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The First Pig to Human Kidney Transplant · What's Your Problem?

0:15
Speaker 1: Pushkin. Rick Slayman is sixty two years old, lives in
0:24
Speaker 1: a suburb of Boston, works for the state Department of Transportation,
0:29
Speaker 1: and about five years ago he got a kidney transplant.
0:33
Speaker 1: Then last year his new kidney stopped working, his health declined.
0:38
Speaker 1: His prognosis was pretty bad, so earlier this year, he
0:42
Speaker 1: and his doctors decided that he would be the first
0:46
Speaker 1: person in the history of the world to get a
0:48
Speaker 1: kidney transplant from a genetically engineered pig. Surgeons did the
0:54
Speaker 1: transplant on March sixteenth, and two weeks later, Rix s
0:58
Speaker 1: Layman walked out of the hospital. It's still too soon
1:02
Speaker 1: to say how he'll do in the coming months, but
1:05
Speaker 1: as of this recording, he's doing well. I'm Jacob Boltstein
1:14
Speaker 1: and this is What's Your Problem, the show where I
1:16
Speaker 1: talk to people who are trying to make technological progress.
1:20
Speaker 1: My guest today is Mike Curtis. He's the CEO of Egenesis,
1:25
Speaker 1: the company that bred the genetically engineered pig that provided
1:29
Speaker 1: the kidney for Rick Slicker. Every year, thousands of people
1:34
Speaker 1: die waiting for an organ transplant that never comes. And
1:37
Speaker 1: so Mike's problem is this, is it possible to genetically
1:42
Speaker 1: engineer pigs to provide organs, kidneys, livers, hearts for people,
1:49
Speaker 1: and in the long run, is it possible to make
1:52
Speaker 1: pig organs that work even better than human organs for
1:56
Speaker 1: human transplant patients. So for a really long time, right,
2:04
Speaker 1: like hundreds of years, people have had this idea of
2:07
Speaker 1: transplanting organs or skin from animals to people, like where
2:14
Speaker 1: do you where do you date the beginning of this
2:17
Speaker 1: idea too?
2:18
Speaker 2: It was it was even pre dated human human transplants.
2:21
Speaker 2: So as soon as you know, physicians realize that organs
2:24
Speaker 2: can fail, I think the first instinct was can we
2:27
Speaker 2: get them from somewhere else? Right? And in the early
2:30
Speaker 2: days of that horribly right, no, no good success. So
2:34
Speaker 2: we kind of pre you know, date that to the
2:36
Speaker 2: dawn of modern medicine. And nothing worked.
2:39
Speaker 1: And nothing worked because basically the human immune system rejected
2:43
Speaker 1: the transplants.
2:44
Speaker 2: And that was before we even knew what that was.
2:45
Speaker 3: But right, yeah, And so to jump forward a very
2:49
Speaker 3: long way, it seems like Crisper, this ability to edit
2:55
Speaker 3: genes is sort of a key breakthrough.
2:58
Speaker 1: Is that the kind of key moment that enables this
3:01
Speaker 1: new era that seems to be beginning right now?
3:04
Speaker 2: Absolutely. There were some challenges in the cross species transplant
3:08
Speaker 2: that just unresolvable until the discovery of Crisper. So the
3:12
Speaker 2: one that we took on was in the nineties, it
3:15
Speaker 2: was discovered that poresign retroviruses that are indigenous in the genome,
3:20
Speaker 2: so they're kind of embedded in the pig genome, could
3:23
Speaker 2: infect human cells. And in the nineties, you know, we
3:25
Speaker 2: were coming out of the HIV epidemic, and we did
3:29
Speaker 2: not want to, you know, cause another problem. So we
3:31
Speaker 2: didn't want to have a cross species zoonotic event. So
3:35
Speaker 2: in many countries around the world they put a moratorium
3:37
Speaker 2: on cross species transplantation because of this risk of indigenous retroviruses.
3:42
Speaker 1: And so I just want to pause here because I
3:46
Speaker 1: didn't know about indogenous retroviruses until I started preparing for
3:50
Speaker 1: this interview, and it totally blew my mind that there
3:54
Speaker 1: is such a thing. Right, So, an indogenous retrovirus, as
3:58
Speaker 1: I understand.
3:59
Speaker 2: It is.
4:02
Speaker 1: Not like a disease that a that an animal has
4:05
Speaker 1: in this case, a poor sign. Indogenous retrovirus obviously is
4:08
Speaker 1: an indogen retrovirus in a pig, and it doesn't mean
4:11
Speaker 1: that the pig is sick It means that in the
4:13
Speaker 1: genome of every pig there is genetic code to code
4:17
Speaker 1: in that pig a retrovirus, right, And similarly, in humans
4:22
Speaker 1: there are other indogenous retroviruses. We have in our genome
4:26
Speaker 1: the code for retroviruses, that's right. Why why do mammals
4:32
Speaker 1: have the code for viruses in our genomes?
4:35
Speaker 2: Yeah? What's interesting because there are some functions that are
4:38
Speaker 2: ascribed to these indigenous retroviruses. So they kind of co evolved,
4:42
Speaker 2: you know, with pigs with people, and they pick up
4:45
Speaker 2: some function, right, And so we don't completely understand why
4:49
Speaker 2: they're there, but they're there and they pose a risk, right,
4:54
Speaker 2: an infectious disease risk to patients, especially when you think
4:59
Speaker 2: about patients who might be under immino suppression.
5:02
Speaker 1: And so, just to be clear, just I won't I
5:04
Speaker 1: don't want to be labor this, but it is really
5:05
Speaker 1: extraordinary coming to it new. The notion is a very
5:11
Speaker 1: very very long time ago, some pig in this case
5:15
Speaker 1: got infected with a virus and that virus made its
5:19
Speaker 1: way into the genome of essentially all the pigs living today,
5:24
Speaker 1: and that genetic code is not harmful to pigs, but
5:30
Speaker 1: there is a fear that if you took a pig kidney, say,
5:33
Speaker 1: and put it in a human being, the code for
5:35
Speaker 1: that virus, which is fine in pigs, might be harmful
5:38
Speaker 1: in people.
5:39
Speaker 2: Exactly. It's an unknown risk, ye.
5:42
Speaker 1: And so in the nineties, particularly as you said, in
5:46
Speaker 1: the context of the fear of HIV, people are thinking
5:48
Speaker 1: about doing could we transplant a pig kidney into a
5:52
Speaker 1: human and regulators essentially are saying, well, one reason you
5:57
Speaker 1: cannot do it is because of these endogenous retroviruses in
6:01
Speaker 1: the pigs DNA.
6:02
Speaker 2: Exactly, and we can't quantify the risk, and so we
6:05
Speaker 2: don't know what will happen, and we actually don't want
6:08
Speaker 2: to know. You need to come up with a way
6:10
Speaker 2: to mitigate the risk of retroviral transmission from the donor
6:14
Speaker 2: to the recipient.
6:15
Speaker 1: Okay, And so that's just like a red light, do
6:19
Speaker 1: not pass. Go stop doing this for a while. Once
6:23
Speaker 1: that happens.
6:23
Speaker 2: In the nineties, exactly, most of the people that were
6:27
Speaker 2: investing in the space stopped investing in the space. The
6:29
Speaker 2: progression towards clinic stopped. It really slowed the whole field
6:32
Speaker 2: down because no one knew exactly how to quantify the
6:34
Speaker 2: risk or then what to do about it. And so
6:37
Speaker 2: any pig genome you'll have between fifty and seventy copies
6:41
Speaker 2: of the retrovirus scattered throughout the genome. And so even
6:44
Speaker 2: if you wanted to go in and remove them, there
6:47
Speaker 2: was no technology available that would allow you to do that.
6:50
Speaker 2: And no one knew of a way to actually actively
6:53
Speaker 2: get rid of these viruses right until the discovery of Crisper.
6:56
Speaker 1: So Crisper comes along what ten issuars twelve years ago,
7:01
Speaker 1: and it's this incredible technology for editing a genome. Right,
7:10
Speaker 1: people think, oh, maybe we could solve that poresine and
7:15
Speaker 1: dogenous retrovirus problem using Crisper.
7:18
Speaker 2: Yeah, so this is what George Church kind of took
7:20
Speaker 2: up at Harvard was like, it kind of what would
7:22
Speaker 2: do we use chrispher for? And this this problem was
7:24
Speaker 2: out there and George took it on and said, well,
7:26
Speaker 2: let's see if you can inactivate all copies of the
7:29
Speaker 2: retroviruses in the pig geno. The beautiful part about Crisper
7:32
Speaker 2: is once you give it a sequence, right, it will
7:35
Speaker 2: edit all copies of that sequence in a given genome. Now,
7:38
Speaker 2: the worry was that you would then create basically Swiss
7:43
Speaker 2: cheese out of the genome. Right, you would create an
7:45
Speaker 2: unviable genome. There's too many edits, was the original thought.
7:48
Speaker 2: But George and the team at Harvard showed that no,
7:50
Speaker 2: you could actually inactivate all copies of the retrovirus and
7:54
Speaker 2: then produce a viable pig.
7:57
Speaker 1: Right, because I suppose the other question is like, even
7:59
Speaker 1: if you can cleanly make all the edits, do does
8:03
Speaker 1: the pig actually need this indogenous retrovirus for a reason
8:07
Speaker 1: we don't understand.
8:08
Speaker 2: Right, And we know it does if you if you
8:10
Speaker 2: completely knock it out or get rid of it, the
8:12
Speaker 2: pigs are not healthy. So we make a relatively subtle
8:16
Speaker 2: change to the viral genome that that prevents the virus
8:19
Speaker 2: from replicating. So with this edit, the virus can no
8:22
Speaker 2: longer replicate hot.
8:24
Speaker 1: But so you don't knock it. You don't entirely remove
8:27
Speaker 1: the sequence from the genome.
8:29
Speaker 2: You just.
8:31
Speaker 1: Edit the genome such that this virus, once it's expressed,
8:35
Speaker 1: cannot replicate.
8:36
Speaker 2: Right, So essentially inactivate those of Dodges viruses.
8:39
Speaker 1: And so this idea from George Churchill was one of
8:42
Speaker 1: the like giant names in genetics. Right famous scientists was
8:46
Speaker 1: that the origin of the company.
8:49
Speaker 2: So it came from from from George's lab and we
8:53
Speaker 2: we one of his postdocs started Egenesis by outlcensing the
8:59
Speaker 2: technology from Harvard. So the original idea was to start
9:03
Speaker 2: Egenesis with the idea of making animals that were retroviray
9:07
Speaker 2: inactivated and then also do the rest of the editing
9:12
Speaker 2: right that made the pigs more compatible with human recipient.
9:15
Speaker 2: So that's how we got into the field. And then
9:17
Speaker 2: from the from then we've built the additional editing to
9:21
Speaker 2: provide organs that are more compatible with first non human
9:24
Speaker 2: primates and then now with people.
9:26
Speaker 1: So you have inactivated the endogenous retrovirus in the pig.
9:32
Speaker 1: This is like step one, right, But at this point,
9:36
Speaker 1: if you tried to take that kidney, even though you've
9:41
Speaker 1: solved the retrovirus problem, it's still a pig kidney, right,
9:45
Speaker 1: and the human body would know that and would not
9:48
Speaker 1: accept it. So what do you have to do next?
9:51
Speaker 2: Sure, and so if you just took an unedited pig
9:54
Speaker 2: kidney and try to put it into a monkey or
9:55
Speaker 2: to a person, to be rejected within minutes. And that's
9:59
Speaker 2: primarily due to what we call hyperacute rejection, where the
10:03
Speaker 2: humans are recognizing the carbohydrate differences between pigs and humans.
10:07
Speaker 2: So carbohydrates are that coat all the cells, and humans
10:12
Speaker 2: have antibodies that can recognize those pig sugars. So what
10:16
Speaker 2: we do is we inactivate three genes responsible for those
10:20
Speaker 2: carbohydrate differences between pigs and humans. Once you do that,
10:23
Speaker 2: we create what we call the triple knockout. So we
10:25
Speaker 2: inactivate those genes, knocking out those carbohydrate differences and eliminating
10:31
Speaker 2: hypercute rejection.
10:34
Speaker 1: And when you create a pig with those particular carbohydrates eliminated,
10:42
Speaker 1: does it matter to the pig? Is the pig sicker?
10:45
Speaker 2: As a result, we haven't seen any impact on the
10:49
Speaker 2: health or longevity of a pig. So, for instance, we
10:52
Speaker 2: have several animals in our colony that are a couple
10:55
Speaker 2: of years old, and so we haven't seen any effects
10:58
Speaker 2: on the longevity of those animals. So no, we haven't
11:01
Speaker 2: seen any downside.
11:02
Speaker 1: Okay, so you've inactivated the endogenous retrovirus and now you've
11:07
Speaker 1: eliminated the carbo hydrates that are causing acute rejection. There's
11:12
Speaker 1: like one more set of changes you've got to make, right,
11:14
Speaker 1: That's right.
11:15
Speaker 2: So what the field has shown over the past forty years.
11:17
Speaker 2: Is that if you add human genes to the pig genome,
11:21
Speaker 2: you can help regulate different areas of incompatibility. So when
11:25
Speaker 2: we think about, for instance, coagulation, right, So the coagulation
11:28
Speaker 2: factors in the pig are not one percent compatible with humans,
11:33
Speaker 2: so we introduce human coagulation factors into the pig.
11:36
Speaker 1: Coagulation factors just what causes the blood.
11:39
Speaker 2: To clot basically or prevent the blood from clotting? Yeah,
11:42
Speaker 2: either way, both both corrections, yep, absolutely. And then we
11:45
Speaker 2: also add regulators of complement activation. The first kind of
11:49
Speaker 2: immune response that you're going to get to a graft
11:52
Speaker 2: in a transplant is what we call compliment activation, and
11:55
Speaker 2: that leads to loss of cells, right, and that leads
11:58
Speaker 2: to death of cells. But by introducing human complement regulators
12:02
Speaker 2: into the poor scine tissue, we can slow down or
12:05
Speaker 2: quiet that complement response. And then we add module later
12:09
Speaker 2: of what we call the innate and adaptive immune response.
12:12
Speaker 2: In total, we add in the animal that was used
12:16
Speaker 2: in mister Slamon's transplant, we introduced a total of seven
12:19
Speaker 2: regulatory human proteins. So if you add it together, it's
12:23
Speaker 2: fifty nine edits to inactivate the retroviruses three edits to
12:27
Speaker 2: improve the carbohydrate compatibility, and then seven edits to introduce
12:32
Speaker 2: human regulatory trans genes, for a total of sixty nine edits.
12:35
Speaker 1: So it's basically the first two categories are make it
12:38
Speaker 1: less like a pig, and then the third category is
12:41
Speaker 1: make it more like a person.
12:43
Speaker 2: Yeah, that's a good way to think about it.
12:44
Speaker 1: That's right, And I mean presumably at some margin you
12:49
Speaker 1: want to make it as little like a pig and
12:53
Speaker 1: as much like a person as possible. But the pig
12:56
Speaker 1: still has to live, to grow up and have a kidney.
13:00
Speaker 2: Right, absolutely, And we've produced animals with more trans genes
13:05
Speaker 2: without any issue. But you can imagine at some point, right,
13:09
Speaker 2: you'll reach a point where the pig no longer can
13:11
Speaker 2: tolerate whatever the editing you're doing. We're actually already impressed
13:14
Speaker 2: that we can produce healthy, viable pigs with this number
13:17
Speaker 2: of edits. If you go back ten fifteen years, nobody
13:20
Speaker 2: thought that you could viably do this. Even in activating
13:24
Speaker 2: fifty nine copies of the retrovirus. Many felt that that
13:27
Speaker 2: was too many and the genome wouldn't be able to
13:29
Speaker 2: handle it. We can tell you that it's not easy,
13:32
Speaker 2: and it's not trivial to do it. It took us
13:34
Speaker 2: a lot of time to figure out how to do it,
13:37
Speaker 2: but now we've shown it it is doable.
13:40
Speaker 1: I'm sure that it's not easy, but I don't know
13:43
Speaker 1: enough to understand, like what's hard about it? Like tell
13:48
Speaker 1: me a thing that you had to figure out.
13:50
Speaker 2: Sure, so when you do that much engineering to the genome,
13:53
Speaker 2: you can get aberrations in the genome that prevents you
13:58
Speaker 2: from making a pig. So one of the things that
14:00
Speaker 2: we do is we do what's called clonal selection. So
14:03
Speaker 2: we'll engineer thousands, tens of thousands of cells and then
14:08
Speaker 2: select genomes based on viability. So, for instance, to so
14:12
Speaker 2: produce our seventeen eighty four donor, we had to screen
14:15
Speaker 2: over four thousand clones to find clones that had the
14:19
Speaker 2: adequate quality of genome to then make pigs.
14:22
Speaker 1: Huh. So let's just let's just talk about that for
14:25
Speaker 1: a minute, like how that actually works, which is the
14:29
Speaker 1: more basic question of just how does the whole thing work?
14:32
Speaker 1: Like I get in a sort of abstracted space what
14:35
Speaker 1: you're doing, but like in whatever in a you know,
14:40
Speaker 1: in a cell, fundamentally there is a cell, right like,
14:42
Speaker 1: what are we starting with.
14:43
Speaker 2: So we'll take a sample of skin from an adult
14:46
Speaker 2: what we call wild type so unedited pig. Then culture
14:50
Speaker 2: those cells, make many cells, and then those are the
14:52
Speaker 2: cells that we're going to edit. So those are the
14:54
Speaker 2: cells that we take crisper. We make the fifty nine edits,
14:57
Speaker 2: we make the triple knockout, and we make the seven
14:59
Speaker 2: trans geens. In the case of the seventeen eighty four animal,
15:03
Speaker 2: we did that through three sequential routes.
15:05
Speaker 1: So just to be clear, the seventeen eighty four animal,
15:07
Speaker 1: this is like one particular pig, the pig that donated
15:10
Speaker 1: the kidney that is in a person right now.
15:12
Speaker 2: So that's the seventeen eighty four refers to the genetics.
15:15
Speaker 2: So we make many seventeen eighty four animals. So it's
15:19
Speaker 2: a particular.
15:20
Speaker 1: Edited genome, and it's the edited genome that you have
15:23
Speaker 1: described to me.
15:24
Speaker 2: Yeah, exactly, okay, right, So to make that animal, we
15:26
Speaker 2: actually went through three rounds of editing, right, So we
15:29
Speaker 2: would make the retroviolent activation make a pig, then take
15:33
Speaker 2: those cells, edit them to make the try add the
15:35
Speaker 2: truckle knockout, make a pig. Then we come back and
15:39
Speaker 2: add the seven trans sheats.
15:40
Speaker 1: So it's multiple generations. You're you are sort of adding
15:45
Speaker 1: changes genetic mutations over successive generations.
15:49
Speaker 2: Exactly why this allows us to select right. So there's
15:54
Speaker 2: there's two there's there's two restrictions the time. Because we're
15:59
Speaker 2: working with primary cells the time, you have to edit
16:02
Speaker 2: them before they what we call sinat. So at some
16:05
Speaker 2: point those cells stop dividing. You need to edit while
16:08
Speaker 2: the cells are still divide, so you have a limited
16:10
Speaker 2: number of days to do the editing, right, So we do.
16:13
Speaker 2: So this is why we were doing three rounds of editing,
16:15
Speaker 2: because we can get the retroviral in make a pig,
16:18
Speaker 2: we can get the triple knockout make a pig. We
16:20
Speaker 2: get the seven genes and make a pig. What's really
16:22
Speaker 2: important to that whole process is at the end of
16:25
Speaker 2: each editing round, we then screen individual cells for the genotype. Right,
16:31
Speaker 2: And this is where we'll go through and screen you know,
16:34
Speaker 2: up to four thousand cells to pick cells that look
16:37
Speaker 2: like they have a good morphology and a good phenotype
16:40
Speaker 2: for which we would then make a pig. So, once
16:42
Speaker 2: we do the editing, we then pick individual cells that
16:45
Speaker 2: we call clones, and then we grow those clones out,
16:49
Speaker 2: and now we have an edited porsone genome, but we
16:52
Speaker 2: still don't have a pig.
16:53
Speaker 1: So you basically have a whatever, a petri dish full
16:56
Speaker 1: of pig skin cells that have the genotype that you want, exactly, okay.
17:01
Speaker 2: And so now we need to make a pig. And
17:02
Speaker 2: the technology we use to turn a single cell into
17:05
Speaker 2: a pig, it's called a somatic cell nuclear transfer. It
17:08
Speaker 2: was similar to tchnology that was used to clone Dolly,
17:11
Speaker 2: where we take the nucleus of the edited cell and
17:14
Speaker 2: basically transfer it into the O site of a pig.
17:18
Speaker 1: An egg cell. And and so this is now a
17:21
Speaker 1: whatever thirty year old technology that they used to clone
17:24
Speaker 1: a sheep with in the nineties exactly.
17:27
Speaker 2: There's been some obviously improvements since then, but the core
17:30
Speaker 2: idea is essentially the same. And then we use that
17:33
Speaker 2: cloning technology to then make pigs. So we make an
17:36
Speaker 2: embryo and then we transfer that embryo into a surrogate
17:39
Speaker 2: sal and then that surrogate sal will carry the piglet
17:42
Speaker 2: to term.
17:44
Speaker 1: There's some ethical dimension to this, like like, what are
17:47
Speaker 1: the relevant ethical dimensions to you?
17:49
Speaker 2: Yeah, our focus is on preserving human health and saving
17:51
Speaker 2: patients who are dying on the transfer wait list, and
17:54
Speaker 2: we believe that this approach is justifiable with that goal
17:58
Speaker 2: in mind. So every day we show up, we focus
18:01
Speaker 2: on patients like mister Slayman. And so this is a
18:03
Speaker 2: means to an end. This is a means to producing
18:06
Speaker 2: organs that currently don't exist. It's to save paces who
18:09
Speaker 2: are imminately dying, but they are. It's a very bleak
18:12
Speaker 2: outlook for some of these folks, right, And so we
18:14
Speaker 2: view that the work that we're doing for engineering the
18:17
Speaker 2: persa and genome and producing compatible organs all about, you know,
18:20
Speaker 2: realizing that mission of helping these patients, and we believe
18:23
Speaker 2: that that puts us on a very firm ethical route.
18:29
Speaker 1: Still to come on the show, how pig hearts might
18:32
Speaker 1: help human babies. How many pigs with this genetic sequence
18:46
Speaker 1: are there?
18:47
Speaker 2: You have about fifty or so animals that are at
18:49
Speaker 2: different ages.
18:50
Speaker 1: So, like, do you have a farm somewhere?
18:54
Speaker 2: So we do. We have two farms we have and
18:56
Speaker 2: they are both out in the Midwest. One is a
18:59
Speaker 2: research more of a research farm. It's a two hundred
19:01
Speaker 2: acre farm where we institute biosecurity. So one of the
19:05
Speaker 2: keys here is to produce animals that are free of
19:07
Speaker 2: pathogens that could put harm to either the organs post
19:11
Speaker 2: transplant or the patient or the recipients. So that farm
19:15
Speaker 2: produces relatively clean animals. But then we have what we
19:18
Speaker 2: call a clinical grade or designated pathogen free facility where
19:22
Speaker 2: the animals are growing inside what we call a barrier.
19:25
Speaker 2: So there we control feed, water, everything that comes in
19:28
Speaker 2: to try to keep pathogens out. So we're actively managing
19:31
Speaker 2: the environment that those animals are raised in. And on
19:35
Speaker 2: top of all of that, we're doing very robust path
19:39
Speaker 2: consistent pathogen testing, so we're constantly monitoring all the animals
19:44
Speaker 2: for any potential pathogens or disease.
19:47
Speaker 1: Right, I mean presumably some kind of like jumping the
19:50
Speaker 1: species barrier or transfer would be one of the like
19:54
Speaker 1: nightmarishly bad outcomes, right.
19:57
Speaker 2: Yes, I mean one of the reasons that we selected
20:00
Speaker 2: pigs as the species is one we've co you know,
20:03
Speaker 2: existed with these animals for thousands of years and we
20:06
Speaker 2: haven't seen that you know, that particular that type of
20:09
Speaker 2: disease transmission, and then we can edit, and then we
20:12
Speaker 2: also know how to grow animals at scale. But yes,
20:15
Speaker 2: we're always on the lookout and I think this is
20:17
Speaker 2: part of surveillance that we'll do for the foreseeable future,
20:21
Speaker 2: is on the lookout for things that we aren't paying
20:23
Speaker 2: attention for. Right.
20:25
Speaker 1: So let's talk about the first patient. Let's talk about
20:27
Speaker 1: Richard slam and the first person ever to be walking
20:30
Speaker 1: the earth with a pig kidney as far as we know, probably.
20:37
Speaker 2: Why him?
20:38
Speaker 1: What was it about his case that made him the
20:40
Speaker 1: right patient?
20:40
Speaker 2: Yeah, So it's a great question, and part of it
20:43
Speaker 2: was inspired by the work that was done at the
20:45
Speaker 2: University of Maryland in the first heart transplants, right, so
20:49
Speaker 2: we refer to those as the Bennett and Fossett transplants.
20:51
Speaker 1: The first pig heart pig heart, Yeah, which just happened.
20:55
Speaker 1: That was like a different project, right, but it just
20:59
Speaker 1: happened in the last year or so, right now, the.
21:01
Speaker 2: Last two years two years, Yeah, absolutely. And there was
21:03
Speaker 2: always this debate in the field of zeno is what
21:06
Speaker 2: patients would constitute the right patient population to go into
21:09
Speaker 2: And the team at Maryland really showed us that there's
21:12
Speaker 2: a case for compassionate use. There's a case for patients
21:14
Speaker 2: who have reached the end of the treatment options and
21:17
Speaker 2: really they're facing imminent death and we have a technology
21:20
Speaker 2: that could save their life, so shouldn't we try now. Unfortunately,
21:23
Speaker 2: you know, those gentlemen passed away within forty or fifty
21:27
Speaker 2: days post transplant. But it showed us that the regulatory
21:31
Speaker 2: agencies were open to the discussion, and we just need
21:34
Speaker 2: to define what is the right patient population in the
21:37
Speaker 2: case of kidney and so we had a discussion with
21:39
Speaker 2: the FDA back in twenty twenty two about what would
21:43
Speaker 2: be the right patient population for a formal phase one
21:45
Speaker 2: clinical study, and we'd come to agreement on patients over fifty,
21:50
Speaker 2: patients on the transplant weightlist, and patients that had failed
21:53
Speaker 2: a previous alo transplant, right, so they'd had a human
21:56
Speaker 2: kidney before, and they had it for a certain duration
21:59
Speaker 2: of time and eventually that kidney fails and you find
22:01
Speaker 2: yourself back on the transplant weightlist. And why that patient
22:04
Speaker 2: population made sense is because those patients have a very
22:07
Speaker 2: low likelihood if you're over fifty with that profile of
22:12
Speaker 2: getting a second kidney. Now, in the case of mister Slamon,
22:15
Speaker 2: are patients like him. He was also losing access to dialysis,
22:19
Speaker 2: so he had a kidney transplant in twenty eighteen. He
22:24
Speaker 2: had been on dialysis for seven years, got a kidney transplant,
22:27
Speaker 2: the kidney function for five years, and then he lost
22:30
Speaker 2: the kidney stop functioning. In twenty twenty three, Okay, he
22:34
Speaker 2: found himself back on dialysis, but he was having trouble
22:37
Speaker 2: with vascular access, so he had to go through multiple
22:40
Speaker 2: surgeries to create access so he could go on dialysis.
22:43
Speaker 1: And just to be clear, dialysis is when your kidneys
22:46
Speaker 1: don't work. There is a machine and they hook you
22:48
Speaker 1: up to the machine and it cleans your blood. It
22:50
Speaker 1: does the work of the kids.
22:51
Speaker 2: Yeah. Usually, you know, the typical schedule would be three
22:53
Speaker 2: times a week, four hours each time.
22:54
Speaker 1: Okay, And so Richard Slaman, you were saying dialysis just
22:58
Speaker 1: wasn't working for him anymore.
23:00
Speaker 2: In some patchion it was just very hard to do.
23:02
Speaker 2: It was working, but he would have to have these
23:04
Speaker 2: vascular access surgery so his blood vessels would acclude and
23:08
Speaker 2: prevent the ability to do dialysis. So we'd have to
23:10
Speaker 2: go through a relatively painful procedure to allow him to
23:13
Speaker 2: get dialysis. And I think, you know, he was and
23:16
Speaker 2: I think his neuprologist, when Williams put it really well,
23:20
Speaker 2: he was kind of losing faith, losing hope, like, huh,
23:23
Speaker 2: is this my life? Is this my future? Like, I'm
23:25
Speaker 2: just going to have to keep doing this and I
23:28
Speaker 2: have no chance of getting a transplant because he had
23:30
Speaker 2: had a transplant for five years, so he knew what
23:32
Speaker 2: that was and now he finds himself on dallasis. So,
23:36
Speaker 2: so we knew at some point mister Sliman would lose
23:39
Speaker 2: access to dialysis and without a transplant, he would he
23:42
Speaker 2: would go to hospice. And so he was a patient
23:45
Speaker 2: that we felt was a good candidate for trying. And
23:49
Speaker 2: so the team at Mass General approached mister Slaman with
23:52
Speaker 2: this idea of he could participate and be the first
23:55
Speaker 2: patient to try this, and this is what we knew,
23:58
Speaker 2: and these were the risks, and I think that's part
24:01
Speaker 2: of one of the biggest challenges, kind of articulating what
24:04
Speaker 2: we know and then articulately what we don't know and
24:06
Speaker 2: how this could go. But much to mister slam his credit, right,
24:10
Speaker 2: he was the one that raised his hand and said
24:12
Speaker 2: he would go first. And then we took it to
24:14
Speaker 2: the FDA and we laid out the case to the
24:16
Speaker 2: FDA that you know mister Slamon's story and kind of
24:20
Speaker 2: where he found himself in his treatment. What we had
24:22
Speaker 2: been doing are non human primate data, all the data
24:25
Speaker 2: on the characterization of our donors. And after a few
24:29
Speaker 2: weeks of discussion, the FDA said, we agree and you
24:32
Speaker 2: guys can try.
24:35
Speaker 1: So what is the path for you for your fore genesis?
24:39
Speaker 2: From here, we believe that there's the opportunity to treat
24:42
Speaker 2: more patients like mister Slimon. He's not unfortunately, he's not
24:46
Speaker 2: unique in this space, and there are other patients that
24:48
Speaker 2: are suffering very similar fate with continued success. Our intention
24:52
Speaker 2: is to do more of these expanded access requests and
24:56
Speaker 2: transplants while we prepare for a formal trial, right so
25:01
Speaker 2: in patients that may be facing less risk than patients
25:04
Speaker 2: like mister Slamon, patients earlier in their dialysis journey, earlier
25:08
Speaker 2: in their their kidney failure progression. But that will come,
25:12
Speaker 2: you know. Our intention is to file something like that
25:14
Speaker 2: at the end of twenty twenty five. Beyond that, you know,
25:18
Speaker 2: we are also exploring patients that are suffering from liver
25:21
Speaker 2: failure as well as heart failure. This past December, we
25:25
Speaker 2: did the longest liver perfusions on liver perfusion in a
25:30
Speaker 2: decedent patient. Ever, we did three days of continuous perfusion.
25:35
Speaker 2: The idea there is you take a patient who may
25:36
Speaker 2: be suffering from liver failure and perfuse them through a
25:40
Speaker 2: pig liver to allow their own liver to recover again.
25:44
Speaker 2: This was something that was demonstrated in the nineties to work.
25:48
Speaker 2: So they took fourteen patients with acute liver failure perfused
25:51
Speaker 2: them through pig livers. All fourteen patients improved. Seven patients
25:55
Speaker 2: were successfully bridged to transplant.
25:58
Speaker 1: So just to unpack that for a sec the pig
26:00
Speaker 1: liver is kind of like when people get put on
26:02
Speaker 1: those like external artificial hearts or something like the outside
26:05
Speaker 1: the body, and it's like or.
26:06
Speaker 2: What you know when think about kidney disease is akin
26:10
Speaker 2: to dialsis right? You hooked up to a machine. In
26:13
Speaker 2: this case, in the machine is a big.
26:14
Speaker 1: Liver, and like, is it in a box?
26:17
Speaker 2: Like yeah, yeah, So it's in a plastic container on
26:21
Speaker 2: a perfusion device.
26:22
Speaker 1: So the pig's liver is doing the work of the
26:25
Speaker 1: liver for the patient while the patient is waiting for
26:28
Speaker 1: a human donor exactly. Like, let me ask the dumb question,
26:32
Speaker 1: why not just put the pigs liver in the person.
26:35
Speaker 2: Because the incompatibilities between a pig liver and the person
26:39
Speaker 2: are still too great. OK, So we could I think
26:43
Speaker 2: we're only going to get a week or two before
26:45
Speaker 2: that gets rejected.
26:47
Speaker 1: And so similarly, does the perfusion just last for a
26:50
Speaker 1: week or two it's just like an emergency bridge.
26:52
Speaker 2: Yeah, so it's a great question, and we started out
26:55
Speaker 2: with a goal of greater than twenty four hours of perfusion.
26:58
Speaker 2: The pen study went for three days. Looking at the
27:00
Speaker 2: histology at the end of the study, we believe it
27:02
Speaker 2: can go for about a week. So we're continuing to
27:05
Speaker 2: push the duration.
27:06
Speaker 1: So that's like a that feels like much more of
27:08
Speaker 1: a kind of edge case than the kidney case.
27:11
Speaker 2: Well, this is the thing. We think there's actually much
27:13
Speaker 2: greater unmet need and liver failure than there even is
27:17
Speaker 2: in kidney failure because these patients, because there is no
27:20
Speaker 2: equivalent of dialysis, they either recover on their own, which
27:24
Speaker 2: is a little bit of like ICU time and hope,
27:27
Speaker 2: or they get transplanted. So we're hoping that we can
27:29
Speaker 2: provide liver support through a poresigne liver, we can bridge
27:33
Speaker 2: more patients to recovery.
27:34
Speaker 1: Okay, and then you're and then hearts.
27:38
Speaker 2: Yeah. So the third setting, again is inspired by the
27:40
Speaker 2: work done at Maryland, but instead of looking at adult
27:44
Speaker 2: patients where the heart has to and heart has to
27:47
Speaker 2: function continuously or the patient passes away, we're focused in
27:51
Speaker 2: the pediatric population. So children who need a heart transplant
27:55
Speaker 2: currently have poor standard of care to bridge them to
27:57
Speaker 2: human heart transplant.
27:58
Speaker 1: And so this is like typically like babies born with
28:02
Speaker 1: genetic anomalies.
28:03
Speaker 2: Yeah, typically children under two is kind of where the
28:06
Speaker 2: focus is and the current support of care. About fifty
28:09
Speaker 2: percent of these children die waiting for a human heart transplant.
28:14
Speaker 1: That is a brutal one. Is a brutal That would
28:17
Speaker 1: be a good one too, Yeah, that would be a
28:18
Speaker 1: good one to tve.
28:20
Speaker 2: And so the idea is if we can simply create
28:22
Speaker 2: one hundred to two hundred day bridge using a Poresigne heart,
28:26
Speaker 2: then at the end of that or sometime in the middle,
28:28
Speaker 2: when the human heart became available, the child would simply
28:30
Speaker 2: get the human heart. So we call that a bridging strategy.
28:34
Speaker 1: And so in that instance, is it a transplant or
28:37
Speaker 1: is it external It's a transplant.
28:38
Speaker 2: Yeah, So the intention is to do the por signed
28:42
Speaker 2: heart transplant allow the patient to go home. They can
28:45
Speaker 2: wait at home right now, they would have to wait
28:47
Speaker 2: in the hospital, but they could wait at home until
28:49
Speaker 2: the human heart becomes available.
28:51
Speaker 1: Okay, So so those are two other organs. When do
28:56
Speaker 1: you think you're going to do those?
28:58
Speaker 2: So the intention, the intention is to do all that
29:00
Speaker 2: this year, right, So, we believe we have the not
29:02
Speaker 2: what we call non clinical data or the primate data
29:05
Speaker 2: to support moving into the clinic. And I do think
29:08
Speaker 2: mister the success so far with mister Slaman's transplant is
29:10
Speaker 2: helpful because the emune of suppression that we plan to
29:13
Speaker 2: use in the pediatric heart setting is very similar to
29:17
Speaker 2: what we're using in mister Slaman's transplant. So we do
29:20
Speaker 2: think that continued success in the kidney transplant will help
29:24
Speaker 2: inform what we're going to be doing at heart.
29:27
Speaker 1: And is it the same set of genetic changes?
29:32
Speaker 2: Yeah, so it's the same genetics of the donor. So
29:35
Speaker 2: the current plan is to use the same donor for
29:37
Speaker 2: both kidney, hearts and livers.
29:41
Speaker 1: And how does how does the immune response to a
29:46
Speaker 1: pig organ compare to the immune response to an organ
29:50
Speaker 1: from another human?
29:52
Speaker 2: Yeah, it's definitely more robust.
29:55
Speaker 1: More robust meaning worse in this concept, it's.
29:57
Speaker 2: Probably going to require you know, we already are using
29:59
Speaker 2: more evenie suppression. Yeah.
30:01
Speaker 1: And is there some medium to long term future where
30:06
Speaker 1: you do more gene editing in order to make that
30:12
Speaker 1: piece of it easier, where you make the pig kidney
30:15
Speaker 1: more like a human kidney.
30:16
Speaker 2: Yeah. Absolutely. The long term vision here is to produce
30:18
Speaker 2: organs that don't require immuno suppression, party.
30:21
Speaker 1: That don't require it at.
30:22
Speaker 2: All at all. I mean, that's the ultimate that's the vision.
30:24
Speaker 1: I mean, if you could do that. Just to be clear,
30:27
Speaker 1: like that vision is a pig kidney is better than
30:30
Speaker 1: a kidney from another human.
30:32
Speaker 2: Right, I mean it sounds like you've been talking to George. Wow.
30:36
Speaker 1: I appreciate that you were skeptical. You were supposed to
30:38
Speaker 1: be high picking up and I'm supposed to be skeptical. No.
30:41
Speaker 1: But if you say, like, is that even plausible? I
30:43
Speaker 1: appreciate that you're skeptical of it. That's good.
30:45
Speaker 2: Yeah, do it might work for me. I think one
30:47
Speaker 2: of the things that transplant World has taught us over
30:49
Speaker 2: the past fifty years is things that we thought were
30:51
Speaker 2: impossible are actually now routine, right, So I think it's
30:54
Speaker 2: a matter of time, effort, and work. I think we
30:58
Speaker 2: can get there, right. I think this initial transplant into
31:01
Speaker 2: patients is a really important step because for us to
31:04
Speaker 2: be informed about what we need to do from an
31:06
Speaker 2: engineering perspective, it is very helpful to have data from
31:09
Speaker 2: humans to feedback into that loop, so we can do
31:13
Speaker 2: lots of things from an engineering perspective. The question is
31:16
Speaker 2: what to do next, and I think the results that
31:18
Speaker 2: will achieve with mister Slayman and patients like him will
31:21
Speaker 2: help inform what else we need to do to really
31:24
Speaker 2: realize this big vision, which is organs that don't require suppression.
31:28
Speaker 1: Organs that don't require suppression, is wildly ambitious, right do you?
31:33
Speaker 1: I mean it seems like, not knowing basically anything about it,
31:37
Speaker 1: it would be a kind of incremental, maybe even as symptotic, like, ah,
31:42
Speaker 1: this will get us to less, This will get us
31:44
Speaker 1: to less as opposed to some binary breakthrough. Does that
31:47
Speaker 1: seem right?
31:48
Speaker 2: Yeah? I think it's incremental. But what we're starting to
31:51
Speaker 2: see is kind of multiplex editing in a way that
31:56
Speaker 2: we couldn't even before Christper, we couldn't conceive of making
31:59
Speaker 2: fifty nine edits for GENO. Okay, now we're conceiving of
32:02
Speaker 2: how would you make a thousand edits to geno? What
32:05
Speaker 2: does that actually look like? And I think that's what's
32:07
Speaker 2: going to be required. Huh.
32:08
Speaker 1: I mean, do you get weird like structural like three
32:11
Speaker 1: D structural problems once you start doing that, like is
32:13
Speaker 1: it even gonna yes work?
32:16
Speaker 2: So there's definitely a lot to solve, right, So how
32:18
Speaker 2: do you make you know, how do you make that
32:19
Speaker 2: many changes without totally destroying the geno? We thought that
32:23
Speaker 2: originally with Crisper and the first retroviolent activation, they thought
32:27
Speaker 2: you would never be able to make that many at it.
32:28
Speaker 2: So we did that. We just have to figure out
32:30
Speaker 2: how to do it. And you know, we don't know
32:32
Speaker 2: how to do it right now, but I do think
32:35
Speaker 2: we'll figure out how to do it.
32:38
Speaker 1: We'll be back in a minute with the lightning. Let's
32:54
Speaker 1: finish with a lightning ground. I won't take much more
32:56
Speaker 1: of your time.
32:57
Speaker 2: Okay, Okay, what's one.
32:59
Speaker 1: Thing that that we don't understand about the human body
33:03
Speaker 1: that you wish we understood?
33:12
Speaker 2: I think, coming from the neuroscience world, I think we
33:15
Speaker 2: have a really poor understanding of mental health and what
33:22
Speaker 2: to do about depression, and because I think those are
33:25
Speaker 2: just paralyzing diseases that we are a long way from
33:30
Speaker 2: really understanding why they exist and actually how to effectively
33:33
Speaker 2: treat them. So if you could generalize that as brain,
33:36
Speaker 2: we still don't really understand in the way we need to,
33:40
Speaker 2: you know, how the brain actually works and what we
33:42
Speaker 2: can do to improve diseases of the brain.
33:46
Speaker 1: Well, I know you worked in pharmaceuticals for decades, right,
33:50
Speaker 1: I don't point on it, Yeah, and so you know
33:53
Speaker 1: it's a famously hard industry. Most drugs fail, right, I'm
33:57
Speaker 1: curious if you have any any tips for dealing with failure.
34:02
Speaker 2: I think you go in with the best hypothesis, you
34:04
Speaker 2: run the most efficient studies you can, and then you
34:07
Speaker 2: pick yourself up and go again, because I think you
34:10
Speaker 2: can't let failure bring you down, right, And we know
34:13
Speaker 2: we're going to fail, and often we learned a tremendous
34:15
Speaker 2: amount from those failures and we just have to build
34:18
Speaker 2: on them. The worst thing you can do is stop.
34:20
Speaker 2: I think you have to always keep going.
34:23
Speaker 1: So if you look back over the thirty years that
34:25
Speaker 1: you worked in the drug industry, I'm curious, like, if
34:27
Speaker 1: you think about when you were getting into the field.
34:30
Speaker 1: What is something that has happened since then, like a breakthrough,
34:34
Speaker 1: a change that you wouldn't have expected that's surprising to you.
34:41
Speaker 2: I think this whole field of genetic medicines, you know
34:45
Speaker 2: the fact that we're now producing potential cures for sickle cell,
34:48
Speaker 2: cures for beta thalsemia. I think those were all visions
34:52
Speaker 2: that we had, you know, fifty sixty one hundred years ago,
34:55
Speaker 2: like could we actually cure diseases that we're now literally
34:58
Speaker 2: on the shelf have cures for. And I think that
35:00
Speaker 2: no one ever thought we would get there, and here
35:02
Speaker 2: we are.
35:03
Speaker 1: So conversely, so that's the happy surprise. Is there something
35:07
Speaker 1: when you got into the field that you fought like,
35:11
Speaker 1: surely we'll figure this out, Surely this will be solved
35:14
Speaker 1: that we haven't figured out.
35:15
Speaker 2: I mean, our inability to really effectively fight viral infection is,
35:19
Speaker 2: you know, our infectious disease broadly. We really haven't evolved
35:23
Speaker 2: our armamentarium against infectious disease very much. I think there
35:27
Speaker 2: we've way under invested and focused on infectious disease. I
35:31
Speaker 2: don't think the current way we fund drug development doesn't
35:35
Speaker 2: support active work there. I think it's the one. It's
35:38
Speaker 2: a blind spot for us, and I think we saw it,
35:40
Speaker 2: you know, during COVID.
35:41
Speaker 1: Yeah, right, so.
35:45
Speaker 2: And it's still a blind spot. What's really sad is
35:46
Speaker 2: I don't think COVID. Actually, I don't think we've done
35:49
Speaker 2: much different than we were.
35:50
Speaker 3: Doing that that that hurts, but I think it's true.
35:58
Speaker 1: Mike Curtis is the CEO of E Genesis. Today's show
36:02
Speaker 1: was produced by Gabriel Hunter Chang. It was edited by
36:06
Speaker 1: Lydia jene Kott and engineered by Sarah. You can email
36:10
Speaker 1: us at problem at Pushkin dot FM. I'm Jacob Goldstein
36:14
Speaker 1: and we'll be back next week with another episode of
36:16
Speaker 1: What's Your Problem.