatment would be 
effective and work, please?
    Dr. Porteus. Yes, thank you very much.
    You have nicely outlined the devastating consequences of 
this disease and why we need better therapies.
    What the strategy that we are developing is the following, 
which is, that a patient who has the disease and has severe 
manifestations of the disease initially--because this will be 
new therapy--will come to our clinic and we will discuss the 
possibility of going through this, what may be a first-in-human 
procedure. They will be a very brave person, and we will 
discuss the potential risks and benefits.
    If we believe that the patient understands the risks and 
benefits, then we will enroll them on the study. I think that 
is a really key point that sometimes we forget about.
    Once they are enrolled on the study, what the process will 
be is that we will harvest their own blood-forming stem cells. 
You make the very important point that these are not cells that 
impact the germline. They are blood-forming stem cells that 
will stay in the body.
    We will then bring them to a specialized manufacturing 
facility in which we will use the CRISPR technology to change 
the sickle cell mutation to the nucleotide, the letter that 
does not cause the disease.
    We will measure the frequency that has occurred in that 
cell population. We will make sure that it passes all of our 
quality control standards. That it does not have any evidence 
that we have done something harmful to the population.
    Once we have that quality control on the population, we 
will then bring the patient back and they will undergo what we 
call an autologous stem cell transplant, in which they will 
receive high doses of chemotherapy to eliminate all of the 
remaining blood stem cells that are in the body, and then we 
will transplant.
    Actually, when you do a stem cell transplant that means 
infusing the cells through an I.V., and the stem cells 
naturally find their way back to the bones, where we hope our 
corrected cells will then reconstitute the blood system and the 
patient will no longer have the disease.
    Senator Scott. That is amazing.
    Dr. Porteus. Yes.
    Senator Scott. In a politically correct word, that is 
pretty cool.
    [Laughter.]
    Senator Scott. Yes, sir. Let me move onto Ms. Bosley here 
quickly.
    I had the good fortune to sit down with one of my good 
friends, a guy named Dr. Tony Coles, who says that you are a 
brilliant young lady there.
    I added the ``young'' in, because he would have too.
    Ms. Bosley. Thank you.
    Senator Scott. The conversation that we had went in many 
directions from crops to humans. Part of it is as I look at the 
opportunity for us to reauthorize bio-defense programs next 
year, it seems to me that CRISPR could have a positive impact 
on the inability of mosquitoes to spread Zika, malaria, or 
other types of diseases.
    Can you expound upon the opportunities of the breakthrough 
technologies in our bio-defense that will be so critically 
important going forward?
    Ms. Bosley. Thank you, Senator, for the question.
    I agree. Dr. Coles is amazing; an incredible leader in our 
industry.
    Senator Scott. Yes, ma'am.
    Ms. Bosley. In terms of the broad applications of CRISPR, 
as you note, it is not just healthcare applications and making 
medicines, which is what we are focused on at Editas, but 
agricultural and also the concerns that it could be misused.
    I think, as Senator Alexander noted in his opening remarks, 
there are folks who are in those specialized areas looking at 
this technology and are there protections that need to be put 
in place?
    It is not my area of expertise, but we certainly have 
sought to also, as a company, make ourselves available to those 
who are engaged in those questions because we are living and 
breathing at the edge of this science every single day.
    We do feel a responsibility to be a resource for those who 
are thinking about what kinds of protections might be needed.
    Senator Scott. Thank you.
    I will say, Mr. Chairman, and my parting comment is that 
someone, somewhere, some Nation will set the ethical boundaries 
for this conversation going forward. It certainly would be 
helpful for the United States of America to establish those 
boundaries to a large extent.
    Thank you, Mr. Chairman.
    The Chairman. Well, thank you, Senator Scott.
    I know of your interest in this over the last year, so we 
will treat this as a beginning of a discussion on the subject. 
We can continue, through roundtables, or hearings, or other 
discussions, about what responsibility we have to create an 
environment where all this can succeed.
    Senator Scott. Thank you, sir.
    I look forward to the next hearing, and perhaps we will 
have one on Cas13, and the next round of RNA, and some things 
that we can do. That would be kind of cool as well.
    Thank you.
    The Chairman. Good. Thanks, Senator Scott.
    Senator Hassan.

                      Statement of Senator Hassan

    Senator Hassan. Well, thank you, Mr. Chair and Ranking 
Member Murray.
    Good morning to the panel. Thank you for your work and it 
is great to have a panel that represents the various 
perspectives and things we need to think about as we engage 
with this incredible cutting edge technology.
    I want to follow-up on what Senator Scott just mentioned 
and I will ask Dr. Porteus. Much of the discussion around 
CRISPR is focused on the CRISPR/Cas9 system, which edits 
sections of DNA with high precision and efficiency.
    The technology is promising, but as I understand it, it is 
not the only CRISPR out there.
    Recently, scientists have developed a new type of CRISPR-
based system called REPAIR, which stands for RNA Editing for 
Programmable A to I Replacement, which uses the Cas13 enzyme to 
edit, not the DNA, but the RNA in cells.
    This technology is still a research tool and is not being 
used in any clinical work. But as I understand it, it could 
allow for temporary gene editing like turning on and off the 
alterations it makes.
    I understand it is really new technology, but can you 
explain a little bit more about how this technology might work. 
What are the implications of editing RNA versus DNA when it 
comes to treating and preventing human diseases?
    Dr. Porteus. Yes, great. Yes, thank you for the question.
    First of all, what I would say is that the challenge of 
taking a discovery in the lab to the clinic requires commitment 
and focus. One of the things that, I think, Ms. Bosley will 
say, and I believe in, is that some times you have to pick your 
horse and run with it as far as you can.
    Senator Hassan. Right.
    Dr. Porteus. But what is fantastic is behind the scenes 
now, not even behind the scenes, but behind that horse are 
people developing more and more tools. The bigger our toolbox 
is, the more likely we are in the future that we are going to 
solve all the problems we need to solve.
    Senator Hassan. Yes.
    Dr. Porteus. What is the potential problem that an RNA 
editing approach might solve that a DNA editing approach might 
not solve?
    You highlighted it in your question or your statement, 
which is that RNA editing will be a more transient way of 
changing how the cell behaves because RNA comes and goes. If 
the unedited RNA gets replaced, or the edited RNA gets replaced 
by unedited RNA, your effect will go.
    In circumstances where you might only want a transient 
effect, that would be a really nice way of doing it.
    It is possible that we will learn of other things or other 
problems that we encounter with the standard DNA editing. 
Having this RNA editing in our back pocket will be good.
    I would say that is, if I had to summarize, I think the 
possibility of doing transient editing for health situations 
that do not need a permanent change, this is a really exciting 
way of thinking about it.
    Senator Hassan. Thank you, and I think we will all be 
excited to learn more about it.
    I wanted to ask you another area, Dr. Porteus, because it 
is my understanding too that CRISPR technology could be useful 
in the area of anti-microbial resistance.
    According to the CDC, at least 2 million people are 
infected annually with bacteria that are resistant to 
antibiotics, and at least 23,000 people die each year as a 
result of such infections.
    As I understand it, gene editing can be used to help humans 
even when the gene editing is not taking place in the human 
genome.
    Dr. Porteus. That is right.
    Senator Hassan. For example, CRISPR/Cas9 is being used to 
specifically target and eliminate harmful bacteria while 
leaving in place the good bacteria, which makes it difficult 
for bacteria to develop resistance.
    Can you walk us through this a little bit? How could CRISPR 
help us 1 day combat antibiotic resistance?
    Dr. Proteus. Yes. So obviously, as an M.D., antibiotic 
resistance is a huge problem and affects my patients every day, 
and so, we need to come up with better solutions. There are 
non-CRISPR based solutions to this problem. I do not want to 
imply that there are only CRISPR based solutions to the issue 
of antibiotic resistance.
    But again, we need more tools. So what is a CRISPR based 
tool that might deal with this problem of antibiotic 
resistance?
    What people are developing is actually the idea that since 
the CRISPR recognition is so precise, you can design it to cut 
the DNA of a pathologic bacteria and not the DNA of a non-
pathologic bacteria.
    The ideal would be that if somebody was colonized in their 
gut with a mixture of both pathologic and non-pathologic 
bacteria, they could take a pill which would infect all of the 
bacteria with the CRISPR, but it would only kill the bacteria 
that were pathologic and not kill the bacteria that were non-
pathologic.
    Again, very early day. Has not even really been done too 
much in animals yet, but it is something that I expect we will 
see a lot of exciting work over the next five to 10 years.
    Senator Hassan. Well, thank you and my time is up.
    To our other two witnesses, Ms. Bosley and Dr. Kahn, thank 
you for your work.
    To all three of you and to the entire scientific community 
that is working on so much cutting edge developments, just know 
how much we appreciate what I know is a lifetime of work, and 
you do not always see the reports right away, and then you get 
a hearing where we all kind of go, ``A-ha!''
    You guys are great and we forget to thank you for the years 
of work and lack of recognition that comes before it.
    Thank you.
    The Chairman. Thank you, Senator Hassan.
    Dr. Porteus, Ms. Bosley, you have told us, but I want to 
see if I understand just where we are.
    Dr. Porteus, you are working in your laboratory with human 
beings who have sickle cell anemia.
    Is that correct?
    Dr. Porteus. Yes, so we are working right now with cells.
    The Chairman. Cells from individuals.
    Dr. Porteus. Human beings with sickle cell anemia.
    The Chairman. Your next step, you were saying, is actually 
to develop a treatment for an individual.
    Dr. Porteus. Yes.
    The Chairman. That would be something that is prior to any 
sort of FDA or NIH approval.
    Is that correct?
    Dr. Porteus. Let me explain.
    Before we would ever administer these cells back into a 
patient, we would have to get FDA approval.
    The Chairman. You would have to?
    Dr. Porteus. We would have to.
    The Chairman. Have you filed any kinds of papers to do 
that?
    Dr. Porteus. What we have had with them is what is called a 
pre-IND meeting where we have proposed what we want to do. We 
have proposed that we will do the following experiments, both 
in terms of efficacy and safety. We have had a conversation 
going back and forth.
    The Chairman. These are research treatments, basically.
    Dr. Porteus. They are research.
    The Chairman. That would be approved by the FDA or that the 
FDA would be aware of?
    Dr. Porteus. No. What they are is a set of studies that the 
FDA will say justifies a treatment that could be tried in 
humans. It would justify giving an IND to allow us to start a 
clinical trial.
    The Chairman. That is a, quote, ``FDA approval'' of a 
treatment.
    Dr. Porteus. Yes.
    The Chairman. Now, Ms. Bosley, you have not yet filed any 
application for an FDA-approved treatment to cure, have you?
    Ms. Bosley. No, not yet.
    The Chairman. But you are about to?
    Ms. Bosley. Yes. Our goal is to file to be able to begin 
investigations. Not for approval, but for that first step to be 
able to test in humans under an investigation.
    The Chairman. Is that the same step he is talking about?
    Ms. Bosley. It is the same step that Dr. Porteus is talking 
about, yes. Similar to Dr. Porteus, we have had initial 
engagement with the FDA.
    I think it is an excellent example of their flexibility, 
particularly for these very new emerging technologies. We work 
within the Office of Tissue and Advanced Therapies. You are 
able to engage with them. Of course, there is the very formal 
documentation, but there is good opportunity for conversation.
    The Chairman. Well, in our 21st Century Cures discussion, 
we went back and forth in one area called regenerative 
medicine----
    Ms. Bosley. Yes.
    The Chairman----and agreed upon some money for some 
research in the National Institutes of Health, and then an 
accelerated pathway for regenerative medicine at the FDA.
    Do the kinds of investigations and treatments you are 
talking about fit within that broad umbrella of regenerative 
medicine?
    Ms. Bosley. My understanding is the FDA is in the process 
of implementing the RMAT designation and I think it is a bit of 
a work in progress.
    I am not fully expert in that particular designation, but I 
think that it was certainly a really promising part of that 
legislation and possibly could be considered to include this 
work.
    The Chairman. Well, let me ask it this way.
    Do you see, based upon your initial meetings, the need for 
any changes in the law that would make it more likely----
    Do you see obstacles in the law to the prompt consideration 
of your research and request for investigations? Either of you.
    Ms. Bosley. Thank you for that question, Senator, because I 
think one thing that we found is the FDA has the appropriate 
authority, and they are exercising it well and thoughtfully. I 
do not see any need for any change in legislation.
    I think the continued support of the FDA, the resources, is 
always critical because in a fast moving field like this, their 
ability to continue to stay with the edge of the science does 
depend upon having the correct resources.
    The Chairman. Yes, well, we just approved $9 billion more 
dollars over the next number of years.
    [Laughter.]
    Ms. Bosley. Thank you for that.
    The Chairman. Dr. Porteus, do you agree with that?
    Dr. Porteus. I would echo those sentiments exactly.
    The Chairman. Okay. No need for us to write any. Dr. 
Gottlieb and his team there are paying attention to it.
    Dr. Porteus. They are.
    Ms. Bosley. Yes, sir.
    The Chairman. I heard, you may know nothing about this, the 
mosquitoes that have been referred to several times, I have 
heard that in other countries that the mosquito which then 
mates with the altered mosquito is the male or is it the 
female?
    Well, if the male is altered that kills the disease 
bearing-mosquito. That is being used in other countries but not 
in the United States because approval of that was hung up at 
the FDA, and that approval is now at the Environmental 
Protection Agency.
    Do you know anything about that? Is that right?
    Dr. Kahn. Yes, I do actually know something.
    The Chairman. What do you know about that? I mean, there 
are lots of people in South Texas and Florida.
    Dr. Kahn. Yes.
    The Chairman. If that is a safe and effective procedure, 
they would be pretty anxious for it to be available.
    Dr. Kahn. Thank you. It is, Senator, a very interesting 
area and it is not approved anywhere. It has been field tested.
    The Chairman. It has been used in Brazil. Right?
    Dr. Kahn. Yes, that is right, and in the Caribbean.
    The Chairman. Did it work?
    Dr. Kahn. That is right, in Brazil in a small test area. It 
has not been approved, I think, for release as a mosquito 
control approach, but rather, they are trying to see whether it 
works.
    The technology that, I think, you are thinking about is 
male-altered mosquitoes that are tetracycline dependent. That 
is, they need tetracycline in their diet. When they are 
released into the wild, they mate and their offspring are also 
tetracycline dependent. There is no tetracycline in the natural 
environment, and so, all of the offspring die.
    The Chairman. Where does this stand now in the United 
States?
    Dr. Kahn. I think, in the United States, there was a 
proposed field trial in the Florida Keys, but that was seeking 
stakeholder engagement and input, and then the hurricanes hit, 
of course. I think that has now been put on hold, so far as I 
understand.
    The Chairman. Which agency has responsibility? Do you know?
    Dr. Kahn. Sorry?
    The Chairman. Which Federal agency has?
    Dr. Kahn. I think that was going through the FDA, so it has 
taken the same path as the Aquasense salmon, if you know that 
technology.
    The Chairman. Senator Murkowski remembers.
    [Laughter.]
    The Chairman. She reminds us about that.
    Dr. Kahn. Exactly. She is not here, I think.
    The Chairman. No.
    Dr. Kahn. Yes.
    The Chairman. Senator Murray reminds us of that.
    Dr. Kahn. The same pathway for approval of that technology 
would be used for the genetically modified mosquito release.
    The Chairman. Well, I am over my time and Senator Warren is 
always under hers, so I do not want to set a bad example. But I 
do have to ask.
    Have you noticed any increase in interest in the study of 
biology as a result of this and other advances in biomedical 
research?
    Dr. Porteus. I can say that I have had the opportunity to 
talk to high school students, and they are so engaged in this 
technology. Not only about the science, but they love to talk 
about how it should be applied; the very same issues that all 
of us in the room are quite interested in. It is really 
exciting to see.
    The Chairman. Thank you.
    Senator Warren.
    Senator Warren. Thank you, Mr. Chairman.
    As people have been discussing this morning, the gene 
editing technologies are already having a transformative effect 
on healthcare, and I just want to ask more about the underlying 
research.
    Funding from the National Institutes of Health, as well as 
other Federal agencies, has been critical to supporting the 
researchers who develop CRISPR and who are putting it to work 
in all the different areas that we have been hearing about 
today.
    In order for scientists to actually conduct genetic 
research, they need genetic material. That means the federally 
funded research that has fueled such exciting breakthroughs in 
gene editing often involves the collection of bio specimens, 
things like tissue, and cells, and blood samples from research 
participants. These bio specimens contain unique genetic 
information of the people who are participating in federally 
funded research projects.
    That means we have an important responsibility for making 
sure that our Nation's privacy protections are keeping up with 
advances in scientific research. Professor Kahn, let me just 
ask you.
    When a researcher generates genomic data through a project 
that is funded by NIH, is the researcher expected to contribute 
that data to a Federal data base?
    Dr. Kahn. Yes.
    Senator Warren. Yes. Does this genomic data contain 
information that could be traced back to the individual if it 
were to become public?
    Dr. Kahn. At this point, genomic information is considered 
identifiable.
    Senator Warren. Okay. I strongly support the data sharing 
requirements for federally funded research. I think it is a key 
reason that genetic research has advanced so quickly. But we 
have to make sure that research participants know that the 
genetic material that they are turning over is properly 
safeguarded.
    That is why Senator Enzi and I worked together last year to 
pass the Genetic Research Privacy Protection Act. Our bill 
requires the NIH to issue certificates of confidentiality to 
all federally funded researchers. These are the legal 
protections that ensure that researchers cannot be compelled to 
release genetic information.
    The bill also protects genetic data from FOIA requests, so 
that the data are only used for research purposes, as intended.
    Ms. Bosley, do companies like yours rely on NIH research to 
develop transformative therapies, support these privacy 
protections for Federal research projects?
    Ms. Bosley. Senator Warren, first of all, thank you for the 
question. Thank you also, for that very kind introduction 
earlier.
    Senator Warren. You bet.
    Ms. Bosley. This is a critical issue. There is no question.
    As you say, it is critical to patients having the 
confidence to participate in research, to know that their most 
personal, identifiable information will, indeed, be 
safeguarded.
    We very much support this, and are very appreciative that 
you and Senator Enzi have made this such a highlighted issue.
    Senator Warren. Good.
    Ms. Bosley. Yes.
    Senator Warren. So good for researchers and good for the 
businesses that are trying to develop this research.
    Ms. Bosley. Absolutely, yes.
    Senator Warren. Now that this bill has become law, the NIH 
is moving ahead with the implementation. As of October 1, any 
NIH funded research that involves the collection or use of bio 
specimens or genomic data of human subjects will automatically 
receive this certificate of confidentiality.
    Other Federal agencies that fund research--like the CDC, or 
the V.A., or the Department of Defense--are also rolling out 
the same protections as we required in this law.
    I just wanted to say I am really glad that we were able to 
get this in our bill when it moved forward, this bipartisan 
piece of legislation protecting the rights of research 
participants will only strengthen the work of the scientists 
and the biotech companies who are doing such exciting work in 
gene editing.
    Thank you very much and thank you all three for the work 
that you are doing. Just terrific.
    Thank you, Mr. Chairman, and I did finish early.
    [Laughter.]
    The Chairman. You did. I knew it. Thank you, Senator 
Warren. Three gold stars to you.
    [Laughter.]
    Thank you for your contribution and with Senator Enzi. I 
believe that your legislation was a part of the 21st Century 
Cures, and is now being implemented, and are very proud of 
that.
    Senator Kaine.

                       Statement of Senator Kaine

    Senator Kaine. Thank you.
    I am so happy Senator Warren ceded her time to me, so I can 
go over.
    [Laughter.]
    Thank you, all of you, for the testimony, for the work.
    I want to talk about two items just for folks who are 
paying attention to this and talk about what gene editing might 
mean to treatment of Alzheimer's and dementia. One of the most 
significant challenges we are facing and it is only likely to 
get worse. Whether it is the human misery, the burden on 
caretakers, or the fiscal consequences to families and to the 
public treasury, this is a mushrooming challenge.
    I introduced a bill with Senator Collins and others this 
week dealing with trying to buildup a workforce that would be 
capable of providing care to those with Alzheimer's.
    But talk about what gene editing might mean for the future 
treatment of dementia and Alzheimer's?
    Ms. Bosley. Senator Kaine, perhaps I will comment on that. 
Thank you for the question because as someone who personally 
understands the impact of this devastating disease, we 
certainly all hold hope for being able to help these patients 
and their families.
    It is a tough disease and it is not one where we deeply 
understand the genetics, and so it is unfortunately not going 
to be one of the first diseases we are able to approach.
    But I think the question is, can we begin to work on it as 
we deepen the capabilities of the basic technology? Can we 
begin to work on other neuro-degenerative diseases that begin 
to point a path toward Alzheimer's?
    What I think may also help support those in basic research, 
one of the aspects of CRISPR as a research tool, so of course, 
we mostly talk about how you make CRISPR based medicines, which 
is very exciting.
    But in the world of biological research, the ability for 
CRISPR to unlock scientists' ability to ask and answer new 
questions, to really understand what underlies Alzheimer's and 
other terrible diseases more deeply. We are at the beginning of 
a tremendous revolution there.
    I think perhaps the more immediate hope might be, as we 
better understand what is driving Alzheimer's, can it show us 
new targets that you might be able to go after with perhaps 
more traditional pharmaceutical approaches, a small molecule, 
or an antibody, or something like that?
    That may be the area where we see progress that is CRISPR-
enabled, but at the basic science level.
    Senator Kaine. Thank you.
    Additional comments?
    Dr. Porteus. Maybe I would just like to echo what was said 
and to give, maybe, a very specific example.
    Supposing basic research was funded and you made a 
discovery that the problem is that cells in patients with 
Alzheimer's disease were missing a signal to allow them to 
survive?
    Now what you could do with the CRISPR technology is 
engineer a cell therapeutic to deliver that signal and protect 
the cells from dying. I do not know what that signal is.
    But I know that if somebody told me, ``Make a cell that 
secretes a signal to protect a neuron not to die,'' I think I 
have an idea how to do that. I just need somebody to tell me 
what to make that cell to make.
    Senator Kaine. I see.
    Dr. Kahn, I have a question for you based on your written 
testimony. I am just mindful that I have 2 minutes left. You 
have an interesting bit of testimony on Page 4 of your written 
testimony.
    ``Just last week in Canada, a major group of researchers 
called for a change in their Federal law that makes it a 
criminal offense with penalties of up to 10 years in prison for 
using gene editing tools on cells that could lead to heritable 
genetic change in humans. The concern expressed by the group is 
that research has been stopped in ways the Canadian scientists 
are falling behind their international colleagues.''
    You then conclude a paragraph later with an interesting bit 
of testimony.
    ``There is no comprehensive regulatory approach,'' and by 
that, I think you mean comprehensive international regulatory 
approach.
    Dr. Kahn. International. Correct.
    Senator Kaine. ``However, the absence of which creates an 
opportunity for some jurisdictions to craft lenient or 
nonexistent regulation, leading to the emergence of so-called 
`regulatory havens,' the encouragement of both scientific 
flight and medical tourism, and more near-term concerns around 
scientific leadership and competitiveness, and a loss of the 
ability to control research that is outside of U.S. 
jurisdiction.''
    That is a big concern. We would want to be the leader. We 
would want to remain in the leadership position in this based 
upon our institutions and individuals.
    How should we start to think about this regulatory issue so 
that we do not run into a position where we are chasing away--
by trying to do the right thing on regulation--we are chasing 
away innovation to other locations?
    The Chairman. Please take the time to fully answer that 
question, because that is an important one.
    Dr. Kahn. Okay.
    Thank you, Senator Kaine, for that. I think you are right. 
It is a critical piece of this discussion.
    As my testimony pointed out, the counterexample to the 
Canadian example is the United Kingdom, which no one would 
accuse of having lax oversight. In fact, they have a very 
strict regulatory control process which allows them to license, 
in a very narrow way, new and emerging biomedical technologies. 
It is a permissive regimen with very tight controls. I think 
that, in fact, is the right approach.
    Prohibitions, Canada would be, not effectively a 
prohibition, but people would behave that way. People do not 
want to go to jail for 10 years for doing science. Driving 
people to places either that have more permissive regimes, 
maybe like the U.K., or to places where there are no rules, 
which is really what we do not want.
    That is bad for a range of reasons as I responded to 
Senator Collins earlier. Not only does it drive science 
underground and in ways that we do not get to control it, but 
we then lack the ability to get that data and the benefits of 
that research. It disappears, effectively.
    We lose in multiple ways when we drive science underground 
and away from where we want it to be done, which is, I think, 
in this country and, as you put it, for other reasons like 
competitiveness and leadership.
    This country has long, really forever, been the leader in 
science in the world and I do not think we want to cede that to 
anybody else.
    Senator Kaine. Thank you, Mr. Chairman.
    The Chairman. Thank you.
    Senator Murray, do you have additional questions?
    Senator Murray. Mr. Chairman, I will submit them for the 
record.
    But I think this has been a fascinating hearing, and I 
really appreciate all of your intuition, and advice, and 
knowledge. We have a whole world in front of us that we need to 
do the right way and your input is extremely helpful.
    I know we have more work to do, Mr. Chairman, and I look 
forward to working with you.
    The Chairman. Thank you, Senator Murray.
    Dr. Kahn, do you think we should have any kind of 
additional regulation on heritable diseases in this country?
    Dr. Kahn. Do you mean genetic modifications that are 
heritable?
    The Chairman. That is what I meant.
    Dr. Kahn. Yes. No, just to be clear.
    I think that the FDA is in a position in conjunction with 
the NIH RAC, which we have mentioned, to evaluate technologies 
that may lead to heritable genetic change.
    The NAS Committee that both Dr. Porteus and I have served 
on listed a set of, I think, ten criteria that would need to be 
met to consider going forward with anything that might lead to 
heritable genetic modification.
    Some have opined that those ten criteria would be 
impossible to meet which, in my written testimony, I say if 
that is the case, then so be it. It is a recipe for a very 
tight control to allow the benefits to go forward in cases 
where there is really no other way to achieve a therapy for a 
particular disease.
    An example would be when both parents are at risk or know 
they would pass on the Huntington's disease mutation. There is 
no way for that couple to have a child who would not inherit 
the Huntington's disease gene, which is a horrible, devastating 
disease and diagnosis.
    We might consider that an example where we would have a 
very tightly controlled way forward for a gene editing approach 
that would, in effect, create heritable genetic change. But we 
might see that as a justifiable so long as it was done with the 
very strict controls.
    The Chairman. Do any of you have a recommendation to 
Senator Murray, or Senator Kaine, and me, and other Members of 
this Committee about what we should be doing, if anything, to 
create an environment in which you can succeed in an 
appropriate way?
    Ms. Bosley. Senator, if I may comment on that. It is an 
excellent question, I think.
    In many respects, the 21st Century Cures legislation, there 
are so many different dimensions of that legislation as well as 
the long history of bipartisan legislation that comes through 
this Committee.
    I think implementing that robustly really continues to 
support a fantastic environment for this technology to mature 
in a careful and thoughtful way.
    Dr. Porteus. I would say two things. One is a continued 
sustained--and as a scientist, of course, I would like to say--
substantial funding to the NIH for basic science research 
because as an investigator taking on real challenges, you have 
to know that you have the opportunity to spend five, or ten, or 
even more years on it.
    If we see funding go up and down, it discourages people to 
taking on those long term challenges. I think that is very 
important.
    Then I think--and again, this is consistent with Scott 
Gottlieb and Peter Marks--is having the FDA have a flexible, 
data-driven approach to the regulation of this field. It is too 
new to think that we know exactly which line should be drawn in 
black ink and which line should be drawn in pencil.
    I think we need to have the regulators be data-driven about 
how we adjust as we get more data from clinical trials about 
safety and efficacy.
    The Chairman. Thank you very much.
    Ironically, the President's--and I do not mean just this 
President--budget always gets lots of attention and never gets 
enacted.
    It is important for the research community to know that 
with the leadership of Senator Blunt of Missouri and Senator 
Murray, who are the chairmen of the Appropriations Committee, 
and the support of a lot of us, we have increased funding for 
the National Institutes of Health by $2 billion for two 
consecutive years and recommended it for a third year, plus the 
$4.8 billion in the 21st Century Cures.
    I mention that not to pat ourselves on the back, but I 
think it is important to send a signal out through the research 
community that we are paying attention, and we understand that 
it is a pretty remarkable time, and we want to attract them.
    Senator Kaine asked about Alzheimer's. There is a BRAIN 
Initiative at NIH and we added money to that. Does any of that 
make it more likely that this technology could be used to deal 
with Alzheimer's?
    Ms. Bosley. Senator, as I mentioned earlier, I think that 
CRISPR is a fantastic tool to begin to further delve into the 
biology that can then help us understand how to address the 
disease itself.
    While I cannot state for a fact, I would suspect the 
researchers benefiting from those funds are absolutely using 
CRISPR as part of how they are pursuing their science.
    The Chairman. Yes. Okay.
    Senator Kaine.
    Senator Kaine. Might I ask just one more question?
    The Chairman. Sure.
    Senator Kaine. It is probably equally a question for the 
chair and ranking as for our witnesses.
    I know the goal of this Committee is to tackle a Higher 
Education reauthorization at some point in the near future. In 
terms of the NIH budget for research, that is one thing, but 
then so much of the research happens in the universities.
    I am wondering whether there are thoughts that we could 
entertain in connection with the Higher Education 
reauthorization when we do that. That might also be an 
accelerator. Assuming that the funding levels, we will work 
hard to make the funding levels, but are there things that we 
can do within the Higher Education Act to make the universities 
as places for this research to be even more cutting edge? It is 
already the case, but there might be things we could do in 
connection with that Act that would accelerate that.
    The Chairman. That is certainly an interesting thought. 
Senator Murray and I are going to visit this week about higher 
education and we will certainly consider that.
    I do not know the exact figures. I think the numbers are 
something like $27 or $28 billion of the $36 billion or so in 
the National Institutes of Health are spent at research 
universities in this country. That is where most of it goes.
    I want to ask you as we conclude, would you be willing to 
say what you think the three or four? You mentioned, there are 
6,000 diseases and 95 percent of them do not have a treatment. 
We have talked about sickle cell anemia.
    What are the three or four other diseases that are most 
promising for cures from the CRISPR technology?
    Ms. Bosley. Thank you for that question because the hope 
and promise of this technology is what excites all of us.
    I am always a bit cautious over the word ``cure,'' because 
we certainly have to provide durable benefits to patients, but 
it is a big word. I want to make sure we are not over-promising 
too soon.
    Other diseases where people are applying CRISPR, there are 
other eye diseases such USH2A, which is a genetic disease of 
the eye. There are other blood diseases such as Beta 
Thalassemia. There are diseases of the liver that are genetic 
diseases of the liver.
    It really does span across a range of other diseases that 
because this technology is so broadly applicable, people are 
pushing it in many different directions right now.
    Dr. Porteus. Yes, as I said before, the great thing about 
this technology is it is a platform technology.
    If we figure out, and we as a community figure out, how to 
cure sickle cell disease with just some subtle tweaks, subtle 
changes in the reagents. We now can cure Severe Combined 
Immunodeficiency, Bubble Boy disease; other primary immuno-
deficiencies; other genetic diseases of neutrophils in the 
immune system; other genetic diseases of the blood. It does not 
take a whole new development to move from one disease to the 
next.
    What I really think is important is that we develop two or 
three cures, I am going to use the word ``cures,'' because I 
will be an academic about it for diseases of the blood, and 
then we need to develop two or three cures for eye diseases. 
Because once you have cures for one disease in an organ, that 
is the platform for the hundreds of other diseases in that same 
organ.
    The Chairman. Dr. Kahn.
    Dr. Porteus. The liver, eye, brain, blood.
    The Chairman. Would you add to that at all?
    Dr. Kahn. Well, I think Matt's point in particular, is 
really important because one thing that we want to make sure is 
that the benefits of these therapies are shared widely and with 
diverse populations.
    I think the idea is that these are platforms which can then 
be wrapped up and used in many other diseases, and not just 
focus on the diseases that affect the most people.
    The Chairman. Yes.
    There is, at the beginning of Thomas Friedman's book, when 
he talks about 10 years ago in 2007, Steve Jobs and John Doerr 
were at a soccer game and Jobs showed him the iPhone. Their 
discussion was about who should do the apps. Apple was planning 
on doing the apps and I think maybe Doerr said, ``Why do you 
not let everybody do them?'' That was a pretty big decision.
    That is the kind of platform you are talking about. Figure 
it out, and then let the world copy it, and see how many 
different inventions we can come with.
    Well, this has been a fascinating discussion. I thank 
Senator Murray for her participation in this.
    I would confess that I told the witnesses, Patty, that I 
was fishing in Canada in August, and I only listened to the 
Canadian Broadcasting System to get the weather, and on came an 
interview about CRISPR. I stopped, and I listened, and I was 
fascinated with it, and I took notes. I said, ``One of the 
privileges of being Chairman of this Committee is I can have a 
hearing on that.''
    [Laughter.]
    That is this hearing.
    I imagine those who listened today are having the same 
thinking about this, as well as students who are in high school 
or college wondering what their major ought to be. This is a 
fascinating future.
    I would like to ask unanimous consent of the statement, by 
Dr. Marcy Darnovsky of the Center for Genetics and Society, be 
submitted into the hearing record.
    The record will remain open for 10 days. Members may submit 
additional information for the record within that time, if they 
would like.
    This Committee will meet again tomorrow, November 15 at 10 
a.m., for a hearing entitled, ``Encouraging Healthy 
Communities: Perspective from the Surgeon General.''
    Thank you for being here.
    The Committee will stand adjourned.
    [Additional Material Follows]
 Response by Matthew Porteus to Questions of Senator Collins, Senator 
            Murray, Senator Bennet, and Senator Whitehouse,
                            senator collins
    1. Advancing and linking animal models to cures is critically 
important in this endeavor. In a blog post earlier this year, NIH 
Director Dr. Francis Collins wrote about the promise of CRISPR gene 
editing in mouse studies in the area of Huntington's Disease as well as 
ongoing questions and potential safety concerns. In Maine, the Jackson 
Laboratory (JAX), distributes more than 3 million mice annually to more 
than 25,000 investigators in 60 countries each year. JAX received an 
NIH grant that will utilize CRISPR to generate, breed, cryopreserve and 
clinically assess the health and well-being of 1,000 lines of mice. The 
research team will work with the scientific community to select genes 
of interest that are predicted to function in select pathways of 
clinical significance. JAX has also received additional grant dollars 
to support research to improve the accuracy and efficiency of genome 
editing for research, drug testing, and future therapeutic delivery.

    Question. Dr. Porteus, as NIH looks to advance this technology, 
what types of resources or funding opportunities are most needed?
    Answer. Thank you for this very important question that goes to the 
heart of how to keep the United States at the forefront of cutting edge 
and transformative research like genome editing and CRISPR/Cas9.
    The support of JAX by the NIH to generate, breed, cryopreserve, and 
clinically assess 1,000 different lines generated by genome editing and 
the CRISPR technology is just one of the many different productive ways 
that the NIHcan advance this technology. In addition to supporting JAX, 
one of the key resources in the biomedical research community, it will 
be important for the NIH provide resources in at least these three 
areas:

    1. Continued broad support for scientifically sound, peer reviewed, 
basic science research. The CRISPR technology arose out of scientific 
research that was unrelated to its use as a powerful genome editing 
tool. Nobody predicted that by studying how bacteria protect themselves 
from infection would lead to the discovery of arguably one of the most 
powerful tools in biomedical research. This is just one example out of 
many of how of basic research leading to unexpected discoveries that 
have tremendous positive impact on human health.
    2. Increased support for the next generation of scientists with the 
development of career opportunities in biomedical scientific research. 
It is this next generation of scientists who are going to use 
technologies like CRISPR and genome editing to improve the lives of 
people in the United States and around the world in ways that we cannot 
even imagine now. The vitality of the biomedical research enterprise in 
the United States depends on the strong financial support of talented 
and creative trainees throughout the country. This includes supporting 
programs to engage high school scientists in the thrill of biomedical 
research, support of undergraduate students interested in STEM careers, 
support of graduate students as they begin to develop their expertise, 
support of post-doctoral trainees as they transition to independent 
careers, and early independent investigators. The training time for a 
person interested in becoming a scientist who might make discoveries 
like CRISPR in the future is much longer than in other fields and 
sustained support from the NIH and the Federal Government for these 
people is essential. Finally, increasingly innovative and cutting edge 
biomedical research is done as teams--the NIH should find mechanisms to 
increase the support and rewards for scientists who participate as 
valuable Team Members rather than primarily rewarding the top of the 
scientific food chain.
    3. Increased NIH support for translational efforts for rare 
diseases. While each disease may only affect tens of people in the 
United States, in sum these rare diseases affect the lives of tens of 
millions of people in our country at great social, personal and 
economic harm. Traditionally the NIH has not provided the larger dollar 
amounts that are necessary to translate a discovery in the lab to an 
approved therapy for patients for rare diseases. Since private entities 
are reluctant to make these investments because the diseases are not 
likely to generate high revenues because of their rarity, it would 
accelerate therapeutic CRISPR/Cas9 genome editing for the NIH and other 
Federal agencies to step into that breach and provide the support 
needed to develop cures for rare diseases.
                             senator murray
    1. In the 21st Century Cures Act, I pushed to secure nearly $5 
billion in Federal funding for the National Institutes of Health (NIH) 
to bolster specific initiatives and to allow the agency to dedicate 
more of its discretionary funding to basic research. Federal support 
for this type of research is especially important for advancing cutting 
edge technology as private entities are less likely to invest in basic 
research when it is unclear what the end product will be. As 
investments like these work to further research using CRISPR and other 
gene editing technology, we must also prioritize upholding the highest 
ethical standards as we support continued advancements.
    Thank you for securing the additional funding for the NIH as part 
of the 21st Century Cures Act! It is funding like this that will keep 
the United States at the forefront in developing cures for patients who 
currently do not have cures.

    Question A. Can you comment on the benefits of having support and 
funding from NIH and other Federal agencies for research using CRISPR 
and other gene editing technologies?
    Answer. The United States has been a world leader in biomedical 
research and the development of transformative technologies like CRISPR 
and gene editing technologies because of the sustained support of the 
NIH for scientifically sound, peer reviewed, basic, translational and 
clinical research. It is well acknowledged that it can take 20, 30, or 
more years to go from a creative idea to a commercial therapy that 
impacts the lives of patients. Almost always support from the NIH has 
been a critical part of this process, particularly in the early stages. 
Where the NIH can begin to help accelerate the process is for the 
agency to have additional resources to support the middle translational 
stages. There are hundreds if not thousands of diseases that the genome 
editing and CRISPR technology might address, many of them rare but 
devastating diseases which might not attract the investment of 
biotechnology or pharmaceutical companies, and with increased support 
these can all be developed. The relatively recent formation of the 
National Center for Advancing Translational Sciences (NCATS) is a good 
step in this direction but NCATS remains relatively under funded to 
fully support the broad vision and mission it has. The funding for 
translational research for rare diseases across the other NIH 
institutes is also less than optimal and if it was increased could 
accelerate the development of the next generation of cures for patients 
who currently have no good treatment.
    On a personal level, the support of the NIH has been instrumental 
in our development of genome editing and CRISPR/Cas9 to treat genetic 
diseases such as sickle cell disease, severe combined immunodeficiency 
(``bubble boy disease'') and HIV. The support from the NHLBI and NIAID 
through KO8, R21, and R01 funding mechanisms have allowed me to hire 
the best people and perform the cutting-edge experiments that has 
brought us to the brink of being able to apply the technology to cure 
people of these diseases in the next 2-5 years.

    Question B. Are there specific circumstances in which current 
restrictions are limiting scientists' ability to conduct research in 
the United States and compete with efforts in other countries?
    Answer. The United States continues to be a leader in genome 
editing and CRISPR/Cas9 technology though there are scientists from 
other countries who have also made and will continue to make important 
contributions. In my direct field of using genome editing of somatic 
cells to treat disease, there are no current restrictions that are 
impeding our ability to compete with scientists in other countries. 
Because of the current restrictions on human embryo research in the 
United States, it is likely that scientists in other countries will 
lead in using genome editing technology to better understand the 
fascinating process of early human development. I recognize that this 
policy choice, however, is based not just on scientific and biomedical 
research considerations.

    Question C. Are there countries that have managed to establish 
guidelines that maintain ethical standards but better allow for 
advances in applying this technology?
    Answer. Thank you for this very probing question. I think that many 
countries are currently thinking carefully about the right standards by 
which genome editing research should be carried out within its borders. 
For somatic cell editing to treatdisease, I believe that, in general, 
the United States has as clear ethical and regulatory standards as any 
country in the world. As the technology develops, I hope that the FDA 
will be able to be flexible and adapt to new information to continue to 
put United States at the leading edge.
    The United Kingdom has established the Human Fertilization and 
Embryology Authority (HFEA) which provides a mechanism to assess the 
ethics and scientific quality of research involving human embryos. This 
structure will probably permit the U.K. to lead in the ethical use of 
genome editing to understand early human development.In contrast to the 
United States where currently such research is prohibited using Federal 
funds and there is no mechanism to evaluate the ethical and scientific 
considerations for such experiments. This lack of a formal mechanism of 
evaluation by experts means that research using private funds might 
occur without ethical and scientific assessment. In contrast, in other 
countries, like China, it is essentially unregulated and thus at higher 
risk for un-ethical experiments to be performed. Thus, the question is 
on point in identifying the continued need to develop a Goldilocks 
(``just right'') approach to establishing guidelines.
    At the hearing, several Members of the Committee discussed the need 
not only for the United States not only to be a scientific leader but 
also an ethical and regulatory leader. I share that sentiment and 
believe there is an opportunity for the United States to be that 
leader.
                             senator bennet
    1. Five years ago, we passed Breakthrough Therapies on which I 
worked with Senators Burr and Hatch. Our goal was to create more 
regulatory certainty at the FDA so that innovative breakthroughs can 
reach the patient as soon as possible. The FDA has now approved over 60 
breakthroughs.
    In Ms. Bosley's testimony, she indicated ``success in this field 
will depend in part upon Congress maintaining the robust, but flexible, 
regulatory system.''
    Mr. Porteus wrote that ``for first in human uses of genome editing, 
the current regulatory structure is appropriate. But if genome editing 
strategies are shown to be safe and are based on a shared platform, the 
regulatory agencies should have the flexibility to standardize a core 
set of experiments to allow investigators to bring transformative 
therapies in a more streamlined fashion to patients.''

    Question A. Is our regulatory framework equipped to keep up with 
gene editing?
    Answer. Thank you for working with Senator's Burr and Hatch on 
establishing the Breakthrough Therapies pathway. I think the field of 
cell and gene therapy is very pleased with how this pathway has 
accelerated the development of new treatments. A recent study shows 
successfully resulted over the last five years in a significantly lower 
median drug development time (4.8 years) than drugs without an 
accelerated pathway (8 years; Hwang TJ, et al., 2017, JAMA 
318(21):2137-2138). Complementing this important regulatory path has 
also been the Orphan Drug Tax Credit which has also been very important 
in providing positive incentives to the private/business sector into 
developing therapies for patients with rare diseases. According to an 
analysis by the National Organization for Rare Disorders and the 
Biotechnology Innovation Organization, approximately 33 percent fewer 
orphan therapies would have been developed over the last 32 years 
without the Orphan Drug Tax Credit. The development of additional 
incentives to compensate for the possible decrease in this tax credit 
could be beneficial in stimulating the development of therapies for 
rare diseases, including rare childhood cancers.
    Thank you for following up on my and Ms. Bosley's testimony 
regarding what I believe is an important pragmatic issue in the field. 
The leadership of the FDA has made it clear that the agency wants to 
provide regulation based on scientific evidence. In my interactions, I 
have been generally impressed with the agencies willingness to engage 
in the science of genome editing. They clearly recognize that they need 
to keep up with the rapidly moving science of genome editing and 
CRISPR/Cas9 technology. That being said, the FDA is not known for being 
the nimblest of organizations, so it remains to be seen if they are 
able to keep up with this rapidly moving field. Activities that empower 
the FDA to be able to act more flexibly and nimbly should help 
accelerate the ability of transformative genome editing based 
therapeutics to reach early clinical trials and then become 
commercially approved. In addition, keeping up with this rapidly 
developing field will require the FDA to be fully staffed and well 
informed which will require sufficient funding to do so. The American 
Society of Cell and Gene Therapy (ASGCT) is interested in helping the 
FDA in keeping abreast of the latest developments and as a Board member 
of the ASGCT I would help facilitate the ASGCT organizing such an 
effort. The FDA approval of three gene therapy products in 2017, 
however, highlights that the FDA is currently doing a good job in not 
inhibiting novel cell and gene therapy therapeutics from reaching 
patients as rapidly as possible within an appropriately prudent 
structure.

    Question B. (For Mr. Porteus) Can you expand on how standardizing a 
core set of experiments can bring these therapies to patients in a more 
streamlined fashion?
    Answer. Establishing transparent and scientifically based standards 
would accelerate the translation of genome editing based therapies. 
Currently, each group developing a genome editing or CRISPR based 
therapy has to negotiate with the FDA about what efficacy, safety and 
toxicology studies are needed to initiate clinical trials and then to 
gain approval. This results in every group more or less having to re-
invent the wheel. In many ways, however, genome editing and CRISPR/Cas9 
are platform technologies whereby a program focused on one disease will 
be nearly identical except for perhaps only subtle differences, from a 
program focused on another disease. Because of this similarity, the two 
programs are likely to have very similar safety profiles. Yet, under 
current guidelines the FDA evaluates the two independently. By 
establishing a core set of safety standards for a given platform, it 
would give clarity to independent groups on what they needed to do and 
funding sources a clearer sense of what levels of support would be 
needed. Moreover, by establishing standards it should also increase the 
efficiency by which the FDA could evaluate new programs. In this way, a 
group developing a genome editing therapy in Colorado would no have to 
go through potentially different process than a group developing one in 
Washington, California, Massachusetts or any other state. These 
standards should be based on scientific evidence rather than 
theoretical concerns or hypothetical scenarios. I believe the National 
Institute of Standards and Technology (NIST) has initiated a project to 
help develop genome editing safety standards that the FDA might adopt.
    2. This year, I worked on the RACE for Children Act with Senator 
Rubio, which directs pharmaceutical companies to study some of the most 
innovative cancer drugs for children when the treatments are effective 
for adults and there may be a benefit for kids.
    During this process, we heard about some of the challenges in 
conducting clinical trials for childhood cancers because they affect 
fewer kids.
    As a practicing pediatric oncologist, I thank you and Senator Rubio 
for working on the RACE for Children Act. While we as a field have made 
tremendous progress in treating children with cancer, there remains 
much work to be done and incentivizing pharmaceutical companies to 
study innovative cancer drugs in children will have great impact.

    Question A. Do you expect similar challenges when it comes to 
genome editing to treat childhood diseases including different cancers?
    Answer. There are similar challenges to applying genome editing to 
treat childhood diseases. The similar challenge is that many of the 
diseases that might be cured by genome editing are rare or so called 
``orphan'' diseases. Developing a new therapeutic, especially one using 
a cutting-edge modality like genome editing, requires a substantial 
investment and commitment in time, resources, and money. As just one 
example, a regulatory path that might be appropriate for a common 
disease, might simply be too burdensome for a rare or orphan disease. 
Thus, finding mechanisms to give incentives to develop genome editing 
therapies and developing an efficient and streamlined regulatory path 
for rare/orphan diseases are both essential.

    Question B. What else should we be doing to ensure that kids with 
rare cancers have the same access to innovative gene therapies?
    Answer. In addition to legislation like the RACE for Children Act 
and the ability to extend patent lifetime by testing a therapy in 
children, an important part of ensuring that children with rare cancers 
get access to innovative gene therapies is to ensure that there is 
strong funding for investigators to test and develop therapies for 
children. The improved treatment of childhood cancer has been catalyzed 
by funding organizations who are dedicated to finding better therapies 
for pediatric cancer. The budgets of these committed organizations, 
however, pale in comparison to the annual budget of the National Cancer 
Institute (NCI). While Congress should not get into the weeds about 
which research grants to fund or not, high level guidance about making 
the funding of programs directed at rare childhood cancers a high 
priority would be important.
    In addition, bringing an innovative new therapy to market is 
costly. Companies will make economic decisions that developing 
therapies for rare childhood cancers is not cost effective even if the 
science and biology suggests it is extremely promising. Thus, creative 
ways to make sure that economic arguments do not impede the development 
of such therapies would be extremely helpful. Such mechanisms might 
include creating better ways for public-private partnerships to work 
for both sides or for there to be ways for entities like the NIH to de-
risk the development such that it would be more cost effective for a 
company to develop an innovative gene therapy for a rare childhood 
cancer.
    While there are appropriately higher standards for testing novel 
therapies in children, there is a risk that the higher standard will 
disincentivise such development. For many diseases, the earlier in 
childhood that it is treated, the more successful the outcome. Thus, 
the FDA should not put undue restrictions in bringing innovative 
therapies to younger patients where they are likely to have the most 
impact.
    The FDA Regenerative Medicine Framework includes a guidance that 
encourages adaptive study design (evaluating the study parameters at 
one or more times during a trial and adjusting them as needed), as well 
as use of novel study endpoints, which could both contribute to earlier 
access to approved therapies. FDA grants for natural history studies of 
rare diseases has also been a positive step this year, as was the 
partnering on this effort by the NCATS Therapeutics for Rare and 
Neglected Diseases program. Such research can inform clinical trial 
development, and may lead to the use of natural history models to 
augment or replace placebo arms in studies of therapies for very rare 
diseases, for which trial recruitment can be difficult and for which 
withholding treatment may pose ethical concerns. Therefore, maximizing 
funding to the FDA Orphan Products Grants Program and the NCATS 
Therapeutics for Rare and Neglected Diseases program could be 
beneficial.

    3. In Colorado, there are researchers at our universities using 
gene editing, specifically CRISPR to cure difficult conditions. At CSU, 
they are using the technology to delete the HIV genome from infected 
cells in order to cure the cells and ultimately get rid of the disease.
    Question A. How is academia currently aligned with industry to 
maximize the progress we are seeing in gene editing?
    Answer. The use of genome editing and CRISPR to provide novel 
therapies for HIV is an extremely exciting application of the 
technology.
    The development of an innovative new therapy, such as by using 
CRISPR to delete the HIV genome from infected cells, requires both 
academia and industry. The nimbleness and scientific risk taking that 
is encouraged in academia is essential to get such projects off the 
ground. Industry is essential to bring such therapies to market. There 
remains, however, what is colloquially called ``the valley of death'' 
in which many exciting ideas that have been developed in academia end 
up dying as they attempt to be translated. There are multiple reasons 
for this, including that some ideas developed in academia turn out on 
further scientific examination not to be good therapies, but improved 
alignment between academia and industry would minimize the attrition. 
At Stanford and other institutions experiments are underway in which 
industry develops closer alignment with academia in the early stages of 
research including through unrestricted funding, through direct 
partnerships, through having academic trainees spend dedicated time 
working in industry as part of their training, and others. These 
experiments need to be carefully monitored, however, so as to assure 
that academic researchers do not develop conflicts of interest that 
bias their research and restrict their freedom and nimbleness. If 
successful, however, these partnerships should enhance how both sides 
think about more efficiently translating exciting ideas in academia to 
true therapies for patients.

    Question B. What else can we do to stimulate genome editing 
research in academia?
    Answer. The most important way to stimulate genome editing research 
in academia is to assure that sustained and substantial funding is 
available for researchers to take chances on innovative ideas. Since 
genome editing was developed out of seemingly unrelated basic science 
work, this means continued support for basic science research--we can 
never predict from where the next exciting breakthrough technology like 
CRISPR might come from. In fact, we can usually be sure it will come 
from some place nobody predicted ahead of time. Since innovative 
discoveries and ideas are most likely to come from young and nimble 
minds, it means dedicated funding should be directed toward training 
the next generation of scientists and funneled primarily to senior 
investigators, even those who have a long track record of success, who 
have established their set ways of thinking of problems. (A my own 
career transitions to ``Senior Investigator hood,'' I will perhaps 
regret this statement in the future. . .). Finally, increased dedicated 
investments in translational research and translational research 
training to allow people to cross ``the valley of death'' will 
stimulate academia to develop genome editing.
    Question C. Are there steps we need to take to harmonize efforts 
internationally?
    Answer. The recent National Academy report entitled ``Human Genome 
Editing: Science, Ethics, and Governance'' (http://
nationalacademies.org/gene-editing/consensus-study/) emphasizes the 
importance of harmonizing the efforts of regulating genome editing 
internationally. The National Academies, in conjunction with the Royal 
Academy of Britain and the Chinese National Academy Sciences are 
planning to have regular conferences to facilitate ongoing discussions 
regarding harmonization. In addition, there are multiple other efforts 
to do the same. These discussions need time to mature, however, before 
any formal guidelines might be established. The field is developing too 
fast for people to know how to gently and appropriately develop such 
harmonization.

    Question D. How can we further support the progress that academia 
is making in genome editing?
    Answer. In addition to assuring sustained and substantial funding 
as discussed in question B., showing continued interest in 
understanding the technology without politicizing the technology would 
be great support. While scientists are inherently self-motivated, there 
is no doubt that as human beings we take on our tasks with renewed 
efforts and energy when we see that what we are working on is seen as 
important and impactful by others. The American Society for Cell and 
Gene Therapy, the leading scientific organization in the field, is 
excited and willing to help educating the public and Congress about the 
science and ethics of genome editing and CRISPR/Cas9 technology.
                           senator whitehouse
    1. The National Academy of Sciences/National Academy of Medicine 
report on gene editing discussed the challenges that remain in 
minimizing unintended results, or ``off-target effects,'' when gene 
therapy is administered to patients. The National Academies report 
concluded that there is ``no single acceptable off-target rate,'' and 
that the acceptable amount of unintended effects will depend on the 
situation.
    Question 1. In your work, how do you assess the off-target effects 
of a therapy, and what criteria do you use to weigh the benefits of a 
therapy versus the costs of its off-target effects?
    Answer. This is a very important question for which in this rapidly 
developing field there is currently no clear answer. As we learn more, 
particularly from the first human clinical trials using genome editing 
and CRISPR/Cas9 technology, we will be more informed to come up with 
better answers. In the meantime, it is why we need to be flexible in 
thinking about how to regulate genome editing technology so that we can 
adapt to new information.
    In our own research, we take the issue of potential off-target 
effects seriously and use the best valuable technology to both measure 
and reduce such potential effects. Using such methods, we now find that 
the frequency of off-target effects for the systems we use is likely 
below the background frequency that changes occur in the genome of 
cells naturally. In addition, we pay close attention to whether cells 
that have been modified by genome editing show any aberrant or abnormal 
behavior. So far, we have never seen that happen. These results give us 
comfort but we still remain vigilant. The field continues to develop 
better methods to both measure and reduce potential off-target effects.
    That being said, we also recognize that the diseases we are 
developing genome editing to treat, such as sickle cell disease, are 
life-threatening diseases with continued need for better therapies, 
including cures. Thus, while we remain vigilant about potential off-
target effects we are also pushing the technology to early clinical 
trials in a prudent but rapid fashion. Ultimately, the true efficacy 
and safety of genome editing technologies will only be determined such 
clinical trials and cannot be fully assessed by studying cells in a 
petri dish or a mouse model.
    The FDA shares this view that a scientific analysis of potential 
risk/benefit is the best way to safely bringing this new approach to 
curing patients to patients in a timely fashion.

    2. Gene editing technologies like CRISPR hold incredible potential 
for treating or even curing diseases for which there are currently no 
available therapies.
    Question A. Given this potential, is gene editing research 
currently receiving adequate Federal support?
    Answer. Increased Federal support would accelerate genome editing 
research. More funding to the NIH would support biomedical research in 
general, since currently the NIH is only able to fund approximately 19 
percent of grant applications. While many scientifically strong genome 
editing programs do receive Federal grant support (my lab, for example, 
has been fortunate enough to be funded by the NIH for our genome 
editing research), there are many other scientifically strong programs 
that do not. These unfunded projects are missed opportunities for the 
field. NIH Director Francis Collins indicated during the HELP Committee 
hearing on the implementation of the 21st Century Cures ACT that early 
in the 21st Century, when more funding was available, 30-35 percent of 
grant applications were funded. Dr. Collins stated that the NIH at that 
time found proposals that scored up to approximately the 30th 
percentile of the total were of a similarly high quality. Therefore, 
more funding to the NIH could fund a great deal more quality research. 
In addition, funding targeted innovative research as defined in the 
National Biomedical Research Act, could also be beneficial to genome 
editing research.
    It is important to emphasize that the key to supporting this 
research is sustained funding. The development of a good genome editing 
idea takes years. While short 1-2 year funding can allow scientists to 
do preliminary testing, it takes much longer to fully scientifically 
develop and prove the idea.

    Question B. Would additional Federal investment help spur 
advancements in gene editing technologies, and if so, what specific 
areas of research would you like to see additional investment in?
    Answer. The specific areas that I would like to see increased 
Federal investments in are the following:

        1. Increased funding for training of the next generation of 
        scientists. These are the scientists who will build on what is 
        being done now and develop even broader applications of the 
        technology.
        2. Continued funding for basic science research--the engine 
        that drives that biomedical innovation. The best tools in 
        genome editing research, for example, were developed out of 
        fields that were seemingly unrelated and were investigating the 
        basic science of different biologic processes.
        3. Increased funding for translational research to facilitate 
        ideas being able to successfully traverse ``the valley of 
        death.'' Translational research is more costly than basic 
        science research for various reasons, including that it 
        requires larger, more plex teams of investigators and has 
        different timeframes. In addition, translational research, 
        almost by definition should not be innovative even though it is 
        impactful. The NIH has historically not had good mechanisms to 
        fund translational research teams and projects.
        4. Increased funding for core infrastructure to help accelerate 
        research. Exciting discoveries are often made in places where 
        it is not readily possible to take the next steps. The Federal 
        Government could accelerate genome editing by establishing 
        centralized core expertise to help such researchers move to the 
        next steps. Such core infrastructure would be a relatively new 
        endeavor for the NIH. This core infrastructure could developed 
        as a partnership with industry. The details of such a 
        partnership, however, would be critical in order not to 
        compromise the integrity of the NIH and the academic 
        investigators by creating real and apparent conflicts of 
        interest.

    3. In the 2016 Worldwide Threat Assessment of the U.S. Intelligence 
Community, former Director of National Intelligence James Clapper 
included gene editing as a potential weapon of mass destruction and 
proliferation, stating, ``Given the broad distribution, low cost, and 
accelerated pace of development... its deliberate or unintentional 
misuse might lead to far-reaching economic and national security 
implications.''
    Question A. How far is gene editing technology from posing a 
serious national security threat?
    Answer. The potential for misuse of genome editing is clearly 
possible and careful thought about how to prevent such misuse is 
important. On the other hand, many of these worries are theoretical at 
this point and it is important that such worries do not create a 
climate of fear around the use of genome editing technology. For 
example, there is speculation about whether genome editing could create 
``super-soldiers.'' While this idea is fun to speculate about, my 
assessment is that the scientific feasibility of genome editing being 
able to create ``super-soldiers'' is essentially nil. If this theoretic 
fear about creating ``super-soldiers'' contaminates the thought process 
about using somatic cell genome editing to cure disease, we will have 
done a disservice to the millions of patients who might benefit from 
genome editing based therapies.
    The potential destructive use and security threat by either the 
overt or inadvertent use of genome editing to alter our ecology, 
environment, or food supply is outside my area of expertise but seems 
like a potential security threat that needs to be evaluated and 
monitored on a continual basis. Again, we need to be careful that such 
evaluation does not create a climate of fear that might impede the use 
of genome editing to create a safer, more robust, more humane and more 
efficient food supply.

    Question B. What steps can the United States take now to reduce the 
potential threat of the misuse of gene editing technology?
    Answer. The most important step that the United States can take to 
reduce the potential threat of the misuse of genome editing technology 
is for it be a leader in assessing this risk in a balanced, transparent 
and scientifically justified manner. By being such a leader, the United 
States can help establish the scientific and ethically permissible uses 
of genome editing and then also establish consequences that the 
international community would commit to for those who violate those 
standards.
                                 ______
                                 
  Response by Katrine Bosley to Questions of Senator Murray, Senator 
                     Casey, and Senator Whitehouse
                             senator murray
    1. While the Food and Drug Administration (FDA) has not yet 
approved any CRISPR therapies or products that use CRISPR in the 
manufacturing process, it is important the agency has the right 
authorities and expertise in place to ensure these products are 
effective, and safe long-term. One of my top priorities during 21st 
Century Cures was ensuring FDA had new hiring authorities to make it 
easier for the agency to recruit and retain the best scientific talent.

    Question. Are there additional authorities or resources that FDA 
needs from Congress to effectively regulate these products?
    Answer. In short, no new authorities or regulations are needed. FDA 
already possesses a robust but flexible regulatory framework that has 
worked well overseeing biotechnology products for over forty years, 
including nearly thirty years of gene therapy experience and several 
recent years with genome editing technologies. Editas Medicine also 
appreciates the Committee's leadership in recently enacting the 21st 
Century Cures Act. We view the Act's Regenerative Medicine Advanced 
Therapy (RMAT) designation as a positive regulatory development that, 
when applied to genome editing products, would allow novel, innovative 
medicines to access FDA's existing expedited review programs.
    Thus far, FDA has also taken initiative staying informed of 
advances in genome editing and has thoughtfully reached out and 
collaborated with both industry and leading academic centers alike. 
These efforts have helped to ensure the continues to understand the 
State of the science in this fast-moving field. The leadership at CBER 
and the Center's new Office of Tissues and Advanced Therapies have done 
a commendable job in this regard.
    We believe it would be particularly important for the Committee to 
support and encourage FDA's continued stakeholder engagement and 
scientific exchange with leading researchers in the genome editing 
field. It will be critical, as the science and technology of our field 
advances, for FDA to sustain this dialog through regular and structured 
fora with universities, leading scientific societies like the American 
Society of Gene & Cell Therapy (ASGCT), and industry groups like BIO.
                             Senator Casey
    1. According to James Clapper, former Director of National 
Intelligence, gene editing may pose a risk to national security. In his 
statement for the record at a hearing before the Senate Armed Services 
Committee last year, Clapper testified that ``given the broad 
distribution, low cost, and accelerated pace of development of this 
dual-use technology, its deliberate or unintentional misuse might lead 
to far-reaching economic and national security implications.''\1\
---------------------------------------------------------------------------
    \1\ James Clapper. Worldwide Threat Assessment of the US 
Intelligence Community. Senate Armed Services Committee Statement for 
the Record. February 9, 2016. https://www.armed-services.senate.gov/
imo/media/doc/Clapper_02-09-16.pdf

    Question A. Based on your familiarity with the technology, please 
comment generally on the potential national security risks associated 
with it.
    Answer. While it can be conceived in the broadest sense, 
applications for bioterrorism are beyond the scope of our expertise at 
Editas Medicine. What we can speak to is the tremendous potential of 
genome editing technology to advance human health in the years ahead. 
Should the Committee wish to explore potential national security issues 
further, it would be our pleasure to reach out to our scientific 
founders and other third-party groups (such as BIO) to facilitate 
additional learnings in this area.

    Question B. In your opinion, is there a need for additional 
biosafety and biosecurity regulations to protect laboratory workers who 
use gene editing in their research? What precautions do staff in your 
labs take to ensure biosecurity?
    Answer. No additional regulations are needed, in our view. With 
respect to biosafety and biosecurity, genome editing is no different 
than other recombinant DNA technologies for which policies and best 
practices currently set by the NIH and CDC have been evolving since the 
1970's. Examples include standardized classifications of laboratory 
biohazard levels and corresponding standards of practice, protective 
equipment, qualifications and procedures.

    2. One of the recommendations borne out of the recent National 
Academy of Sciences/National Academy of Medicine International Study 
Committee entitled ``Human Genome Editing: Science, Ethics and 
Governance'' was that researchers should incorporate public engagement 
to assess the risks and benefits of genome editing technologies.\2\
---------------------------------------------------------------------------
    \2\ National Academies of Sciences, Engineering, and Medicine. 
2017. Human Genome Editing: Science, Ethics, and Governance. 
Washington, DC: The National Academies Press. https://doi.org/10.17226/
24623

    Question A. As Editas is working on a product to correct vision 
loss and blindness, how is the blind community being consulted and 
included in your work, the development of products, and in overseeing 
and evaluating the research?
    Answer. We strongly agree with the Academies' view of the 
importance of public engagement and dialog. We believe that it is 
essential to develop ocular therapies through a collaborative process 
with patient organizations that represent the blind community. We have 
an established relationship with the Foundation Fighting Blindness 
(FFB) as well as many local and international patient advocacy groups 
with whom we consult regularly. These organizations are supporting our 
efforts to enroll our recently announced LCA10 Natural History Study, a 
non-interventional study designed to advance our understanding of 
disease variability and inform our clinical development plan.

    Question B. How are you addressing any potential concerns raised by 
advocacy communities and stakeholders, including those with 
disabilities, as you design clinical trials?
    Answer. We are actively engaged in an ongoing dialog with the blind 
community through the patient advocacy organizations that represent 
them. We believe that we are well-positioned to learn of any questions 
or concerns that may exist within the community and are committed to 
open and transparent communication.

    3. As the first gene therapies are coming to market, we are seeing 
manufacturers and payers consider new types of outcomes-based payment 
arrangements to mitigate the high costs of these drugs. However, I 
remain concerned that new gene therapies may end up being unaffordable 
for the patients who need them.

    Question. How can we ensure these technologies, once in use, are 
affordable for all Americans?
    Answer. The U.S. reimbursement system was built to pay for 
comparatively smaller increments required every year to manage people's 
chronic diseases. We believe that an evolution must take place within 
the reimbursement system to support access for all of the Americans 
that need these potentially transformative therapies. This evolution 
includes the implementation of value-based models of reimbursement. As 
part of this, we are actively participating in multi-stakeholder 
consortiums with leaders from across healthcare and academia aimed at 
informing the changes required to support this evolution.

                             Senator Bennet
    1. Five years ago, we passed Breakthrough Therapies on which I 
worked with Senators Burr and Hatch. Our goal was to create more 
regulatory certainty at the FDA so that innovative breakthroughs can 
reach the patient as soon as possible. The FDA has now approved over 60 
breakthroughs.
    In Ms. Bosley's testimony, she indicated ``success in this field 
will depend in part upon Congress maintaining the robust, but flexible, 
regulatory system.''
    Mr. Porteus wrote that ``for first in human uses of genome editing, 
the current regulatory structure is appropriate. But if genome editing 
strategies are shown to be safe and are based on a shared platform, the 
regulatory agencies should have the flexibility to standardize a core 
set of experiments to allow investigators to bring transformative 
therapies in a more streamlined fashion to patients.''

    Question. Is our regulatory framework equipped to keep up with gene 
editing?
    Answer. In short: yes. FDA already possesses a robust but flexible 
regulatory framework that has worked well overseeing biotechnology 
products for over forty years, including nearly thirty years of gene 
therapy experience and several recent years with genome editing 
technologies. From a company perspective, the tools that Congress has 
provided in Breakthrough Therapy and Regenerative Medicine Advanced 
Therapy (RMAT) designations are positive developments that, when 
applied to genome editing products, would allow novel, innovative 
medicines to access FDA's expedited review programs. We believe FDA 
will continue to implement the law consistent with congressional intent 
to assure that highly promising advances, like gene editing products, 
will qualify and benefit from these important programs.

    Thus far, FDA has also taken initiative staying informed of 
advances in genome editing and has thoughtfully reached out and 
collaborated with both industry and leading academic centers alike. 
These efforts have helped to ensure the Agency continues to understand 
the State of the science in this fast-moving field. The leadership at 
CBER and the Center's new Office of Tissues and Advanced Therapies have 
done a commendable job in this regard.
    We believe it would be particularly important for the Committee to 
support and encourage FDA's stakeholder engagement and scientific 
exchange with researchers in the field. It will be critical, as the 
science and technology of our field advance, for FDA to sustain this 
dialog through regular and structured fora with universities, leading 
specialty societies like the American Society of Gene & Cell Therapy 
(ASGCT), and industry groups like BIO.

    2. In Colorado, there are researchers at our universities using 
gene editing, specifically CRISPR to cure difficult conditions. At CSU, 
they are using the technology to delete the HIV genome from infected 
cells in order to cure the cells and ultimately get rid of the disease.

    Question A. How is academia currently aligned with industry to 
maximize the progress we are seeing in gene editing?
    Answer. Genome editing technologies are widely used in research at 
academic institutions and universities, and there is very strong 
alignment between these centers and leading biotechnology companies. 
Our own company has many active collaborations underway with 
researchers at academic institutions. We view these collaborations as 
being critically important to our efforts to translate the very 
promising technology and science of genome editing into medicines for 
patients.

    Question B. What else can we do to stimulate genome editing 
research in academia?
    Answer. We believe that this field is already flourishing, both in 
the United States and around the globe. Genome editing technologies are 
widely used in research at academic institutions and universities. 
Additionally, as Dr. Porteus noted during the Committee's hearing on 
gene editing, even high school students ``are so engaged in this 
technology, not only about the science, but they love to talk about how 
it should be applied--the very same issues that all of us in the room 
are quite interested in, and it's really exciting to see.''

    Question C. Are there steps we need to take to harmonize efforts 
internationally?
    Answer. Continuing to encourage international harmonization broadly 
is certainly helpful to the field of biotechnology. As it relates to 
genome editing, international regulators are building off of thirty 
years of gene therapy experience, and as a result the U.S. in 
particular has a robust and flexible regulatory system in place. 
Nonetheless, in our view it will be critical that regulators continue 
engaging in professional dialog and exchange with leaders in the genome 
editing field. The EMA recently convened a meeting for this purpose, 
and we hope the FDA continues to do so as well.

    Question D. How can we further support the progress that academia 
is making in genome editing?
    Answer. Ensuring that research funding for genome editing remains 
available through NIH, or even increasing that funding, would certainly 
benefit researchers in the genome editing field. Additionally, we 
encourage the Committee to seek a statement from the National 
Institutes of Health (NIH) regarding the totality of its intramural and 
extramural research funding for genome editing technology, and any 
recommendations that Dr. Collins, the NIH director, would have to 
augment or better prioritize these investments. Last, we would also 
recommend that the Committee explore opportunities for NIH and FDA to 
coordinate outreach to universities, researchers, innovative companies, 
clinicians and patients, to maintain the ongoing dialog on genome 
editing technology and ongoing technical developments, and determine 
whether cross-cutting, multi-sectoral engagement by both agencies could 
be formalized on a systematic, ongoing basis.

                           Senator Whitehouse
    1. The National Academy of Sciences/National Academy of Medicine 
report on gene editing discussed the challenges that remain in 
minimizing unintended results, or ``off-target effects,'' when gene 
therapy is administered to patients. The National Academies report 
concluded that there is ``no single acceptable off-target rate,'' and 
that the acceptable amount of unintended effects will depend on the 
situation.

    Question. In your work, how do you assess the off-target effects of 
a therapy, and what criteria do you use to weigh the benefits of a 
therapy versus the costs of its off-target effects?
    Answer. Our goal is to make CRISPR medicines with a favorable risk-
benefit profile, and one part of how we think about this has to do with 
our CRISPR molecules' specificity: their observed performance 
exclusively editing a targeted DNA sequence. We have published 
extensively on our approaches to improving specificity and have 
demonstrated that we can make CRISPR molecules with no detectable off-
target effects. Other important factors affecting risk-benefit 
assessments include disease severity and unmet medical need. As each of 
these will vary depending on the disease, risk-benefit assessments will 
need to occur on a case-by-case basis.
    In this regard, we are confident that the FDA is equipped to 
evaluate the risks, benefits, safety and efficacy of CRISPR medicines, 
and look forward to working with them closely.

    2. Gene editing technologies like CRISPR hold incredible potential 
for treating or even curing diseases for which there are currently no 
available therapies.

    Question A. Given this potential, is gene editing research 
currently receiving adequate Federal support?
    Answer. While we are not familiar with the details of the NIH 
budget as it relates to genome editing support, we do believe robust 
NIH funding can play an important role in advancing cutting-edge 
scientific advances. This includes robust funding of genome editing 
programs at the NIH.

    Question B. Would additional Federal investment help spur 
advancements in gene editing technologies, and if so, what specific 
areas of research would you like to see additional investment in?
    Answer. Ensuring that research funding for genome editing remains 
available through NIH, or even increasing that funding, would certainly 
benefit researchers in the genome editing field. Additionally, we 
encourage the Committee to seek a statement from the National 
Institutes of Health (NIH) regarding the totality of its intramural and 
extramural research funding for genome editing technology, and any 
recommendations that Dr. Collins, the NIH director, would have to 
augment or better prioritize these investments. Last, we would also 
recommend that the Committee explore opportunities for NIH and FDA to 
coordinate outreach to universities, researchers, innovative companies, 
clinicians and patients, to maintain the ongoing dialog on genome 
editing technology and ongoing technical developments, and determine 
whether cross-cutting, multi-sectoral engagement by both agencies could 
be formalized on a systematic, ongoing basis.
    3. In the 2016 Worldwide Threat Assessment of the U.S. Intelligence 
Community, former Director of National Intelligence James Clapper 
included gene editing as a potential weapon of mass destruction and 
proliferation, stating, ``Given the broad distribution, low cost, and 
accelerated pace of development. its deliberate or unintentional misuse 
might lead to far-reaching economic and national security 
implications.''
    Question A. How far is gene editing technology from posing a 
serious national security threat?
    Answer. While it can be conceived in the broadest sense, 
applications for bioterrorism are beyond the scope of our expertise at 
Editas Medicine. What we can speak to is the tremendous potential of 
genome editing technology to advance human health in the years ahead. 
Should the Committee wish to explore potential national security issues 
further, it would be our pleasure to reach out to our scientific 
founders and other third-party groups (such as BIO) to facilitate 
additional learnings in this area.

    Question B. What steps can the United States take now to reduce the 
potential threat of the misuse of gene editing technology?
    Answer. While it can be conceived in the broadest sense, 
applications for bioterrorism are beyond the scope of our expertise at 
Editas Medicine. What we can speak to is the tremendous potential of 
genome editing technology to advance human health in the years ahead. 
Should the Committee wish to explore potential national security issues 
further, it would be our pleasure to reach out to our scientific 
founders and other third-party groups (such as BIO) to facilitate 
additional learnings in this area.
    [Whereupon, at 11:24 a.m., the hearing was adjourned.]

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