AI transcript
0:00:00 [MUSIC]
0:00:06 Pushkin.
0:00:06 [MUSIC]
0:00:11 >> Hey everybody, I’m Kai Rizdal, the host of Marketplace,
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0:00:37 [MUSIC]
0:00:41 Rick Slayman is 62 years old,
0:00:44 lives in a suburb of Boston, works for the State Department of Transportation.
0:00:50 And about five years ago, he got a kidney transplant.
0:00:54 Then last year, his new kidney stopped working.
0:00:58 His health declined, his prognosis was pretty bad.
0:01:02 So earlier this year, he and his doctors decided that he would be
0:01:06 the first person in the history of the world to get a kidney transplant
0:01:11 from a genetically engineered pig.
0:01:14 Surgeons did the transplant on March 16th.
0:01:18 And two weeks later, Rick Slayman walked out of the hospital.
0:01:22 It’s still too soon to say how he’ll do in the coming months.
0:01:25 But as of this recording, he’s doing well.
0:01:29 [MUSIC]
0:01:34 I’m Jacob Goldstein, and this is What’s Your Problem,
0:01:37 the show where I talk to people who are trying to make technological progress.
0:01:41 My guest today is Mike Curtis.
0:01:43 He’s the CEO of E-Genesis, the company that bred the genetically engineered
0:01:49 pig that provided the kidney for Rick Slayman.
0:01:53 Every year, thousands of people die waiting for an organ transplant that never comes.
0:01:58 And so, Mike’s problem is this.
0:02:02 Is it possible to genetically engineer pigs to provide organs,
0:02:06 kidneys, livers, hearts, for people?
0:02:10 And in the long run, is it possible to make pig organs that work even better
0:02:16 than human organs for human transplant patients?
0:02:19 [MUSIC]
0:02:22 >> So for a really long time, like hundreds of years,
0:02:26 people have had this idea of transplanting organs or skin from animals to people.
0:02:35 Like, where do you date the beginning of this idea to?
0:02:39 >> It was even predated human-to-human transplant.
0:02:42 So as soon as physicians realize that organs can fail,
0:02:46 I think the first instinct was can we get them from somewhere else, right?
0:02:50 And the early days of that went horribly, no good success.
0:02:54 So we kind of predate that to the dawn of modern medicine, and nothing worked.
0:03:00 >> And nothing worked because basically the human immune system rejected the transplants.
0:03:05 >> Right, and that was before we even knew what that was, but right, yeah, yeah.
0:03:08 >> And so to jump forward a very long way,
0:03:11 it seems like CRISPR, this ability to edit genes, is sort of a key breakthrough.
0:03:19 Is that the kind of key moment that enables this new era that seems to be beginning right now?
0:03:25 >> Absolutely, there were some challenges in the cross-species transplant
0:03:30 that were just unresolvable until the discovery of CRISPR.
0:03:32 So the one that we took on was in the ’90s,
0:03:36 it was discovered that porcine retroviruses that are endogenous in the genome,
0:03:41 so they’re kind of embedded in the pig genome, could infect human cells.
0:03:45 And in the ’90s, we were coming out of the HIV epidemic.
0:03:49 And we did not want to cause another problem.
0:03:52 So we didn’t want to have a cross-species zoonotic event.
0:03:55 So in many countries around the world, they put a moratorium on cross-species transplantation
0:04:00 because of this risk of endogenous retroviruses.
0:04:03 >> And so I just want to pause here because I didn’t know about endogenous retroviruses
0:04:10 until I started preparing for this interview.
0:04:13 And it totally blew my mind that there is such a thing, right?
0:04:16 So an endogenous retrovirus, as I understand it,
0:04:21 is not like a disease that an animal has.
0:04:26 In this case, a porcine endogenous retrovirus, obviously,
0:04:29 is an endogenous retrovirus in a pig.
0:04:31 And it doesn’t mean that the pig is sick.
0:04:33 It means that in the genome of every pig,
0:04:36 there is genetic code to code in that pig a retrovirus, right?
0:04:41 And similarly, in humans, there are other endogenous retroviruses.
0:04:45 We have in our genome the code for retroviruses.
0:04:50 >> That’s right.
0:04:51 >> Why do mammals have the code for viruses in our genomes?
0:04:56 >> Yeah, well, it’s interesting because there are some functions
0:04:59 that are ascribed to these endogenous retroviruses.
0:05:01 So they kind of co-evolve with pigs, with people,
0:05:06 and they pick up some function, right?
0:05:07 And so we don’t completely understand why they’re there, but they’re there.
0:05:12 And they pose a risk, an infectious disease risk, to patients,
0:05:19 especially when you think about patients
0:05:21 who might be under immunosuppression.
0:05:23 >> And so just to be clear, I don’t want to belabor this,
0:05:26 but it is really extraordinary coming to it new.
0:05:30 The notion is a very, very, very long time ago,
0:05:33 some pig, in this case, got infected with a virus,
0:05:38 and that virus made its way into the genome of, essentially,
0:05:42 all the pigs living today.
0:05:45 And that genetic code is not harmful to pigs.
0:05:50 But there is a fear that if you took a pig kidney, say,
0:05:54 and put it in a human being, the code for that virus,
0:05:57 which is fine in pigs, might be harmful in people.
0:06:00 >> Exactly. It’s an unknown risk.
0:06:03 >> And so in the ’90s, particularly as you said,
0:06:07 in the context of the fear of HIV,
0:06:09 people are thinking about doing, could we transplant a pig kidney
0:06:13 into a human?
0:06:14 And regulators, essentially, are saying,
0:06:17 well, one reason you cannot do it
0:06:19 is because of these endogenous retroviruses in the pig’s DNA.
0:06:23 >> Exactly. And we can’t quantify the risk.
0:06:26 And so we don’t know what will happen,
0:06:28 and we actually don’t want to know.
0:06:30 You need to come up with a way to mitigate the risk
0:06:33 of retroviral transmission from the donor to the recipient.
0:06:36 >> Okay. And so that’s just like a red light.
0:06:40 Do not pass go. Stop doing this for a while
0:06:44 once that happens in the ’90s.
0:06:45 >> Exactly. Most of the people that were investing in the space
0:06:49 stopped investing in the space.
0:06:50 The progression towards clinics stopped.
0:06:52 It really slowed the whole field down
0:06:54 because no one knew exactly how to quantify the risk
0:06:56 or then what to do about it.
0:06:58 And so any pig genome, you’ll have between 50 and 70 copies
0:07:02 of the retrovirus scattered throughout the genome.
0:07:04 And so even if you wanted to go in and remove them,
0:07:07 there was no technology available that would allow you to do that.
0:07:11 And no one knew of a way to actually actively get rid
0:07:14 of these viruses until the discovery of CRISPR.
0:07:17 >> So CRISPR comes along, what, 10-ish years ago?
0:07:21 >> About 12 years ago now. >> 12 years ago.
0:07:23 And it’s this incredible technology for editing a genome, right?
0:07:29 And people think, “Oh, maybe we could solve
0:07:34 that porousine endogenous retrovirus problem using CRISPR.”
0:07:39 >> Yeah, so this is what George Church kind of took up at Harvard.
0:07:42 Was like, “What would we use CRISPR for?”
0:07:44 And this problem was out there and George took it on and said,
0:07:47 “Well, let’s see if we can inactivate
0:07:49 all copies of the retroviruses in the pig genome.”
0:07:51 The beautiful part about CRISPR is once you give it a sequence,
0:07:55 it will edit all copies of that sequence in a given genome.
0:07:59 Now, the worry was that you would then create basically
0:08:03 Swiss cheese out of the genome, right?
0:08:05 You would create an unviable genome.
0:08:07 There’s too many edits, was the original thought.
0:08:09 But George and the team at Harvard showed that, no,
0:08:11 you could actually inactivate all copies of the retrovirus
0:08:15 and then produce a viable pig.
0:08:18 >> Right, because I suppose the other question is like,
0:08:20 even if you can cleanly make all the edits,
0:08:24 does the pig actually need this endogenous retrovirus
0:08:28 for a reason we don’t understand?
0:08:29 >> Right, and we know it does.
0:08:30 If you completely knock it out or get rid of it,
0:08:33 the pigs are not healthy.
0:08:35 So we make a relatively subtle change to the viral genome
0:08:39 that prevents the virus from replicating.
0:08:42 So with this edit, the virus can no longer replicate.
0:08:45 >> Ha, but so you don’t entirely remove the sequence
0:08:49 from the genome, you just edit the genome
0:08:53 such that this virus, once it’s expressed, cannot replicate.
0:08:57 >> Right, so essentially inactivate those endogenous viruses.
0:09:00 >> And so this idea from George Churchill
0:09:02 is one of the like giant names in genetics, right?
0:09:06 Famous scientists.
0:09:07 Was that the origin of the company?
0:09:10 >> So it came from George’s lab.
0:09:13 And one of his postdocs started eGenesis
0:09:18 by out licensing the technology from Harvard.
0:09:22 So the original idea was to start eGenesis
0:09:25 with the idea of making animals
0:09:28 that were retroviral inactivated.
0:09:30 And then also do the rest of the editing, right?
0:09:33 That made the pigs more compatible with human recipients.
0:09:36 So that’s how we got into the field.
0:09:38 And then from then we’ve built the additional editing
0:09:42 to provide organs that are more compatible
0:09:45 with first not human primates and then now with people.
0:09:47 >> So you have inactivated the endogenous retrovirus
0:09:52 in the pig.
0:09:53 This is like step one, right?
0:09:55 But at this point, if you tried to take that kidney
0:10:00 even though you’ve solved the retrovirus problem,
0:10:04 it’s still a pig kidney, right?
0:10:06 And the human body would know that and would not accept it.
0:10:10 So what do you have to do next?
0:10:12 >> Sure, and so if you just took an unedited pig kidney
0:10:15 and try to put it into a monkey
0:10:17 to a person to be rejected within minutes.
0:10:19 And that’s primarily due to what we call hyperacute rejection
0:10:23 where the humans are recognizing the carbohydrate differences
0:10:27 between pigs and humans.
0:10:28 So carbohydrates are sugars that coat all the cells
0:10:32 and humans have antibodies
0:10:34 that can recognize those pig sugars.
0:10:37 So what we do is we inactivate three genes
0:10:40 responsible for those carbohydrate differences
0:10:42 between pigs and humans.
0:10:44 Once you do that,
0:10:45 we create what we call the triple knockout.
0:10:46 So we inactivate those genes,
0:10:48 knocking out those carbohydrate differences
0:10:51 and eliminating hyperacute rejection.
0:10:54 >> And when you create a pig with those particular
0:11:00 carbohydrates eliminated, does it matter to the pig?
0:11:05 Is the pig sicker as a result?
0:11:07 >> We haven’t seen any impact on the health
0:11:11 or longevity of a pig.
0:11:12 So for instance, we have several animals in our colony
0:11:16 that are a couple of years old.
0:11:18 And so we haven’t seen any effects
0:11:20 on the longevity of those animals.
0:11:21 So no, we haven’t seen any downside.
0:11:23 >> Okay, so you’ve inactivated the endogenous retrovirus
0:11:27 and now you’ve eliminated these carbohydrates
0:11:30 that are causing acute rejection.
0:11:33 There’s like one more set of changes you’ve got to make,
0:11:35 right? >> That’s right.
0:11:36 So what the field has shown over the past 40 years
0:11:38 is that if you add human genes to the pig genome,
0:11:42 you can help regulate different areas of incompatibility.
0:11:45 So when we think about, for instance, coagulation.
0:11:48 So the coagulation factors in the pig
0:11:51 are not 100% compatible with humans.
0:11:54 So we introduce human coagulation factors into the pig.
0:11:57 >> Coagulation factors, just what causes the blood
0:12:00 to clot, basically?
0:12:00 >> Yes, or prevent the blood from clotting.
0:12:02 >> Excuse me, yeah.
0:12:03 >> Either way, both directions, yep, absolutely.
0:12:06 And then we also add regulators of complement activation.
0:12:09 The first kind of immune response
0:12:11 that you’re going to get to a graft in a transplant
0:12:14 is what we call complement activation.
0:12:16 And that leads to loss of cells, right?
0:12:18 And that leads to death of cells.
0:12:20 But by introducing human complement regulators
0:12:23 into the porcine tissue, we can slow down or quiet
0:12:27 that complement response.
0:12:28 And then we add modulators of what we call
0:12:31 the innate and adaptive immune response.
0:12:33 In total, the animal that was used
0:12:37 in Mr. Slamann’s transplant,
0:12:38 we introduced a total of seven regulatory human proteins.
0:12:42 So if you add it together,
0:12:44 it’s 59 edits to inactivate the retroviruses,
0:12:47 three edits to improve the carbohydrate compatibility,
0:12:50 and then seven edits to introduce
0:12:53 human regulatory transgreens for a total of 69 edits.
0:12:56 >> So it’s basically, the first two categories are,
0:12:59 make it less like a pig.
0:13:01 And then the third category is, make it more like a person.
0:13:04 >> Yeah, that’s a good way to think about it.
0:13:06 That’s right.
0:13:06 >> And I mean, presumably at some margin,
0:13:10 you want to make it as little like a pig
0:13:13 and as much like a person as possible,
0:13:16 but the pig still has to live to grow up and have a kidney,
0:13:21 right?
0:13:22 >> Absolutely.
0:13:24 We’ve produced animals with more transgreens
0:13:26 without any issue, but you can imagine at some point,
0:13:30 that you’ll reach a point where the pig
0:13:31 no longer can tolerate whatever the editing you’re doing.
0:13:34 We’re actually already impressed
0:13:36 that we can produce healthy, viable pigs
0:13:38 with this number of edits.
0:13:39 If you go back 10, 15 years,
0:13:41 nobody thought that you could viably do this.
0:13:44 Even in activating 59 copies of the retrovirus,
0:13:47 many felt that that was too many
0:13:49 and that in the genome would be able to handle it.
0:13:51 We can tell you that it’s not easy
0:13:53 and it’s not trivial to do it.
0:13:55 It took us a lot of time to figure out how to do it,
0:13:58 but now we’ve shown it is doable.
0:14:01 >> I’m sure that it’s not easy,
0:14:03 but I don’t know enough to understand like,
0:14:06 what’s hard about it?
0:14:07 Like, tell me a thing that you had to figure out.
0:14:11 >> Sure, so when you do that much engineering to the genome,
0:14:14 you can get aberrations in the genome
0:14:18 that prevents you from making a pig.
0:14:20 So one of the things that we do
0:14:22 is we do what’s called clonal selection.
0:14:24 So we’ll engineer thousands,
0:14:27 tens of thousands of cells
0:14:29 and then select genomes based on viability.
0:14:32 So for instance, to produce our 1784 donor,
0:14:35 we had to screen over 4,000 clones to find clones
0:14:39 that had the adequate quality of genome to then make pigs.
0:14:43 >> Huh, so let’s just talk about that for a minute,
0:14:46 like how that actually works,
0:14:48 which is the more basic question of just,
0:14:51 how does the whole thing work?
0:14:54 Like I get in a sort of abstracted space,
0:14:56 what you’re doing,
0:14:57 but like in whatever, you know, in a cell,
0:15:02 fundamentally there is a cell, right?
0:15:03 Like what are we starting with?
0:15:04 >> So we’ll take a sample of skin from an adult,
0:15:07 what we call wild type, so unedited pig.
0:15:10 It will then culture those cells, make many cells,
0:15:13 and then those are the cells that we’re going to edit.
0:15:15 So those are the cells that we take CRISPR,
0:15:17 we make the 59 edits, we make the triple knockout
0:15:19 and we make the seven trans genes.
0:15:21 In the case of the 1784 animal,
0:15:24 we did that through three sequential rounds.
0:15:26 >> So just to be clear, the 1784 animal,
0:15:28 this is like one particular pig,
0:15:30 the pig that donated the kidney that is in a person right now.
0:15:33 >> So that’s the, 1784 refers to the genetics.
0:15:36 So we make many 1784 animals,
0:15:40 but they all have the same genetics.
0:15:41 >> So it’s a particular edited genome
0:15:42 and it’s the edited genome that you have described to me.
0:15:45 >> Yeah, exactly.
0:15:46 >> Okay.
0:15:46 >> So to make that animal,
0:15:47 we actually went through three rounds of editing, right?
0:15:50 So we would make the retroviral and activation, make a pig,
0:15:54 then take those cells, edit them to make the triple knockout,
0:15:57 make a pig, then we come back and add the seven trans genes.
0:16:01 >> So it’s multiple generations.
0:16:03 You are sort of adding changes,
0:16:07 genetic mutations over successive generations.
0:16:10 >> Exactly.
0:16:11 And so- >> Why?
0:16:12 >> This allows us to select, right?
0:16:15 So there’s two restrictions.
0:16:19 The time, because we’re working with primary cells,
0:16:22 the time you have to edit them
0:16:23 before they, what we call senes,
0:16:25 so at some point those cells stop dividing.
0:16:28 You need to edit while the cells are still dividing.
0:16:30 So you have a limited number of days
0:16:32 to do the editing, right?
0:16:33 So this is why we were doing three rounds of editing,
0:16:37 because we can get the retroviral in, make a pig,
0:16:39 we can get the triple knockout, make a pig,
0:16:41 we get the seven genes and make a pig.
0:16:43 What’s really important to that whole process
0:16:45 is at the end of each editing round,
0:16:47 we then screen individual cells for the genotype, right?
0:16:52 And this is where we’ll go through in screen,
0:16:55 up to 4,000 cells to pick cells that look
0:16:58 like they have a good morphology and a good phenotype
0:17:01 for which we would then make a pig.
0:17:02 So once we do the editing,
0:17:05 we then pick individual cells that we call clones
0:17:08 and then we grow those clones out.
0:17:10 And now we have an edited porcine genome,
0:17:13 but we still don’t have a pig.
0:17:14 – So you basically have a, whatever,
0:17:16 a petri dish full of pig skin cells
0:17:19 that have the genotype that you want.
0:17:21 – Exactly.
0:17:22 And so now we need to make a pig.
0:17:23 And the technology we use to turn a single cell
0:17:25 into a pig, it’s called a somatic cell nuclear transfer.
0:17:29 It was a similar technology that was used to clone dolly,
0:17:32 where we take the nucleus of the edited cell
0:17:34 and basically transfer it into the oocyte of a pig.
0:17:39 – An egg cell, an oocyte to an egg cell.
0:17:40 And so this is now a, whatever, 30-year-old technology
0:17:45 that they used to clone a sheep with in the ’90s, basically.
0:17:48 – There’s been some obviously improvements since then,
0:17:50 but the core idea is essentially the same.
0:17:53 And then we use that cloning technology to then make pigs.
0:17:56 So we make an embryo, and then we transfer that embryo
0:17:59 into a surrogate cell.
0:18:01 And then that surrogate cell will carry the piglet to term.
0:18:04 – There’s some ethical dimension to this.
0:18:07 Like, what are the relevant ethical dimensions to you?
0:18:10 – Yeah, our focus is on preserving human health
0:18:12 and saving patients who are dying
0:18:14 on the transfer wait list.
0:18:15 And we believe that this approach is justifiable
0:18:19 with that goal in mind.
0:18:20 So every day we show up, we focus on patients
0:18:23 like Mr. Slaman.
0:18:24 And so this is a means to an end.
0:18:26 This is a means to producing organs
0:18:28 that currently don’t exist.
0:18:29 It’s to save patients who are imminently dying.
0:18:31 But they are, it’s a very bleak outlook
0:18:33 for some of these folks, right?
0:18:35 And so we view that the work that we’re doing
0:18:37 for engineering the porcine genome
0:18:38 and producing compatible organs,
0:18:40 all about realizing that mission
0:18:43 of helping these patients.
0:18:44 And we believe that that puts us
0:18:46 on a very firm, ethical ground.
0:18:47 – Still to come on the show,
0:18:52 how pig hearts might help human babies.
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0:19:44 (upbeat music)
0:19:47 – Hey everybody, I’m Kai Rizdal,
0:19:49 the host of Marketplace,
0:19:50 your daily download on the economy.
0:19:52 Money influences so much of what we do and how we live.
0:19:56 That’s why it’s essential to understand
0:19:58 how this economy works.
0:20:00 At Marketplace, we break down everything
0:20:02 from inflation and student loans to the future of AI
0:20:05 so that you can understand what it all means for you.
0:20:08 Marketplace is your secret weapon
0:20:10 for understanding this economy.
0:20:11 Listen, wherever you get your podcasts.
0:20:14 – How many pigs with this genetic sequence are there?
0:20:20 We have about 50 or so animals that are at different ages.
0:20:24 – So like, do you have a farm somewhere?
0:20:27 – So we do, we have two farms.
0:20:29 We have, they’re both out in the Midwest.
0:20:32 One is a research, more of a research farm.
0:20:34 It’s a 200 acre farm where we institute biosecurity.
0:20:37 So one of the keys here is to produce animals
0:20:40 that are free of pathogens that could pose a harm
0:20:43 to either the organs, post transplant,
0:20:45 or the patient or the recipients.
0:20:47 So that farm produces relatively clean animals,
0:20:50 but then we have what we call a clinical grade
0:20:53 or designated pathogen free facility
0:20:55 where the animals are grown inside what we call a barrier.
0:20:59 So there we control feed, water,
0:21:01 everything that comes in to try to keep pathogens out.
0:21:03 So we’re actively managing the environment
0:21:06 that those animals are raised in.
0:21:08 And on top of all of that,
0:21:10 we’re doing very robust, consistent pathogen testing.
0:21:15 So we’re constantly monitoring all the animals
0:21:18 for any potential pathogens or disease.
0:21:20 – Right, I mean, presumably some kind of like
0:21:23 jumping the species barrier transfer
0:21:26 would be one of the like nightmarishly bad outcomes, right?
0:21:30 – Yes, I mean, one of the reasons that we selected pigs
0:21:34 as the species is one, we’ve coexisted with these animals
0:21:38 for thousands of years.
0:21:39 So, and we haven’t seen that type of disease transmission.
0:21:44 And then we can edit and then we also know
0:21:46 how to grow animals at scale.
0:21:48 But yes, we’re always on the lookout.
0:21:50 And I think this is part of surveillance
0:21:51 that we’ll do for the foreseeable future
0:21:54 is on the lookout for things
0:21:55 that we aren’t paying attention for, right?
0:21:58 – So let’s talk about the first patient.
0:22:00 Let’s talk about Richard Slayman,
0:22:01 the first person ever to be walking the earth
0:22:04 with a pig kidney as far as we know, probably.
0:22:08 Why him?
0:22:11 What was it about his case that made him the right patient?
0:22:14 – Yeah, so it’s a great question.
0:22:15 And part of it was inspired by the work
0:22:18 that was done at the University of Maryland
0:22:20 in the first heart transplants, right?
0:22:22 So we refer to those as the Bennett and Fawcett transplants.
0:22:25 – The first pig heart transplants, just to be clear.
0:22:28 Which just happened, that was like a different project, right?
0:22:31 – Yeah.
0:22:32 – But it just happened the last year or so, right?
0:22:35 – The last two years, yeah, absolutely.
0:22:37 And there was always this debate in the field of Zeno
0:22:39 is what patients would constitute
0:22:40 the right patient population to go into.
0:22:43 And the team at Maryland really showed us that
0:22:45 there’s a case for compassionate use.
0:22:47 There’s a case for patients
0:22:48 who have reached the end of the treatment options.
0:22:50 And really they’re facing imminent death.
0:22:52 And we have a technology that could save their life.
0:22:54 So shouldn’t we try?
0:22:56 Now, unfortunately, those gentlemen passed away
0:22:59 within 40 or 50 days post transplant.
0:23:02 But it showed us that the regulatory agencies
0:23:05 were open to the discussion.
0:23:07 And we just need to define
0:23:08 what is the right patient population in the case of kidney?
0:23:12 And so we had a discussion with the FDA back in 2022
0:23:15 about what would be the right patient population
0:23:17 for a formal phase one clinical study.
0:23:20 And we’d come to agreement on patients over 50,
0:23:24 patients on the transplant wait list
0:23:26 and patients that had failed a previous allotransplant, right?
0:23:29 So they’d had a human kidney before
0:23:31 and they had it for a certain duration of time.
0:23:32 And eventually that kidney fails
0:23:34 and you find yourself back on the transplant wait list.
0:23:37 And why that patient population made sense
0:23:39 is because those patients have a very low likelihood
0:23:42 if you’re over 50 with that profile
0:23:45 of getting a second kidney.
0:23:47 Now, in the case of Mr. Slaminger, patients like him,
0:23:49 he was also losing access to dialysis, right?
0:23:53 So he had a kidney transplant in 2018.
0:23:56 He had been on dialysis for seven years,
0:23:59 got a kidney transplant, the kidney function for five years
0:24:03 and then he locked the kidney stop functioning in 2023.
0:24:07 He found himself back on dialysis,
0:24:09 but he was having trouble with vascular access.
0:24:12 So he had to go through multiple surgeries
0:24:14 to create access so he could go on dialysis.
0:24:17 – And just to be clear, dialysis is
0:24:19 when your kidneys don’t work,
0:24:20 there is a machine and they hook you up to the machine
0:24:22 and it cleans your blood.
0:24:23 It does the work of the kidney.
0:24:24 – Yeah, typical schedule would be three times a week,
0:24:27 four hours each time.
0:24:28 – Okay.
0:24:29 And so Richard Slaminger, you were saying dialysis
0:24:31 just wasn’t working for him anymore in some fashion?
0:24:34 – It was just very hard to do.
0:24:36 It was working,
0:24:36 but he would have to have these vascular access surgeries.
0:24:39 So his blood vessels would occlude
0:24:42 and prevent the ability to do dialysis.
0:24:43 So he’d have to go through a relatively painful procedure
0:24:46 to allow him to get dialysis.
0:24:48 And I think his nephrologist,
0:24:52 when Williams put it really well,
0:24:53 he was kind of losing faith, losing hope.
0:24:56 Like, is this my life?
0:24:58 Is this my future?
0:24:58 Like, I’m just gonna have to keep doing this.
0:25:01 And I have no chance of getting a transplant
0:25:03 because he had had a transplant for five years.
0:25:05 So he knew what that was.
0:25:07 And now he finds himself on dialysis.
0:25:09 So we knew at some point,
0:25:12 Mr. Slaminger would lose access to dialysis.
0:25:14 And without a transplant, he would go to hospice.
0:25:17 And so he was a patient that we felt
0:25:19 was a good candidate for trying.
0:25:23 And so the team at Mass General approached Mr. Slaminger
0:25:26 with this idea of he could participate
0:25:28 and be the first patient to try this.
0:25:30 And this is what we knew.
0:25:32 And these were the risks.
0:25:33 And I think that’s part of the,
0:25:35 one of the biggest challenges is kind of articulating
0:25:37 what we know and then articulate what we don’t know
0:25:39 and how this could go.
0:25:41 But much to Mr. Slaminger’s credit,
0:25:43 he was the one that raised his hand
0:25:45 and said he would go first.
0:25:46 And then we took it to the FDA
0:25:48 and we laid out the case to the FDA
0:25:51 that Mr. Slaminger’s story
0:25:53 and kind of where he found himself in his treatment,
0:25:55 what we had been doing, our non-human primate data,
0:25:58 all the data on the characterization of our donors.
0:26:01 And after a few weeks of discussion,
0:26:04 the FDA said we agree and you guys can try.
0:26:07 – So what is the path for you,
0:26:11 for your, for eGenesis from here?
0:26:13 – We believe that there’s the opportunity
0:26:16 to treat more patients like Mr. Slaminger.
0:26:18 He’s not, unfortunately, he’s not unique in this space.
0:26:21 And there are other patients
0:26:22 that are suffering very similar fate.
0:26:24 With continued success, our intention is to do more
0:26:27 of these expanded access requests and transplants.
0:26:30 While we prepare for a formal trial.
0:26:34 So in patients that may be facing less risk
0:26:37 than patients like Mr. Slaminger.
0:26:38 Patients earlier in their dialysis journey,
0:26:41 earlier in their kidney failure progression.
0:26:45 But that will come, our intention is to file something
0:26:47 like that at the end of 2025.
0:26:50 Beyond that, we are also exploring patients
0:26:54 that are suffering from liver failure
0:26:55 as well as heart failure.
0:26:57 This past December, we did the longest liver perfusion,
0:27:02 poor sign liver perfusion in a decedent patient ever.
0:27:05 We did three days of continuous perfusion.
0:27:08 The idea there is you take a patient
0:27:10 who may be suffering from liver failure
0:27:12 and perfuse them through a pig liver
0:27:15 to allow their own liver to recover.
0:27:17 Again, this was something that was demonstrated
0:27:19 in the 90s to work.
0:27:21 So they took 14 patients with acute liver failure,
0:27:24 perfused them through pig livers.
0:27:26 All 14 patients improved,
0:27:28 seven patients were successfully bridged to transplant.
0:27:31 – So just to unpack that for a sec.
0:27:33 The pig liver is kind of like when people get put on those
0:27:35 like external artificial hearts or something
0:27:37 like outside the body and it’s like,
0:27:39 or what’s, how does that work?
0:27:41 – When you think about kidney disease,
0:27:43 it’s akin to dialysis, right?
0:27:44 You hooked up to a machine.
0:27:46 In this case, in the machine is a pig liver.
0:27:48 – And like, is it in a box?
0:27:50 Like, yeah.
0:27:52 – Yeah, so it’s in a plastic container
0:27:54 on a perfusion device.
0:27:55 – So the pig’s liver is doing the work of the liver
0:27:58 for the patient while the patient is waiting
0:28:01 for a human donor?
0:28:03 – Exactly.
0:28:04 – Like, let me ask the dumb question.
0:28:05 Why not just put the pig’s liver in the person?
0:28:08 – ‘Cause the incompatibilities between a pig liver
0:28:12 and the person are still too great.
0:28:14 – Okay.
0:28:14 – So we could, I think we’re only gonna get a week or two
0:28:19 before that gets rejected.
0:28:20 – And so similarly, does the perfusion just last
0:28:23 for a week or two?
0:28:24 It’s just like an emergency bridge?
0:28:26 – Yeah, so it’s a great question.
0:28:27 And we started out with a goal
0:28:29 of greater than 24 hours of perfusion.
0:28:31 The Penn study went for three days.
0:28:33 Looking at the histology at the end of the study,
0:28:35 we believe we can go for about a week.
0:28:37 So we’re continuing to push the duration.
0:28:39 – So that’s like a, that feels like much more
0:28:42 of a kind of edge case than the kidney case.
0:28:45 – Well, this is the thing.
0:28:46 We think there’s actually a much greater unmet need
0:28:48 in liver failure than there even is in kidney failure.
0:28:51 Because these patients,
0:28:53 because there is no equivalent of dialysis,
0:28:55 they either recover on their own,
0:28:57 which is a little bit of like ICU time and hope,
0:29:00 or they get transplanted.
0:29:02 So we’re hoping that if we can provide liver support
0:29:04 through a porcine liver,
0:29:05 we can bridge more patients to recovery.
0:29:08 – Okay.
0:29:09 And then hearts.
0:29:12 – Yeah, so the third setting, again,
0:29:13 is inspired by the work done at Maryland.
0:29:16 But instead of looking at adult patients
0:29:19 where the heart has to,
0:29:20 porcine heart has to function continuously
0:29:22 or the patient passes away,
0:29:24 we’re focused in the pediatric population.
0:29:26 So children who need a heart transplant
0:29:28 currently have poor standard of care
0:29:30 to bridge them to human heart transplant.
0:29:32 – And so this is like typically like babies born
0:29:35 with genetic anomalies?
0:29:37 – Yeah, typically children under two
0:29:39 is kind of where the focus is.
0:29:41 And the current supportive care,
0:29:42 about 50% of these children die
0:29:45 waiting for a human heart transplant.
0:29:48 – That is a brutal one.
0:29:49 – It’s a brutal space.
0:29:50 – That would be a good one to solve.
0:29:53 – And so the idea is if we can simply create
0:29:55 a 100 to 200 day bridge using a porcine heart,
0:29:59 then at the end of that or sometime in the middle,
0:30:01 when the human heart became available,
0:30:03 the child would simply get the human heart.
0:30:05 So we call that a bridging strategy.
0:30:07 – And so in that instance,
0:30:09 is it a transplant or is it external?
0:30:11 – It’s a transplant, yeah.
0:30:12 So the intention is to do the porcine heart transplant,
0:30:16 allow the patient to go home.
0:30:18 They can wait at home.
0:30:19 Right now they would have to wait in the hospital,
0:30:21 but they could wait at home
0:30:22 until the human heart becomes available.
0:30:24 – Okay, so those are two other organs.
0:30:29 When do you think you’re gonna do those?
0:30:31 – So the intention is to do all of that this year, right?
0:30:34 So we believe we have what we call non-clinical data
0:30:37 or the primate data to support moving into the clinic.
0:30:40 And I do think the success so far
0:30:42 with Mr. Slayman’s transplant is helpful
0:30:45 because the immunosuppression that we plan to use
0:30:48 in the pediatric heart setting is very similar
0:30:50 to what we’re using in Mr. Slayman’s transplant.
0:30:53 So we do think that continued success
0:30:56 in the kidney transplant will help inform
0:30:59 what we’re gonna be doing in heart.
0:31:01 – And is it the same set of genetic changes?
0:31:06 – Yeah, so it’s the same genetics of the donor.
0:31:07 So the current plan is to use the same donor
0:31:10 for both kidney, heart, and livers.
0:31:14 And how does the immune response to a pig organ
0:31:19 compare to the immune response to an organ
0:31:24 from another human?
0:31:26 – Yeah, it’s definitely more robust.
0:31:28 – More robust, meaning worse in this context.
0:31:31 – It’s probably gonna require,
0:31:32 we already are using more immunosuppression.
0:31:34 – Yeah, and is there some medium to long-term future
0:31:39 where you do more gene editing
0:31:44 in order to make that piece of it easier?
0:31:47 Where you make the pig kidney more like a human kidney?
0:31:50 – Yeah, absolutely.
0:31:50 The long-term vision here is to produce organs
0:31:52 that don’t require immunosuppression.
0:31:54 – Part of that. – That don’t require it at all?
0:31:56 – At all.
0:31:56 I mean, that’s the vision.
0:31:58 – I mean, if you could do that just to be clear,
0:32:00 like that vision is a pig kidney is better
0:32:04 than a kidney from another human, right?
0:32:05 – Yes, sounds like you’ve been talking to George.
0:32:08 – Well, I appreciate that you were skeptical.
0:32:11 Wait, you were supposed to be high-pigging up
0:32:12 but I’m supposed to be skeptical.
0:32:14 No, but if you say, like, is that even plausible?
0:32:17 I appreciate that you’re skeptical of it.
0:32:18 That’s good, you’re doing my work for me.
0:32:20 – I think one of the things
0:32:21 that Transplant World has taught us
0:32:22 over the past 50 years is things that we thought
0:32:25 were impossible are actually now routine, right?
0:32:27 So I think it’s a matter of time, effort, and work.
0:32:31 I think we can get there, right?
0:32:32 I think this initial transplant into patients
0:32:36 is a really important step because for us to be informed
0:32:39 about what we need to do from an engineering perspective,
0:32:41 it is very helpful to have data from humans
0:32:44 to feed back into that loop.
0:32:45 So we can do lots of things from an engineering perspective.
0:32:49 The question is what to do next?
0:32:50 And I think the results that we’ll achieve
0:32:53 with Mr. Slayman and patients like him
0:32:55 will help inform what else we need to do
0:32:58 to really realize this big vision,
0:32:59 which is organs that don’t require suppression.
0:33:01 – Organs that don’t require suppression
0:33:03 is wildly ambitious, right?
0:33:05 – Yeah.
0:33:06 – Do you, I mean, it seems like
0:33:08 not knowing basically anything about it,
0:33:10 it would be a kind of incremental,
0:33:13 maybe even asymptotic, like this will get us to less,
0:33:17 this will get us to less,
0:33:18 as opposed to some binary breakthrough.
0:33:20 Does that seem right?
0:33:21 – Yeah, I think it’s incremental,
0:33:23 but what we’re starting to see is kind of multiplex editing
0:33:28 in a way that we couldn’t even,
0:33:31 like before CRISPR, we couldn’t conceive
0:33:32 of making 59 edits to a genome.
0:33:34 – Yeah.
0:33:35 – Okay, now we’re conceiving of,
0:33:36 how would you make 1,000 edits to a genome?
0:33:38 What does that actually look like?
0:33:39 So, and I think that’s what’s gonna be required.
0:33:41 – I mean, do you get weird like structural,
0:33:43 like 3D structural problems once you start doing that?
0:33:47 Like, is it even gonna work?
0:33:48 – Yeah, so there’s definitely a lot to solve, right?
0:33:51 So how do you make that many changes
0:33:54 without totally destroying the genome?
0:33:56 We thought that originally with CRISPR
0:33:58 and the first retroviral in activation,
0:34:00 they thought you would never be able
0:34:01 to make that many edits.
0:34:02 So we did that, we just had to figure out how to do it.
0:34:04 And we don’t know how to do it right now,
0:34:07 but I do think we’ll figure out how to do that.
0:34:10 – We’ll be back in a minute with the lightning.
0:34:14 (upbeat music)
0:34:17 – Hey everybody, I’m Kai Rizdal,
0:34:29 the host of Marketplace,
0:34:30 your daily download on the economy.
0:34:32 Money influences so much of what we do and how we live.
0:34:36 That’s why it’s essential to understand
0:34:38 how this economy works.
0:34:40 At Marketplace, we break down everything from inflation
0:34:43 and student loans to the future of AI
0:34:45 so that you can understand what it all means for you.
0:34:48 Marketplace is your secret weapon
0:34:50 for understanding this economy.
0:34:52 Listen, wherever you get your podcasts.
0:34:54 – Let’s finish with a lightning round.
0:34:59 I won’t take much more of your time.
0:35:01 – Okay.
0:35:02 – What’s one thing that we don’t understand
0:35:06 about the human body that you wish we understood?
0:35:09 – I think coming from the neuroscience world,
0:35:19 I think we have a really poor understanding of mental health
0:35:23 and what to do about depression.
0:35:28 ‘Cause I think those are just paralyzing diseases
0:35:31 that we are a long way from really understanding
0:35:35 why they exist and actually how to effectively treat them.
0:35:37 So if we could generalize that as brain,
0:35:40 we still don’t really understand in the way we need to,
0:35:44 how the brain actually works
0:35:45 and what we can do to improve diseases of the brain.
0:35:48 – Well, I know you worked in pharmaceuticals for decades,
0:35:53 right, I don’t want to put too far the point on it, yeah.
0:35:56 And so it’s a famously hard industry.
0:35:58 Most drugs fail, right?
0:36:00 I’m curious if you have any tips for dealing with failure.
0:36:05 – I think you go in with the best hypothesis.
0:36:08 You run the most efficient studies you can
0:36:11 and then you pick yourself up and go again.
0:36:13 ‘Cause I think you can’t let failure bring you down, right?
0:36:16 And we know we’re going to fail
0:36:18 and often we learn a tremendous amount from those failures
0:36:21 and we just have to build on them.
0:36:22 The worst thing you can do is stop.
0:36:24 I think you have to always keep going.
0:36:27 – So if you look back over the 30 years
0:36:28 that you worked in the drug industry,
0:36:30 I’m curious like if you think about
0:36:31 when you were getting into the field,
0:36:34 what is something that has happened since then,
0:36:36 like a breakthrough, a change that you wouldn’t have expected.
0:36:39 That’s surprising too.
0:36:41 – I think this whole field of genetic medicines,
0:36:49 the fact that we’re now producing potential cures
0:36:51 for sickle cell, cures for beta thalassemia,
0:36:54 I think those were all visions that we had 50, 60,
0:36:57 100 years ago.
0:36:58 Like could we actually cure diseases
0:37:00 that we’re now literally on the shelf have cures for?
0:37:03 And I think that no one ever thought we would get there.
0:37:05 And here we are.
0:37:06 – So conversely, so that’s the happy surprise.
0:37:09 Is there something when you got into the field
0:37:12 that you thought like surely we’ll figure this out,
0:37:16 surely this will be solved that we haven’t figured out?
0:37:19 – I mean, our inability to really effectively
0:37:21 fight viral infection is, you know,
0:37:24 or infectious disease broadly,
0:37:25 we really haven’t evolved our armamentarium
0:37:28 against infectious disease very much.
0:37:31 I think we’ve way under invested
0:37:33 and focused on infectious disease.
0:37:35 I don’t think the current way we fund drug development
0:37:38 doesn’t support active work there.
0:37:41 I think it’s the one, it’s a blind spot for us.
0:37:43 And I think we saw it, you know, during COVID.
0:37:45 – Yeah, I think so.
0:37:46 – And it’s still a blind spot.
0:37:49 What’s really sad is I don’t think COVID,
0:37:51 actually, I don’t think we’ve done much different
0:37:54 than we were doing before COVID.
0:37:55 – That is, that hurts.
0:37:57 That hurts. – I think it’s true.
0:37:59 – Mike Curtis is the CEO of eGenesis.
0:38:05 Today’s show was produced by Gabriel Hunter-Chang.
0:38:08 It was edited by Lydia Jean-Cott
0:38:10 and engineered by Sara Rue.
0:38:13 You can email us at problem@pushkin.fm.
0:38:17 I’m Jacob Goldstein and we’ll be back next week
0:38:19 with another episode of “What’s Your Problem?”
0:38:21 (upbeat music)
0:38:24 – Hey everybody, I’m Kai Rizdal,
0:38:35 the host of Marketplace, your daily download
0:38:38 on the economy.
0:38:39 Money influences so much of what we do and how we live.
0:38:42 That’s why it’s essential to understand
0:38:45 how this economy works.
0:38:46 At Marketplace, we break down everything
0:38:48 from inflation and student loans
0:38:50 to the future of AI so that you can understand
0:38:53 what it all means for you.
0:38:55 Marketplace is your secret weapon
0:38:56 for understanding this economy.
0:38:58 Listen wherever you get your podcasts.
0:39:00 (upbeat music)
0:00:06 Pushkin.
0:00:06 [MUSIC]
0:00:11 >> Hey everybody, I’m Kai Rizdal, the host of Marketplace,
0:00:13 your daily download on the economy.
0:00:16 Money influences so much of what we do and how we live.
0:00:19 That’s why it’s essential to understand how this economy works.
0:00:23 At Marketplace, we break down everything from inflation and
0:00:26 student loans to the future of AI so
0:00:29 that you can understand what it all means for you.
0:00:32 Marketplace is your secret weapon for understanding this economy.
0:00:35 Listen wherever you get your podcasts.
0:00:37 [MUSIC]
0:00:41 Rick Slayman is 62 years old,
0:00:44 lives in a suburb of Boston, works for the State Department of Transportation.
0:00:50 And about five years ago, he got a kidney transplant.
0:00:54 Then last year, his new kidney stopped working.
0:00:58 His health declined, his prognosis was pretty bad.
0:01:02 So earlier this year, he and his doctors decided that he would be
0:01:06 the first person in the history of the world to get a kidney transplant
0:01:11 from a genetically engineered pig.
0:01:14 Surgeons did the transplant on March 16th.
0:01:18 And two weeks later, Rick Slayman walked out of the hospital.
0:01:22 It’s still too soon to say how he’ll do in the coming months.
0:01:25 But as of this recording, he’s doing well.
0:01:29 [MUSIC]
0:01:34 I’m Jacob Goldstein, and this is What’s Your Problem,
0:01:37 the show where I talk to people who are trying to make technological progress.
0:01:41 My guest today is Mike Curtis.
0:01:43 He’s the CEO of E-Genesis, the company that bred the genetically engineered
0:01:49 pig that provided the kidney for Rick Slayman.
0:01:53 Every year, thousands of people die waiting for an organ transplant that never comes.
0:01:58 And so, Mike’s problem is this.
0:02:02 Is it possible to genetically engineer pigs to provide organs,
0:02:06 kidneys, livers, hearts, for people?
0:02:10 And in the long run, is it possible to make pig organs that work even better
0:02:16 than human organs for human transplant patients?
0:02:19 [MUSIC]
0:02:22 >> So for a really long time, like hundreds of years,
0:02:26 people have had this idea of transplanting organs or skin from animals to people.
0:02:35 Like, where do you date the beginning of this idea to?
0:02:39 >> It was even predated human-to-human transplant.
0:02:42 So as soon as physicians realize that organs can fail,
0:02:46 I think the first instinct was can we get them from somewhere else, right?
0:02:50 And the early days of that went horribly, no good success.
0:02:54 So we kind of predate that to the dawn of modern medicine, and nothing worked.
0:03:00 >> And nothing worked because basically the human immune system rejected the transplants.
0:03:05 >> Right, and that was before we even knew what that was, but right, yeah, yeah.
0:03:08 >> And so to jump forward a very long way,
0:03:11 it seems like CRISPR, this ability to edit genes, is sort of a key breakthrough.
0:03:19 Is that the kind of key moment that enables this new era that seems to be beginning right now?
0:03:25 >> Absolutely, there were some challenges in the cross-species transplant
0:03:30 that were just unresolvable until the discovery of CRISPR.
0:03:32 So the one that we took on was in the ’90s,
0:03:36 it was discovered that porcine retroviruses that are endogenous in the genome,
0:03:41 so they’re kind of embedded in the pig genome, could infect human cells.
0:03:45 And in the ’90s, we were coming out of the HIV epidemic.
0:03:49 And we did not want to cause another problem.
0:03:52 So we didn’t want to have a cross-species zoonotic event.
0:03:55 So in many countries around the world, they put a moratorium on cross-species transplantation
0:04:00 because of this risk of endogenous retroviruses.
0:04:03 >> And so I just want to pause here because I didn’t know about endogenous retroviruses
0:04:10 until I started preparing for this interview.
0:04:13 And it totally blew my mind that there is such a thing, right?
0:04:16 So an endogenous retrovirus, as I understand it,
0:04:21 is not like a disease that an animal has.
0:04:26 In this case, a porcine endogenous retrovirus, obviously,
0:04:29 is an endogenous retrovirus in a pig.
0:04:31 And it doesn’t mean that the pig is sick.
0:04:33 It means that in the genome of every pig,
0:04:36 there is genetic code to code in that pig a retrovirus, right?
0:04:41 And similarly, in humans, there are other endogenous retroviruses.
0:04:45 We have in our genome the code for retroviruses.
0:04:50 >> That’s right.
0:04:51 >> Why do mammals have the code for viruses in our genomes?
0:04:56 >> Yeah, well, it’s interesting because there are some functions
0:04:59 that are ascribed to these endogenous retroviruses.
0:05:01 So they kind of co-evolve with pigs, with people,
0:05:06 and they pick up some function, right?
0:05:07 And so we don’t completely understand why they’re there, but they’re there.
0:05:12 And they pose a risk, an infectious disease risk, to patients,
0:05:19 especially when you think about patients
0:05:21 who might be under immunosuppression.
0:05:23 >> And so just to be clear, I don’t want to belabor this,
0:05:26 but it is really extraordinary coming to it new.
0:05:30 The notion is a very, very, very long time ago,
0:05:33 some pig, in this case, got infected with a virus,
0:05:38 and that virus made its way into the genome of, essentially,
0:05:42 all the pigs living today.
0:05:45 And that genetic code is not harmful to pigs.
0:05:50 But there is a fear that if you took a pig kidney, say,
0:05:54 and put it in a human being, the code for that virus,
0:05:57 which is fine in pigs, might be harmful in people.
0:06:00 >> Exactly. It’s an unknown risk.
0:06:03 >> And so in the ’90s, particularly as you said,
0:06:07 in the context of the fear of HIV,
0:06:09 people are thinking about doing, could we transplant a pig kidney
0:06:13 into a human?
0:06:14 And regulators, essentially, are saying,
0:06:17 well, one reason you cannot do it
0:06:19 is because of these endogenous retroviruses in the pig’s DNA.
0:06:23 >> Exactly. And we can’t quantify the risk.
0:06:26 And so we don’t know what will happen,
0:06:28 and we actually don’t want to know.
0:06:30 You need to come up with a way to mitigate the risk
0:06:33 of retroviral transmission from the donor to the recipient.
0:06:36 >> Okay. And so that’s just like a red light.
0:06:40 Do not pass go. Stop doing this for a while
0:06:44 once that happens in the ’90s.
0:06:45 >> Exactly. Most of the people that were investing in the space
0:06:49 stopped investing in the space.
0:06:50 The progression towards clinics stopped.
0:06:52 It really slowed the whole field down
0:06:54 because no one knew exactly how to quantify the risk
0:06:56 or then what to do about it.
0:06:58 And so any pig genome, you’ll have between 50 and 70 copies
0:07:02 of the retrovirus scattered throughout the genome.
0:07:04 And so even if you wanted to go in and remove them,
0:07:07 there was no technology available that would allow you to do that.
0:07:11 And no one knew of a way to actually actively get rid
0:07:14 of these viruses until the discovery of CRISPR.
0:07:17 >> So CRISPR comes along, what, 10-ish years ago?
0:07:21 >> About 12 years ago now. >> 12 years ago.
0:07:23 And it’s this incredible technology for editing a genome, right?
0:07:29 And people think, “Oh, maybe we could solve
0:07:34 that porousine endogenous retrovirus problem using CRISPR.”
0:07:39 >> Yeah, so this is what George Church kind of took up at Harvard.
0:07:42 Was like, “What would we use CRISPR for?”
0:07:44 And this problem was out there and George took it on and said,
0:07:47 “Well, let’s see if we can inactivate
0:07:49 all copies of the retroviruses in the pig genome.”
0:07:51 The beautiful part about CRISPR is once you give it a sequence,
0:07:55 it will edit all copies of that sequence in a given genome.
0:07:59 Now, the worry was that you would then create basically
0:08:03 Swiss cheese out of the genome, right?
0:08:05 You would create an unviable genome.
0:08:07 There’s too many edits, was the original thought.
0:08:09 But George and the team at Harvard showed that, no,
0:08:11 you could actually inactivate all copies of the retrovirus
0:08:15 and then produce a viable pig.
0:08:18 >> Right, because I suppose the other question is like,
0:08:20 even if you can cleanly make all the edits,
0:08:24 does the pig actually need this endogenous retrovirus
0:08:28 for a reason we don’t understand?
0:08:29 >> Right, and we know it does.
0:08:30 If you completely knock it out or get rid of it,
0:08:33 the pigs are not healthy.
0:08:35 So we make a relatively subtle change to the viral genome
0:08:39 that prevents the virus from replicating.
0:08:42 So with this edit, the virus can no longer replicate.
0:08:45 >> Ha, but so you don’t entirely remove the sequence
0:08:49 from the genome, you just edit the genome
0:08:53 such that this virus, once it’s expressed, cannot replicate.
0:08:57 >> Right, so essentially inactivate those endogenous viruses.
0:09:00 >> And so this idea from George Churchill
0:09:02 is one of the like giant names in genetics, right?
0:09:06 Famous scientists.
0:09:07 Was that the origin of the company?
0:09:10 >> So it came from George’s lab.
0:09:13 And one of his postdocs started eGenesis
0:09:18 by out licensing the technology from Harvard.
0:09:22 So the original idea was to start eGenesis
0:09:25 with the idea of making animals
0:09:28 that were retroviral inactivated.
0:09:30 And then also do the rest of the editing, right?
0:09:33 That made the pigs more compatible with human recipients.
0:09:36 So that’s how we got into the field.
0:09:38 And then from then we’ve built the additional editing
0:09:42 to provide organs that are more compatible
0:09:45 with first not human primates and then now with people.
0:09:47 >> So you have inactivated the endogenous retrovirus
0:09:52 in the pig.
0:09:53 This is like step one, right?
0:09:55 But at this point, if you tried to take that kidney
0:10:00 even though you’ve solved the retrovirus problem,
0:10:04 it’s still a pig kidney, right?
0:10:06 And the human body would know that and would not accept it.
0:10:10 So what do you have to do next?
0:10:12 >> Sure, and so if you just took an unedited pig kidney
0:10:15 and try to put it into a monkey
0:10:17 to a person to be rejected within minutes.
0:10:19 And that’s primarily due to what we call hyperacute rejection
0:10:23 where the humans are recognizing the carbohydrate differences
0:10:27 between pigs and humans.
0:10:28 So carbohydrates are sugars that coat all the cells
0:10:32 and humans have antibodies
0:10:34 that can recognize those pig sugars.
0:10:37 So what we do is we inactivate three genes
0:10:40 responsible for those carbohydrate differences
0:10:42 between pigs and humans.
0:10:44 Once you do that,
0:10:45 we create what we call the triple knockout.
0:10:46 So we inactivate those genes,
0:10:48 knocking out those carbohydrate differences
0:10:51 and eliminating hyperacute rejection.
0:10:54 >> And when you create a pig with those particular
0:11:00 carbohydrates eliminated, does it matter to the pig?
0:11:05 Is the pig sicker as a result?
0:11:07 >> We haven’t seen any impact on the health
0:11:11 or longevity of a pig.
0:11:12 So for instance, we have several animals in our colony
0:11:16 that are a couple of years old.
0:11:18 And so we haven’t seen any effects
0:11:20 on the longevity of those animals.
0:11:21 So no, we haven’t seen any downside.
0:11:23 >> Okay, so you’ve inactivated the endogenous retrovirus
0:11:27 and now you’ve eliminated these carbohydrates
0:11:30 that are causing acute rejection.
0:11:33 There’s like one more set of changes you’ve got to make,
0:11:35 right? >> That’s right.
0:11:36 So what the field has shown over the past 40 years
0:11:38 is that if you add human genes to the pig genome,
0:11:42 you can help regulate different areas of incompatibility.
0:11:45 So when we think about, for instance, coagulation.
0:11:48 So the coagulation factors in the pig
0:11:51 are not 100% compatible with humans.
0:11:54 So we introduce human coagulation factors into the pig.
0:11:57 >> Coagulation factors, just what causes the blood
0:12:00 to clot, basically?
0:12:00 >> Yes, or prevent the blood from clotting.
0:12:02 >> Excuse me, yeah.
0:12:03 >> Either way, both directions, yep, absolutely.
0:12:06 And then we also add regulators of complement activation.
0:12:09 The first kind of immune response
0:12:11 that you’re going to get to a graft in a transplant
0:12:14 is what we call complement activation.
0:12:16 And that leads to loss of cells, right?
0:12:18 And that leads to death of cells.
0:12:20 But by introducing human complement regulators
0:12:23 into the porcine tissue, we can slow down or quiet
0:12:27 that complement response.
0:12:28 And then we add modulators of what we call
0:12:31 the innate and adaptive immune response.
0:12:33 In total, the animal that was used
0:12:37 in Mr. Slamann’s transplant,
0:12:38 we introduced a total of seven regulatory human proteins.
0:12:42 So if you add it together,
0:12:44 it’s 59 edits to inactivate the retroviruses,
0:12:47 three edits to improve the carbohydrate compatibility,
0:12:50 and then seven edits to introduce
0:12:53 human regulatory transgreens for a total of 69 edits.
0:12:56 >> So it’s basically, the first two categories are,
0:12:59 make it less like a pig.
0:13:01 And then the third category is, make it more like a person.
0:13:04 >> Yeah, that’s a good way to think about it.
0:13:06 That’s right.
0:13:06 >> And I mean, presumably at some margin,
0:13:10 you want to make it as little like a pig
0:13:13 and as much like a person as possible,
0:13:16 but the pig still has to live to grow up and have a kidney,
0:13:21 right?
0:13:22 >> Absolutely.
0:13:24 We’ve produced animals with more transgreens
0:13:26 without any issue, but you can imagine at some point,
0:13:30 that you’ll reach a point where the pig
0:13:31 no longer can tolerate whatever the editing you’re doing.
0:13:34 We’re actually already impressed
0:13:36 that we can produce healthy, viable pigs
0:13:38 with this number of edits.
0:13:39 If you go back 10, 15 years,
0:13:41 nobody thought that you could viably do this.
0:13:44 Even in activating 59 copies of the retrovirus,
0:13:47 many felt that that was too many
0:13:49 and that in the genome would be able to handle it.
0:13:51 We can tell you that it’s not easy
0:13:53 and it’s not trivial to do it.
0:13:55 It took us a lot of time to figure out how to do it,
0:13:58 but now we’ve shown it is doable.
0:14:01 >> I’m sure that it’s not easy,
0:14:03 but I don’t know enough to understand like,
0:14:06 what’s hard about it?
0:14:07 Like, tell me a thing that you had to figure out.
0:14:11 >> Sure, so when you do that much engineering to the genome,
0:14:14 you can get aberrations in the genome
0:14:18 that prevents you from making a pig.
0:14:20 So one of the things that we do
0:14:22 is we do what’s called clonal selection.
0:14:24 So we’ll engineer thousands,
0:14:27 tens of thousands of cells
0:14:29 and then select genomes based on viability.
0:14:32 So for instance, to produce our 1784 donor,
0:14:35 we had to screen over 4,000 clones to find clones
0:14:39 that had the adequate quality of genome to then make pigs.
0:14:43 >> Huh, so let’s just talk about that for a minute,
0:14:46 like how that actually works,
0:14:48 which is the more basic question of just,
0:14:51 how does the whole thing work?
0:14:54 Like I get in a sort of abstracted space,
0:14:56 what you’re doing,
0:14:57 but like in whatever, you know, in a cell,
0:15:02 fundamentally there is a cell, right?
0:15:03 Like what are we starting with?
0:15:04 >> So we’ll take a sample of skin from an adult,
0:15:07 what we call wild type, so unedited pig.
0:15:10 It will then culture those cells, make many cells,
0:15:13 and then those are the cells that we’re going to edit.
0:15:15 So those are the cells that we take CRISPR,
0:15:17 we make the 59 edits, we make the triple knockout
0:15:19 and we make the seven trans genes.
0:15:21 In the case of the 1784 animal,
0:15:24 we did that through three sequential rounds.
0:15:26 >> So just to be clear, the 1784 animal,
0:15:28 this is like one particular pig,
0:15:30 the pig that donated the kidney that is in a person right now.
0:15:33 >> So that’s the, 1784 refers to the genetics.
0:15:36 So we make many 1784 animals,
0:15:40 but they all have the same genetics.
0:15:41 >> So it’s a particular edited genome
0:15:42 and it’s the edited genome that you have described to me.
0:15:45 >> Yeah, exactly.
0:15:46 >> Okay.
0:15:46 >> So to make that animal,
0:15:47 we actually went through three rounds of editing, right?
0:15:50 So we would make the retroviral and activation, make a pig,
0:15:54 then take those cells, edit them to make the triple knockout,
0:15:57 make a pig, then we come back and add the seven trans genes.
0:16:01 >> So it’s multiple generations.
0:16:03 You are sort of adding changes,
0:16:07 genetic mutations over successive generations.
0:16:10 >> Exactly.
0:16:11 And so- >> Why?
0:16:12 >> This allows us to select, right?
0:16:15 So there’s two restrictions.
0:16:19 The time, because we’re working with primary cells,
0:16:22 the time you have to edit them
0:16:23 before they, what we call senes,
0:16:25 so at some point those cells stop dividing.
0:16:28 You need to edit while the cells are still dividing.
0:16:30 So you have a limited number of days
0:16:32 to do the editing, right?
0:16:33 So this is why we were doing three rounds of editing,
0:16:37 because we can get the retroviral in, make a pig,
0:16:39 we can get the triple knockout, make a pig,
0:16:41 we get the seven genes and make a pig.
0:16:43 What’s really important to that whole process
0:16:45 is at the end of each editing round,
0:16:47 we then screen individual cells for the genotype, right?
0:16:52 And this is where we’ll go through in screen,
0:16:55 up to 4,000 cells to pick cells that look
0:16:58 like they have a good morphology and a good phenotype
0:17:01 for which we would then make a pig.
0:17:02 So once we do the editing,
0:17:05 we then pick individual cells that we call clones
0:17:08 and then we grow those clones out.
0:17:10 And now we have an edited porcine genome,
0:17:13 but we still don’t have a pig.
0:17:14 – So you basically have a, whatever,
0:17:16 a petri dish full of pig skin cells
0:17:19 that have the genotype that you want.
0:17:21 – Exactly.
0:17:22 And so now we need to make a pig.
0:17:23 And the technology we use to turn a single cell
0:17:25 into a pig, it’s called a somatic cell nuclear transfer.
0:17:29 It was a similar technology that was used to clone dolly,
0:17:32 where we take the nucleus of the edited cell
0:17:34 and basically transfer it into the oocyte of a pig.
0:17:39 – An egg cell, an oocyte to an egg cell.
0:17:40 And so this is now a, whatever, 30-year-old technology
0:17:45 that they used to clone a sheep with in the ’90s, basically.
0:17:48 – There’s been some obviously improvements since then,
0:17:50 but the core idea is essentially the same.
0:17:53 And then we use that cloning technology to then make pigs.
0:17:56 So we make an embryo, and then we transfer that embryo
0:17:59 into a surrogate cell.
0:18:01 And then that surrogate cell will carry the piglet to term.
0:18:04 – There’s some ethical dimension to this.
0:18:07 Like, what are the relevant ethical dimensions to you?
0:18:10 – Yeah, our focus is on preserving human health
0:18:12 and saving patients who are dying
0:18:14 on the transfer wait list.
0:18:15 And we believe that this approach is justifiable
0:18:19 with that goal in mind.
0:18:20 So every day we show up, we focus on patients
0:18:23 like Mr. Slaman.
0:18:24 And so this is a means to an end.
0:18:26 This is a means to producing organs
0:18:28 that currently don’t exist.
0:18:29 It’s to save patients who are imminently dying.
0:18:31 But they are, it’s a very bleak outlook
0:18:33 for some of these folks, right?
0:18:35 And so we view that the work that we’re doing
0:18:37 for engineering the porcine genome
0:18:38 and producing compatible organs,
0:18:40 all about realizing that mission
0:18:43 of helping these patients.
0:18:44 And we believe that that puts us
0:18:46 on a very firm, ethical ground.
0:18:47 – Still to come on the show,
0:18:52 how pig hearts might help human babies.
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0:20:14 – How many pigs with this genetic sequence are there?
0:20:20 We have about 50 or so animals that are at different ages.
0:20:24 – So like, do you have a farm somewhere?
0:20:27 – So we do, we have two farms.
0:20:29 We have, they’re both out in the Midwest.
0:20:32 One is a research, more of a research farm.
0:20:34 It’s a 200 acre farm where we institute biosecurity.
0:20:37 So one of the keys here is to produce animals
0:20:40 that are free of pathogens that could pose a harm
0:20:43 to either the organs, post transplant,
0:20:45 or the patient or the recipients.
0:20:47 So that farm produces relatively clean animals,
0:20:50 but then we have what we call a clinical grade
0:20:53 or designated pathogen free facility
0:20:55 where the animals are grown inside what we call a barrier.
0:20:59 So there we control feed, water,
0:21:01 everything that comes in to try to keep pathogens out.
0:21:03 So we’re actively managing the environment
0:21:06 that those animals are raised in.
0:21:08 And on top of all of that,
0:21:10 we’re doing very robust, consistent pathogen testing.
0:21:15 So we’re constantly monitoring all the animals
0:21:18 for any potential pathogens or disease.
0:21:20 – Right, I mean, presumably some kind of like
0:21:23 jumping the species barrier transfer
0:21:26 would be one of the like nightmarishly bad outcomes, right?
0:21:30 – Yes, I mean, one of the reasons that we selected pigs
0:21:34 as the species is one, we’ve coexisted with these animals
0:21:38 for thousands of years.
0:21:39 So, and we haven’t seen that type of disease transmission.
0:21:44 And then we can edit and then we also know
0:21:46 how to grow animals at scale.
0:21:48 But yes, we’re always on the lookout.
0:21:50 And I think this is part of surveillance
0:21:51 that we’ll do for the foreseeable future
0:21:54 is on the lookout for things
0:21:55 that we aren’t paying attention for, right?
0:21:58 – So let’s talk about the first patient.
0:22:00 Let’s talk about Richard Slayman,
0:22:01 the first person ever to be walking the earth
0:22:04 with a pig kidney as far as we know, probably.
0:22:08 Why him?
0:22:11 What was it about his case that made him the right patient?
0:22:14 – Yeah, so it’s a great question.
0:22:15 And part of it was inspired by the work
0:22:18 that was done at the University of Maryland
0:22:20 in the first heart transplants, right?
0:22:22 So we refer to those as the Bennett and Fawcett transplants.
0:22:25 – The first pig heart transplants, just to be clear.
0:22:28 Which just happened, that was like a different project, right?
0:22:31 – Yeah.
0:22:32 – But it just happened the last year or so, right?
0:22:35 – The last two years, yeah, absolutely.
0:22:37 And there was always this debate in the field of Zeno
0:22:39 is what patients would constitute
0:22:40 the right patient population to go into.
0:22:43 And the team at Maryland really showed us that
0:22:45 there’s a case for compassionate use.
0:22:47 There’s a case for patients
0:22:48 who have reached the end of the treatment options.
0:22:50 And really they’re facing imminent death.
0:22:52 And we have a technology that could save their life.
0:22:54 So shouldn’t we try?
0:22:56 Now, unfortunately, those gentlemen passed away
0:22:59 within 40 or 50 days post transplant.
0:23:02 But it showed us that the regulatory agencies
0:23:05 were open to the discussion.
0:23:07 And we just need to define
0:23:08 what is the right patient population in the case of kidney?
0:23:12 And so we had a discussion with the FDA back in 2022
0:23:15 about what would be the right patient population
0:23:17 for a formal phase one clinical study.
0:23:20 And we’d come to agreement on patients over 50,
0:23:24 patients on the transplant wait list
0:23:26 and patients that had failed a previous allotransplant, right?
0:23:29 So they’d had a human kidney before
0:23:31 and they had it for a certain duration of time.
0:23:32 And eventually that kidney fails
0:23:34 and you find yourself back on the transplant wait list.
0:23:37 And why that patient population made sense
0:23:39 is because those patients have a very low likelihood
0:23:42 if you’re over 50 with that profile
0:23:45 of getting a second kidney.
0:23:47 Now, in the case of Mr. Slaminger, patients like him,
0:23:49 he was also losing access to dialysis, right?
0:23:53 So he had a kidney transplant in 2018.
0:23:56 He had been on dialysis for seven years,
0:23:59 got a kidney transplant, the kidney function for five years
0:24:03 and then he locked the kidney stop functioning in 2023.
0:24:07 He found himself back on dialysis,
0:24:09 but he was having trouble with vascular access.
0:24:12 So he had to go through multiple surgeries
0:24:14 to create access so he could go on dialysis.
0:24:17 – And just to be clear, dialysis is
0:24:19 when your kidneys don’t work,
0:24:20 there is a machine and they hook you up to the machine
0:24:22 and it cleans your blood.
0:24:23 It does the work of the kidney.
0:24:24 – Yeah, typical schedule would be three times a week,
0:24:27 four hours each time.
0:24:28 – Okay.
0:24:29 And so Richard Slaminger, you were saying dialysis
0:24:31 just wasn’t working for him anymore in some fashion?
0:24:34 – It was just very hard to do.
0:24:36 It was working,
0:24:36 but he would have to have these vascular access surgeries.
0:24:39 So his blood vessels would occlude
0:24:42 and prevent the ability to do dialysis.
0:24:43 So he’d have to go through a relatively painful procedure
0:24:46 to allow him to get dialysis.
0:24:48 And I think his nephrologist,
0:24:52 when Williams put it really well,
0:24:53 he was kind of losing faith, losing hope.
0:24:56 Like, is this my life?
0:24:58 Is this my future?
0:24:58 Like, I’m just gonna have to keep doing this.
0:25:01 And I have no chance of getting a transplant
0:25:03 because he had had a transplant for five years.
0:25:05 So he knew what that was.
0:25:07 And now he finds himself on dialysis.
0:25:09 So we knew at some point,
0:25:12 Mr. Slaminger would lose access to dialysis.
0:25:14 And without a transplant, he would go to hospice.
0:25:17 And so he was a patient that we felt
0:25:19 was a good candidate for trying.
0:25:23 And so the team at Mass General approached Mr. Slaminger
0:25:26 with this idea of he could participate
0:25:28 and be the first patient to try this.
0:25:30 And this is what we knew.
0:25:32 And these were the risks.
0:25:33 And I think that’s part of the,
0:25:35 one of the biggest challenges is kind of articulating
0:25:37 what we know and then articulate what we don’t know
0:25:39 and how this could go.
0:25:41 But much to Mr. Slaminger’s credit,
0:25:43 he was the one that raised his hand
0:25:45 and said he would go first.
0:25:46 And then we took it to the FDA
0:25:48 and we laid out the case to the FDA
0:25:51 that Mr. Slaminger’s story
0:25:53 and kind of where he found himself in his treatment,
0:25:55 what we had been doing, our non-human primate data,
0:25:58 all the data on the characterization of our donors.
0:26:01 And after a few weeks of discussion,
0:26:04 the FDA said we agree and you guys can try.
0:26:07 – So what is the path for you,
0:26:11 for your, for eGenesis from here?
0:26:13 – We believe that there’s the opportunity
0:26:16 to treat more patients like Mr. Slaminger.
0:26:18 He’s not, unfortunately, he’s not unique in this space.
0:26:21 And there are other patients
0:26:22 that are suffering very similar fate.
0:26:24 With continued success, our intention is to do more
0:26:27 of these expanded access requests and transplants.
0:26:30 While we prepare for a formal trial.
0:26:34 So in patients that may be facing less risk
0:26:37 than patients like Mr. Slaminger.
0:26:38 Patients earlier in their dialysis journey,
0:26:41 earlier in their kidney failure progression.
0:26:45 But that will come, our intention is to file something
0:26:47 like that at the end of 2025.
0:26:50 Beyond that, we are also exploring patients
0:26:54 that are suffering from liver failure
0:26:55 as well as heart failure.
0:26:57 This past December, we did the longest liver perfusion,
0:27:02 poor sign liver perfusion in a decedent patient ever.
0:27:05 We did three days of continuous perfusion.
0:27:08 The idea there is you take a patient
0:27:10 who may be suffering from liver failure
0:27:12 and perfuse them through a pig liver
0:27:15 to allow their own liver to recover.
0:27:17 Again, this was something that was demonstrated
0:27:19 in the 90s to work.
0:27:21 So they took 14 patients with acute liver failure,
0:27:24 perfused them through pig livers.
0:27:26 All 14 patients improved,
0:27:28 seven patients were successfully bridged to transplant.
0:27:31 – So just to unpack that for a sec.
0:27:33 The pig liver is kind of like when people get put on those
0:27:35 like external artificial hearts or something
0:27:37 like outside the body and it’s like,
0:27:39 or what’s, how does that work?
0:27:41 – When you think about kidney disease,
0:27:43 it’s akin to dialysis, right?
0:27:44 You hooked up to a machine.
0:27:46 In this case, in the machine is a pig liver.
0:27:48 – And like, is it in a box?
0:27:50 Like, yeah.
0:27:52 – Yeah, so it’s in a plastic container
0:27:54 on a perfusion device.
0:27:55 – So the pig’s liver is doing the work of the liver
0:27:58 for the patient while the patient is waiting
0:28:01 for a human donor?
0:28:03 – Exactly.
0:28:04 – Like, let me ask the dumb question.
0:28:05 Why not just put the pig’s liver in the person?
0:28:08 – ‘Cause the incompatibilities between a pig liver
0:28:12 and the person are still too great.
0:28:14 – Okay.
0:28:14 – So we could, I think we’re only gonna get a week or two
0:28:19 before that gets rejected.
0:28:20 – And so similarly, does the perfusion just last
0:28:23 for a week or two?
0:28:24 It’s just like an emergency bridge?
0:28:26 – Yeah, so it’s a great question.
0:28:27 And we started out with a goal
0:28:29 of greater than 24 hours of perfusion.
0:28:31 The Penn study went for three days.
0:28:33 Looking at the histology at the end of the study,
0:28:35 we believe we can go for about a week.
0:28:37 So we’re continuing to push the duration.
0:28:39 – So that’s like a, that feels like much more
0:28:42 of a kind of edge case than the kidney case.
0:28:45 – Well, this is the thing.
0:28:46 We think there’s actually a much greater unmet need
0:28:48 in liver failure than there even is in kidney failure.
0:28:51 Because these patients,
0:28:53 because there is no equivalent of dialysis,
0:28:55 they either recover on their own,
0:28:57 which is a little bit of like ICU time and hope,
0:29:00 or they get transplanted.
0:29:02 So we’re hoping that if we can provide liver support
0:29:04 through a porcine liver,
0:29:05 we can bridge more patients to recovery.
0:29:08 – Okay.
0:29:09 And then hearts.
0:29:12 – Yeah, so the third setting, again,
0:29:13 is inspired by the work done at Maryland.
0:29:16 But instead of looking at adult patients
0:29:19 where the heart has to,
0:29:20 porcine heart has to function continuously
0:29:22 or the patient passes away,
0:29:24 we’re focused in the pediatric population.
0:29:26 So children who need a heart transplant
0:29:28 currently have poor standard of care
0:29:30 to bridge them to human heart transplant.
0:29:32 – And so this is like typically like babies born
0:29:35 with genetic anomalies?
0:29:37 – Yeah, typically children under two
0:29:39 is kind of where the focus is.
0:29:41 And the current supportive care,
0:29:42 about 50% of these children die
0:29:45 waiting for a human heart transplant.
0:29:48 – That is a brutal one.
0:29:49 – It’s a brutal space.
0:29:50 – That would be a good one to solve.
0:29:53 – And so the idea is if we can simply create
0:29:55 a 100 to 200 day bridge using a porcine heart,
0:29:59 then at the end of that or sometime in the middle,
0:30:01 when the human heart became available,
0:30:03 the child would simply get the human heart.
0:30:05 So we call that a bridging strategy.
0:30:07 – And so in that instance,
0:30:09 is it a transplant or is it external?
0:30:11 – It’s a transplant, yeah.
0:30:12 So the intention is to do the porcine heart transplant,
0:30:16 allow the patient to go home.
0:30:18 They can wait at home.
0:30:19 Right now they would have to wait in the hospital,
0:30:21 but they could wait at home
0:30:22 until the human heart becomes available.
0:30:24 – Okay, so those are two other organs.
0:30:29 When do you think you’re gonna do those?
0:30:31 – So the intention is to do all of that this year, right?
0:30:34 So we believe we have what we call non-clinical data
0:30:37 or the primate data to support moving into the clinic.
0:30:40 And I do think the success so far
0:30:42 with Mr. Slayman’s transplant is helpful
0:30:45 because the immunosuppression that we plan to use
0:30:48 in the pediatric heart setting is very similar
0:30:50 to what we’re using in Mr. Slayman’s transplant.
0:30:53 So we do think that continued success
0:30:56 in the kidney transplant will help inform
0:30:59 what we’re gonna be doing in heart.
0:31:01 – And is it the same set of genetic changes?
0:31:06 – Yeah, so it’s the same genetics of the donor.
0:31:07 So the current plan is to use the same donor
0:31:10 for both kidney, heart, and livers.
0:31:14 And how does the immune response to a pig organ
0:31:19 compare to the immune response to an organ
0:31:24 from another human?
0:31:26 – Yeah, it’s definitely more robust.
0:31:28 – More robust, meaning worse in this context.
0:31:31 – It’s probably gonna require,
0:31:32 we already are using more immunosuppression.
0:31:34 – Yeah, and is there some medium to long-term future
0:31:39 where you do more gene editing
0:31:44 in order to make that piece of it easier?
0:31:47 Where you make the pig kidney more like a human kidney?
0:31:50 – Yeah, absolutely.
0:31:50 The long-term vision here is to produce organs
0:31:52 that don’t require immunosuppression.
0:31:54 – Part of that. – That don’t require it at all?
0:31:56 – At all.
0:31:56 I mean, that’s the vision.
0:31:58 – I mean, if you could do that just to be clear,
0:32:00 like that vision is a pig kidney is better
0:32:04 than a kidney from another human, right?
0:32:05 – Yes, sounds like you’ve been talking to George.
0:32:08 – Well, I appreciate that you were skeptical.
0:32:11 Wait, you were supposed to be high-pigging up
0:32:12 but I’m supposed to be skeptical.
0:32:14 No, but if you say, like, is that even plausible?
0:32:17 I appreciate that you’re skeptical of it.
0:32:18 That’s good, you’re doing my work for me.
0:32:20 – I think one of the things
0:32:21 that Transplant World has taught us
0:32:22 over the past 50 years is things that we thought
0:32:25 were impossible are actually now routine, right?
0:32:27 So I think it’s a matter of time, effort, and work.
0:32:31 I think we can get there, right?
0:32:32 I think this initial transplant into patients
0:32:36 is a really important step because for us to be informed
0:32:39 about what we need to do from an engineering perspective,
0:32:41 it is very helpful to have data from humans
0:32:44 to feed back into that loop.
0:32:45 So we can do lots of things from an engineering perspective.
0:32:49 The question is what to do next?
0:32:50 And I think the results that we’ll achieve
0:32:53 with Mr. Slayman and patients like him
0:32:55 will help inform what else we need to do
0:32:58 to really realize this big vision,
0:32:59 which is organs that don’t require suppression.
0:33:01 – Organs that don’t require suppression
0:33:03 is wildly ambitious, right?
0:33:05 – Yeah.
0:33:06 – Do you, I mean, it seems like
0:33:08 not knowing basically anything about it,
0:33:10 it would be a kind of incremental,
0:33:13 maybe even asymptotic, like this will get us to less,
0:33:17 this will get us to less,
0:33:18 as opposed to some binary breakthrough.
0:33:20 Does that seem right?
0:33:21 – Yeah, I think it’s incremental,
0:33:23 but what we’re starting to see is kind of multiplex editing
0:33:28 in a way that we couldn’t even,
0:33:31 like before CRISPR, we couldn’t conceive
0:33:32 of making 59 edits to a genome.
0:33:34 – Yeah.
0:33:35 – Okay, now we’re conceiving of,
0:33:36 how would you make 1,000 edits to a genome?
0:33:38 What does that actually look like?
0:33:39 So, and I think that’s what’s gonna be required.
0:33:41 – I mean, do you get weird like structural,
0:33:43 like 3D structural problems once you start doing that?
0:33:47 Like, is it even gonna work?
0:33:48 – Yeah, so there’s definitely a lot to solve, right?
0:33:51 So how do you make that many changes
0:33:54 without totally destroying the genome?
0:33:56 We thought that originally with CRISPR
0:33:58 and the first retroviral in activation,
0:34:00 they thought you would never be able
0:34:01 to make that many edits.
0:34:02 So we did that, we just had to figure out how to do it.
0:34:04 And we don’t know how to do it right now,
0:34:07 but I do think we’ll figure out how to do that.
0:34:10 – We’ll be back in a minute with the lightning.
0:34:14 (upbeat music)
0:34:17 – Hey everybody, I’m Kai Rizdal,
0:34:29 the host of Marketplace,
0:34:30 your daily download on the economy.
0:34:32 Money influences so much of what we do and how we live.
0:34:36 That’s why it’s essential to understand
0:34:38 how this economy works.
0:34:40 At Marketplace, we break down everything from inflation
0:34:43 and student loans to the future of AI
0:34:45 so that you can understand what it all means for you.
0:34:48 Marketplace is your secret weapon
0:34:50 for understanding this economy.
0:34:52 Listen, wherever you get your podcasts.
0:34:54 – Let’s finish with a lightning round.
0:34:59 I won’t take much more of your time.
0:35:01 – Okay.
0:35:02 – What’s one thing that we don’t understand
0:35:06 about the human body that you wish we understood?
0:35:09 – I think coming from the neuroscience world,
0:35:19 I think we have a really poor understanding of mental health
0:35:23 and what to do about depression.
0:35:28 ‘Cause I think those are just paralyzing diseases
0:35:31 that we are a long way from really understanding
0:35:35 why they exist and actually how to effectively treat them.
0:35:37 So if we could generalize that as brain,
0:35:40 we still don’t really understand in the way we need to,
0:35:44 how the brain actually works
0:35:45 and what we can do to improve diseases of the brain.
0:35:48 – Well, I know you worked in pharmaceuticals for decades,
0:35:53 right, I don’t want to put too far the point on it, yeah.
0:35:56 And so it’s a famously hard industry.
0:35:58 Most drugs fail, right?
0:36:00 I’m curious if you have any tips for dealing with failure.
0:36:05 – I think you go in with the best hypothesis.
0:36:08 You run the most efficient studies you can
0:36:11 and then you pick yourself up and go again.
0:36:13 ‘Cause I think you can’t let failure bring you down, right?
0:36:16 And we know we’re going to fail
0:36:18 and often we learn a tremendous amount from those failures
0:36:21 and we just have to build on them.
0:36:22 The worst thing you can do is stop.
0:36:24 I think you have to always keep going.
0:36:27 – So if you look back over the 30 years
0:36:28 that you worked in the drug industry,
0:36:30 I’m curious like if you think about
0:36:31 when you were getting into the field,
0:36:34 what is something that has happened since then,
0:36:36 like a breakthrough, a change that you wouldn’t have expected.
0:36:39 That’s surprising too.
0:36:41 – I think this whole field of genetic medicines,
0:36:49 the fact that we’re now producing potential cures
0:36:51 for sickle cell, cures for beta thalassemia,
0:36:54 I think those were all visions that we had 50, 60,
0:36:57 100 years ago.
0:36:58 Like could we actually cure diseases
0:37:00 that we’re now literally on the shelf have cures for?
0:37:03 And I think that no one ever thought we would get there.
0:37:05 And here we are.
0:37:06 – So conversely, so that’s the happy surprise.
0:37:09 Is there something when you got into the field
0:37:12 that you thought like surely we’ll figure this out,
0:37:16 surely this will be solved that we haven’t figured out?
0:37:19 – I mean, our inability to really effectively
0:37:21 fight viral infection is, you know,
0:37:24 or infectious disease broadly,
0:37:25 we really haven’t evolved our armamentarium
0:37:28 against infectious disease very much.
0:37:31 I think we’ve way under invested
0:37:33 and focused on infectious disease.
0:37:35 I don’t think the current way we fund drug development
0:37:38 doesn’t support active work there.
0:37:41 I think it’s the one, it’s a blind spot for us.
0:37:43 And I think we saw it, you know, during COVID.
0:37:45 – Yeah, I think so.
0:37:46 – And it’s still a blind spot.
0:37:49 What’s really sad is I don’t think COVID,
0:37:51 actually, I don’t think we’ve done much different
0:37:54 than we were doing before COVID.
0:37:55 – That is, that hurts.
0:37:57 That hurts. – I think it’s true.
0:37:59 – Mike Curtis is the CEO of eGenesis.
0:38:05 Today’s show was produced by Gabriel Hunter-Chang.
0:38:08 It was edited by Lydia Jean-Cott
0:38:10 and engineered by Sara Rue.
0:38:13 You can email us at problem@pushkin.fm.
0:38:17 I’m Jacob Goldstein and we’ll be back next week
0:38:19 with another episode of “What’s Your Problem?”
0:38:21 (upbeat music)
0:38:24 – Hey everybody, I’m Kai Rizdal,
0:38:35 the host of Marketplace, your daily download
0:38:38 on the economy.
0:38:39 Money influences so much of what we do and how we live.
0:38:42 That’s why it’s essential to understand
0:38:45 how this economy works.
0:38:46 At Marketplace, we break down everything
0:38:48 from inflation and student loans
0:38:50 to the future of AI so that you can understand
0:38:53 what it all means for you.
0:38:55 Marketplace is your secret weapon
0:38:56 for understanding this economy.
0:38:58 Listen wherever you get your podcasts.
0:39:00 (upbeat music)
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?
See omnystudio.com/listener for privacy information.