CRISPR, DNA and Genomics: Dr. Samuel Sternberg Examines This Game-Changing Technology

Dr Samuel Sternberg - CRISPR

[Mus ic]

Margaret Flinter: Welcome to Conversations on Health Care with Mark Masselli and
Margaret Flinter , a weekly show where we speak to the top thought
leaders in health innovation, health policy, care delivery , and the
great minds who are shaping the h ealth care of the future. This week ,
Mark and Margaret speak with Dr. Samuel Sternberg , renowned
expert on the leading edge of CRISPR gene editing technology and co -
author of A Crack in Creation : Gene Editing and the Unthinkable
Power to Control Evolution , which examines the limitless potential of
this emerging approach to editing DNA.

Lori Robertson also checks in , the managing editor of FactCheck.org ,
looks at misstatements spoken about health policy in the public
domain , separating the fake from the fac ts . We end with a bright idea
that’s improving health and well - being in everyday lives. If you have
comments , please email us at [email protected] or find us on
Facebook or Twitter. We love hearing from you . You can find us on
iTunes , or Stitcher , or wherever you listen to podcasts. Please feel
free to leave us a review. Now , stay tuned for our interview with
CRISPR expert , Dr. Samuel Sternberg , on Conversations on Health
Care .

Mark Masselli : We're speaking today wit h Samuel Sternberg , Ph.D. , biochemist , an
internationally renowned expert on C R ISPR gene editing technology.
Dr. Sternberg is a n assistant professor in the department of
biochemistry and molecular biophysics at Columbia University , w ho
also runs a research lab , developing new tools for advancing genome
engineering technology. He earned his Ph.D. in chemistry from the
University of California , Berkeley , under the mentorship of Dr.
Jennifer Doudna , co - creator of the CRISPR technology for genome
editing. He's also written extensively as an expert on the subject ,
including co - writing with Dr. Doudna , A Crack in Creation : Gene
Editing and the Unthinkable Power to Control Evolution . Dr.
Sternberg , welcome to Conversations on Health Care .

Dr. Samuel Sternberg: Good to be with you.

Mark Masselli : Sam , CRISPR technology has brought us to the brink of unprecedented
potential for scientific breakthroughs. You're one of a small cadre of
scientists who are on the leading edge of this technology . I wonder if
you could shar e with our listeners just how vast the potential is and
conversely the possible Pandora's box of harm that could be
unleashed with CRISPR - Cas9 .

Dr. Samuel Sternberg: I think that the potential to do good in the world is unprecedented
because for so long we 've been limited by relying on natural random
mutations as a way of being the work stuff of evolution. Now with
tools like CRISPR , scientists have the capability to go into the genome ,

Dr Samuel Sternberg - CRISPR

which is made up of DNA , and make pinpointed precision changes to
that genetic material. That can really change the way that scientists
think about treating disease in human patients and editing the DNA of
plants and animals that we rely on for food and other kinds of
industrial biotechnology. Already we've seen a complete
tr ansformation of the way that biomedical research is being done
because of the ability to now go into the genome and make changes
as a way of designing better experiments to understand things like the
way that cancerous cells proliferate , how we can design better drugs
to target those cells , and really virtually any sector of biological
research can be now studied better with tools like CRISPR.

Margaret Flinter: Sam , in your book and in your many speeches around the world on
CRISPR technology , y ou start by a sking the question , what if it were as
easy to edit faulty genes in our DNA as it is to fix a typo in Microsoft
Word ? You sa y that's exactly what C RISPR - Cas 9 technology has the
potential to do , that's fast by most research standards , and it's
efficient. Th e million dollar question for our listeners I think is can you
help them understand exactly how CRISPR works to achieve these
dramatic results?

Dr. Samuel Sternberg: Yeah . CRISPR is often described as a pair of molecular scissors that run
based on a pair o f GPS coordinates , provided by a molecule , called
RNA , or r ibonucleic acid . The general premise is we have a way of
c utting DNA in defined locations , and then repairing th at broken DNA
using the repair mechanisms that cells are very good at doing .
Program the CRISPR molecules in a way that we can edit the gene that
we might be interested in studying or in repairing. CRISPR was
certainly invented as a technology . It comes from a very natural
immune system that we discovered in bacteria . It kind of came out o f
this decades long struggle to understand what these funky CRISPR
molecules are even doing in nature. Once we and others had solved
that problem , it became very clear how we c ould harness those same
biomolecules for this kind of molecular scissors cut and paste
functionality . Pretty much any cell type or organ ism you can think of
studying in the laboratory has now bee n edited with CRISPR
technology.

Mark Masselli : You can do it on one cell. I think the question is , how do you spread it
to the billions of c ells that might be in the body to effectuate change ?
Maybe walk through -- d on't get to o sciency on us , for the lay listener ,
but how does it scale up in the body ? What techniques are out there
t o spread it to a billion cells?

Dr. Samuel Sternberg: Yes . Th at's going to be the big question and the big hurdle in reali z ing
the potential for harnessing CRISPR as a therapeutic tool for treating
disease because you have to actually deliver CRISPR into every cell
you'd like to edit . It's not going to spread on its own unless you can

Dr Samuel Sternberg - CRISPR

edit stem cells inside the body. Actually we can start with disorders of
the bloodstream , which are some of the first that are being tackled
because it's possible to edit cells that are blood stem cells , meaning if
you edit just a small number of blood stem cells , those will end up
proliferating and turning into cells like red blood cells w h ere disorders
such as beta thalassemia or sickle cell disease have the ir greatest
effect.

One type of therapy , if you were targeting these blood dise ases ,
would be editing blood stem cells . In the laboratory , you can actually
remove those cells from patients , r epair the causative mutation in the
lab , and then return those edited stem cells back into the patient's
bone marrow. This would now give that p atient a new reservoir of
stem cells , from which healthy blood cells could be produced for the
remainder of that patient's lifetime. When you talk about now th e
neurological diseases , diseases that affect organs like the heart or the
lungs , n ow we have a m uch greater challenge because those
therapies [inaudible 00:06:41] delivered directly into the patient's
body in a way that can target many , many different cells of a given
tissue type or organ.

Researchers are looking at using different kinds of viral vec tors to try
to spread those CRISPR molecules into many cells as possible in the
patient . As you can imagine , this is going to be very , very difficult . I
think there's a big gap between how easy it ’ s become to do this cut
and paste in the laboratory versus transforming this into a therapy
that's go ing to work in living patients.

Margaret Flinter: I have something similar to the feeling that I had when I learned that
we had completed the full mapping of the Human Genome Project ,
which was something like the w ay I felt when we saw the first step on
the moon , just huge world changing events . All these achievements
come about through collaboration , and in this case , really a pretty
global collaboration among thousands of scientists working together.

There ’s alway s an element of competition in discovery . I understand
there's been some competition between the labs , including Dr.
Do udna’s lab at Berkeley and another group at MIT. As scientists
around the world work to apply CRISPR technology to new protocols ,
how do you find the right balance between collaboratio n and
competition in this really very ne w and emerging body of science?

Dr. Samuel Sternberg: Well , I think there are very few people I can think of that are holding
on to knowledge . Even with this ongoing pat ent dispute , any
researcher in the world that wants to be using CRISPR can actually go
to a not - for - profit company , called Ad dgene , and obtain the resources
they need for just $ 6 0 to start developing CRISPR tools in their own
laboratory. I actually think t he collaboration is something we can
celebrate here. Even the work that came in out of Jennifer's lab , that

Dr Samuel Sternberg - CRISPR

was actually a very productive collaboration between Jennifer and
Emmanuelle Charpentier, who ’s now leading a Max Planck Institute in
Germany . Feng Zhang , Private MIT , has done incredible work .

I think what's really exciting for someone like myself, who's been a
researcher starting as a Ph.D. student , now starting my own lab , is
seeing new discoveries coming out every day in scientific journals ,
meeti ng people at conferences , and brainstorming together. I think
it's exciting that many people are working in this space . I think at the
end of the day , it's just exciting to have so many different brilliant
minds , focusing on this problem , and thinking crea tively about how to
develop the technology quicker , better , faster , and how to start
realizing some of these lofty goals that I think are going t o be made
possible with CRISPR.

Mark Masselli : We're speaking today with Samuel Sternberg , bio chemist , an assis tant
professor in the department of biochemistry and molecular biophysics
at Columbia University , where he also runs a research lab aimed at
developing new tools for advancing genome engineering. He is the co -
author along with CRISPR co - c reator , Jennifer D oudna , A Crack in
Creation .

Sam , this technology does not come without so me controversy. It's
also being engaged in across the globe. I know there are Chinese
scientists. There is some fear about doing experiments on embryos ,
leading to fears of baby engin eering. Recently it was reported that
some CRISPR experiments unleashed an uncontrolled chain reaction .
How founded are some of these fears ? How do we mitigate the
threat?

Dr. Samuel Sternberg: Maybe the last thing you mentioned is these unintended effects of
CRISPR , genomic events that CRISPR can cause that are often not
what scientists are attempting to do. There's a major body of research
right now aimed at making sure CRISPR can be developed as safely as
possible , and that if you are using CRISPR to let 's say repair genetic
mutation , that we really understand exactly what's happening at the
cellular and at the DNA level w hen CRISPR goes in and makes that
edit .

There's been a couple of high profile papers in the last few months
that there are some risks a ssociated with making edits to the genome ,
which can involve either making additional mutations elsewhere in
the genome at unintended sites , or even the edits being something
that can't be easily controlled , where you accidentally deleted a
whole big chunk of the gen e that you're trying to repair. I think in
terms of safely deploying CRISPR , whether it's human therapeutics , or
an agricultural , or a research tool , we're still learning how to best use
this tool and use it in a way that ’ s safe and predictable .

Dr Samuel Sternberg - CRISPR

Then we can talk certainly about the other very controversial aspect
of CRISPR , which is , as you mentioned , researchers have also shown
that it can be delivered into human embryos as a way of installing
genetic changes at the earliest point in sexual repr oduction and
development . That brings about this kind of futuristic scenario where
m y parents use a tool of CRISPR in the context of an in vitro
fertilization clinic to make designer changes to their future children.
That ’ s something that is no longer pure ly the stuff of science fiction
because tools like CRISPR now make that feasible . There ’ s a growing
body of researchers , of ethicists , of regulators , of religious leaders
who are grappling with this question of what kinds of applications
should we really b e pursuing with this technology.

Margaret Flinter: We in health care have the option to be so saddened by the really
devastating diseases and conditions that families experience in the
realm of inherited diseases , cystic fibrosis , and sickle cell , and
cert ainly Alzheimer ’ s and Huntington's. We now think of that in some
way . You've really laid out the potential for appending the whole
approach to disease cures and possibly even prevention with CRISPR
technology . How soon you see this having an impact on actu ally
treating and preventing some of the most dreaded diseases ?

Dr. Samuel Sternberg: Well , I think for just about all of the diseases you just mentioned ,
there have been multiple publications already showing that CRISPR
can repair the mutations associated with those diseases. In terms of
the core technological platform to make these changes , CRISPR has
been proven to be effective at doing that . In terms of these yielding
real therapies that work in patients , that comes back to these
challenges about delive ry , about how to introduce CRISPR into the
body . I think it's still going to be many years until we see therapies
making their way through clinical trials.

I will say that there's been one area of therapeutics where CRISPR is
already being tested . That's i n the treatment of cancer where CRISPR
is used to engineer immune cells in the area of cancer therapy , called
cancer immunotherapy , whereby patient ’ s own immune cells can be
engineered to become better at hunting down cancer cells in the
body.

I think that might be one of the areas where we see the first
commercialized drugs that use CRISPR as a way of engineering the
genome in cells being used as the main mode of this therapy . There's
a number of different trials that are already ongoing . I believe they're
slated to begin later this year for skin cancer , if I’m not mistaken. I
think cancer immunotherapy is where we might see therapies come
the quickest . Many of those other diseases , it's going to be a matter
of taking these experimental successes and transi tioning them into
clinical trials that are tested on patients .

Dr Samuel Sternberg - CRISPR

Mark Masselli : Well , with such excitement around the new technologies that CRISPR
potentially offers , t hen one starts to think about what the cost will be .
While you say that developing the CRI SPR intervention s is actually
quite affordable by scientific research standards , cost often escalates.
How do you envision the cost of these highly personalized
approaches ? As we move forward with CRISPR - a ided interventions ,
how do you see this intersectio n of that venture capital w e talked
about with the ultimate cost of any therapies that get develo ped?

Dr. Samuel Sternberg: Yeah , that's something I struggle with . That's something I don't know
a lot about beyond the fact that it's extremely expensive . Cer tainly
when you move towards personalized therapies , the price is going to
go even higher than drugs that are going to be broadly effective.
While the initial therapies are going to be very expensive , that's
hopefully just one time point on a path towards the core technology
becoming better , such that over time the costs will go down. I can't
really speak to how that's going to be possible . I think we got to start
somewhere . Hopefully we'll get there.

Margaret Flinter: Well , one thing that seems really clea r to me is that all this is going to
have quite a profound effect on how we educate and train the next
generation of health care professionals and the research scientists .
I'm curious , is there much talk yet about how this really is going to
change the edu cation of both the clinical people , physicians , and
nurses , and genetic counselors. Even those of us in primary care th en
have to be sort of educated to a whole new special area of talking
with patients about what we assume at some point will be a differen t
level of screening and mapping . What changes to e ducation are going
to be needed?

Dr. Samuel Sternberg: Well , I'll tell you one thing that's been pretty amazing for me to
experience is going and giving some talks and having high school
students come up t o me afterwards , and not just say they know what
CRISPR is , but they've actually done CRISPR experiments in high
school in their biology laboratories. I think that gives you a sense for
how quickly this technology has spread beyond the confines of Ph.D.
an d post - doctoral level research into back down to high school ,
certainly to the undergraduate level , and I think increasingly into the
health care arena . I think the impact for patients , that will take much
longer to come about . T ools like CRISPR and other [inaudible
00:16:41] approaches , I think they've already transformed the way
that we think about how we can study the genome.

You cannot really be a biologist today and be maximally successful if
you don't have an understanding of how these technologies wo rk
because i t's really changing the way that we can think about designing
experiments . Maybe in the 10, 20 years , it’s going to change the way
that we need to think about how to treat disease. I think maybe the

Dr Samuel Sternberg - CRISPR

dream is that we'll be able to say goodbye to the days when a genetic
disease had to always be treated by daily or weekly injections of some
enzyme . Hopefully we can welcome a new era where you might have
a one shot therapeutic that permanently repairs the causative
mutation and permanently reverses the symptoms in patients
w orking w ith that disease. I think that's the kind of the Holy Grail of a
dream that we could be working towards in the health care are n a.

Mark Masselli : We ’ve been speaking with Dr. Samuel Sternberg , assistant professor
in the dep artment of biochemistry and molecular biophysics at
Columbia University , and co - author of A Crack in Creation with Dr.
Jennifer Doudna. You can learn more about his work by going to
sh sternberg. com , or you can follow him on Twitter @ shsternberg .
Also , you can see him present his latest findings at this year's
Jacques's Health Forum , Dr. Ed Lu ’s Shop here in Farmington
Connecticut on October 24th and 25th.

Sam , thank you for sharing your exciting and pioneering work in this
growing field and for joining us o n Conversations on Health Care
today.

Dr. Samuel Sternberg: Thanks , Mark and Margaret . It's been a pleasure.

[Music]

Mark Masselli : At Conversations on Health Care , we want our audience to be truly in
the know when it comes to the facts about health care r eform and
policy . Lori Robertson is an award - winning journalist and managing
editor of FactCheck.org , a nonpartisan , nonprofit consumer advocate
for voters that aim to reduce the level of deception in U.S. politics.
L ori , what have you got for us this week ?

Lori Robertson: President Donald Trump touted “ record business for new health
insurance plans under a federal rule that hasn't yet gone into effect. ”
In fact , since at least December 2017 , he has periodically and
prematurely boasted that millions of peop le are already signing up for
these association health plans. The federal rule pertaining to those
plans takes effect August 20 th. It doesn't start applying to association
plans until September 1st. At a July 26 roundtable discussion in Iowa ,
the president singled out Labor Secretary , Alex Acosta , whose
department is responsible for the new rule on association health
plans. He said he heard there had been a record business and
incredible numbers for plan s that he said “ just opened about two
months ago. ” Ass ociation health plans are created by a group of
employers such as those in a similar industry. The Labor Department
has been working on a new federal rule to expand and change the
regulation of these plans and is sued its final rule on June 19.

The final ru le though says it won't begin applying to association plans

Dr Samuel Sternberg - CRISPR

until September 1st. Yet the president has been talking about millions
of people signing up for these plans for months . For example , at a
rally in North Dakota in June , Trump said that “ m illions a nd millions of
people are signing up .” Now , it's quite possible that millions of people
will eventually sign up for these plans under the new regulations. The
nonpartisan Congressional Budget Office estimated in May that the
then proposed rule would result in about 4 million people joining
association plans starting in 2023. Avalere Health estimated that the
proposed rule would cause 2.4 million to 4.3 million people over five
years to move to association plans .

Under the new rule , associations could form f or those in the same
trade , or industry , or for businesses in the same state or metropolitan
area . They would need to have at least one business purpose
unrelated to providing insurance , provided couldn't deny coverage or
charge more based on health status . The plans could be cheaper than
other options on the individual market . T hey could offer more limited
benefits . That's my fact check for this week. I'm Lori Robertson ,
managing editor of FactCheck.org.

[Music]

Margaret Flinter: FactCheck.org is committed to factual accuracy from the country's
major political players and is a project of the Annenberg Public Policy
Center at the University of Pennsylvania. If you have a fact that you'd
like check ed , email us at chc radio . com. We'll have FactCheck.org’s
Lori Robertson check it out for you here on Conversations on Health
Care .

Each week , Conversations highlight s a bright idea about how to make
wildness a part of our communities and everyday lives. It's estimated
that a majority of a person's lifelong health exp enditures are often
spent in the final months of life . Death is one of those topics that
generates the least amount of conversation in the clinical setting and
American health care . For folks who end up critically ill or facing a
terminal diagnosis like la te stage cancer , this can often lead to poorly
communicated end of life wishes being discussed with the clinician
who then often resorts to extreme interventions .

Female : In oncology , notoriously , we are under prepared to have these
conversations with pati ents . Actually most studies have shown that
when you provide honest prognostic information to patients and
allow pati ents to be part of the decision - making about their goals of
care , th ey are more appreciative of it.

Margaret Flinter: Dr. Manal i Patel is a clinical researcher at Stanford University School
of Medicine. Her earlier research had yielded an interesting finding.
Patients felt more comfortable talking abou t end of life issues with a
lay person as opposed to a clinician . She and her fellow research ers

Dr Samuel Sternberg - CRISPR

followed patients at the Veterans Administration Palo Alto Health
Care System for 15 months after they were diagnosed with stage 3 , or
4 , or recurrent cancer. Half the people were randomly assigned to
speak with a lay worker abo ut the goals of care ove r a six - month
period. The control group was given no such intervention . The lay
workers were given a rigorous 80 - hour course and clinical
observations befo re being assigned to the study.

Female: We found that she learned as she went . At the end , she was
co mpletely proficient. She came to that realization that these
conversations really are not scary and shouldn't be medicaliz e d , and
maybe she didn't need all that training. We had hired her because she
had a very supportive [inaudible 00:23:25] .

Margaret Fli nter: 92 % of the participants who received the layperson intervention
compared to only 18 % of the control group were likely to have end of
life directives in their electronic health record and more likely to have
communicated their wishes to their clinicia ns as well , o ften choosing
hospice over emergency room interventions as their conditions
deteriorated. The average cost of care for the intervention group in
the last month of life was about $1,000 versus $ 23 , 000 for the control
group . Dr. Patel said one o f the more interesting findings was much
higher patient satisfaction among those who'd received t he
intervention.

Female: We found overwhelmingly that the patient s in the intervention arm
were very satisfied with the decisions that they had made regarding
their medical treatments and regarding their li fe .

Margaret Flinter: The results are published in this month's JAMA O ncology . A low
resource, patient - centered intervention that assists terminally ill
patients , their families , and their clinicians to have a frank discussion
about end of life wishes , i mproving patient satisfaction at such a
sensitive and challeng ing time , t hat's a bright idea.

[Music]

Mark Masselli : You've been listening to Conversations on Health Care . I'm Mark
Masselli .

Margaret Flinter: I' m Margaret Flinter .

Mark Masselli : Peace and health.

Margaret Flinter: Conversations on Health Care is recorded at WESU at Wesleyan
University , streaming live at chcradio .com , iTunes , or wherever you
listen to podcasts. If you have comments , please email u s at
[email protected] , or find us on Facebook or Twitter. We love
hearing from you. This show is brought to you by the Community
Health Center.

Dr Samuel Sternberg - CRISPR
[Music]