[MUSIC PLAYING]
DAVID FREEMAN: Hello
everybody, and welcome.
My name is David Freeman.
I'm the editorial
director of NBC News MACH.
Which is all about
science and technology,
including biomedicine.
So I will be here today to
moderate this panel discussion
on gene editing.
Which is a pretty big topic,
so we've got a lot of ground
to cover.
We're going to talk mostly
about human health applications.
We'll talk about
what the tools are.
What does gene
editing, itself, mean?
What are the potential uses
to combat various diseases?
And what are the
ethical implications?
So the panels here--
starting from my
immediate right--
George Church, a professor of
genetics at Harvard Medical
School and co-founder
of Editas and Egenesis.
Flaminia Catteruccia,
associate professor
of immunology and infectious
diseases at the Harvard T.H.
Chan School of Public Health.
Howard Kaufman, a
surgical oncologist
at the Rutgers Cancer
Institute of New Jersey,
and a member of the recombinant
DNA advisory committee at NIH,
National Institutes of Health.
George Annas, distinguished
Professor at Boston University,
and Director of the Center for
Health Law, Ethics and Human
Rights at BU School
of Public Health.
This is presented jointly
with NBC News Digital,
and the program is also
part of the Andelot
Series on current
science controversies.
We're streaming live on
the websites of the forum
and at NBC News MACH.
We're also streaming
on Facebook.
And we'll have a
brief Q&A at the end.
And you can email questions to
the forum at hsph.harvard.edu.
That's the forum at
hsph.harvard.edu.
And you can participate
in a live chat
that's happening right on
the forum site right now.
So gene editing can be a
powerful tool against disease,
but so far it's use in humans
has been rather limited.
We have a clip that tells
a story of a little girl
in London, who's Leukemia
was treated using engineered
T-cells, and a tool--
not CRISPR-- but talen,
as a last ditch effort
to save her life.
This clip's from
2015, and is provided
courtesy of NBC Nightly News.
[VIDEO PLAYBACK]
- We are back with a
fascinating new frontier
in targeting cancer.
A first success for
a technique that
appears to have
worked in treating
a little girl with leukemia.
It involves a
donor's immune cells
that were genetically modified
to fight the girl's cancer.
We get details tonight
from Keir Simmons.
- It's like a dream.
- This 1-year-old girl may owe
her short life to an exciting
medical advance.
And for her parents
decision to take a risk.
- We didn't see it
as a tough decision.
We saw it as the only decision.
There was no other option.
- Layla was dying
of acute leukemia.
Her mom and dad
agreed to a treatment,
in a London hospital,
never used before.
It seems to have kicked
her cancer into remission.
- So far, so good.
She's just well.
- The technique is
called gene editing.
Some of the body's
immune system cells
are removed, and tweaked to
recognize cancer, and attack
it.
When these supercharged cells
are returned to the patients,
they act like guided
missiles, targeting leukemia
without damaging the
surrounding area.
In Layla's case, there was no
need to find a matched donor,
because the genetics
can be modified.
That's the most
exciting development.
It's a technique
doctors in the US say
could be used for
other types of disease,
like breast and
pancreatic cancer.
[END PLAYBACK]
DAVID FREEMAN: So that
sounds pretty amazing.
I wondered if you could put that
into context for us, George.
GEORGE CHURCH: Yeah, I
think it's a great example.
For one thing, it shows that
this is a much bigger thing
than CRISPR, which gets, I
think, an inordinate amount
of the headlines.
Talens are just as
viable of a strategy.
And that's what was
used in this case.
The key point is that we can
now, not only, add a gene--
which was classic gene therapy--
but we can also
subtract or edit genes.
And this particular
kind of cancer therapy
could be highly personalized.
But it also illustrates
another interesting point.
Which is that we're
getting to the point
where the donor doesn't have
to be matched to the recipient.
That was never possible
before because you couldn't
edit either the donor
or the recipient
to be immunologically
compatible.
Now you can.
And that opens up even further,
so that we can get organ donors
as far away as pig-to-human.
So this ability to
manipulate the immune system
through genome editing is
going to be very powerful.
Both for this kind
of T-cell therapy
we saw for this little girl.
But a much broader
set of therapies via
stem cells and pig organs.
DAVID FREEMAN: We'll
talk about pig organs
a little bit-- edited pig
organs-- a bit later on, also.
Gene drives, too-- you
did mention malaria,
the use of gene trials
as a potential tool
in insect-borne
illnesses like malaria.
But that's another big
application for this
possibly, right?
GEORGE CHURCH:
Malaria, Lyme disease--
more close to home--
a whole variety that are
not only insect-borne,
but through rodents.
DAVID FREEMAN: I
think we do have
another clip that's
up now-- that we
can see what it's about.
This is a clip of a video
from the Wyss Institute,
here at Harvard, that helps
explain how gene drives work.
[VIDEO PLAYBACK]
- Historically
scientists have been
able to alter the traits
of domesticated plants
and animals.
But have not been able to
do this to wild populations.
Here we use mosquitoes
as an example
to explain why most genome
alterations, designed
by humans, don't
persist in nature.
And how a recently proposed
technology could change that.
The transgenic
mosquito, tinted blue,
has an altered gene inserted
into one of its chromosomes.
When it mates with the
wild type mosquito,
each parent contributes
one copy of each chromosome
to their offspring.
Thus, only 50% of offspring
will carry the altered gene.
While the other half will
inherit the wild type version
from both parents.
Even if the altered gene
doesn't reduce the likelihood
of each mosquito
surviving and reproducing,
it may persist at a low
frequency in the ocean
of wild mosquitoes.
Or it might go extinct
after several generations
of especially
unlucky inheritance.
This process is what keeps us
from altering wild mosquitoes
to prevent them from
transmitting diseases
such as malaria or dengue.
A team led by Kevin
Esvelt at the Wyss
Institute of the
Harvard Medical School,
and the Harvard School
of Public Health,
has now outlined a way
to build gene drive, that
can improve the odds that
almost any altered gene will
be inherited.
Potentially allowing
them to spread
through even wild populations.
The proposal relies on
the CRISPR/Cas9 system,
a new genome editing
technology co-developed
by the same researchers
at the Wyss.
Gene drive mosquitoes carry
both the altered gene,
the genes for the Cas9 enzyme,
and several guide RNAs,
that tell it where to cut.
When passed to
offspring, the guide RNA
is direct Cas9 to
cut the wild type
version of the gene inherited
from the wild-type parent.
The cell then copies both the
altered gene, and the drive,
when it repairs the damage.
Because the mosquito now has
two identical copies, one
on each chromosome,
all of its offspring
will inherit the alteration
and the gene drive.
This same process
will be repeated
in subsequent
generations, causing
the alteration,
and the gene drive,
to spread through
the population.
[END PLAYBACK]
DAVID FREEMAN: That's
pretty much, basically,
what you're working on.
You're working on gene drives
to help in the technology
to be used against malaria,
dengue, Zika, and so on.
Tell us a bit more about that.
FLAMINIA CATTERUCCIA:
Yes, as the clip said,
gene drives our
new technology-- is
based on the use of
genetic elements,
such as CRISPR, that
have the ability
to bias their inheritance,
and so to increase
in frequency in our population.
And we can exploit this ability
of these genetic elements
to spread the desired genetic
traits into species that,
for instance, pose a
threat for human health,
such as mosquitoes.
Mosquitoes transmit a variety
of diseases, including
dengue, and Zika, and malaria.
Malaria Is the most
dangerous of all,
because about half a
million people, mostly
young children in Africa, die
because of malaria every year.
And gene drives can really
help our fight against Malaria.
Because they give
us the possibility
to modify entire mosquito
populations in the field.
And how can we modify
these mosquito populations?
We can, for instance,
provide them
with factors that will
kill malaria parasites.
So that those
mosquitoes will not
be able to transmit
those parasites
from one person to the next.
Or we can target the
mosquitoes themselves.
And introduce genetic traits
that induce sterility,
so that the reproductive
output of those mosquitoes,
would be reduced.
And eventually there would
be fewer mosquitoes that
can transmit the disease and
even mosquito populations
can be eliminated
from any given area.
And this was unimaginable,
or very difficult
to imagine before the discovery
of CRISPR and other gene
editing tools.
But now it's a
concrete possibility,
that can also be used outside of
public health for us to target,
for instance,
agricultural pests--
all pests that are a
problem for agriculture.
And also to target possibly
[? invasive ?] species,
such as black rats.
And because it's
a new technology,
and there's still
underdevelopment in the lab,
and there's still a few
technical issues that
have to be sorted.
But also it's a technology
that poses a lot of risks.
Because if a gene
drive works, then that
will mean that it will
propagate through populations.
And the effects would
probably be irreversible.
So this obviously
poses a new question
in terms of a possible
impact for the environment.
What if we eliminate
a mosquito species?
What will happen
to the environment,
and what would happen
to the empty niche?
And also, in terms
of governance,
who will have the
final word in deciding
whether this gene
drive can be released?
After all, mosquitoes don't
stop at national borders.
So this would have to be
an international decision.
DAVID FREEMAN:
Well, I'll tell you
what, I'll save you in
the decision making.
Howard, you are kind of
well-positioned to talk
about that.
You're a surgical oncologist
but you're also a member
of this biosafety committee.
So can you tell us a bit
about your work with--
or possibly using
CRISPR or other gene
editing technologies
to treat cancer?
And also about the
regulatory issues.
HOWARD KAUFMAN: Yeah so,
cancer is a genetic disease.
So that's the basic
problem there.
And I think that we're now
witnessing a major paradigm
shift in how we approach
patients with cancer.
Precision medicine really seeks
to identify specific mutations
in genes within
the cancer patient.
And then to either
change that, or to block
various signaling
pathways that are mediated
by some of these oncogenes.
And I think immunotherapy has
become very well established
as a way to treat cancer.
And I think the
little girl that you
saw was actually
getting a T-cell, which
is part of the immune system.
And these now can be
manipulated to be very specific
for an individual-- very small
peptide within a cancer cell.
So as these new
technologies go out,
one of my areas of
research interest
is using oncolytic viruses.
Which actually uses a virus
to go right to the tumor cell.
And these can also be used as
gene therapy delivery tools.
So the virus that actually
just got the first approval
for treating melanoma, actually
delivers an immune gene
directly into melanoma cells.
And so, not only does the
virus kill the melanoma cell,
but it initiates
an immune response.
So in order to get these
new technologies out there,
I think it's important that
there is some oversight.
Because for every
drug that we have
that treats any human
disease, there's
always a risk of
potential side effects.
And with some of the
new technologies,
we don't necessarily
fully understand
what the implications
of those can be.
So there can be implications
to an individual patient.
And in oncology it
may be easy to say
the risk-benefit
ratio here makes
it valid to use the agent.
But in other cases, there may
be more widespread problems
down the line, such as
environmental issues,
or transmission from a patient
to a normal individual.
So to address that, I think
what the NIH has done,
is set up what now we call
the RAC, the recombinant DNA
advisory committee.
And the committee has
evolved over the years.
So it became a
protocol review body
to take a look at any
kind of therapeutic trial
that was going on.
And really charged with looking
at both basic and clinical
activity with recombinant DNA.
Not to really create barriers
to getting these things done,
but rather to provide
some oversight,
to develop some common dialogue
so that the field could
be advanced more quickly.
And to really look for what
kind of safety features
we might want to watch, and how
to collect that information.
In part, to help
other investigators
who were working in this field.
And also to really
learn about this
as these new therapeutic
strategies get implemented.
So some of the new technology
today is really interesting.
It's very exciting.
And I think that we
have to roll it out.
We have to do studies to
understand its real benefit.
But we also have to
provide oversight.
And so the RAC committee
is a public forum.
It's recently been
restructured into the Office
of Science Policy at the NIH.
And instead of reviewing
every protocol,
the RAC committee is really only
reviewing selected protocols.
Or providing policy advice,
and educational programs.
So when we do see, for
example, the adoptive T-cells
have led to some
interesting side
effects that weren't
previously known,
because this was a new therapy.
And we recently
had a joint meeting
with the NIH, the
RAC, and the FDA
to kind of go through
the side effects.
And also come up with
ways to manage them.
So I don't think this
has slowed us down.
I think in some ways having
some regulatory oversight
and some process to
do this, has allowed
us to potentially speed up the
development of these agents.
DAVID FREEMAN: So the
oversight clearly seems
like it's a big concern
for a lot of people
with these powerful
technologies.
And there are also ethical
concerns, as well as
safety concerns.
George, you thought
a lot about that.
What are some of the
concerns that you have about
the deployment-- the wide
deployment use of these tools--
gene editing in
human populations?
GEORGE ANNAS: Whenever you
go into a human population
for the first time,
obviously as you've said,
the major issue is
safety and risk.
What is going to happen?
Is this the right thing to do?
And what we've relied upon
historically, are two things.
One, a review board of some
sort, looks at the science
and looks at the
medicine and says,
yeah this could be
safe for humans.
And here are some possible risks
you want to tell people about.
And the second thing
is informed consent,
which I don't think works here.
You saw the little
girl and her mother,
and her mother said
we had no choice.
Whatever this was,
we had to do it.
So, no, you don't.
You didn't have to do it.
I mean it worked.
And we were all happy.
And it was great.
It could have killed her.
And she could have died
a slow miserable death.
In which case we would never
have heard about it, probably.
And trial and
error is a problem.
So I really think
we want to build
in both rigorous scientific
review, before we go to humans.
But then we have to be
realistic with humans
as to what's going to happen.
I think this is the
only case we have.
Is that right, George--
of this T-cell procedure that
the little girl went through?
GEORGE CHURCH: It is, yes.
The talen based procedure
is the furthest along.
But there are some
CRISPR procedures
that are coming along.
GEORGE ANNAS: But they haven't
actually been used in humans,
is my understanding.
Is that true?
GEORGE CHURCH: The
Chinese have done it.
GEORGE ANNAS: Well, China, OK--
OK, it started in the UK.
GEORGE CHURCH: Just like us, so.
GEORGE ANNAS: OK, all right.
In any event, you could be--
as the NBC clip we saw--
you could think from that--
this is ready to
go and available.
And if my child
has this disease,
I should get access to this.
Not unless you go to
China, apparently.
So we do want to
worry about that.
And we want to
worry about humans.
We have a lot of experience
with humans, actually.
With mosquitoes, and going into
the wild, what we worry about
is exactly what Flaminia said.
We worry about it
exploding, and you
not being able to
reverse it, that there
are no countermeasures.
There's no red button that
you can press to say, stop it.
So you want to, I
think, be sure that you
have some countermeasures.
That you can avoid, at least,
the known potential hazards.
And not put
something in the wild
that has a major normal
potential hazard.
DAVID FREEMAN: But you all --
I think, everyone
here probably agrees
the need for regulation on
this kind of new technology.
Right?
And what's your
perspective on this?
You support regulation here.
Do you worry about--
that we're going
to do something that we
might not be able to foresee?
Or is that kind of
overblown, that risk?
GEORGE CHURCH: I'm very
supportive of regulation.
I think there's a
stereotype that scientists
don't want regulation.
I think it protects us.
From things like thalidomide
and Vioxx, and so forth.
Occasionally it
doesn't protect us.
So, no, I haven't run into a
case where it slowed things
down unnecessarily.
GEORGE ANNAS: You know,
the British actually
have the most vigorous
type of oversight
in genetics and reproduction.
And they are much further
along than we are.
They wind up doing--
well, cloning wasn't
in humans, but they
did cloning-- they did
mitochondrial DNA replacements.
[INTERPOSING VOICES]
GEORGE ANNAS: And they
have very public oversight.
They have debates
in the parliament.
And mostly the public
approves of this stuff,
as long as it's reasonable.
And that's the only
question-- what's reasonable?
DAVID FREEMAN: Well, the
thalidomide story kind
of played out in England, right?
So, is that kind of the
origin of their concern?
GEORGE ANNAS: That's one of
the worst case examples, right?
DAVID FREEMAN: Right,
so, Howard, what's--
are we well protected from RAC
and other biosafety group's
regulations?
HOWARD KAUFMAN: Well
the thalidomide story
is a good one to
bring up, I think.
So thalidomide has
anti-cancer activity.
And so it was under intense
investigation for a long time.
And as you can imagine
trying to write a study,
and do informed consent--
GEORGE ANNAS: To get
people to take it.
HOWARD KAUFMAN: Having--
giving people thalidomide
was a problem.
And so, I think, by having
a regulatory body to take
a look at that-- one of the
things that we came up with,
was that there was a
registration program.
So, as a physician
prescribing it, I did this.
I prescribed the thalidomide.
You had to be registered.
You had to report
every patient in.
We were able to develop
a national consent form.
So the bioethicists weighed in.
We made-- really
talked to the patients
about the potential risks.
Thalidomide was a pill.
It's an oral agent.
So, if you take that home
and somebody gets into it,
they could potentially
get exposed.
So there were a lot of issues.
But I think, by getting
together in a national forum
we were able to address that.
And we successfully
did the studies.
Unfortunately, it didn't
work at the end of the day,
as an effective cancer therapy.
But we were able to study it.
DAVID FREEMAN: But it's
interesting, beyond this.
The safety of humans were
involved in these things.
Seems to me some other bigger--
more existential issues.
And we talked about
this before, Flaminia,
about the idea with
the gene drive.
We might be able to
extinct a species.
Take a species that's been here
forever, for millions of years,
and get rid of it.
Does that give you pause?
Or do you think
that the possibility
of saving hundreds of
thousands of lives a year,
say, to Malaria, outweighs that
kind of difficult question?
FLAMINIA CATTERUCCIA: Yes,
it's interesting, and sort of
important, that we are
having this conversation now,
about the possible
impact of gene drives.
If you think that we've been
trying to kill and eliminate
mosquitoes for many decades,
using very toxic pesticides.
It's great that
now the possibility
of using powerful gene editing,
is actually stimulating,
again, this conversation
about the role
of mosquitoes in the ecosystem.
And what would
happen if mosquitoes
didn't exist anymore?
So the beauty
about gene drive is
that they are species-specific.
So they are highly,
highly specific,
for the species that
you want to target.
Therefore, it's believed
that the overall impact
on the environment will be
minimized, by the fear that you
would target only one
mosquito species, or one
inter-species at a time.
Contrary to what happens with
pesticides or insecticides,
for instance.
However, the question of what
would happen to the empty niche
if a mosquito population was
eliminated, is a true question.
And a true concern
for ecologists
and environmental biologists
to get together to address.
And the truth is
that, we don't really
understand enough, what's
the role of mosquitoes
in the environment.
And therefore, if we
decided to go and proceed
with a gene drive that
suppresses populations, then
the monitoring side
of the release,
or what happens after these
mosquitoes are released,
will be really, really,
really, important to detect
possible unintended
consequences,
as early as possible.
So that we can--
DAVID FREEMAN:
George said, maybe,
it's too late at
that point, right?
Is that-- something
untoward happens,
and it may be hard to push the
red button that doesn't exist,
right?
FLAMINIA CATTERUCCIA:
Yes, so with gene drives,
the problem is that, if
the work effectively--
potentially-- that it might
not be possible to reverse
their effects.
Although there might
be possibilities
of releasing a second
reversal trial,
that would prevent
the first one to work.
Of course, there is no
guarantee that that would work.
That's why monitoring and early
action would be essential.
DAVID FREEMAN: Another issue--
weighing all these
risks against potential
to save lots and lots of lives.
And another thing
that's come up, too,
is the way CRISPR
and gene editing
is a way to solve the
shortage of organ--
human organs available
for donation,
or for transplantation.
And I don't know
what the number is.
I think it's dozens of people
die a day waiting for organs.
You may know the number.
But you're involved in this
idea of editing pig organs,
so they would be transplantable
without an immune response
in people, right?
GEORGE CHURCH: Right, you have
less issues about wild release.
But the same issues, having to
do with safety and efficacy,
as you have with any drug
or environmental release.
The advantage here
is that millions
of people that could benefit
from a safe, and readily
available organ donation, if you
can make it that the organ is
compatible and virus free.
One of the things that derailed
it about a couple decades ago,
after a couple of a billion
dollars of investment,
was that the virus was released
into an immune-compromised
patient.
We've now shown in
the laboratory we can
eliminate all of those viruses.
Even if there are 62 of them
from the genome of the pigs.
So that's a fairly
monumental editing task
we've now shown
as quite feasible,
without causing any
damage to the pig itself.
DAVID FREEMAN: And
how far along is that?
Would you hazard a
guess, as to when
it might be possible,
to start transplanting
pig organs into humans?
GEORGE CHURCH: You
know, I think there's--
almost all of the component
changes, maybe a hundred
of them, have been
tested at this point.
It's now making that
final pig strain.
And probably within
a year of that--
it could be as little as a
couple of years from now,
we'll be doing clinical trials.
DAVID FREEMAN: But you're
smiling about this.
What are you smiling about?
GEORGE ANNAS: People
have been talking
about doing-- using different
sources for transplants,
forever.
Right now, the big
debate now is, can you
use organs from people
who have hepatitis C?
Right?
Because we can treat
hepatitis c, for $100,000.
So you could do the
transplant for a kidney,
and cure the hepatitis
C. And basically double
the cost of the transplant.
From a public
health perspective,
really, you want to
put your emphasis,
not on transplants, but on
preventing the diseases that
make people need transplants.
It can't prevent every
disease, obviously, but--
we treat transplants
as if they are--
and there's nothing
bad about transplants--
but if they are the
most important thing
we do in medicine.
Which is weird.
I always find that weird.
Because historically, it's
always taken the death--
the sudden death, of an
otherwise healthy person
to be an organ donor.
Now we use different
people for organ donors
But to me transplantation
is always a public health
disaster.
Now, if it's a pig
you're taking it from,
then we don't require
the death of a pig.
Maybe, that's OK.
Some of you are old enough
to remember baby Fae though,
which is the only xenograft
done in this country ever--
with a baboon's heart to
a little baby, who died
a horrible death after that.
And it was never done again.
This is a trial-and-error
type of experiment.
My guess is we're going to be
extraordinarily careful to do
the first pig transfer.
Extraordinarily careful.
As we should be.
GEORGE CHURCH: I hope so.
GEORGE ANNAS: Yeah, yup.
But it'll still be
trial-and-error.
If the first person gets a
bad reaction from a pig organ,
we won't do it again.
DAVID FREEMAN: What about
this idea of informed consent?
Because all these experimental
treatments on people, require,
I guess, the consent of
the people being treated.
GEORGE ANNAS: Oh they do.
DAVID FREEMAN: But,
Howard, is it your--
are we-- and, George,
you were talking
about how the woman said she
didn't have a choice here.
But she did have a choice.
How do these gene
editing techniques
raise any new issues about
informed consent in patients?
Howard?
HOWARD KAUFMAN:
So, everything we
do in medicine, we look at
the potential for benefit,
and the potential risk.
And you have to weigh that out.
That's what we do as
clinicians every day.
And it's, unfortunately,
what patients
have to go through at the
worst time of their lives.
But one thing-- I'm curious
to get your reaction to this--
50 years ago, if you were
going to go into a cancer
clinical trial, the
likelihood of a drug working
was very, very low.
I think we had like one in
1,000 drugs even moved forward.
Today, I think the
science is much better.
It's informing
where we're going.
And so we're able to
come up with, I think,
much more rational strategies.
And so the likelihood
of a benefit,
seems to be much higher.
And this actually came up
at one of our RAC meetings.
And some of the
bioethicists said, maybe,
the potential benefit has
shifted over the last 50 years.
And we need to reconsider
that in the consent language.
GEORGE ANNAS: Yeah,
it's very difficult.
I've been one of
the people arguing
against saying
that there's going
to be a benefit to
this research trial.
Because that's
why it's research.
We don't know if it is
going to benefit or not.
Now we may feel better about
it than we used to feel.
But, it's virtually--
it's very difficult
to get informed consent from
someone who is terminally ill.
And you're basically
telling them,
we got nothing for you,
except to try this experiment.
Right?
We have this weird movement
in the United States--
and I really think
it's weird, and wrong--
called the right-to-try.
There's like more than half the
states have passed laws, that
say you have a right-to-try
experimental drugs, that
have only gone through phase
1, or initial safety phase.
They have no efficacy,
that we know of.
I mean, they may.
But the fact that
these people are dying,
they and their families are
demanding something be done--
and you know, that's
an emotional reaction.
I can totally
sympathize with it.
But we can't support that.
Like the FDA and
regulatory agencies
really, really should
not support that.
Because that is not
scientifically based.
And it's a big problem when we
moved from not scientifically
based, to how people feel--
and then the people who--
mostly this involves children
who are dying-- which is like,
the worst for parents.
I can't even begin to think
about how bad that is.
Nonetheless, they're very
subject to exploitation.
And it's very difficult to make
any kind of reasoned decision.
So Informed consent alone,
can't protect us there.
We really do need--
we need the FDA.
HOWARD KAUFMAN: But I think, the
only way we can move forward,
particularly from a public
health perspective, I think,
is to do clinical research.
GEORGE ANNAS: No, I'm not
against clinical research.
But there's when-- when you're
ready to try it in humans
for the first time, right?
HOWARD KAUFMAN: Well,
so I study melanoma--
is the disease I look at.
And this is a disease
where we had, essentially,
no effective therapies for
many, many, many years.
Except maybe for high
dose interleukin 2.
And we now have 11
agents that were
FDA approved in the
last five years,
completely changing the field.
And it was going
so rapidly, that--
in something I've never
seen in my career--
the FDA was beginning to
approve these drugs off phase 1
studies, because the response
rates were so dramatic.
Including some
complete responses.
But there was this
period, where the only way
you could access these drugs,
was to go on a clinical study.
And so as the clinician, who
has to be the objective person,
and going between
the consent form,
and what's best for the patient,
and what's best for the field,
became very challenging.
Because I do think, that it
would be in my patient's best
interest to go on this study.
And get a drug
where we now we're
getting increasing
amounts of information,
albeit, small numbers.
And so, the pig
transplant may not work.
But what if it does work?
And what if that transforms
all of transplantation
and this becomes a standard?
It's got to start somewhere.
DAVID FREEMAN: But,
there's the possibility--
is the idea of informed
consent different now?
Because there might be
downstream effects in people's
offspring.
Because it's a genetic
change, is that
different from previous
kinds of drug treatments?
Or is it the same?
GEORGE ANNAS: In some
senses it's the same, cause
the person survives,
and then can reproduce.
And we'd say, before
they had the treatment,
they wouldn't survive, and
they wouldn't reproduce.
On the other hand, this
whole argument about germline
genetics-- whether you should be
able to manipulate an embryo--
which is going to grow into a
child, whose genes are then--
new genes are going to
pass on to their children
and their children.
And we've literally been
debating this for 40 years.
Nonetheless, it has
not been resolved.
And it's still a
really good question.
DAVID FREEMAN: And
it's obviously--
the potential-- the promise of
these gene editing techniques
are so extraordinary, that
it's hard to kind of try
to do anything to slow
it down, emotionally.
We want to get good
news and solve things.
What is the biggest
thing, malaria?
Is it crop production?
This has agricultural
uses, as well, right?
They are making drugs-- or
plants resistant to bugs
or to temperature changes.
What are the other
big things that might
be brought from gene editing?
GEORGE CHURCH: Well, I
think, the interesting thread
through all of those
agriculture germline--
most of the editing
attention right now
is on adults or crops.
If you have a choice between
random mutations-- so
chemotherapy could affect your
germline, but in a random way.
You can change your crops by
allowing random radiation to--
which is the standard
way of doing it.
And that could cause allergens.
Most allergens are the
process of evolutionary time
frame, random mutations.
Or you could do it in a very
targeted way, and avoid that.
So, I think, there
is a potential
for people to get excited
about, and less concerned about,
GM crops.
And, for that matter,
they're already
accepting of GM
medicines, like insulin,
that's produced in bacteria.
Because it's life
and death and all.
And there are some crops,
like golden rice, where there
is a public health component.
A milliion people die
of vitamin A deficiency,
and that's a
potential fix for it.
But the key new thing is, is
cisgenic versus transgenic.
Transgenic was kind of the third
rail, the really hot button
item.
Where you're moving
a gene from--
between two radically
different organisms,
that normally wouldn't
exchange genetic material.
With cisgenic you're
changing it within.
You're making a simple
change, like adding a G
to a T, something like that.
That may be more
acceptable, than either
the transgenic approach,
or the completely shotgun
random approach.
DAVID FREEMAN: Is
that a good argument,
that it's happening
in evolution--
it's a messy process anyway?
We can let it happen
naturally, or we can intervene.
Is that a good argument--
are you guys convinced?
GEORGE CHURCH: Well,
it's within the organism,
versus between species,
is the key argument now.
GEORGE ANNAS: The multi-species
argument, that's a good one.
The fact it's
happening naturally,
we go back and forth about that.
Normally, we don't
use nature as a guide.
If we did, we wouldn't
have medicine at all.
Because diseases are
naturally caused too.
One of the things-- just to
say what's the most important
thing, what's the thing
the public wants the most--
is where we started,
with cancer.
You know we want to cure cancer.
We've been trying to
cure cancer forever.
And cancer is a genetic disease.
And it does seem we should
be able to work on it.
We have done melanomas, a lot
better than we did before.
Most of the cancers, we're
not doing that great on.
HOWARD KAUFMAN: I
think it is changing
though, I think we're doing
better and better with cancer.
And I do think that the
outcome for cancer patients
is the best it's ever been.
And I think, it's been partly
because we've made advances
on the therapeutic side.
But also there's been a lot of
work on the prevention side,
not enough.
And these things, I think,
are impacting the disease.
And I think we have to
continue to do both of those.
And cancer, I think,
is a good example,
where you could argue
that for a cancer
patient to go into
a risky study,
they're willing to
take that chance.
Because these can
be fatal diseases.
I think when you go
to diabetes, or you
go to other diseases, that
are maybe not as serious,
then I think the ethical
issues become more problematic.
DAVID FREEMAN: But it's also
the issue of making decisions
based on big populations.
So the gene drive
brings up another issue.
Who's going to make
the decision to put--
release these mosquitoes
in Brazil, or in Africa,
where Malaria is, or Asia.
How do we-- who
gets to decide that?
Whether something--
we're going to do this,
something might have
these untoward effects,
or it might save
everyone's life.
How do you do that, who decides?
FLAMINIA CATTERUCCIA:
So yes, also going back
to what George was saying,
earlier about transgenic
versus cisgenic.
Not many people
realize, that actually,
there are transgenic
releases already happening.
And they've been happening in--
started in Cayman
Islands, and then
in Panama, and Malaysia,
and Brazil, more recently.
And now they're also
discussed for Florida.
For instance, where
there's a UK based company
that has generated this
genetically manipulated
mosquitoes, that are those
that transmit dengue virus,
and Zika, and other
viral diseases.
It's expressed like a lethal
gene that is kept quiet
in laboratory conditions.
But then it's activated once
these mosquitoes are released.
So when males are released, and
they would mate with females,
their progeny is killed
by the lethal gene.
And therefore, those few females
are virtually sterilized.
And then if this happens
over a long period of time,
and repeatedly, then
eventually that population
can collapse, and can
not transmit disease.
And it's been very
interesting to see
what happened in
Florida, last year
during the general elections,
where residents of the Florida
Keys were asked to vote
on this technology.
And so the residents
of Key Haven, which
was the location where the
releases should have happened,
were asked, as well as
residents of the Monroe County.
And while residents
in Monroe county
voted in favor of
these releases,
residents in Key Haven, which
was the location more closely
affected by the
releases, voted against.
Which brings up all
the different issues
of how the general public
perceives these technologies.
But also, there are
genetic control strategies
that are used, as we
speak, against a number
of agricultural pests.
Where insects are manipulated
by using irradiations
that render them sterile.
So they're not
transgenic, as such,
but they're genetically
modified insects,
that then are released, to
suppress the population.
So these things are already
happening, as we speak.
DAVID FREEMAN: So, I think,
we have some questions.
We'll take some from online
first, then from the audience.
LISA MIROWITZ: Right, thank you.
We have a lot of
questions coming in here.
And they're on all
different topics.
So let's start with this one.
It's from Christopher Brown.
If gene editing becomes
readily available,
will it be totally exclusive,
only for the rich, and wealthy
people of the world?
Or will it be
available to everyone,
regardless of financial status?
GEORGE CHURCH: I'll take that.
So, I think, one of
the few technologies
in the history of the planet,
that is available to everyone
equally--
so not nutrition, not hygiene,
and clean water, and not
even vaccines--
until they drive
something to extinction.
So smallpox is extinct.
Guinea worm, and
polio are close to it.
And when that
happens, then it is
available to everybody on the
planet for free, in perpetuity.
So, I think, that's
an example of--
if malaria is something
that could be extinct,
even without making a
single mosquito extinct.
And that would be a benefit
to everybody on the planet.
GEORGE ANNAS: Sounds
good, but smallpox now
reappears as a bioweapon.
It was the main theory of
why we went to war in Iraq.
Because they had
smallpox as a weapon.
You don't want to
oversimplify it.
Nobody wants smallpox.
It's a horrible disease.
It's a great public
health victory to do that.
But, in fact, there are--
GEORGE CHURCH:
You can continue--
[INTERPOSING VOICES]
GEORGE CHURCH: You could
still continue to vaccinate,
if you were really
concerned about it.
I think, that's not an
argument, for why you shouldn't
make something extinct.
But it's a good point.
We shouldn't over simplify.
GEORGE ANNAS: There
are some risks.
DAVID FREEMAN: But I
think the other thing
that people talk about, is
this idea of designer babies.
Right?
That there may be
a rich-poor divide.
Who gets access to something--
GEORGE ANNAS: The
idea in general,
that everybody's going to
have access to everything,
is just ridiculous.
Just look at the world
the way it is now.
Look at the United
States, which we're
the richest country
in the world,
and we can't deliver basic
health care to everybody.
No, there's definitely going to
be a rich-poor divide in this.
There's no way to
get around that.
GEORGE CHURCH: But the question
is, is that getting bigger,
or could it get smaller?
GEORGE ANNAS: Could
it get smaller?
[INTERPOSING VOICES]
GEORGE CHURCH: I mean,
there are occasions
where it does get delivered to
everybody, or to a very large,
large fraction of society.
For example,
electronics is getting
delivered to a much larger set
of society than ever before.
LISA MIROWITZ: That's a
great point, thank you.
GEORGE ANNAS: And vaccines too.
LISA MIROWITZ: Great, thank you.
So people are writing
in, of course,
about very specific diseases--
with questions about them.
So I'll just take this one.
It's from Queensland, Australia,
from Jack Doyle, a year 12
high school student.
What are the
legalities behind using
IVF to treat genetic
diseases, such as hemophilia?
Are there any current
issues with the law?
If so, what are the issues?
I think this question
may be referring to gene
editing rather than IVF.
GEORGE CHURCH: Well, you can
use gene editing with IVF.
You can also use IVF--
so, I think, something that's
not always brought out,
and maybe this is an
opportunity to bring it out--
is that an alternative to
gene therapy, in some cases,
is genetic counseling.
It's considerably less
expensive at this point,
but that could change.
Which means that if
everybody knows their genome,
they know whether their
children are at risk.
And they can take action
before the disease occurs.
So IVF is not necessarily
the most cost effective.
And it's not an entirely
pleasant experience.
Whether it's for
selection, or for therapy.
I don't think it is, right now--
IVF plus gene therapy--
a combination that many
people are embracing.
Partly because the embryos are
a complex mixture of outcomes.
So it's just not
effective yet, basically.
GEORGE ANNAS: And there's
no law against that,
but we do have a law
in the United States
against spending federal funds
to do any research on embryos--
that destroys embryos, or
creates them for research.
LISA MIROWITZ: Thank you
for pointing that out.
So because we have
a lot of questions--
I'm just going to
kind of clump them.
There are a number of
questions coming in about,
why aren't we just doing this
research on somatic cells?
And why can't we focus it
that way, instead of germline?
So perhaps you
could address that.
GEORGE CHURCH:
That's an easy one.
We are focusing
on somatic cells.
There's almost zero
work on germ therapy.
But it doesn't
mean that that's--
the National Academy
of Sciences said
that there will be circumstances
where that is the case.
But there are 2,400 gene
therapies in clinical trials
right now.
None of them are germline,
zero out of 2,400.
But there is a scenario
where it would be
or it could be suitable.
Where you would reduce
embryo loss due to,
the now standard
practice, of abortion.
You could eliminate abortion
if the germline were treated.
So I think that's going to be a
non-obvious conversation we're
going to be having
going forward.
LISA MIROWITZ: Great, thank you.
I don't know if anyone in the
studio audience has a question.
Hi, my name is Lindsay Brownell.
And my question has to do with
the public perception of gene
editing going forward.
Because a large portion
of the population
has a very negative
view of GMOs.
And there are lots
of labels on food
that promise that the food
within them is non-GMO.
But the reality is,
that most of the soybean
crops in the country, and most
of the corn in the country,
is in fact genetically modified.
So there is this
negative perception
of the idea of genetically
modified organisms.
And I think that among the
scientific community and people
who are familiar with
gene editing, that
is the community that sees it
as a big benefit to society.
But I think, sort of,
the initial introduction
of GMOs into the public
conception was negative.
So how can we change that
perception going forward?
Or how can we ensure that
the public sees editing
as a positive thing?
While, at the same
time, still being aware
of all of the
concerns that we've
been discussing
today in the forum.
GEORGE CHURCH: Well, I
think that the public--
the same critics of--
I wouldn't say GMOs,
I'd say GM foods.
The critics of GM
foods rarely, if ever,
criticized GMOs use for
manufacturing insulin,
and other human protein
pharmaceuticals.
That's one positive thing.
We should talk about
that a little bit more.
Distinguish between
GMOs and GM foods.
I think GM foods is a
particularly poor choice
of battleground for technology.
Because literally, you
would go into a supermarket,
and you can't see any advantage
to the consumer for GM foods.
So any risk whatsoever, even
hypothetical, raises a problem.
I think where GM
foods will change--
and the USDA has already weighed
in on 30 different genetically
modified organisms,
that will not
be regulated the way
that transgenics are.
So these include mushrooms,
and various plants--
that because they're
cisgenic, because they're
such small changes in there,
that exactly the sort of thing
you could obtain by
random mutation--
I think that the
legislative direction
is to have those not regulated.
And that's probably worldwide
but we'll have to wait and see
whether that ...
And that changes
the conversation
in a very dramatic way.
Even though it seems subtle.
It changes it from
the line being
drawn between high technology
and low tech, both of which
are tech.
Now the line is between
moving between species,
and not moving between species.
And I think that's
a big improvement
in the conversation.
DAVID FREEMAN: Just
real quick, I just
wondered-- you were talking
about these misconceptions,
that people have about these
techniques, these tools.
Are there other kinds
of misconceptions
that are out in the public, that
we need to disabuse them of?
What are the misconceptions
about gene editing, right now,
that are a problem?
GEORGE ANNAS: Well, I wouldn't
say disabusing the public.
I don't think you want to
start with the assumption
that the public is stupid.
[INTERPOSING VOICES]
GEORGE ANNAS: I understand, but
almost every panel, including
the National
Academy of Sciences,
has recommended more public
discussion, more education,
and more listening to
the public as well.
And I think that's right.
I think the public
has to be involved
in all of these decisions.
And they can't be because if
they don't understand them--
so our education--
and we don't have
to go back-- but our education
system is really horrible.
And it's especially
horrible in science.
And you're not going to
change that overnight.
But, I think, you
have to attack there.
It's not just people--
even George, going in front
of people, to say here's
what the science says,
and this is the end of it.
So just do what I say--
not going to happen.
HOWARD KAUFMAN:
Yes, but I do think
we have a responsibility
as scientists
to educate the public.
Because I think that
perception sometimes
is maybe misplaced, because
they don't really understand it.
And not everyone is
trained in science,
and necessarily understands us.
And that, maybe, we do
need to think about how
to do a better job of that.
GEORGE CHURCH: In some
countries, like China,
80% of the top
politicians have degrees
in science and engineering.
In the United States
it's closer to 1%.
But it needs to be a dialogue.
There needs to be more
enthusiasm and engagement.
LISA MIROWITZ: Let's
see, we'll take this one.
Aren't the health risks with
CRISPR basically the same
as with any gene therapy?
Isn't the main issue trying
to target the therapy only
to the cells you want
to hit, without it
traveling through the body, and
getting into other areas you're
not targeting?
In fact, haven't
past gene therapies
led to cancer in some
patients, for this very reason?
I think this is for you,
Howard, this question.
HOWARD KAUFMAN:
Yes, so depending
on what your sequence is,
and how you target it,
these gene segments can wind up
in places you don't want them.
And that's one of the
reasons we monitor
patients on these studies.
There was a study of an
adeno-associated virus gene
therapy.
And it turned out,
that later, we
didn't realize that it
could get into hepatocytes
and it was actually inducing
hepatocellular cancers
in some patients.
I think that's part of
the reason we do carefully
conducted research, and
we follow the patients--
and that came to attention.
And I think these AAV
vectors sort of fell out
of favor because of that.
There are other
viruses that can be
used that don't get
into the genome,
and you don't have to worry
about insertional mutagenesis.
And so that may be an
advantage in using them.
But I think that is a risk.
And George, you may want to
talk more about on-target
versus off-target affects.
But, in general,
I think CRISPR is
very similar to any other
sort of gene therapy.
And the efficiency may be
a little bit different.
But I think the potential for
having an off-target effect,
is still the same.
GEORGE CHURCH: The real
problem in the early days,
about a decade
ago, that did cause
some deaths were retroviruses
that would insert next
to oncogene, like elmo2.
The possibility of CRISPR is
that you have no insertions
at all.
You simply have a free-floating
RNA and protein, that
then edit the particular site.
You have, instead, the
off-target but the off-target
now is not random integration.
It is dictated by the
guide RNA that both
determines the on-target
and the off target.
So that is now controllable.
The key thing is doing very
careful preclinical animal
trials.
And then really
monitoring the human.
LISA MIROWITZ: Great, thank you.
I encourage everyone
to go on our chat
because we do have
a lot of questions.
But I know we have to
wrap up, so thank you.
DAVID FREEMAN: Yes, we've just
got a few minutes left so,
if everyone can think--
what's a single policy
take-away-- that your
message-- that you'd
like to share with
thought leaders,
or influencing policy makers.
Who wants to go first?
GEORGE ANNAS: My takeaway is
we need more public discussion.
And we need to actually plan for
it, and make sure it happens.
And policymakers,
since they generally
try to get the public's
favor, should work on that.
HOWARD KAUFMAN: I think
this is an exciting time
in human history when
we're making big advances
against many human diseases.
And so now is not the
time to get scared.
But now's the time to step
up, and have more discussion.
And really sort out the
policy and regulatory issues,
so we can move these things
forward more rapidly.
FLAMINIA CATTERUCCIA: Yes, for
me, in relation to gene drives
in particular,
safety is paramount.
And so having that way to
assess risks associated
with this technology.
And so having cross-disciplinary
panels and committees
that can evaluate each
case individually.
Because the risks
will be different
depending on the organisms that
we target, and the way we're
going to target these organisms.
And they can set
a recommendation
for key experiments
that have to be provided
for the general public,
in order to determine
what are the risks associated.
And, apart from the benefits, I
think this would be essential.
GEORGE CHURCH: Yes, I
agree that we need to have,
not only more discussion
of the science,
but also of the economics.
I think, one of the reasons
this is an exciting time
to be alive, is we have
exponentially decreasing
costs, and quality, and safety.
All of these are on
exponential curves.
And preventative
medicine, I think,
is preferable in many cases,
as we've just touched upon.
And we have to realize the
revolution here is not CRISPR,
it's not editing, it's
not even gene therapy.
It's this whole collection of
being able to read genomes.
It's very hard to edit a
book that you haven't read.
And there's a lot
of things you can
do with reading and
genetic counseling, that
is less expensive, less
invasive, and better
for public health.
That just involves
counseling and reading.
DAVID FREEMAN: So I
think that's where--
about time to wrap up.
If there's anything else--
well, I think, the people who
can continue this conversation
on the forum website right
now-- which is forumhsph.org
and keep things going.
And, I guess, even
more and more things
like this to increase--
to educate the public.
And hold them to account--
I mean the sciences to account,
as well as to apply them
for all this great stuff.
Anyway, thank you
very much, really fun
talking with you guys.
Thank you.
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and others like this,
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