>>Corey: Yeah, let's begin to move into the
topic of today's discussion which is these
CRISPR babies that recently generated in China.
>>Steve: CRISPR babies, designer babies.
>>Corey: And so this touches on your interest
in genomics.
>>Steve: It does.
>>Corey: And so let's get a little background
about this.
Let's talk a little about CRISPR first.
And I have to say, first of all, these babies
aren't in some sense a surprise.
We've been talking quite a lot about when
this was going to happen.
>>Steve: Absolutely.
We've been anticipating it for several years.
>>Corey: There's a theory which is, in technology
anything that's possible will eventually happen.
And so you can't be surprise by this.
But give a little background about what you
know about this particular case and what happened.
Many people [inaudible 00:00:45] gene editing
to some degree.
>>Steve: So recently, I'd say what?, five
years ago, big breakthrough in gene editing
technology.
Something called CRISPR.
I think you actually deserve credit for making
Michigan state institutionally aware of CRISPR,
running some big meetings on it, helping set
up a gene editing lab here.
So you probably actually, in a sense, know
more about CRISPR than I do.
But you could just say we now have the ability
to very selectively edit a genome with relatively
low, whether it's exactly zero or not, low,
off-target mistaken edit rate.
And so there are now many possible applications.
One of the applications is, if you're going
through in vitro fertilization and you have
an embryo, you might edit the genome of that
embryo.
And you could edit it, edit the genome in
a way, making a change that isn't present
in the mother or the father.
So a de novo change in the child that makes
it inevitably very different, genetically
very different from the parents.
And so what was done in this first experiment
was they actually...
Because many embryos had been edited before
and testing had been done to see how effective
the edit was.
This is the first time the embryo was implanted
and actually became, in this case, twin baby
girls.
>>Corey: And so this has caused enormous controversy.
>>Steve: Yes.
>>Corey: It was announced at a meeting on
genome editing in Taiwan.
>>Steve: Hong Kong, Hong Kong.
>>Corey: Hong Kong.
Yeah, Hong Kong.
And it's interesting because I guess there...
I saw an article in MIT Technology Review.
It seems like there were signals early on
this might be happening.
>>Steve: The reporter at MIT Technology Review,
whom I actually know, he broke the story through
some actual gumshoe reporting.
He was kind of aware that stuff like this
was going on, and he found the record, online
record, of the experiment at this hospital
website.
So he actually broke the story.
>>Corey: So give us a little background.
What was edited and what was the researcher
trying to accomplish by doing it?
>>Steve: Right.
So this researcher was a very interesting
guy.
His background's actually physics.
And he did his post doc at a very famous lab
at Stanford, who's run by another physics
guy who went into genomics and molecular biology.
So he's a little bit of an outsider to the
mainstream genomics world.
He's actually more a bioengineer.
He has that physicist view of things like,
"Oh, great thing.
Let's do it."
So this guy, who's a professor at a university
in China, he ran this experiment where he
recruited couples to be part of the experiment.
They gave them free IVF.
And his goal, I think, all along was to produce
the first gene-edited baby.
And the edit that he made was an edit to a
particular gene, CCR5, that actually, if it's
done correctly, and it's not clear is was
actually done correctly in these two, that
it actually worked properly in these two girls,
gives you resistance against HIV.
And there's actually about, I think the percentage
might be 10% in Europe.
>>Corey: Something like that, yeah.
Right.
>>Steve: There's some percentage of the European
population actually has this mutation and
is very resistant to HIV.
The father of the girls is HIV positive and
was very, I guess, according to what was said,
extremely traumatized by becoming HIV positive.
And so he had a very strong desire that his
daughters would be HIV resistant.
Now, a lot of what's reported in the press
doesn't take into account all the information
that we know.
Because this guy, the researcher's named He,
he gave a talk at this meeting in Hong Kong.
And he went over his description of the experiment
and what had been done.
And a lot of the facts that...
Now, again, he might have lying.
But if he was telling the truth about what
he did, those are important facts which are
seldom reported by the press.
>>Corey: True.
>>Steve: So one of the things he said was
both parents are highly educated.
This process takes time because you have to
go through the IVF process and collect the
embryos, and then do the editing, and then
sequence the embryos to make sure the off-targets
aren't there, and then communicate with the
parents.
So there's a lot of time over which he was
communicating with these parents.
And so he claimed that they had a good understanding
of the science and the technology behind all
this.
And what he told them at this point, when
the embryos had been edited, was, "We found
what might be an off-target in one of the
embryos."
But when you're sequencing an embryo, you're
only taking, I think in his case they just
took one cell off the embryo.
And so it's a noisy method of sequencing.
>>Corey: How many cells are there at his point
in time?
>>Steve: 50 to 100 typically.
>>Corey: Okay.
>>Steve: And so they take as few as possible.
Because you don't want to damage the embryo.
So they took one cell off and they sequenced
it.
And he said to the parents, "We found some
evidence of an off-target.
We're not sure, it could be an error in just
the sequencing.
We won't know until the kid is actually born
whether that is really an off-target mutation."
And he said that the parents were offered
the choice of using, to complete the IVF cycle,
either the edited pair or some other unedited
embryos.
There were unedited embryos that came from
this mother and father.
And they had the option of using those.
So at that moment it was parental choice to
implant.
And the editing of embryos is not controversial
generally.
So that scientifically has been done many
places around the world.
>>Steve: So the key decision here was actually
made by the parents, not by the researcher.
If the parents had just said, "Okay, let's
stop.
Let's just use the unedited embryos to finish
the pregnancy," you would've never heard about
this.
This would just be one of dozens of, "Well,
okay, they're testing the CRISPR technology.
It works.
We checked the embryo."
So the parents went ahead and had the kid.
And it turns out the off-target isn't really
there.
It was actually an artifact of the sequencing.
And so that aspect of it, I have not seen
reported anywhere.
So it kind of changes the tenor of the whole
thing.
>>Corey: Now I think it's been really interesting
to watch the response to this.
Because there's been uproar within the scientific
community.
And the researcher's been denounced as having
done something unethical.
And I think there are an enormous number of
complexities here, but I have to say I think
the scientific position may not be tenable
actually, the idea that you should be allowed
to edit an embryo but it's somehow immoral
to implant the embryo.
As if this embryo somehow needs to be obligatorily
destroyed.
>>Steve: If you're a Catholic...
What's totally legal in I think all of the
United States, to go and abort something that
actually looks like a baby.
It's not a bundle, a soccer ball of 50 cells,
but a baby or what some people would call
a baby.
You're allowed to abort that.
How can there be moral equivalency between
the question of, "Oh, I want to make one tiny
change to the genome of this embryo, or implant
or not implant this embryo," those decisions
seem very minor to me compared to decisions
made every day by potential mothers about
abortion, right?
So I think people are just doing what they're...
So the thing they're accustomed to, they don't
question.
The new thing, they question a lot in this
context.
>>Corey: I think it's very common.
One interesting issue is going to be how this
will evolve as this practice probably becomes
more common, whether people's attitudes will
change.
There's a Pew survey actually, a couple years
ago, about attitudes towards gene editing.
It turns out the US public is morally split
right down the middle as to whether they would
support editing to bring about exactly what
they did in this case, which is disease resistance.
People more religious were more opposed while
people who knew more about CRISPR were more
supportive.
>>Steve: Right.
>>Corey: But it seems like it's an issue that
[crosstalk 00:08:40].
>>Steve: At the very same conference in Hong
Kong, the Dean of Harvard Medical School,
who is himself I think a stem cell or, anyway,
some kind of molecular biology researcher,
he gave a talk.
And he was on a panel in 2015 that set forth
a bunch of guidelines for when CRISPR could
be used in a clinical setting.
And 2015 was far enough away that they could
be rational as opposed to what people are
doing now, talking about what happened.
So he gave his talk and he actually just said,
"Well, these are the things that we thought
in 2015 would have to be in place before we
could do it.
And frankly, we're pretty close.
We're pretty sure that it works well.
It's effective.
It's safe.
We can carefully monitor what's going on.
We can make sure the parents understand and
give informed consent."
So he actually said something which was quite
supportive, not of this particular researcher,
He, who everybody says is a villain now, but
of the general trend.
He was quite supportive.
And then it was announced.
I think it was revealed that some Harvard
researchers are doing CRISPR on sperm right
now.
So it's going to happen.
There's no question it's going to happen.
>>Corey: It's interesting, a lot of our casual
conversations are [inaudible 00:09:51].
Again, the cat's out of the bag.
People are going to do this.
We're thinking, is it going to be Russia?
Is it going to be China?
>>Steve: Right, right.
>>Corey: And those seem to be the two leading
cases.
>>Steve: Right.
>>Corey: And it looks like it was China.
>>Steve: It's funny because the Chinese scientists
who are all sort of cowardly conformists,
they were the most vociferous in denouncing
He when this happened.
And the most supportive guys were the Dean
of Harvard Medical School and George Church,
who's also at Harvard Medical School.
>>Corey: That's right.
Yeah, George Church came [inaudible 00:10:17]
criticism over this.
>>Steve: Yeah.
So it's funny.
And the most amusing thing is if you go on
YouTube and you watch the video of...
This guy had a video all set up of just an
interview of him in his own lab talking about
what had been done, that he himself put on
YouTube, when the story broke.
And you read, there must be like 5,000 comments
on YouTube under this video.
And every comment from a Chinese person is
like, "I am a life scientist and He has disgraced,
has shamed the Chinese people, and he should
never have done this because, well, the international
people don't like it."
>>Corey: Is the last part key to that comment?
[crosstalk 00:10:53]
>>Steve: Yeah, it is.
It is.
It's all about, "Oh, well, if the international
thinks this is bad, this is..."
Anyway.
This is YouTube, right?
So then there are thousands of comments by
people, mostly Americans and Europeans, saying,
"Hey, it's awesome man.
Technology is going to happen.
What are you coming down on this guy so hard?"
So it's amazing the dichotomy of those comments.
>>Corey: Of course.
>>Steve: Yeah.
But in the US press, of course, "The Chinese,
they don't have morals like we do and they're
going to edit all their babies."
>>Corey: People should just look at this Pew
survey of Americans, where essentially half
of them said that they thought that this was
acceptable.
So in this same survey, people were very resistant
to things like editing to increase intelligence.
And we're going to get into this too because
this is actually something I think that you've
written about, that you are supportive of.
>>Steve: Right.
Well,...
>>Corey: Okay, okay.
>>Steve: Let's be careful about that.
>>Corey: Okay, we'll be careful about that.
>>Steve: All right.
>>Corey: What's interesting is this gene in
particular has other effects.
>>Steve: Yes.
>>Corey: And this gene looks like it's also
involved in contextual memory, at least in
mice.
>>Steve: Yes.
>>Corey: Even heterozygotes, where one copy
of the gene is disabled and one is normal,
those mice look like they had better memories
than regular mice do.
>>Steve: Yep.
>>Corey: And the question is how will this
work out in these children?
It's quite possible that these edits may give
some cognitive enhancement in these children.
>>Steve: Yep.
>>Corey: Do you have any thoughts about that?
>>Steve: Well, so I'm pretty sure the parents
didn't do it for cognitive enhancement.
I think the story about the father being really
traumatized about by accident becoming HIV
positive and wanting his kids to be resistant,
it has the ring of truth to me.
And it didn't seem like the parents were trying
to enhance.
This is a weird way to enhance the intelligence
of your kids.
>>Corey: Sure.
>>Steve: Because the effect is not that big.
But whether we'll see people making active
edits to accomplish goals which are not related
to disease, yeah, we might eventually see
that.
I think the biggest barrier, which people
do not understand...
So people are very focused on CRISPR, the
technology, how well can we edit, are there
off-target edits made.
The thing people don't understand is that
the more informatical problem of actually
figuring out what pieces of the genome are
affecting which traits and in what way, that's
a huge machine-learning, AI problem.
That's what I work on.
And that is not a solve problem.
If you gave me today a super CRISPR, a vector,
that could edit 1,000 places in the genome
instantaneously with no error, we wouldn't
know how to use it.
>>Corey: Of course not.
>>Steve: Because we actually do not know the
specific edits that we want to make.
And so people misunderstand what is the gap,
the barrier that needs to be crossed before
all the nightmare scenarios of blond, six
foot-five, super-genius decathlete babies
can be produces.
We haven't solved the problem yet actually.
>>Corey: I want to say that I think part of
the story is that this is new technology.
But let's be honest, people are already in
the process of trying to produce blond, six
foot tall babies by simply having Scandinavians
be perhaps the largest sperm donors in the
world.
>>Steve: Sure, right.
Right.
>>Corey: [crosstalk 00:14:10] which is people
get all upset about CRISPR.
People are already making choice about their
genome.
They're already seeking out particular kinds
of mates.
This is only using a very different technology.
But the fact is, these kinds of decisions
are being made by most women all the time.
>>Steve: Absolutely, yeah.
>>Corey: And men actually, if they're looking
for an egg donor.
>>Steve: Egg donation in the US is somewhat...
I don't know if it's regulated.
But statistics are gathered.
And so, for example, there's a famous plot,
I think I put it on my blog a few years ago,
but the data was gathered by researchers.
On the horizontal axis is the SAT score of
the egg donor.
And then the vertical access is the price
paid by the parents for the egg.
And it's like this.
So, yes, people are already doing this kind
of thing.
>>Corey: I willing to bet height is actually
a similar [crosstalk 00:14:58].
>>Steve: Yeah.
And if you look at the ads, if you go to the
Crimson or the Yale Daily, whatever it is,
the ad will usually say, "We want a smart,
Yale student who's also an athlete to donate
eggs.
And we'll pay."
>>Corey: There's a famous case, I think maybe
10 or 15 years ago, of a young woman who was
I think six foot tall, athlete, and she was
selling her eggs for $50,000.
>>Steve: There's you go, yeah.
>>Corey: So just to say, I think-
>>Steve: The free market, man.
>>Corey: Yeah, it's interesting.
I think people have gotten used to it so they
don't say anything about it.
But I personally don't see any principle difference
between people making these kind of choices.
It's a matter of degree, it's a matter of
perplexity.
>>Steve: Principled, I agree.
I totally agree with you.
I know some of the people who were the early
pioneers in IVF, IVF itself, which is not
30+, 40 years old I think.
You can go back and read what were the reactions.
What did The New York Times say?
What did bioethicists say when the first test
tube...
I remember this being on TV.
>>Corey: Of course.
>>Steve: I was eating dinner, Dan Rather was
on TV.
>>Corey: It was '78.
>>Steve: Yeah, with my parents.
>>Corey: You were 12.
>>Steve: Yeah, I was a little kid and was
like, "Dad, test tube babies."
And so I remember how freaked out people were
then.
Now, you might be surprised that a million
test tube babies are born each year.
In many European countries, 5% of all births
are through IVF.
In Denmark, it's 10%.
>>Corey: Wow.
>>Steve: In Japan, it's 5%.
And it's just a consequence of women having
more professional, more career options and
tending to have the kids later.
>>Corey: Sure.
>>Steve: And then there's maybe a fertility
issue.
And so they go through IVF.
But what was reviled and thought to be a milestone
in...
>>Corey: [crosstalk 00:16:38]
>>Steve: Yeah, evil progress of science, cold
technology, now has become a way to produce
5% or 10% of all babies in France or in Denmark.
>>Corey: It's interesting.
And in my state, Massachusetts, I think right
around the turn of this millennium became
the first state where more women over 30 had
children than women under 30.
>>Steve: It's exactly it.
>>Corey: And that's clearly driving this.
>>Steve: I think all young women should be
told that fertility decline in women happens
between the ages of 30 and 40, for almost
everybody.
And if you're lucky, it's in your late 30s.
And if you're unlucky, it's in your early
30s.
And so there are many women who, "Wow, you
look still pretty young and you're looking
for a husband.
And you've got a great career going, you're
a lawyer," you've already had fertility decline.
You just don't know it.
>>Corey: I think we have friends where we've
seen it become an issue.
>>Steve: Exactly, yep.
>>Corey: But you're involved in a startup
actually that's...
>>Steve: I'm a founder of a startup that does
advanced genetic testing of embryos.
>>Corey: And how does that work?
>>Steve: Well, it's very similar to the He,
Megele story.
I'm just kidding.
So it's standard practice now to let the embryo
grow to 50 or 100 cells.
And then you can take a few cells off for
genotyping.
And then they freeze it.
They actually freeze it in liquid nitrogen.
And the freezing and thawing doesn't seem
to harm the embryo.
And so there are a lot of women who are actually
advised, if they're high-powered career women,
to freeze embryos so that they can use them
later.
That little sample that's taken off now, the
DNA from those few calls can be amplified
and we can get a full, relatively inexpensively,
we can get a full 23andMe level genotype for
each of the embryos.
And then you can predict certain things like
disease risk.
So you can detect mutations that are dangerous
and you can also predict polygenic disease
risk.
So, for example, the probability that someone
gets breast cancer or the probability that
someone had heart disease is actually controlled
by many genes.
But the machine learning is getting good enough
that we can, from this measurement of the
genome, actually make meaningful predictions
about whether a particular embryo is going
to be an outlier for a particular health risk.
>>Steve: And so if you have multiple embryos
and you're only going to use maybe one or
two of these multiple embryos, you can now
make a more informed decision than you could
just a year or two ago.
>>Corey: And it's known that taking these
cells off of the embryo has no negative health
effects.
>>Steve: So no detectable ones yet.
So so far there have been no statistically
significant results shown about the viability
of the embryo post-biopsy.
It could turn out there's some slight effect
from the biopsy.
But so far it's not been detected.
>>Corey: And there's no negative effects to
the freezing long term?
>>Steve: Actually, the freezing thing is actually
positive, possibly for reasons that embryos
that look okay but there's some problem with
the way that they're developing, those, when
they thaw out, are not viable.
And the ones that are able to go through the
thawing process are viable.
And so the actual success rates of frozen
and thawed embryos is actually significantly
higher...
>>Corey: That's interesting.
>>Steve: ... than, yeah, than just fresh [crosstalk
00:19:49]
>>Corey: So it's almost like an evolutionary
test of fitness.
>>Steve: It is.
That's exactly what it is.
It's a filter for fitness.
But it doesn't actually impact most of the
embryos at all.
>>Corey: And so where do you see this story
going?
We're this far, these babies are now born.
>>Steve: And there's another pregnant woman
too, I'm pretty sure.
>>Corey: What's your expectation for the next
year or two?
>>Steve: Well I think the bigger story is
actually selection, not editing, for the reason
that I stated, which is that we don't really...
Even if I gave you a super CRISPR, at this
moment in our scientific knowledge, we don't
know exactly what edits we would make.
The predictors rely on correlations.
If you're going to edit stuff, you have to
know about causation.
And so you can know ahead of time that, "Okay,
this distribution of genes in this embryo
predisposes it to, it has a higher probability
of having breast cancer," but you don't know
how to change the genome necessarily to make
it resistant to breast cancer.
So that science I think is going to take at
least another five or 10 years, if not more,
to develop before we can, if you wanted to,
go hog wild on editing.
Because you need to know what to edit.
>>Steve: However, the strength of these predictors
is increasing very rapidly because machine
learning just needs data.
And there's more and more data.
And so the number of traits that we can predict
from genome alone is going up and up and up.
And we don't really even need to fully predict
the trait, we just need to figure out who's
an outlier.
So if I'm just trying to warn you about, "Hey,
embryo four may have much worse health, much
decreased expected longevity than the other
ones.
Maybe you should use one of the other ones,"
that kind of differentiation is already possible,
and it'll just get better and better.
>>Corey: So how much does this process cost
now via your startup?
>>Steve: I think the price...
I'm not involved in the day to day of the
startup.
I'm one of the founders and I'm on the board
of directors, but I'm not really directly
involved.
So I might say something that's wrong.
But I think the pricing is $400 an embryo
for the advanced testing.
It's very affordable.
>>Corey: How does that compare to the price
of the IVF [crosstalk 00:22:04]?
>>Steve: I think an IVF cycle, it really depends
on where you do it.
If you do it in Korea or Taiwan, it's actually
pretty inexpensive.
It could be like a few thousand dollars for
an IVF cycle, I think.
But in the US, maybe it's more like $5,000,
$10,000.
But it's a [inaudible 00:22:17].
>>Corey: Sure.
>>Steve: It's a small correction to the overall
cost.
>>Corey: That'd be fabulous.
>>Steve: Okay, so let's just cut it there.
And until the next time.
>>Corey: Fabulous.
>>Steve: All right.
