May 2, 2024 • 36 mins
This March, doctors successfully transplanted a pig kidney into a person for the first time in history. Mike Curtis is the CEO of eGenesis, the company that raised the pig whose kidney was used for the procedure. Mike's problem is this: How do you genetically engineer pigs to provide organs – kidneys, hearts, livers – for people?
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Speaker 1 (00:15):
Pushkin. Rick Slayman is sixty two years old, lives in
a suburb of Boston, works for the state Department of Transportation,
and about five years ago he got a kidney transplant.
Then last year his new kidney stopped working, his health declined.
(00:38):
His prognosis was pretty bad, so earlier this year, he
and his doctors decided that he would be the first
person in the history of the world to get a
kidney transplant from a genetically engineered pig. Surgeons did the
transplant on March sixteenth, and two weeks later, Rix s
(00:58):
Layman walked out of the hospital. It's still too soon
to say how he'll do in the coming months, but
as of this recording, he's doing well. I'm Jacob Boltstein
and this is What's Your Problem, the show where I
talk to people who are trying to make technological progress.
(01:20):
My guest today is Mike Curtis. He's the CEO of Egenesis,
the company that bred the genetically engineered pig that provided
the kidney for Rick Slicker. Every year, thousands of people
die waiting for an organ transplant that never comes. And
so Mike's problem is this, is it possible to genetically
(01:42):
engineer pigs to provide organs, kidneys, livers, hearts for people,
and in the long run, is it possible to make
pig organs that work even better than human organs for
human transplant patients. So for a really long time, right,
(02:04):
like hundreds of years, people have had this idea of
transplanting organs or skin from animals to people, like where
do you where do you date the beginning of this
idea too?
Speaker 2 (02:18):
It was it was even pre dated human human transplants.
So as soon as you know, physicians realize that organs
can fail, I think the first instinct was can we
get them from somewhere else? Right? And in the early
days of that horribly right, no, no good success. So
we kind of pre you know, date that to the
dawn of modern medicine. And nothing worked.
Speaker 1 (02:39):
And nothing worked because basically the human immune system rejected
the transplants.
Speaker 2 (02:44):
And that was before we even knew what that was.
Speaker 3 (02:45):
But right, yeah, And so to jump forward a very
long way, it seems like Crisper, this ability to edit
genes is sort of a key breakthrough.
Speaker 1 (02:58):
Is that the kind of key moment that enables this
new era that seems to be beginning right now?
Speaker 2 (03:04):
Absolutely. There were some challenges in the cross species transplant
that just unresolvable until the discovery of Crisper. So the
one that we took on was in the nineties, it
was discovered that poresign retroviruses that are indigenous in the genome,
so they're kind of embedded in the pig genome, could
infect human cells. And in the nineties, you know, we
(03:25):
were coming out of the HIV epidemic, and we did
not want to, you know, cause another problem. So we
didn't want to have a cross species zoonotic event. So
in many countries around the world they put a moratorium
on cross species transplantation because of this risk of indigenous retroviruses.
Speaker 1 (03:42):
And so I just want to pause here because I
didn't know about indogenous retroviruses until I started preparing for
this interview, and it totally blew my mind that there
is such a thing. Right, So, an indogenous retrovirus, as
I understand.
Speaker 2 (03:59):
It is.
Speaker 1 (04:02):
Not like a disease that a that an animal has
in this case, a poor sign. Indogenous retrovirus obviously is
an indogen retrovirus in a pig, and it doesn't mean
that the pig is sick It means that in the
genome of every pig there is genetic code to code
in that pig a retrovirus, right, And similarly, in humans
(04:22):
there are other indogenous retroviruses. We have in our genome
the code for retroviruses, that's right. Why why do mammals
have the code for viruses in our genomes?
Speaker 2 (04:35):
Yeah? What's interesting because there are some functions that are
ascribed to these indigenous retroviruses. So they kind of co evolved,
you know, with pigs with people, and they pick up
some function, right, And so we don't completely understand why
they're there, but they're there and they pose a risk, right,
an infectious disease risk to patients, especially when you think
(04:59):
about patients who might be under immino suppression.
Speaker 1 (05:02):
And so, just to be clear, just I won't I
don't want to be labor this, but it is really
extraordinary coming to it new. The notion is a very
very very long time ago, some pig in this case
got infected with a virus and that virus made its
way into the genome of essentially all the pigs living today,
(05:24):
and that genetic code is not harmful to pigs, but
there is a fear that if you took a pig kidney, say,
and put it in a human being, the code for
that virus, which is fine in pigs, might be harmful
in people.
Speaker 2 (05:39):
Exactly. It's an unknown risk, ye.
Speaker 1 (05:42):
And so in the nineties, particularly as you said, in
the context of the fear of HIV, people are thinking
about doing could we transplant a pig kidney into a
human and regulators essentially are saying, well, one reason you
cannot do it is because of these endogenous retroviruses in
the pigs DNA.
Speaker 2 (06:02):
Exactly, and we can't quantify the risk, and so we
don't know what will happen, and we actually don't want
to know. You need to come up with a way
to mitigate the risk of retroviral transmission from the donor
to the recipient.
Speaker 1 (06:15):
Okay, And so that's just like a red light, do
not pass. Go stop doing this for a while. Once
that happens.
Speaker 2 (06:23):
In the nineties, exactly, most of the people that were
investing in the space stopped investing in the space. The
progression towards clinic stopped. It really slowed the whole field
down because no one knew exactly how to quantify the
risk or then what to do about it. And so
any pig genome you'll have between fifty and seventy copies
of the retrovirus scattered throughout the genome. And so even
(06:44):
if you wanted to go in and remove them, there
was no technology available that would allow you to do that.
And no one knew of a way to actually actively
get rid of these viruses right until the discovery of Crisper.
Speaker 1 (06:56):
So Crisper comes along what ten issuars twelve years ago,
and it's this incredible technology for editing a genome. Right,
people think, oh, maybe we could solve that poresine and
dogenous retrovirus problem using Crisper.
Speaker 2 (07:18):
Yeah, so this is what George Church kind of took
up at Harvard was like, it kind of what would
do we use chrispher for? And this this problem was
out there and George took it on and said, well,
let's see if you can inactivate all copies of the
retroviruses in the pig geno. The beautiful part about Crisper
is once you give it a sequence, right, it will
edit all copies of that sequence in a given genome. Now,
(07:38):
the worry was that you would then create basically Swiss
cheese out of the genome. Right, you would create an
unviable genome. There's too many edits, was the original thought.
But George and the team at Harvard showed that no,
you could actually inactivate all copies of the retrovirus and
then produce a viable pig.
Speaker 1 (07:57):
Right, because I suppose the other question is like, even
if you can cleanly make all the edits, do does
the pig actually need this indogenous retrovirus for a reason
we don't understand.
Speaker 2 (08:08):
Right, And we know it does if you if you
completely knock it out or get rid of it, the
pigs are not healthy. So we make a relatively subtle
change to the viral genome that that prevents the virus
from replicating. So with this edit, the virus can no
longer replicate hot.
Speaker 1 (08:24):
But so you don't knock it. You don't entirely remove
the sequence from the genome.
Speaker 2 (08:29):
You just.
Speaker 1 (08:31):
Edit the genome such that this virus, once it's expressed,
cannot replicate.
Speaker 2 (08:36):
Right, So essentially inactivate those of Dodges viruses.
Speaker 1 (08:39):
And so this idea from George Churchill was one of
the like giant names in genetics. Right famous scientists was
that the origin of the company.
Speaker 2 (08:49):
So it came from from from George's lab and we
we one of his postdocs started Egenesis by outlcensing the
technology from Harvard. So the original idea was to start
Egenesis with the idea of making animals that were retroviray
inactivated and then also do the rest of the editing
(09:12):
right that made the pigs more compatible with human recipient.
So that's how we got into the field. And then
from the from then we've built the additional editing to
provide organs that are more compatible with first non human
primates and then now with people.
Speaker 1 (09:26):
So you have inactivated the endogenous retrovirus in the pig.
This is like step one, right, But at this point,
if you tried to take that kidney, even though you've
solved the retrovirus problem, it's still a pig kidney, right,
and the human body would know that and would not
(09:48):
accept it. So what do you have to do next?
Speaker 2 (09:51):
Sure, and so if you just took an unedited pig
kidney and try to put it into a monkey or
to a person, to be rejected within minutes. And that's
primarily due to what we call hyperacute rejection, where the
humans are recognizing the carbohydrate differences between pigs and humans.
So carbohydrates are that coat all the cells, and humans
(10:12):
have antibodies that can recognize those pig sugars. So what
we do is we inactivate three genes responsible for those
carbohydrate differences between pigs and humans. Once you do that,
we create what we call the triple knockout. So we
inactivate those genes, knocking out those carbohydrate differences and eliminating
hypercute rejection.
Speaker 1 (10:34):
And when you create a pig with those particular carbohydrates eliminated,
does it matter to the pig? Is the pig sicker?
Speaker 2 (10:45):
As a result, we haven't seen any impact on the
health or longevity of a pig. So, for instance, we
have several animals in our colony that are a couple
of years old, and so we haven't seen any effects
on the longevity of those animals. So no, we haven't
seen any downside.
Speaker 1 (11:02):
Okay, so you've inactivated the endogenous retrovirus and now you've
eliminated the carbo hydrates that are causing acute rejection. There's
like one more set of changes you've got to make, right,
That's right.
Speaker 2 (11:15):
So what the field has shown over the past forty years.
Is that if you add human genes to the pig genome,
you can help regulate different areas of incompatibility. So when
we think about, for instance, coagulation, right, So the coagulation
factors in the pig are not one percent compatible with humans,
so we introduce human coagulation factors into the pig.
Speaker 1 (11:36):
Coagulation factors just what causes the blood.
Speaker 2 (11:39):
To clot basically or prevent the blood from clotting? Yeah,
either way, both both corrections, yep, absolutely. And then we
also add regulators of complement activation. The first kind of
immune response that you're going to get to a graft
in a transplant is what we call compliment activation, and
that leads to loss of cells, right, and that leads
to death of cells. But by introducing human complement regulators
(12:02):
into the poor scine tissue, we can slow down or
quiet that complement response. And then we add module later
of what we call the innate and adaptive immune response.
In total, we add in the animal that was used
in mister Slamon's transplant, we introduced a total of seven
regulatory human proteins. So if you add it together, it's
(12:23):
fifty nine edits to inactivate the retroviruses three edits to
improve the carbohydrate compatibility, and then seven edits to introduce
human regulatory trans genes, for a total of sixty nine edits.
Speaker 1 (12:35):
So it's basically the first two categories are make it
less like a pig, and then the third category is
make it more like a person.
Speaker 2 (12:43):
Yeah, that's a good way to think about it.
Speaker 1 (12:44):
That's right, And I mean presumably at some margin you
want to make it as little like a pig and
as much like a person as possible. But the pig
still has to live, to grow up and have a kidney.
Speaker 2 (13:00):
Right, absolutely, And we've produced animals with more trans genes
without any issue. But you can imagine at some point, right,
you'll reach a point where the pig no longer can
tolerate whatever the editing you're doing. We're actually already impressed
that we can produce healthy, viable pigs with this number
of edits. If you go back ten fifteen years, nobody
thought that you could viably do this. Even in activating
(13:24):
fifty nine copies of the retrovirus. Many felt that that
was too many and the genome wouldn't be able to
handle it. We can tell you that it's not easy,
and it's not trivial to do it. It took us
a lot of time to figure out how to do it,
but now we've shown it it is doable.
Speaker 1 (13:40):
I'm sure that it's not easy, but I don't know
enough to understand, like what's hard about it? Like tell
me a thing that you had to figure out.
Speaker 2 (13:50):
Sure, so when you do that much engineering to the genome,
you can get aberrations in the genome that prevents you
from making a pig. So one of the things that
we do is we do what's called clonal selection. So
we'll engineer thousands, tens of thousands of cells and then
select genomes based on viability. So, for instance, to so
(14:12):
produce our seventeen eighty four donor, we had to screen
over four thousand clones to find clones that had the
adequate quality of genome to then make pigs.
Speaker 1 (14:22):
Huh. So let's just let's just talk about that for
a minute, like how that actually works, which is the
more basic question of just how does the whole thing work?
Like I get in a sort of abstracted space what
you're doing, but like in whatever in a you know,
in a cell, fundamentally there is a cell, right like,
(14:42):
what are we starting with.
Speaker 2 (14:43):
So we'll take a sample of skin from an adult
what we call wild type so unedited pig. Then culture
those cells, make many cells, and then those are the
cells that we're going to edit. So those are the
cells that we take crisper. We make the fifty nine edits,
we make the triple knockout, and we make the seven
trans geens. In the case of the seventeen eighty four animal,
we did that through three sequential routes.
Speaker 1 (15:05):
So just to be clear, the seventeen eighty four animal,
this is like one particular pig, the pig that donated
the kidney that is in a person right now.
Speaker 2 (15:12):
So that's the seventeen eighty four refers to the genetics.
So we make many seventeen eighty four animals. So it's
a particular.
Speaker 1 (15:20):
Edited genome, and it's the edited genome that you have
described to me.
Speaker 2 (15:24):
Yeah, exactly, okay, right, So to make that animal, we
actually went through three rounds of editing, right, So we
would make the retroviolent activation make a pig, then take
those cells, edit them to make the try add the
truckle knockout, make a pig. Then we come back and
add the seven trans sheats.
Speaker 1 (15:40):
So it's multiple generations. You're you are sort of adding
changes genetic mutations over successive generations.
Speaker 2 (15:49):
Exactly why this allows us to select right. So there's
there's two there's there's two restrictions the time. Because we're
working with primary cells the time, you have to edit
them before they what we call sinat. So at some
point those cells stop dividing. You need to edit while
the cells are still divide, so you have a limited
(16:10):
number of days to do the editing, right, So we do.
So this is why we were doing three rounds of editing,
because we can get the retroviral in make a pig,
we can get the triple knockout make a pig. We
get the seven genes and make a pig. What's really
important to that whole process is at the end of
each editing round, we then screen individual cells for the genotype. Right,
(16:31):
And this is where we'll go through and screen you know,
up to four thousand cells to pick cells that look
like they have a good morphology and a good phenotype
for which we would then make a pig. So, once
we do the editing, we then pick individual cells that
we call clones, and then we grow those clones out,
and now we have an edited porsone genome, but we
(16:52):
still don't have a pig.
Speaker 1 (16:53):
So you basically have a whatever, a petri dish full
of pig skin cells that have the genotype that you want, exactly, okay.
Speaker 2 (17:01):
And so now we need to make a pig. And
the technology we use to turn a single cell into
a pig, it's called a somatic cell nuclear transfer. It
was similar to tchnology that was used to clone Dolly,
where we take the nucleus of the edited cell and
basically transfer it into the O site of a pig.
Speaker 1 (17:18):
An egg cell. And and so this is now a
whatever thirty year old technology that they used to clone
a sheep with in the nineties exactly.
Speaker 2 (17:27):
There's been some obviously improvements since then, but the core
idea is essentially the same. And then we use that
cloning technology to then make pigs. So we make an
embryo and then we transfer that embryo into a surrogate
sal and then that surrogate sal will carry the piglet
to term.
Speaker 1 (17:44):
There's some ethical dimension to this, like like, what are
the relevant ethical dimensions to you?
Speaker 2 (17:49):
Yeah, our focus is on preserving human health and saving
patients who are dying on the transfer wait list, and
we believe that this approach is justifiable with that goal
in mind. So every day we show up, we focus
on patients like mister Slayman. And so this is a
means to an end. This is a means to producing
organs that currently don't exist. It's to save paces who
(18:09):
are imminately dying, but they are. It's a very bleak
outlook for some of these folks, right, And so we
view that the work that we're doing for engineering the
persa and genome and producing compatible organs all about, you know,
realizing that mission of helping these patients, and we believe
that that puts us on a very firm ethical route.
Speaker 1 (18:29):
Still to come on the show, how pig hearts might
help human babies. How many pigs with this genetic sequence
are there?
Speaker 2 (18:47):
You have about fifty or so animals that are at
different ages.
Speaker 1 (18:50):
So, like, do you have a farm somewhere?
Speaker 2 (18:54):
So we do. We have two farms we have and
they are both out in the Midwest. One is a
research more of a research farm. It's a two hundred
acre farm where we institute biosecurity. So one of the
keys here is to produce animals that are free of
pathogens that could put harm to either the organs post
transplant or the patient or the recipients. So that farm
(19:15):
produces relatively clean animals. But then we have what we
call a clinical grade or designated pathogen free facility where
the animals are growing inside what we call a barrier.
So there we control feed, water, everything that comes in
to try to keep pathogens out. So we're actively managing
the environment that those animals are raised in. And on
(19:35):
top of all of that, we're doing very robust path
consistent pathogen testing, so we're constantly monitoring all the animals
for any potential pathogens or disease.
Speaker 1 (19:47):
Right, I mean presumably some kind of like jumping the
species barrier or transfer would be one of the like
nightmarishly bad outcomes, right.
Speaker 2 (19:57):
Yes, I mean one of the reasons that we selected
pigs as the species is one we've co you know,
existed with these animals for thousands of years and we
haven't seen that you know, that particular that type of
disease transmission, and then we can edit, and then we
also know how to grow animals at scale. But yes,
we're always on the lookout and I think this is
(20:17):
part of surveillance that we'll do for the foreseeable future,
is on the lookout for things that we aren't paying
attention for. Right.
Speaker 1 (20:25):
So let's talk about the first patient. Let's talk about
Richard slam and the first person ever to be walking
the earth with a pig kidney as far as we know, probably.
Speaker 2 (20:37):
Why him?
Speaker 1 (20:38):
What was it about his case that made him the
right patient?
Speaker 2 (20:40):
Yeah, So it's a great question, and part of it
was inspired by the work that was done at the
University of Maryland in the first heart transplants, right, so
we refer to those as the Bennett and Fossett transplants.
Speaker 1 (20:51):
The first pig heart pig heart, Yeah, which just happened.
That was like a different project, right, but it just
happened in the last year or so, right now, the.
Speaker 2 (21:01):
Last two years two years, Yeah, absolutely. And there was
always this debate in the field of zeno is what
patients would constitute the right patient population to go into
And the team at Maryland really showed us that there's
a case for compassionate use. There's a case for patients
who have reached the end of the treatment options and
really they're facing imminent death and we have a technology
that could save their life, so shouldn't we try now. Unfortunately,
(21:23):
you know, those gentlemen passed away within forty or fifty
days post transplant. But it showed us that the regulatory
agencies were open to the discussion, and we just need
to define what is the right patient population in the
case of kidney and so we had a discussion with
the FDA back in twenty twenty two about what would
be the right patient population for a formal phase one
(21:45):
clinical study, and we'd come to agreement on patients over fifty,
patients on the transplant weightlist, and patients that had failed
a previous alo transplant, right, so they'd had a human
kidney before, and they had it for a certain duration
of time and eventually that kidney fails and you find
yourself back on the transplant weightlist. And why that patient
population made sense is because those patients have a very
(22:07):
low likelihood if you're over fifty with that profile of
getting a second kidney. Now, in the case of mister Slamon,
are patients like him. He was also losing access to dialysis,
so he had a kidney transplant in twenty eighteen. He
had been on dialysis for seven years, got a kidney transplant,
the kidney function for five years, and then he lost
(22:30):
the kidney stop functioning. In twenty twenty three, Okay, he
found himself back on dialysis, but he was having trouble
with vascular access, so he had to go through multiple
surgeries to create access so he could go on dialysis.
Speaker 1 (22:43):
And just to be clear, dialysis is when your kidneys
don't work. There is a machine and they hook you
up to the machine and it cleans your blood. It
does the work of the kids.
Speaker 2 (22:51):
Yeah. Usually, you know, the typical schedule would be three
times a week, four hours each time.
Speaker 1 (22:54):
Okay, And so Richard Slaman, you were saying dialysis just
wasn't working for him anymore.
Speaker 2 (23:00):
In some patchion it was just very hard to do.
It was working, but he would have to have these
vascular access surgery so his blood vessels would acclude and
prevent the ability to do dialysis. So we'd have to
go through a relatively painful procedure to allow him to
get dialysis. And I think, you know, he was and
I think his neuprologist, when Williams put it really well,
(23:20):
he was kind of losing faith, losing hope, like, huh,
is this my life? Is this my future? Like, I'm
just going to have to keep doing this and I
have no chance of getting a transplant because he had
had a transplant for five years, so he knew what
that was and now he finds himself on dallasis. So,
so we knew at some point mister Sliman would lose
access to dialysis and without a transplant, he would he
(23:42):
would go to hospice. And so he was a patient
that we felt was a good candidate for trying. And
so the team at Mass General approached mister Slaman with
this idea of he could participate and be the first
patient to try this, and this is what we knew,
and these were the risks, and I think that's part
of one of the biggest challenges, kind of articulating what
(24:04):
we know and then articulately what we don't know and
how this could go. But much to mister slam his credit, right,
he was the one that raised his hand and said
he would go first. And then we took it to
the FDA and we laid out the case to the
FDA that you know mister Slamon's story and kind of
where he found himself in his treatment. What we had
been doing are non human primate data, all the data
(24:25):
on the characterization of our donors. And after a few
weeks of discussion, the FDA said, we agree and you
guys can try.
Speaker 1 (24:35):
So what is the path for you for your fore genesis?
Speaker 2 (24:39):
From here, we believe that there's the opportunity to treat
more patients like mister Slimon. He's not unfortunately, he's not
unique in this space, and there are other patients that
are suffering very similar fate with continued success. Our intention
is to do more of these expanded access requests and
transplants while we prepare for a formal trial, right so
(25:01):
in patients that may be facing less risk than patients
like mister Slamon, patients earlier in their dialysis journey, earlier
in their their kidney failure progression. But that will come,
you know. Our intention is to file something like that
at the end of twenty twenty five. Beyond that, you know,
we are also exploring patients that are suffering from liver
(25:21):
failure as well as heart failure. This past December, we
did the longest liver perfusions on liver perfusion in a
decedent patient. Ever, we did three days of continuous perfusion.
The idea there is you take a patient who may
be suffering from liver failure and perfuse them through a
pig liver to allow their own liver to recover again.
(25:44):
This was something that was demonstrated in the nineties to work.
So they took fourteen patients with acute liver failure perfused
them through pig livers. All fourteen patients improved. Seven patients
were successfully bridged to transplant.
Speaker 1 (25:58):
So just to unpack that for a sec the pig
liver is kind of like when people get put on
those like external artificial hearts or something like the outside
the body, and it's like or.
Speaker 2 (26:06):
What you know when think about kidney disease is akin
to dialsis right? You hooked up to a machine. In
this case, in the machine is a big.
Speaker 1 (26:14):
Liver, and like, is it in a box?
Speaker 2 (26:17):
Like yeah, yeah, So it's in a plastic container on
a perfusion device.
Speaker 1 (26:22):
So the pig's liver is doing the work of the
liver for the patient while the patient is waiting for
a human donor exactly. Like, let me ask the dumb question,
why not just put the pigs liver in the person.
Speaker 2 (26:35):
Because the incompatibilities between a pig liver and the person
are still too great. OK, So we could I think
we're only going to get a week or two before
that gets rejected.
Speaker 1 (26:47):
And so similarly, does the perfusion just last for a
week or two it's just like an emergency bridge.
Speaker 2 (26:52):
Yeah, so it's a great question, and we started out
with a goal of greater than twenty four hours of perfusion.
The pen study went for three days. Looking at the
histology at the end of the study, we believe it
can go for about a week. So we're continuing to
push the duration.
Speaker 1 (27:06):
So that's like a that feels like much more of
a kind of edge case than the kidney case.
Speaker 2 (27:11):
Well, this is the thing. We think there's actually much
greater unmet need and liver failure than there even is
in kidney failure because these patients, because there is no
equivalent of dialysis, they either recover on their own, which
is a little bit of like ICU time and hope,
or they get transplanted. So we're hoping that we can
provide liver support through a poresigne liver, we can bridge
(27:33):
more patients to recovery.
Speaker 1 (27:34):
Okay, and then you're and then hearts.
Speaker 2 (27:38):
Yeah. So the third setting, again is inspired by the
work done at Maryland, but instead of looking at adult
patients where the heart has to and heart has to
function continuously or the patient passes away, we're focused in
the pediatric population. So children who need a heart transplant
currently have poor standard of care to bridge them to
human heart transplant.
Speaker 1 (27:58):
And so this is like typically like babies born with
genetic anomalies.
Speaker 2 (28:03):
Yeah, typically children under two is kind of where the
focus is and the current support of care. About fifty
percent of these children die waiting for a human heart transplant.
Speaker 1 (28:14):
That is a brutal one. Is a brutal That would
be a good one too, Yeah, that would be a
good one to tve.
Speaker 2 (28:20):
And so the idea is if we can simply create
one hundred to two hundred day bridge using a Poresigne heart,
then at the end of that or sometime in the middle,
when the human heart became available, the child would simply
get the human heart. So we call that a bridging strategy.
Speaker 1 (28:34):
And so in that instance, is it a transplant or
is it external It's a transplant.
Speaker 2 (28:38):
Yeah, So the intention is to do the por signed
heart transplant allow the patient to go home. They can
wait at home right now, they would have to wait
in the hospital, but they could wait at home until
the human heart becomes available.
Speaker 1 (28:51):
Okay, So so those are two other organs. When do
you think you're going to do those?
Speaker 2 (28:58):
So the intention, the intention is to do all that
this year, right, So, we believe we have the not
what we call non clinical data or the primate data
to support moving into the clinic. And I do think
mister the success so far with mister Slaman's transplant is
helpful because the emune of suppression that we plan to
use in the pediatric heart setting is very similar to
what we're using in mister Slaman's transplant. So we do
(29:20):
think that continued success in the kidney transplant will help
inform what we're going to be doing at heart.
Speaker 1 (29:27):
And is it the same set of genetic changes?
Speaker 2 (29:32):
Yeah, so it's the same genetics of the donor. So
the current plan is to use the same donor for
both kidney, hearts and livers.
Speaker 1 (29:41):
And how does how does the immune response to a
pig organ compare to the immune response to an organ
from another human?
Speaker 2 (29:52):
Yeah, it's definitely more robust.
Speaker 1 (29:55):
More robust meaning worse in this concept, it's.
Speaker 2 (29:57):
Probably going to require you know, we already are using
more evenie suppression. Yeah.
Speaker 1 (30:01):
And is there some medium to long term future where
you do more gene editing in order to make that
piece of it easier, where you make the pig kidney
more like a human kidney.
Speaker 2 (30:16):
Yeah. Absolutely. The long term vision here is to produce
organs that don't require immuno suppression, party.
Speaker 1 (30:21):
That don't require it at.
Speaker 2 (30:22):
All at all. I mean, that's the ultimate that's the vision.
Speaker 1 (30:24):
I mean, if you could do that. Just to be clear,
like that vision is a pig kidney is better than
a kidney from another human.
Speaker 2 (30:32):
Right, I mean it sounds like you've been talking to George. Wow.
Speaker 1 (30:36):
I appreciate that you were skeptical. You were supposed to
be high picking up and I'm supposed to be skeptical. No.
But if you say, like, is that even plausible? I
appreciate that you're skeptical of it. That's good.
Speaker 2 (30:45):
Yeah, do it might work for me. I think one
of the things that transplant World has taught us over
the past fifty years is things that we thought were
impossible are actually now routine, right, So I think it's
a matter of time, effort, and work. I think we
can get there, right. I think this initial transplant into
patients is a really important step because for us to
be informed about what we need to do from an
(31:06):
engineering perspective, it is very helpful to have data from
humans to feedback into that loop, so we can do
lots of things from an engineering perspective. The question is
what to do next, and I think the results that
will achieve with mister Slayman and patients like him will
help inform what else we need to do to really
realize this big vision, which is organs that don't require suppression.
Speaker 1 (31:28):
Organs that don't require suppression, is wildly ambitious, right do you?
I mean it seems like, not knowing basically anything about it,
it would be a kind of incremental, maybe even as symptotic, like, ah,
this will get us to less, This will get us
to less as opposed to some binary breakthrough. Does that
seem right?
Speaker 2 (31:48):
Yeah? I think it's incremental. But what we're starting to
see is kind of multiplex editing in a way that
we couldn't even before Christper, we couldn't conceive of making
fifty nine edits for GENO. Okay, now we're conceiving of
how would you make a thousand edits to geno? What
does that actually look like? And I think that's what's
going to be required. Huh.
Speaker 1 (32:08):
I mean, do you get weird like structural like three
D structural problems once you start doing that, like is
it even gonna yes work?
Speaker 2 (32:16):
So there's definitely a lot to solve, right, So how
do you make you know, how do you make that
many changes without totally destroying the geno? We thought that
originally with Crisper and the first retroviolent activation, they thought
you would never be able to make that many at it.
So we did that. We just have to figure out
how to do it. And you know, we don't know
how to do it right now, but I do think
we'll figure out how to do it.
Speaker 1 (32:38):
We'll be back in a minute with the lightning. Let's
finish with a lightning ground. I won't take much more
of your time.
Speaker 2 (32:57):
Okay, Okay, what's one.
Speaker 1 (32:59):
Thing that that we don't understand about the human body
that you wish we understood?
Speaker 2 (33:12):
I think, coming from the neuroscience world, I think we
have a really poor understanding of mental health and what
to do about depression, and because I think those are
just paralyzing diseases that we are a long way from
really understanding why they exist and actually how to effectively
(33:33):
treat them. So if you could generalize that as brain,
we still don't really understand in the way we need to,
you know, how the brain actually works and what we
can do to improve diseases of the brain.
Speaker 1 (33:46):
Well, I know you worked in pharmaceuticals for decades, right,
I don't point on it, Yeah, and so you know
it's a famously hard industry. Most drugs fail, right, I'm
curious if you have any any tips for dealing with failure.
Speaker 2 (34:02):
I think you go in with the best hypothesis, you
run the most efficient studies you can, and then you
pick yourself up and go again, because I think you
can't let failure bring you down, right, And we know
we're going to fail, and often we learned a tremendous
amount from those failures and we just have to build
on them. The worst thing you can do is stop.
I think you have to always keep going.
Speaker 1 (34:23):
So if you look back over the thirty years that
you worked in the drug industry, I'm curious, like, if
you think about when you were getting into the field.
What is something that has happened since then, like a breakthrough,
a change that you wouldn't have expected that's surprising to you.
Speaker 2 (34:41):
I think this whole field of genetic medicines, you know
the fact that we're now producing potential cures for sickle cell,
cures for beta thalsemia. I think those were all visions
that we had, you know, fifty sixty one hundred years ago,
like could we actually cure diseases that we're now literally
on the shelf have cures for. And I think that
no one ever thought we would get there, and here
(35:02):
we are.
Speaker 1 (35:03):
So conversely, so that's the happy surprise. Is there something
when you got into the field that you fought like,
surely we'll figure this out, Surely this will be solved
that we haven't figured out.
Speaker 2 (35:15):
I mean, our inability to really effectively fight viral infection is,
you know, our infectious disease broadly. We really haven't evolved
our armamentarium against infectious disease very much. I think there
we've way under invested and focused on infectious disease. I
don't think the current way we fund drug development doesn't
support active work there. I think it's the one. It's
(35:38):
a blind spot for us, and I think we saw it,
you know, during COVID.
Speaker 1 (35:41):
Yeah, right, so.
Speaker 2 (35:45):
And it's still a blind spot. What's really sad is
I don't think COVID. Actually, I don't think we've done
much different than we were.
Speaker 3 (35:50):
Doing that that that hurts, but I think it's true.
Speaker 1 (35:58):
Mike Curtis is the CEO of E Genesis. Today's show
was produced by Gabriel Hunter Chang. It was edited by
Lydia jene Kott and engineered by Sarah. You can email
us at problem at Pushkin dot FM. I'm Jacob Goldstein
and we'll be back next week with another episode of
What's Your Problem.
Pushkin. Rick Slayman is sixty two years old, lives in
a suburb of Boston, works for the state Department of Transportation,
and about five years ago he got a kidney transplant.
Then last year his new kidney stopped working, his health declined.
(00:38):
His prognosis was pretty bad, so earlier this year, he
and his doctors decided that he would be the first
person in the history of the world to get a
kidney transplant from a genetically engineered pig. Surgeons did the
transplant on March sixteenth, and two weeks later, Rix s
(00:58):
Layman walked out of the hospital. It's still too soon
to say how he'll do in the coming months, but
as of this recording, he's doing well. I'm Jacob Boltstein
and this is What's Your Problem, the show where I
talk to people who are trying to make technological progress.
(01:20):
My guest today is Mike Curtis. He's the CEO of Egenesis,
the company that bred the genetically engineered pig that provided
the kidney for Rick Slicker. Every year, thousands of people
die waiting for an organ transplant that never comes. And
so Mike's problem is this, is it possible to genetically
(01:42):
engineer pigs to provide organs, kidneys, livers, hearts for people,
and in the long run, is it possible to make
pig organs that work even better than human organs for
human transplant patients. So for a really long time, right,
(02:04):
like hundreds of years, people have had this idea of
transplanting organs or skin from animals to people, like where
do you where do you date the beginning of this
idea too?
Speaker 2 (02:18):
It was it was even pre dated human human transplants.
So as soon as you know, physicians realize that organs
can fail, I think the first instinct was can we
get them from somewhere else? Right? And in the early
days of that horribly right, no, no good success. So
we kind of pre you know, date that to the
dawn of modern medicine. And nothing worked.
Speaker 1 (02:39):
And nothing worked because basically the human immune system rejected
the transplants.
Speaker 2 (02:44):
And that was before we even knew what that was.
Speaker 3 (02:45):
But right, yeah, And so to jump forward a very
long way, it seems like Crisper, this ability to edit
genes is sort of a key breakthrough.
Speaker 1 (02:58):
Is that the kind of key moment that enables this
new era that seems to be beginning right now?
Speaker 2 (03:04):
Absolutely. There were some challenges in the cross species transplant
that just unresolvable until the discovery of Crisper. So the
one that we took on was in the nineties, it
was discovered that poresign retroviruses that are indigenous in the genome,
so they're kind of embedded in the pig genome, could
infect human cells. And in the nineties, you know, we
(03:25):
were coming out of the HIV epidemic, and we did
not want to, you know, cause another problem. So we
didn't want to have a cross species zoonotic event. So
in many countries around the world they put a moratorium
on cross species transplantation because of this risk of indigenous retroviruses.
Speaker 1 (03:42):
And so I just want to pause here because I
didn't know about indogenous retroviruses until I started preparing for
this interview, and it totally blew my mind that there
is such a thing. Right, So, an indogenous retrovirus, as
I understand.
Speaker 2 (03:59):
It is.
Speaker 1 (04:02):
Not like a disease that a that an animal has
in this case, a poor sign. Indogenous retrovirus obviously is
an indogen retrovirus in a pig, and it doesn't mean
that the pig is sick It means that in the
genome of every pig there is genetic code to code
in that pig a retrovirus, right, And similarly, in humans
(04:22):
there are other indogenous retroviruses. We have in our genome
the code for retroviruses, that's right. Why why do mammals
have the code for viruses in our genomes?
Speaker 2 (04:35):
Yeah? What's interesting because there are some functions that are
ascribed to these indigenous retroviruses. So they kind of co evolved,
you know, with pigs with people, and they pick up
some function, right, And so we don't completely understand why
they're there, but they're there and they pose a risk, right,
an infectious disease risk to patients, especially when you think
(04:59):
about patients who might be under immino suppression.
Speaker 1 (05:02):
And so, just to be clear, just I won't I
don't want to be labor this, but it is really
extraordinary coming to it new. The notion is a very
very very long time ago, some pig in this case
got infected with a virus and that virus made its
way into the genome of essentially all the pigs living today,
(05:24):
and that genetic code is not harmful to pigs, but
there is a fear that if you took a pig kidney, say,
and put it in a human being, the code for
that virus, which is fine in pigs, might be harmful
in people.
Speaker 2 (05:39):
Exactly. It's an unknown risk, ye.
Speaker 1 (05:42):
And so in the nineties, particularly as you said, in
the context of the fear of HIV, people are thinking
about doing could we transplant a pig kidney into a
human and regulators essentially are saying, well, one reason you
cannot do it is because of these endogenous retroviruses in
the pigs DNA.
Speaker 2 (06:02):
Exactly, and we can't quantify the risk, and so we
don't know what will happen, and we actually don't want
to know. You need to come up with a way
to mitigate the risk of retroviral transmission from the donor
to the recipient.
Speaker 1 (06:15):
Okay, And so that's just like a red light, do
not pass. Go stop doing this for a while. Once
that happens.
Speaker 2 (06:23):
In the nineties, exactly, most of the people that were
investing in the space stopped investing in the space. The
progression towards clinic stopped. It really slowed the whole field
down because no one knew exactly how to quantify the
risk or then what to do about it. And so
any pig genome you'll have between fifty and seventy copies
of the retrovirus scattered throughout the genome. And so even
(06:44):
if you wanted to go in and remove them, there
was no technology available that would allow you to do that.
And no one knew of a way to actually actively
get rid of these viruses right until the discovery of Crisper.
Speaker 1 (06:56):
So Crisper comes along what ten issuars twelve years ago,
and it's this incredible technology for editing a genome. Right,
people think, oh, maybe we could solve that poresine and
dogenous retrovirus problem using Crisper.
Speaker 2 (07:18):
Yeah, so this is what George Church kind of took
up at Harvard was like, it kind of what would
do we use chrispher for? And this this problem was
out there and George took it on and said, well,
let's see if you can inactivate all copies of the
retroviruses in the pig geno. The beautiful part about Crisper
is once you give it a sequence, right, it will
edit all copies of that sequence in a given genome. Now,
(07:38):
the worry was that you would then create basically Swiss
cheese out of the genome. Right, you would create an
unviable genome. There's too many edits, was the original thought.
But George and the team at Harvard showed that no,
you could actually inactivate all copies of the retrovirus and
then produce a viable pig.
Speaker 1 (07:57):
Right, because I suppose the other question is like, even
if you can cleanly make all the edits, do does
the pig actually need this indogenous retrovirus for a reason
we don't understand.
Speaker 2 (08:08):
Right, And we know it does if you if you
completely knock it out or get rid of it, the
pigs are not healthy. So we make a relatively subtle
change to the viral genome that that prevents the virus
from replicating. So with this edit, the virus can no
longer replicate hot.
Speaker 1 (08:24):
But so you don't knock it. You don't entirely remove
the sequence from the genome.
Speaker 2 (08:29):
You just.
Speaker 1 (08:31):
Edit the genome such that this virus, once it's expressed,
cannot replicate.
Speaker 2 (08:36):
Right, So essentially inactivate those of Dodges viruses.
Speaker 1 (08:39):
And so this idea from George Churchill was one of
the like giant names in genetics. Right famous scientists was
that the origin of the company.
Speaker 2 (08:49):
So it came from from from George's lab and we
we one of his postdocs started Egenesis by outlcensing the
technology from Harvard. So the original idea was to start
Egenesis with the idea of making animals that were retroviray
inactivated and then also do the rest of the editing
(09:12):
right that made the pigs more compatible with human recipient.
So that's how we got into the field. And then
from the from then we've built the additional editing to
provide organs that are more compatible with first non human
primates and then now with people.
Speaker 1 (09:26):
So you have inactivated the endogenous retrovirus in the pig.
This is like step one, right, But at this point,
if you tried to take that kidney, even though you've
solved the retrovirus problem, it's still a pig kidney, right,
and the human body would know that and would not
(09:48):
accept it. So what do you have to do next?
Speaker 2 (09:51):
Sure, and so if you just took an unedited pig
kidney and try to put it into a monkey or
to a person, to be rejected within minutes. And that's
primarily due to what we call hyperacute rejection, where the
humans are recognizing the carbohydrate differences between pigs and humans.
So carbohydrates are that coat all the cells, and humans
(10:12):
have antibodies that can recognize those pig sugars. So what
we do is we inactivate three genes responsible for those
carbohydrate differences between pigs and humans. Once you do that,
we create what we call the triple knockout. So we
inactivate those genes, knocking out those carbohydrate differences and eliminating
hypercute rejection.
Speaker 1 (10:34):
And when you create a pig with those particular carbohydrates eliminated,
does it matter to the pig? Is the pig sicker?
Speaker 2 (10:45):
As a result, we haven't seen any impact on the
health or longevity of a pig. So, for instance, we
have several animals in our colony that are a couple
of years old, and so we haven't seen any effects
on the longevity of those animals. So no, we haven't
seen any downside.
Speaker 1 (11:02):
Okay, so you've inactivated the endogenous retrovirus and now you've
eliminated the carbo hydrates that are causing acute rejection. There's
like one more set of changes you've got to make, right,
That's right.
Speaker 2 (11:15):
So what the field has shown over the past forty years.
Is that if you add human genes to the pig genome,
you can help regulate different areas of incompatibility. So when
we think about, for instance, coagulation, right, So the coagulation
factors in the pig are not one percent compatible with humans,
so we introduce human coagulation factors into the pig.
Speaker 1 (11:36):
Coagulation factors just what causes the blood.
Speaker 2 (11:39):
To clot basically or prevent the blood from clotting? Yeah,
either way, both both corrections, yep, absolutely. And then we
also add regulators of complement activation. The first kind of
immune response that you're going to get to a graft
in a transplant is what we call compliment activation, and
that leads to loss of cells, right, and that leads
to death of cells. But by introducing human complement regulators
(12:02):
into the poor scine tissue, we can slow down or
quiet that complement response. And then we add module later
of what we call the innate and adaptive immune response.
In total, we add in the animal that was used
in mister Slamon's transplant, we introduced a total of seven
regulatory human proteins. So if you add it together, it's
(12:23):
fifty nine edits to inactivate the retroviruses three edits to
improve the carbohydrate compatibility, and then seven edits to introduce
human regulatory trans genes, for a total of sixty nine edits.
Speaker 1 (12:35):
So it's basically the first two categories are make it
less like a pig, and then the third category is
make it more like a person.
Speaker 2 (12:43):
Yeah, that's a good way to think about it.
Speaker 1 (12:44):
That's right, And I mean presumably at some margin you
want to make it as little like a pig and
as much like a person as possible. But the pig
still has to live, to grow up and have a kidney.
Speaker 2 (13:00):
Right, absolutely, And we've produced animals with more trans genes
without any issue. But you can imagine at some point, right,
you'll reach a point where the pig no longer can
tolerate whatever the editing you're doing. We're actually already impressed
that we can produce healthy, viable pigs with this number
of edits. If you go back ten fifteen years, nobody
thought that you could viably do this. Even in activating
(13:24):
fifty nine copies of the retrovirus. Many felt that that
was too many and the genome wouldn't be able to
handle it. We can tell you that it's not easy,
and it's not trivial to do it. It took us
a lot of time to figure out how to do it,
but now we've shown it it is doable.
Speaker 1 (13:40):
I'm sure that it's not easy, but I don't know
enough to understand, like what's hard about it? Like tell
me a thing that you had to figure out.
Speaker 2 (13:50):
Sure, so when you do that much engineering to the genome,
you can get aberrations in the genome that prevents you
from making a pig. So one of the things that
we do is we do what's called clonal selection. So
we'll engineer thousands, tens of thousands of cells and then
select genomes based on viability. So, for instance, to so
(14:12):
produce our seventeen eighty four donor, we had to screen
over four thousand clones to find clones that had the
adequate quality of genome to then make pigs.
Speaker 1 (14:22):
Huh. So let's just let's just talk about that for
a minute, like how that actually works, which is the
more basic question of just how does the whole thing work?
Like I get in a sort of abstracted space what
you're doing, but like in whatever in a you know,
in a cell, fundamentally there is a cell, right like,
(14:42):
what are we starting with.
Speaker 2 (14:43):
So we'll take a sample of skin from an adult
what we call wild type so unedited pig. Then culture
those cells, make many cells, and then those are the
cells that we're going to edit. So those are the
cells that we take crisper. We make the fifty nine edits,
we make the triple knockout, and we make the seven
trans geens. In the case of the seventeen eighty four animal,
we did that through three sequential routes.
Speaker 1 (15:05):
So just to be clear, the seventeen eighty four animal,
this is like one particular pig, the pig that donated
the kidney that is in a person right now.
Speaker 2 (15:12):
So that's the seventeen eighty four refers to the genetics.
So we make many seventeen eighty four animals. So it's
a particular.
Speaker 1 (15:20):
Edited genome, and it's the edited genome that you have
described to me.
Speaker 2 (15:24):
Yeah, exactly, okay, right, So to make that animal, we
actually went through three rounds of editing, right, So we
would make the retroviolent activation make a pig, then take
those cells, edit them to make the try add the
truckle knockout, make a pig. Then we come back and
add the seven trans sheats.
Speaker 1 (15:40):
So it's multiple generations. You're you are sort of adding
changes genetic mutations over successive generations.
Speaker 2 (15:49):
Exactly why this allows us to select right. So there's
there's two there's there's two restrictions the time. Because we're
working with primary cells the time, you have to edit
them before they what we call sinat. So at some
point those cells stop dividing. You need to edit while
the cells are still divide, so you have a limited
(16:10):
number of days to do the editing, right, So we do.
So this is why we were doing three rounds of editing,
because we can get the retroviral in make a pig,
we can get the triple knockout make a pig. We
get the seven genes and make a pig. What's really
important to that whole process is at the end of
each editing round, we then screen individual cells for the genotype. Right,
(16:31):
And this is where we'll go through and screen you know,
up to four thousand cells to pick cells that look
like they have a good morphology and a good phenotype
for which we would then make a pig. So, once
we do the editing, we then pick individual cells that
we call clones, and then we grow those clones out,
and now we have an edited porsone genome, but we
(16:52):
still don't have a pig.
Speaker 1 (16:53):
So you basically have a whatever, a petri dish full
of pig skin cells that have the genotype that you want, exactly, okay.
Speaker 2 (17:01):
And so now we need to make a pig. And
the technology we use to turn a single cell into
a pig, it's called a somatic cell nuclear transfer. It
was similar to tchnology that was used to clone Dolly,
where we take the nucleus of the edited cell and
basically transfer it into the O site of a pig.
Speaker 1 (17:18):
An egg cell. And and so this is now a
whatever thirty year old technology that they used to clone
a sheep with in the nineties exactly.
Speaker 2 (17:27):
There's been some obviously improvements since then, but the core
idea is essentially the same. And then we use that
cloning technology to then make pigs. So we make an
embryo and then we transfer that embryo into a surrogate
sal and then that surrogate sal will carry the piglet
to term.
Speaker 1 (17:44):
There's some ethical dimension to this, like like, what are
the relevant ethical dimensions to you?
Speaker 2 (17:49):
Yeah, our focus is on preserving human health and saving
patients who are dying on the transfer wait list, and
we believe that this approach is justifiable with that goal
in mind. So every day we show up, we focus
on patients like mister Slayman. And so this is a
means to an end. This is a means to producing
organs that currently don't exist. It's to save paces who
(18:09):
are imminately dying, but they are. It's a very bleak
outlook for some of these folks, right, And so we
view that the work that we're doing for engineering the
persa and genome and producing compatible organs all about, you know,
realizing that mission of helping these patients, and we believe
that that puts us on a very firm ethical route.
Speaker 1 (18:29):
Still to come on the show, how pig hearts might
help human babies. How many pigs with this genetic sequence
are there?
Speaker 2 (18:47):
You have about fifty or so animals that are at
different ages.
Speaker 1 (18:50):
So, like, do you have a farm somewhere?
Speaker 2 (18:54):
So we do. We have two farms we have and
they are both out in the Midwest. One is a
research more of a research farm. It's a two hundred
acre farm where we institute biosecurity. So one of the
keys here is to produce animals that are free of
pathogens that could put harm to either the organs post
transplant or the patient or the recipients. So that farm
(19:15):
produces relatively clean animals. But then we have what we
call a clinical grade or designated pathogen free facility where
the animals are growing inside what we call a barrier.
So there we control feed, water, everything that comes in
to try to keep pathogens out. So we're actively managing
the environment that those animals are raised in. And on
(19:35):
top of all of that, we're doing very robust path
consistent pathogen testing, so we're constantly monitoring all the animals
for any potential pathogens or disease.
Speaker 1 (19:47):
Right, I mean presumably some kind of like jumping the
species barrier or transfer would be one of the like
nightmarishly bad outcomes, right.
Speaker 2 (19:57):
Yes, I mean one of the reasons that we selected
pigs as the species is one we've co you know,
existed with these animals for thousands of years and we
haven't seen that you know, that particular that type of
disease transmission, and then we can edit, and then we
also know how to grow animals at scale. But yes,
we're always on the lookout and I think this is
(20:17):
part of surveillance that we'll do for the foreseeable future,
is on the lookout for things that we aren't paying
attention for. Right.
Speaker 1 (20:25):
So let's talk about the first patient. Let's talk about
Richard slam and the first person ever to be walking
the earth with a pig kidney as far as we know, probably.
Speaker 2 (20:37):
Why him?
Speaker 1 (20:38):
What was it about his case that made him the
right patient?
Speaker 2 (20:40):
Yeah, So it's a great question, and part of it
was inspired by the work that was done at the
University of Maryland in the first heart transplants, right, so
we refer to those as the Bennett and Fossett transplants.
Speaker 1 (20:51):
The first pig heart pig heart, Yeah, which just happened.
That was like a different project, right, but it just
happened in the last year or so, right now, the.
Speaker 2 (21:01):
Last two years two years, Yeah, absolutely. And there was
always this debate in the field of zeno is what
patients would constitute the right patient population to go into
And the team at Maryland really showed us that there's
a case for compassionate use. There's a case for patients
who have reached the end of the treatment options and
really they're facing imminent death and we have a technology
that could save their life, so shouldn't we try now. Unfortunately,
(21:23):
you know, those gentlemen passed away within forty or fifty
days post transplant. But it showed us that the regulatory
agencies were open to the discussion, and we just need
to define what is the right patient population in the
case of kidney and so we had a discussion with
the FDA back in twenty twenty two about what would
be the right patient population for a formal phase one
(21:45):
clinical study, and we'd come to agreement on patients over fifty,
patients on the transplant weightlist, and patients that had failed
a previous alo transplant, right, so they'd had a human
kidney before, and they had it for a certain duration
of time and eventually that kidney fails and you find
yourself back on the transplant weightlist. And why that patient
population made sense is because those patients have a very
(22:07):
low likelihood if you're over fifty with that profile of
getting a second kidney. Now, in the case of mister Slamon,
are patients like him. He was also losing access to dialysis,
so he had a kidney transplant in twenty eighteen. He
had been on dialysis for seven years, got a kidney transplant,
the kidney function for five years, and then he lost
(22:30):
the kidney stop functioning. In twenty twenty three, Okay, he
found himself back on dialysis, but he was having trouble
with vascular access, so he had to go through multiple
surgeries to create access so he could go on dialysis.
Speaker 1 (22:43):
And just to be clear, dialysis is when your kidneys
don't work. There is a machine and they hook you
up to the machine and it cleans your blood. It
does the work of the kids.
Speaker 2 (22:51):
Yeah. Usually, you know, the typical schedule would be three
times a week, four hours each time.
Speaker 1 (22:54):
Okay, And so Richard Slaman, you were saying dialysis just
wasn't working for him anymore.
Speaker 2 (23:00):
In some patchion it was just very hard to do.
It was working, but he would have to have these
vascular access surgery so his blood vessels would acclude and
prevent the ability to do dialysis. So we'd have to
go through a relatively painful procedure to allow him to
get dialysis. And I think, you know, he was and
I think his neuprologist, when Williams put it really well,
(23:20):
he was kind of losing faith, losing hope, like, huh,
is this my life? Is this my future? Like, I'm
just going to have to keep doing this and I
have no chance of getting a transplant because he had
had a transplant for five years, so he knew what
that was and now he finds himself on dallasis. So,
so we knew at some point mister Sliman would lose
access to dialysis and without a transplant, he would he
(23:42):
would go to hospice. And so he was a patient
that we felt was a good candidate for trying. And
so the team at Mass General approached mister Slaman with
this idea of he could participate and be the first
patient to try this, and this is what we knew,
and these were the risks, and I think that's part
of one of the biggest challenges, kind of articulating what
(24:04):
we know and then articulately what we don't know and
how this could go. But much to mister slam his credit, right,
he was the one that raised his hand and said
he would go first. And then we took it to
the FDA and we laid out the case to the
FDA that you know mister Slamon's story and kind of
where he found himself in his treatment. What we had
been doing are non human primate data, all the data
(24:25):
on the characterization of our donors. And after a few
weeks of discussion, the FDA said, we agree and you
guys can try.
Speaker 1 (24:35):
So what is the path for you for your fore genesis?
Speaker 2 (24:39):
From here, we believe that there's the opportunity to treat
more patients like mister Slimon. He's not unfortunately, he's not
unique in this space, and there are other patients that
are suffering very similar fate with continued success. Our intention
is to do more of these expanded access requests and
transplants while we prepare for a formal trial, right so
(25:01):
in patients that may be facing less risk than patients
like mister Slamon, patients earlier in their dialysis journey, earlier
in their their kidney failure progression. But that will come,
you know. Our intention is to file something like that
at the end of twenty twenty five. Beyond that, you know,
we are also exploring patients that are suffering from liver
(25:21):
failure as well as heart failure. This past December, we
did the longest liver perfusions on liver perfusion in a
decedent patient. Ever, we did three days of continuous perfusion.
The idea there is you take a patient who may
be suffering from liver failure and perfuse them through a
pig liver to allow their own liver to recover again.
(25:44):
This was something that was demonstrated in the nineties to work.
So they took fourteen patients with acute liver failure perfused
them through pig livers. All fourteen patients improved. Seven patients
were successfully bridged to transplant.
Speaker 1 (25:58):
So just to unpack that for a sec the pig
liver is kind of like when people get put on
those like external artificial hearts or something like the outside
the body, and it's like or.
Speaker 2 (26:06):
What you know when think about kidney disease is akin
to dialsis right? You hooked up to a machine. In
this case, in the machine is a big.
Speaker 1 (26:14):
Liver, and like, is it in a box?
Speaker 2 (26:17):
Like yeah, yeah, So it's in a plastic container on
a perfusion device.
Speaker 1 (26:22):
So the pig's liver is doing the work of the
liver for the patient while the patient is waiting for
a human donor exactly. Like, let me ask the dumb question,
why not just put the pigs liver in the person.
Speaker 2 (26:35):
Because the incompatibilities between a pig liver and the person
are still too great. OK, So we could I think
we're only going to get a week or two before
that gets rejected.
Speaker 1 (26:47):
And so similarly, does the perfusion just last for a
week or two it's just like an emergency bridge.
Speaker 2 (26:52):
Yeah, so it's a great question, and we started out
with a goal of greater than twenty four hours of perfusion.
The pen study went for three days. Looking at the
histology at the end of the study, we believe it
can go for about a week. So we're continuing to
push the duration.
Speaker 1 (27:06):
So that's like a that feels like much more of
a kind of edge case than the kidney case.
Speaker 2 (27:11):
Well, this is the thing. We think there's actually much
greater unmet need and liver failure than there even is
in kidney failure because these patients, because there is no
equivalent of dialysis, they either recover on their own, which
is a little bit of like ICU time and hope,
or they get transplanted. So we're hoping that we can
provide liver support through a poresigne liver, we can bridge
(27:33):
more patients to recovery.
Speaker 1 (27:34):
Okay, and then you're and then hearts.
Speaker 2 (27:38):
Yeah. So the third setting, again is inspired by the
work done at Maryland, but instead of looking at adult
patients where the heart has to and heart has to
function continuously or the patient passes away, we're focused in
the pediatric population. So children who need a heart transplant
currently have poor standard of care to bridge them to
human heart transplant.
Speaker 1 (27:58):
And so this is like typically like babies born with
genetic anomalies.
Speaker 2 (28:03):
Yeah, typically children under two is kind of where the
focus is and the current support of care. About fifty
percent of these children die waiting for a human heart transplant.
Speaker 1 (28:14):
That is a brutal one. Is a brutal That would
be a good one too, Yeah, that would be a
good one to tve.
Speaker 2 (28:20):
And so the idea is if we can simply create
one hundred to two hundred day bridge using a Poresigne heart,
then at the end of that or sometime in the middle,
when the human heart became available, the child would simply
get the human heart. So we call that a bridging strategy.
Speaker 1 (28:34):
And so in that instance, is it a transplant or
is it external It's a transplant.
Speaker 2 (28:38):
Yeah, So the intention is to do the por signed
heart transplant allow the patient to go home. They can
wait at home right now, they would have to wait
in the hospital, but they could wait at home until
the human heart becomes available.
Speaker 1 (28:51):
Okay, So so those are two other organs. When do
you think you're going to do those?
Speaker 2 (28:58):
So the intention, the intention is to do all that
this year, right, So, we believe we have the not
what we call non clinical data or the primate data
to support moving into the clinic. And I do think
mister the success so far with mister Slaman's transplant is
helpful because the emune of suppression that we plan to
use in the pediatric heart setting is very similar to
what we're using in mister Slaman's transplant. So we do
(29:20):
think that continued success in the kidney transplant will help
inform what we're going to be doing at heart.
Speaker 1 (29:27):
And is it the same set of genetic changes?
Speaker 2 (29:32):
Yeah, so it's the same genetics of the donor. So
the current plan is to use the same donor for
both kidney, hearts and livers.
Speaker 1 (29:41):
And how does how does the immune response to a
pig organ compare to the immune response to an organ
from another human?
Speaker 2 (29:52):
Yeah, it's definitely more robust.
Speaker 1 (29:55):
More robust meaning worse in this concept, it's.
Speaker 2 (29:57):
Probably going to require you know, we already are using
more evenie suppression. Yeah.
Speaker 1 (30:01):
And is there some medium to long term future where
you do more gene editing in order to make that
piece of it easier, where you make the pig kidney
more like a human kidney.
Speaker 2 (30:16):
Yeah. Absolutely. The long term vision here is to produce
organs that don't require immuno suppression, party.
Speaker 1 (30:21):
That don't require it at.
Speaker 2 (30:22):
All at all. I mean, that's the ultimate that's the vision.
Speaker 1 (30:24):
I mean, if you could do that. Just to be clear,
like that vision is a pig kidney is better than
a kidney from another human.
Speaker 2 (30:32):
Right, I mean it sounds like you've been talking to George. Wow.
Speaker 1 (30:36):
I appreciate that you were skeptical. You were supposed to
be high picking up and I'm supposed to be skeptical. No.
But if you say, like, is that even plausible? I
appreciate that you're skeptical of it. That's good.
Speaker 2 (30:45):
Yeah, do it might work for me. I think one
of the things that transplant World has taught us over
the past fifty years is things that we thought were
impossible are actually now routine, right, So I think it's
a matter of time, effort, and work. I think we
can get there, right. I think this initial transplant into
patients is a really important step because for us to
be informed about what we need to do from an
(31:06):
engineering perspective, it is very helpful to have data from
humans to feedback into that loop, so we can do
lots of things from an engineering perspective. The question is
what to do next, and I think the results that
will achieve with mister Slayman and patients like him will
help inform what else we need to do to really
realize this big vision, which is organs that don't require suppression.
Speaker 1 (31:28):
Organs that don't require suppression, is wildly ambitious, right do you?
I mean it seems like, not knowing basically anything about it,
it would be a kind of incremental, maybe even as symptotic, like, ah,
this will get us to less, This will get us
to less as opposed to some binary breakthrough. Does that
seem right?
Speaker 2 (31:48):
Yeah? I think it's incremental. But what we're starting to
see is kind of multiplex editing in a way that
we couldn't even before Christper, we couldn't conceive of making
fifty nine edits for GENO. Okay, now we're conceiving of
how would you make a thousand edits to geno? What
does that actually look like? And I think that's what's
going to be required. Huh.
Speaker 1 (32:08):
I mean, do you get weird like structural like three
D structural problems once you start doing that, like is
it even gonna yes work?
Speaker 2 (32:16):
So there's definitely a lot to solve, right, So how
do you make you know, how do you make that
many changes without totally destroying the geno? We thought that
originally with Crisper and the first retroviolent activation, they thought
you would never be able to make that many at it.
So we did that. We just have to figure out
how to do it. And you know, we don't know
how to do it right now, but I do think
we'll figure out how to do it.
Speaker 1 (32:38):
We'll be back in a minute with the lightning. Let's
finish with a lightning ground. I won't take much more
of your time.
Speaker 2 (32:57):
Okay, Okay, what's one.
Speaker 1 (32:59):
Thing that that we don't understand about the human body
that you wish we understood?
Speaker 2 (33:12):
I think, coming from the neuroscience world, I think we
have a really poor understanding of mental health and what
to do about depression, and because I think those are
just paralyzing diseases that we are a long way from
really understanding why they exist and actually how to effectively
(33:33):
treat them. So if you could generalize that as brain,
we still don't really understand in the way we need to,
you know, how the brain actually works and what we
can do to improve diseases of the brain.
Speaker 1 (33:46):
Well, I know you worked in pharmaceuticals for decades, right,
I don't point on it, Yeah, and so you know
it's a famously hard industry. Most drugs fail, right, I'm
curious if you have any any tips for dealing with failure.
Speaker 2 (34:02):
I think you go in with the best hypothesis, you
run the most efficient studies you can, and then you
pick yourself up and go again, because I think you
can't let failure bring you down, right, And we know
we're going to fail, and often we learned a tremendous
amount from those failures and we just have to build
on them. The worst thing you can do is stop.
I think you have to always keep going.
Speaker 1 (34:23):
So if you look back over the thirty years that
you worked in the drug industry, I'm curious, like, if
you think about when you were getting into the field.
What is something that has happened since then, like a breakthrough,
a change that you wouldn't have expected that's surprising to you.
Speaker 2 (34:41):
I think this whole field of genetic medicines, you know
the fact that we're now producing potential cures for sickle cell,
cures for beta thalsemia. I think those were all visions
that we had, you know, fifty sixty one hundred years ago,
like could we actually cure diseases that we're now literally
on the shelf have cures for. And I think that
no one ever thought we would get there, and here
(35:02):
we are.
Speaker 1 (35:03):
So conversely, so that's the happy surprise. Is there something
when you got into the field that you fought like,
surely we'll figure this out, Surely this will be solved
that we haven't figured out.
Speaker 2 (35:15):
I mean, our inability to really effectively fight viral infection is,
you know, our infectious disease broadly. We really haven't evolved
our armamentarium against infectious disease very much. I think there
we've way under invested and focused on infectious disease. I
don't think the current way we fund drug development doesn't
support active work there. I think it's the one. It's
(35:38):
a blind spot for us, and I think we saw it,
you know, during COVID.
Speaker 1 (35:41):
Yeah, right, so.
Speaker 2 (35:45):
And it's still a blind spot. What's really sad is
I don't think COVID. Actually, I don't think we've done
much different than we were.
Speaker 3 (35:50):
Doing that that that hurts, but I think it's true.
Speaker 1 (35:58):
Mike Curtis is the CEO of E Genesis. Today's show
was produced by Gabriel Hunter Chang. It was edited by
Lydia jene Kott and engineered by Sarah. You can email
us at problem at Pushkin dot FM. I'm Jacob Goldstein
and we'll be back next week with another episode of
What's Your Problem.
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