[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
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Available via the World Wide Web: http://www.govinfo.gov
___________
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
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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
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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.]
[all]