1 00:00:15,356 --> 00:00:24,076 Speaker 1: Pushkin. Rick Slayman is sixty two years old, lives in 2 00:00:24,116 --> 00:00:28,116 Speaker 1: a suburb of Boston, works for the state Department of Transportation, 3 00:00:29,036 --> 00:00:32,436 Speaker 1: and about five years ago he got a kidney transplant. 4 00:00:33,436 --> 00:00:37,996 Speaker 1: Then last year his new kidney stopped working, his health declined. 5 00:00:38,436 --> 00:00:42,956 Speaker 1: His prognosis was pretty bad, so earlier this year, he 6 00:00:42,996 --> 00:00:46,116 Speaker 1: and his doctors decided that he would be the first 7 00:00:46,156 --> 00:00:48,676 Speaker 1: person in the history of the world to get a 8 00:00:48,756 --> 00:00:54,196 Speaker 1: kidney transplant from a genetically engineered pig. Surgeons did the 9 00:00:54,196 --> 00:00:58,836 Speaker 1: transplant on March sixteenth, and two weeks later, Rix s 10 00:00:58,916 --> 00:01:02,276 Speaker 1: Layman walked out of the hospital. It's still too soon 11 00:01:02,316 --> 00:01:04,796 Speaker 1: to say how he'll do in the coming months, but 12 00:01:05,316 --> 00:01:14,476 Speaker 1: as of this recording, he's doing well. I'm Jacob Boltstein 13 00:01:14,556 --> 00:01:16,756 Speaker 1: and this is What's Your Problem, the show where I 14 00:01:16,836 --> 00:01:20,276 Speaker 1: talk to people who are trying to make technological progress. 15 00:01:20,716 --> 00:01:25,276 Speaker 1: My guest today is Mike Curtis. He's the CEO of Egenesis, 16 00:01:25,556 --> 00:01:29,716 Speaker 1: the company that bred the genetically engineered pig that provided 17 00:01:29,716 --> 00:01:33,956 Speaker 1: the kidney for Rick Slicker. Every year, thousands of people 18 00:01:34,156 --> 00:01:37,436 Speaker 1: die waiting for an organ transplant that never comes. And 19 00:01:37,716 --> 00:01:42,676 Speaker 1: so Mike's problem is this, is it possible to genetically 20 00:01:42,756 --> 00:01:48,996 Speaker 1: engineer pigs to provide organs, kidneys, livers, hearts for people, 21 00:01:49,756 --> 00:01:52,236 Speaker 1: and in the long run, is it possible to make 22 00:01:52,356 --> 00:01:56,596 Speaker 1: pig organs that work even better than human organs for 23 00:01:56,876 --> 00:02:03,996 Speaker 1: human transplant patients. So for a really long time, right, 24 00:02:04,076 --> 00:02:07,716 Speaker 1: like hundreds of years, people have had this idea of 25 00:02:07,836 --> 00:02:14,396 Speaker 1: transplanting organs or skin from animals to people, like where 26 00:02:14,436 --> 00:02:17,076 Speaker 1: do you where do you date the beginning of this 27 00:02:17,196 --> 00:02:17,676 Speaker 1: idea too? 28 00:02:18,356 --> 00:02:21,396 Speaker 2: It was it was even pre dated human human transplants. 29 00:02:21,436 --> 00:02:24,476 Speaker 2: So as soon as you know, physicians realize that organs 30 00:02:24,476 --> 00:02:27,356 Speaker 2: can fail, I think the first instinct was can we 31 00:02:27,396 --> 00:02:30,036 Speaker 2: get them from somewhere else? Right? And in the early 32 00:02:30,116 --> 00:02:33,996 Speaker 2: days of that horribly right, no, no good success. So 33 00:02:34,156 --> 00:02:36,076 Speaker 2: we kind of pre you know, date that to the 34 00:02:36,316 --> 00:02:38,836 Speaker 2: dawn of modern medicine. And nothing worked. 35 00:02:39,036 --> 00:02:43,196 Speaker 1: And nothing worked because basically the human immune system rejected 36 00:02:43,316 --> 00:02:44,076 Speaker 1: the transplants. 37 00:02:44,236 --> 00:02:45,676 Speaker 2: And that was before we even knew what that was. 38 00:02:45,716 --> 00:02:49,556 Speaker 3: But right, yeah, And so to jump forward a very 39 00:02:49,596 --> 00:02:55,116 Speaker 3: long way, it seems like Crisper, this ability to edit 40 00:02:55,556 --> 00:02:58,036 Speaker 3: genes is sort of a key breakthrough. 41 00:02:58,516 --> 00:03:01,276 Speaker 1: Is that the kind of key moment that enables this 42 00:03:01,356 --> 00:03:04,196 Speaker 1: new era that seems to be beginning right now? 43 00:03:04,436 --> 00:03:08,956 Speaker 2: Absolutely. There were some challenges in the cross species transplant 44 00:03:08,956 --> 00:03:12,276 Speaker 2: that just unresolvable until the discovery of Crisper. So the 45 00:03:12,276 --> 00:03:15,116 Speaker 2: one that we took on was in the nineties, it 46 00:03:15,156 --> 00:03:20,316 Speaker 2: was discovered that poresign retroviruses that are indigenous in the genome, 47 00:03:20,356 --> 00:03:23,076 Speaker 2: so they're kind of embedded in the pig genome, could 48 00:03:23,076 --> 00:03:25,316 Speaker 2: infect human cells. And in the nineties, you know, we 49 00:03:25,316 --> 00:03:29,236 Speaker 2: were coming out of the HIV epidemic, and we did 50 00:03:29,236 --> 00:03:31,956 Speaker 2: not want to, you know, cause another problem. So we 51 00:03:31,956 --> 00:03:34,996 Speaker 2: didn't want to have a cross species zoonotic event. So 52 00:03:35,276 --> 00:03:37,476 Speaker 2: in many countries around the world they put a moratorium 53 00:03:37,636 --> 00:03:42,676 Speaker 2: on cross species transplantation because of this risk of indigenous retroviruses. 54 00:03:42,756 --> 00:03:46,556 Speaker 1: And so I just want to pause here because I 55 00:03:46,596 --> 00:03:50,636 Speaker 1: didn't know about indogenous retroviruses until I started preparing for 56 00:03:50,676 --> 00:03:54,436 Speaker 1: this interview, and it totally blew my mind that there 57 00:03:54,516 --> 00:03:58,836 Speaker 1: is such a thing. Right, So, an indogenous retrovirus, as 58 00:03:58,876 --> 00:03:59,916 Speaker 1: I understand. 59 00:03:59,556 --> 00:04:00,436 Speaker 2: It is. 60 00:04:02,036 --> 00:04:05,396 Speaker 1: Not like a disease that a that an animal has 61 00:04:05,396 --> 00:04:08,556 Speaker 1: in this case, a poor sign. Indogenous retrovirus obviously is 62 00:04:08,556 --> 00:04:11,516 Speaker 1: an indogen retrovirus in a pig, and it doesn't mean 63 00:04:11,516 --> 00:04:13,436 Speaker 1: that the pig is sick It means that in the 64 00:04:13,516 --> 00:04:17,436 Speaker 1: genome of every pig there is genetic code to code 65 00:04:17,476 --> 00:04:22,116 Speaker 1: in that pig a retrovirus, right, And similarly, in humans 66 00:04:22,156 --> 00:04:25,796 Speaker 1: there are other indogenous retroviruses. We have in our genome 67 00:04:26,196 --> 00:04:32,476 Speaker 1: the code for retroviruses, that's right. Why why do mammals 68 00:04:32,516 --> 00:04:35,236 Speaker 1: have the code for viruses in our genomes? 69 00:04:35,316 --> 00:04:38,396 Speaker 2: Yeah? What's interesting because there are some functions that are 70 00:04:38,476 --> 00:04:42,596 Speaker 2: ascribed to these indigenous retroviruses. So they kind of co evolved, 71 00:04:42,956 --> 00:04:45,836 Speaker 2: you know, with pigs with people, and they pick up 72 00:04:45,836 --> 00:04:49,596 Speaker 2: some function, right, And so we don't completely understand why 73 00:04:49,596 --> 00:04:54,516 Speaker 2: they're there, but they're there and they pose a risk, right, 74 00:04:54,836 --> 00:04:59,196 Speaker 2: an infectious disease risk to patients, especially when you think 75 00:04:59,196 --> 00:05:01,756 Speaker 2: about patients who might be under immino suppression. 76 00:05:02,036 --> 00:05:04,036 Speaker 1: And so, just to be clear, just I won't I 77 00:05:04,036 --> 00:05:05,796 Speaker 1: don't want to be labor this, but it is really 78 00:05:05,836 --> 00:05:11,356 Speaker 1: extraordinary coming to it new. The notion is a very 79 00:05:11,476 --> 00:05:15,276 Speaker 1: very very long time ago, some pig in this case 80 00:05:15,316 --> 00:05:19,436 Speaker 1: got infected with a virus and that virus made its 81 00:05:19,476 --> 00:05:22,916 Speaker 1: way into the genome of essentially all the pigs living today, 82 00:05:24,316 --> 00:05:29,956 Speaker 1: and that genetic code is not harmful to pigs, but 83 00:05:30,076 --> 00:05:33,556 Speaker 1: there is a fear that if you took a pig kidney, say, 84 00:05:33,556 --> 00:05:35,756 Speaker 1: and put it in a human being, the code for 85 00:05:35,836 --> 00:05:38,356 Speaker 1: that virus, which is fine in pigs, might be harmful 86 00:05:38,356 --> 00:05:38,796 Speaker 1: in people. 87 00:05:39,116 --> 00:05:42,356 Speaker 2: Exactly. It's an unknown risk, ye. 88 00:05:42,796 --> 00:05:46,556 Speaker 1: And so in the nineties, particularly as you said, in 89 00:05:46,596 --> 00:05:48,836 Speaker 1: the context of the fear of HIV, people are thinking 90 00:05:48,876 --> 00:05:52,836 Speaker 1: about doing could we transplant a pig kidney into a 91 00:05:52,916 --> 00:05:57,476 Speaker 1: human and regulators essentially are saying, well, one reason you 92 00:05:57,516 --> 00:06:01,236 Speaker 1: cannot do it is because of these endogenous retroviruses in 93 00:06:01,276 --> 00:06:02,436 Speaker 1: the pigs DNA. 94 00:06:02,596 --> 00:06:05,676 Speaker 2: Exactly, and we can't quantify the risk, and so we 95 00:06:05,716 --> 00:06:08,756 Speaker 2: don't know what will happen, and we actually don't want 96 00:06:08,796 --> 00:06:10,676 Speaker 2: to know. You need to come up with a way 97 00:06:10,676 --> 00:06:14,436 Speaker 2: to mitigate the risk of retroviral transmission from the donor 98 00:06:14,476 --> 00:06:15,756 Speaker 2: to the recipient. 99 00:06:15,396 --> 00:06:19,556 Speaker 1: Okay, And so that's just like a red light, do 100 00:06:19,716 --> 00:06:23,156 Speaker 1: not pass. Go stop doing this for a while. Once 101 00:06:23,196 --> 00:06:23,676 Speaker 1: that happens. 102 00:06:23,716 --> 00:06:27,396 Speaker 2: In the nineties, exactly, most of the people that were 103 00:06:27,436 --> 00:06:29,556 Speaker 2: investing in the space stopped investing in the space. The 104 00:06:29,596 --> 00:06:32,836 Speaker 2: progression towards clinic stopped. It really slowed the whole field 105 00:06:32,836 --> 00:06:34,796 Speaker 2: down because no one knew exactly how to quantify the 106 00:06:34,876 --> 00:06:37,156 Speaker 2: risk or then what to do about it. And so 107 00:06:37,236 --> 00:06:40,636 Speaker 2: any pig genome you'll have between fifty and seventy copies 108 00:06:41,076 --> 00:06:44,316 Speaker 2: of the retrovirus scattered throughout the genome. And so even 109 00:06:44,356 --> 00:06:46,956 Speaker 2: if you wanted to go in and remove them, there 110 00:06:47,036 --> 00:06:49,356 Speaker 2: was no technology available that would allow you to do that. 111 00:06:50,596 --> 00:06:53,316 Speaker 2: And no one knew of a way to actually actively 112 00:06:53,356 --> 00:06:56,196 Speaker 2: get rid of these viruses right until the discovery of Crisper. 113 00:06:56,836 --> 00:07:01,596 Speaker 1: So Crisper comes along what ten issuars twelve years ago, 114 00:07:01,956 --> 00:07:07,636 Speaker 1: and it's this incredible technology for editing a genome. Right, 115 00:07:10,636 --> 00:07:14,996 Speaker 1: people think, oh, maybe we could solve that poresine and 116 00:07:15,116 --> 00:07:17,636 Speaker 1: dogenous retrovirus problem using Crisper. 117 00:07:18,036 --> 00:07:19,996 Speaker 2: Yeah, so this is what George Church kind of took 118 00:07:20,036 --> 00:07:22,396 Speaker 2: up at Harvard was like, it kind of what would 119 00:07:22,356 --> 00:07:24,436 Speaker 2: do we use chrispher for? And this this problem was 120 00:07:24,476 --> 00:07:26,436 Speaker 2: out there and George took it on and said, well, 121 00:07:26,476 --> 00:07:29,156 Speaker 2: let's see if you can inactivate all copies of the 122 00:07:29,156 --> 00:07:31,876 Speaker 2: retroviruses in the pig geno. The beautiful part about Crisper 123 00:07:32,556 --> 00:07:35,076 Speaker 2: is once you give it a sequence, right, it will 124 00:07:35,156 --> 00:07:38,636 Speaker 2: edit all copies of that sequence in a given genome. Now, 125 00:07:38,676 --> 00:07:43,036 Speaker 2: the worry was that you would then create basically Swiss 126 00:07:43,076 --> 00:07:45,156 Speaker 2: cheese out of the genome. Right, you would create an 127 00:07:45,236 --> 00:07:48,076 Speaker 2: unviable genome. There's too many edits, was the original thought. 128 00:07:48,476 --> 00:07:50,756 Speaker 2: But George and the team at Harvard showed that no, 129 00:07:50,836 --> 00:07:54,516 Speaker 2: you could actually inactivate all copies of the retrovirus and 130 00:07:54,596 --> 00:07:56,596 Speaker 2: then produce a viable pig. 131 00:07:57,156 --> 00:07:59,196 Speaker 1: Right, because I suppose the other question is like, even 132 00:07:59,236 --> 00:08:03,796 Speaker 1: if you can cleanly make all the edits, do does 133 00:08:03,836 --> 00:08:07,676 Speaker 1: the pig actually need this indogenous retrovirus for a reason 134 00:08:07,716 --> 00:08:08,996 Speaker 1: we don't understand. 135 00:08:08,636 --> 00:08:10,516 Speaker 2: Right, And we know it does if you if you 136 00:08:10,556 --> 00:08:12,516 Speaker 2: completely knock it out or get rid of it, the 137 00:08:12,516 --> 00:08:16,156 Speaker 2: pigs are not healthy. So we make a relatively subtle 138 00:08:16,236 --> 00:08:19,716 Speaker 2: change to the viral genome that that prevents the virus 139 00:08:19,716 --> 00:08:22,636 Speaker 2: from replicating. So with this edit, the virus can no 140 00:08:22,676 --> 00:08:24,156 Speaker 2: longer replicate hot. 141 00:08:24,196 --> 00:08:27,676 Speaker 1: But so you don't knock it. You don't entirely remove 142 00:08:27,756 --> 00:08:29,036 Speaker 1: the sequence from the genome. 143 00:08:29,116 --> 00:08:29,716 Speaker 2: You just. 144 00:08:31,356 --> 00:08:35,156 Speaker 1: Edit the genome such that this virus, once it's expressed, 145 00:08:35,516 --> 00:08:36,396 Speaker 1: cannot replicate. 146 00:08:36,596 --> 00:08:39,436 Speaker 2: Right, So essentially inactivate those of Dodges viruses. 147 00:08:39,756 --> 00:08:42,116 Speaker 1: And so this idea from George Churchill was one of 148 00:08:42,156 --> 00:08:46,396 Speaker 1: the like giant names in genetics. Right famous scientists was 149 00:08:46,476 --> 00:08:49,196 Speaker 1: that the origin of the company. 150 00:08:49,356 --> 00:08:53,076 Speaker 2: So it came from from from George's lab and we 151 00:08:53,076 --> 00:08:59,356 Speaker 2: we one of his postdocs started Egenesis by outlcensing the 152 00:08:59,396 --> 00:09:03,316 Speaker 2: technology from Harvard. So the original idea was to start 153 00:09:03,316 --> 00:09:07,956 Speaker 2: Egenesis with the idea of making animals that were retroviray 154 00:09:07,996 --> 00:09:11,876 Speaker 2: inactivated and then also do the rest of the editing 155 00:09:12,156 --> 00:09:15,276 Speaker 2: right that made the pigs more compatible with human recipient. 156 00:09:15,316 --> 00:09:17,396 Speaker 2: So that's how we got into the field. And then 157 00:09:17,516 --> 00:09:21,956 Speaker 2: from the from then we've built the additional editing to 158 00:09:21,996 --> 00:09:24,956 Speaker 2: provide organs that are more compatible with first non human 159 00:09:24,956 --> 00:09:26,436 Speaker 2: primates and then now with people. 160 00:09:26,796 --> 00:09:31,836 Speaker 1: So you have inactivated the endogenous retrovirus in the pig. 161 00:09:32,316 --> 00:09:35,996 Speaker 1: This is like step one, right, But at this point, 162 00:09:36,116 --> 00:09:41,116 Speaker 1: if you tried to take that kidney, even though you've 163 00:09:41,116 --> 00:09:45,236 Speaker 1: solved the retrovirus problem, it's still a pig kidney, right, 164 00:09:45,316 --> 00:09:47,516 Speaker 1: and the human body would know that and would not 165 00:09:48,196 --> 00:09:51,276 Speaker 1: accept it. So what do you have to do next? 166 00:09:51,436 --> 00:09:54,396 Speaker 2: Sure, and so if you just took an unedited pig 167 00:09:54,476 --> 00:09:55,916 Speaker 2: kidney and try to put it into a monkey or 168 00:09:55,956 --> 00:09:59,356 Speaker 2: to a person, to be rejected within minutes. And that's 169 00:09:59,396 --> 00:10:02,996 Speaker 2: primarily due to what we call hyperacute rejection, where the 170 00:10:03,116 --> 00:10:07,396 Speaker 2: humans are recognizing the carbohydrate differences between pigs and humans. 171 00:10:07,396 --> 00:10:12,676 Speaker 2: So carbohydrates are that coat all the cells, and humans 172 00:10:12,716 --> 00:10:16,236 Speaker 2: have antibodies that can recognize those pig sugars. So what 173 00:10:16,276 --> 00:10:19,996 Speaker 2: we do is we inactivate three genes responsible for those 174 00:10:20,036 --> 00:10:23,756 Speaker 2: carbohydrate differences between pigs and humans. Once you do that, 175 00:10:23,796 --> 00:10:25,716 Speaker 2: we create what we call the triple knockout. So we 176 00:10:25,836 --> 00:10:31,236 Speaker 2: inactivate those genes, knocking out those carbohydrate differences and eliminating 177 00:10:31,956 --> 00:10:32,916 Speaker 2: hypercute rejection. 178 00:10:34,156 --> 00:10:41,676 Speaker 1: And when you create a pig with those particular carbohydrates eliminated, 179 00:10:42,756 --> 00:10:45,596 Speaker 1: does it matter to the pig? Is the pig sicker? 180 00:10:45,636 --> 00:10:49,316 Speaker 2: As a result, we haven't seen any impact on the 181 00:10:49,636 --> 00:10:52,356 Speaker 2: health or longevity of a pig. So, for instance, we 182 00:10:52,436 --> 00:10:55,796 Speaker 2: have several animals in our colony that are a couple 183 00:10:55,836 --> 00:10:58,836 Speaker 2: of years old, and so we haven't seen any effects 184 00:10:58,876 --> 00:11:01,516 Speaker 2: on the longevity of those animals. So no, we haven't 185 00:11:01,516 --> 00:11:02,396 Speaker 2: seen any downside. 186 00:11:02,596 --> 00:11:07,316 Speaker 1: Okay, so you've inactivated the endogenous retrovirus and now you've 187 00:11:07,356 --> 00:11:12,236 Speaker 1: eliminated the carbo hydrates that are causing acute rejection. There's 188 00:11:12,316 --> 00:11:14,796 Speaker 1: like one more set of changes you've got to make, right, 189 00:11:14,836 --> 00:11:15,196 Speaker 1: That's right. 190 00:11:15,516 --> 00:11:17,636 Speaker 2: So what the field has shown over the past forty years. 191 00:11:17,676 --> 00:11:21,156 Speaker 2: Is that if you add human genes to the pig genome, 192 00:11:21,556 --> 00:11:25,036 Speaker 2: you can help regulate different areas of incompatibility. So when 193 00:11:25,076 --> 00:11:28,516 Speaker 2: we think about, for instance, coagulation, right, So the coagulation 194 00:11:28,636 --> 00:11:32,716 Speaker 2: factors in the pig are not one percent compatible with humans, 195 00:11:33,076 --> 00:11:36,356 Speaker 2: so we introduce human coagulation factors into the pig. 196 00:11:36,716 --> 00:11:39,356 Speaker 1: Coagulation factors just what causes the blood. 197 00:11:39,036 --> 00:11:42,276 Speaker 2: To clot basically or prevent the blood from clotting? Yeah, 198 00:11:42,316 --> 00:11:45,516 Speaker 2: either way, both both corrections, yep, absolutely. And then we 199 00:11:45,556 --> 00:11:49,356 Speaker 2: also add regulators of complement activation. The first kind of 200 00:11:49,396 --> 00:11:51,796 Speaker 2: immune response that you're going to get to a graft 201 00:11:52,236 --> 00:11:55,476 Speaker 2: in a transplant is what we call compliment activation, and 202 00:11:55,516 --> 00:11:58,316 Speaker 2: that leads to loss of cells, right, and that leads 203 00:11:58,356 --> 00:12:02,036 Speaker 2: to death of cells. But by introducing human complement regulators 204 00:12:02,276 --> 00:12:05,396 Speaker 2: into the poor scine tissue, we can slow down or 205 00:12:05,476 --> 00:12:09,436 Speaker 2: quiet that complement response. And then we add module later 206 00:12:09,636 --> 00:12:12,076 Speaker 2: of what we call the innate and adaptive immune response. 207 00:12:12,636 --> 00:12:16,076 Speaker 2: In total, we add in the animal that was used 208 00:12:16,116 --> 00:12:19,076 Speaker 2: in mister Slamon's transplant, we introduced a total of seven 209 00:12:19,676 --> 00:12:23,076 Speaker 2: regulatory human proteins. So if you add it together, it's 210 00:12:23,156 --> 00:12:27,716 Speaker 2: fifty nine edits to inactivate the retroviruses three edits to 211 00:12:27,796 --> 00:12:32,476 Speaker 2: improve the carbohydrate compatibility, and then seven edits to introduce 212 00:12:32,556 --> 00:12:35,356 Speaker 2: human regulatory trans genes, for a total of sixty nine edits. 213 00:12:35,476 --> 00:12:38,836 Speaker 1: So it's basically the first two categories are make it 214 00:12:38,916 --> 00:12:41,676 Speaker 1: less like a pig, and then the third category is 215 00:12:41,876 --> 00:12:43,116 Speaker 1: make it more like a person. 216 00:12:43,316 --> 00:12:44,796 Speaker 2: Yeah, that's a good way to think about it. 217 00:12:44,916 --> 00:12:49,516 Speaker 1: That's right, And I mean presumably at some margin you 218 00:12:49,636 --> 00:12:52,916 Speaker 1: want to make it as little like a pig and 219 00:12:53,076 --> 00:12:56,396 Speaker 1: as much like a person as possible. But the pig 220 00:12:56,436 --> 00:13:01,276 Speaker 1: still has to live, to grow up and have a kidney. 221 00:13:00,996 --> 00:13:05,636 Speaker 2: Right, absolutely, And we've produced animals with more trans genes 222 00:13:05,676 --> 00:13:08,916 Speaker 2: without any issue. But you can imagine at some point, right, 223 00:13:09,156 --> 00:13:11,076 Speaker 2: you'll reach a point where the pig no longer can 224 00:13:11,116 --> 00:13:14,516 Speaker 2: tolerate whatever the editing you're doing. We're actually already impressed 225 00:13:14,876 --> 00:13:17,596 Speaker 2: that we can produce healthy, viable pigs with this number 226 00:13:17,636 --> 00:13:20,876 Speaker 2: of edits. If you go back ten fifteen years, nobody 227 00:13:20,916 --> 00:13:24,956 Speaker 2: thought that you could viably do this. Even in activating 228 00:13:24,956 --> 00:13:27,476 Speaker 2: fifty nine copies of the retrovirus. Many felt that that 229 00:13:27,596 --> 00:13:29,636 Speaker 2: was too many and the genome wouldn't be able to 230 00:13:29,676 --> 00:13:32,196 Speaker 2: handle it. We can tell you that it's not easy, 231 00:13:32,236 --> 00:13:34,676 Speaker 2: and it's not trivial to do it. It took us 232 00:13:34,676 --> 00:13:36,916 Speaker 2: a lot of time to figure out how to do it, 233 00:13:37,436 --> 00:13:39,636 Speaker 2: but now we've shown it it is doable. 234 00:13:40,396 --> 00:13:42,916 Speaker 1: I'm sure that it's not easy, but I don't know 235 00:13:43,076 --> 00:13:48,396 Speaker 1: enough to understand, like what's hard about it? Like tell 236 00:13:48,436 --> 00:13:50,076 Speaker 1: me a thing that you had to figure out. 237 00:13:50,236 --> 00:13:53,396 Speaker 2: Sure, so when you do that much engineering to the genome, 238 00:13:53,436 --> 00:13:58,236 Speaker 2: you can get aberrations in the genome that prevents you 239 00:13:58,276 --> 00:14:00,276 Speaker 2: from making a pig. So one of the things that 240 00:14:00,316 --> 00:14:03,636 Speaker 2: we do is we do what's called clonal selection. So 241 00:14:03,756 --> 00:14:08,396 Speaker 2: we'll engineer thousands, tens of thousands of cells and then 242 00:14:08,516 --> 00:14:12,356 Speaker 2: select genomes based on viability. So, for instance, to so 243 00:14:12,476 --> 00:14:15,356 Speaker 2: produce our seventeen eighty four donor, we had to screen 244 00:14:15,436 --> 00:14:19,036 Speaker 2: over four thousand clones to find clones that had the 245 00:14:19,076 --> 00:14:21,796 Speaker 2: adequate quality of genome to then make pigs. 246 00:14:22,036 --> 00:14:25,076 Speaker 1: Huh. So let's just let's just talk about that for 247 00:14:25,076 --> 00:14:29,036 Speaker 1: a minute, like how that actually works, which is the 248 00:14:29,036 --> 00:14:32,916 Speaker 1: more basic question of just how does the whole thing work? 249 00:14:32,996 --> 00:14:35,556 Speaker 1: Like I get in a sort of abstracted space what 250 00:14:35,596 --> 00:14:40,396 Speaker 1: you're doing, but like in whatever in a you know, 251 00:14:40,436 --> 00:14:42,756 Speaker 1: in a cell, fundamentally there is a cell, right like, 252 00:14:42,756 --> 00:14:43,556 Speaker 1: what are we starting with. 253 00:14:43,756 --> 00:14:46,476 Speaker 2: So we'll take a sample of skin from an adult 254 00:14:46,796 --> 00:14:49,996 Speaker 2: what we call wild type so unedited pig. Then culture 255 00:14:50,036 --> 00:14:52,796 Speaker 2: those cells, make many cells, and then those are the 256 00:14:52,836 --> 00:14:54,476 Speaker 2: cells that we're going to edit. So those are the 257 00:14:54,516 --> 00:14:57,196 Speaker 2: cells that we take crisper. We make the fifty nine edits, 258 00:14:57,236 --> 00:14:59,156 Speaker 2: we make the triple knockout, and we make the seven 259 00:14:59,236 --> 00:15:02,996 Speaker 2: trans geens. In the case of the seventeen eighty four animal, 260 00:15:03,036 --> 00:15:05,356 Speaker 2: we did that through three sequential routes. 261 00:15:05,396 --> 00:15:07,636 Speaker 1: So just to be clear, the seventeen eighty four animal, 262 00:15:07,716 --> 00:15:10,436 Speaker 1: this is like one particular pig, the pig that donated 263 00:15:10,476 --> 00:15:12,396 Speaker 1: the kidney that is in a person right now. 264 00:15:12,476 --> 00:15:15,596 Speaker 2: So that's the seventeen eighty four refers to the genetics. 265 00:15:15,876 --> 00:15:19,516 Speaker 2: So we make many seventeen eighty four animals. So it's 266 00:15:19,556 --> 00:15:20,796 Speaker 2: a particular. 267 00:15:20,716 --> 00:15:23,236 Speaker 1: Edited genome, and it's the edited genome that you have 268 00:15:23,316 --> 00:15:23,956 Speaker 1: described to me. 269 00:15:24,036 --> 00:15:26,636 Speaker 2: Yeah, exactly, okay, right, So to make that animal, we 270 00:15:26,636 --> 00:15:29,156 Speaker 2: actually went through three rounds of editing, right, So we 271 00:15:29,196 --> 00:15:33,436 Speaker 2: would make the retroviolent activation make a pig, then take 272 00:15:33,476 --> 00:15:35,796 Speaker 2: those cells, edit them to make the try add the 273 00:15:35,836 --> 00:15:38,436 Speaker 2: truckle knockout, make a pig. Then we come back and 274 00:15:39,156 --> 00:15:40,476 Speaker 2: add the seven trans sheats. 275 00:15:40,276 --> 00:15:43,956 Speaker 1: So it's multiple generations. You're you are sort of adding 276 00:15:45,716 --> 00:15:49,276 Speaker 1: changes genetic mutations over successive generations. 277 00:15:49,516 --> 00:15:54,916 Speaker 2: Exactly why this allows us to select right. So there's 278 00:15:54,956 --> 00:15:59,676 Speaker 2: there's two there's there's two restrictions the time. Because we're 279 00:15:59,676 --> 00:16:02,116 Speaker 2: working with primary cells the time, you have to edit 280 00:16:02,156 --> 00:16:05,276 Speaker 2: them before they what we call sinat. So at some 281 00:16:05,316 --> 00:16:08,236 Speaker 2: point those cells stop dividing. You need to edit while 282 00:16:08,236 --> 00:16:10,636 Speaker 2: the cells are still divide, so you have a limited 283 00:16:10,756 --> 00:16:13,236 Speaker 2: number of days to do the editing, right, So we do. 284 00:16:13,516 --> 00:16:15,596 Speaker 2: So this is why we were doing three rounds of editing, 285 00:16:15,796 --> 00:16:18,676 Speaker 2: because we can get the retroviral in make a pig, 286 00:16:18,716 --> 00:16:20,356 Speaker 2: we can get the triple knockout make a pig. We 287 00:16:20,396 --> 00:16:22,476 Speaker 2: get the seven genes and make a pig. What's really 288 00:16:22,516 --> 00:16:25,036 Speaker 2: important to that whole process is at the end of 289 00:16:25,076 --> 00:16:31,596 Speaker 2: each editing round, we then screen individual cells for the genotype. Right, 290 00:16:31,636 --> 00:16:33,916 Speaker 2: And this is where we'll go through and screen you know, 291 00:16:34,276 --> 00:16:37,276 Speaker 2: up to four thousand cells to pick cells that look 292 00:16:37,716 --> 00:16:40,076 Speaker 2: like they have a good morphology and a good phenotype 293 00:16:40,196 --> 00:16:42,876 Speaker 2: for which we would then make a pig. So, once 294 00:16:42,876 --> 00:16:45,876 Speaker 2: we do the editing, we then pick individual cells that 295 00:16:45,916 --> 00:16:49,236 Speaker 2: we call clones, and then we grow those clones out, 296 00:16:49,396 --> 00:16:52,196 Speaker 2: and now we have an edited porsone genome, but we 297 00:16:52,196 --> 00:16:53,116 Speaker 2: still don't have a pig. 298 00:16:53,316 --> 00:16:56,556 Speaker 1: So you basically have a whatever, a petri dish full 299 00:16:56,556 --> 00:17:01,636 Speaker 1: of pig skin cells that have the genotype that you want, exactly, okay. 300 00:17:01,476 --> 00:17:02,836 Speaker 2: And so now we need to make a pig. And 301 00:17:02,996 --> 00:17:05,036 Speaker 2: the technology we use to turn a single cell into 302 00:17:05,076 --> 00:17:08,156 Speaker 2: a pig, it's called a somatic cell nuclear transfer. It 303 00:17:08,236 --> 00:17:10,716 Speaker 2: was similar to tchnology that was used to clone Dolly, 304 00:17:11,316 --> 00:17:13,996 Speaker 2: where we take the nucleus of the edited cell and 305 00:17:14,156 --> 00:17:18,236 Speaker 2: basically transfer it into the O site of a pig. 306 00:17:18,076 --> 00:17:21,476 Speaker 1: An egg cell. And and so this is now a 307 00:17:21,716 --> 00:17:24,996 Speaker 1: whatever thirty year old technology that they used to clone 308 00:17:24,996 --> 00:17:26,796 Speaker 1: a sheep with in the nineties exactly. 309 00:17:27,516 --> 00:17:30,116 Speaker 2: There's been some obviously improvements since then, but the core 310 00:17:30,276 --> 00:17:33,196 Speaker 2: idea is essentially the same. And then we use that 311 00:17:33,236 --> 00:17:36,116 Speaker 2: cloning technology to then make pigs. So we make an 312 00:17:36,116 --> 00:17:39,276 Speaker 2: embryo and then we transfer that embryo into a surrogate 313 00:17:39,356 --> 00:17:42,716 Speaker 2: sal and then that surrogate sal will carry the piglet 314 00:17:42,796 --> 00:17:43,396 Speaker 2: to term. 315 00:17:44,116 --> 00:17:47,116 Speaker 1: There's some ethical dimension to this, like like, what are 316 00:17:47,156 --> 00:17:48,796 Speaker 1: the relevant ethical dimensions to you? 317 00:17:49,116 --> 00:17:51,956 Speaker 2: Yeah, our focus is on preserving human health and saving 318 00:17:51,996 --> 00:17:54,916 Speaker 2: patients who are dying on the transfer wait list, and 319 00:17:54,956 --> 00:17:58,676 Speaker 2: we believe that this approach is justifiable with that goal 320 00:17:58,716 --> 00:18:01,476 Speaker 2: in mind. So every day we show up, we focus 321 00:18:01,556 --> 00:18:03,836 Speaker 2: on patients like mister Slayman. And so this is a 322 00:18:03,876 --> 00:18:06,436 Speaker 2: means to an end. This is a means to producing 323 00:18:06,556 --> 00:18:09,476 Speaker 2: organs that currently don't exist. It's to save paces who 324 00:18:09,476 --> 00:18:12,316 Speaker 2: are imminately dying, but they are. It's a very bleak 325 00:18:12,356 --> 00:18:14,596 Speaker 2: outlook for some of these folks, right, And so we 326 00:18:14,716 --> 00:18:17,036 Speaker 2: view that the work that we're doing for engineering the 327 00:18:17,036 --> 00:18:20,596 Speaker 2: persa and genome and producing compatible organs all about, you know, 328 00:18:20,676 --> 00:18:23,756 Speaker 2: realizing that mission of helping these patients, and we believe 329 00:18:23,756 --> 00:18:28,196 Speaker 2: that that puts us on a very firm ethical route. 330 00:18:29,916 --> 00:18:32,476 Speaker 1: Still to come on the show, how pig hearts might 331 00:18:32,596 --> 00:18:46,596 Speaker 1: help human babies. How many pigs with this genetic sequence 332 00:18:46,636 --> 00:18:46,996 Speaker 1: are there? 333 00:18:47,036 --> 00:18:49,756 Speaker 2: You have about fifty or so animals that are at 334 00:18:49,796 --> 00:18:50,476 Speaker 2: different ages. 335 00:18:50,796 --> 00:18:53,636 Speaker 1: So, like, do you have a farm somewhere? 336 00:18:54,076 --> 00:18:56,676 Speaker 2: So we do. We have two farms we have and 337 00:18:56,796 --> 00:18:59,356 Speaker 2: they are both out in the Midwest. One is a 338 00:18:59,396 --> 00:19:01,556 Speaker 2: research more of a research farm. It's a two hundred 339 00:19:01,596 --> 00:19:05,036 Speaker 2: acre farm where we institute biosecurity. So one of the 340 00:19:05,116 --> 00:19:07,716 Speaker 2: keys here is to produce animals that are free of 341 00:19:07,836 --> 00:19:11,356 Speaker 2: pathogens that could put harm to either the organs post 342 00:19:11,356 --> 00:19:15,156 Speaker 2: transplant or the patient or the recipients. So that farm 343 00:19:15,196 --> 00:19:18,036 Speaker 2: produces relatively clean animals. But then we have what we 344 00:19:18,076 --> 00:19:22,676 Speaker 2: call a clinical grade or designated pathogen free facility where 345 00:19:22,716 --> 00:19:24,756 Speaker 2: the animals are growing inside what we call a barrier. 346 00:19:25,516 --> 00:19:28,676 Speaker 2: So there we control feed, water, everything that comes in 347 00:19:28,716 --> 00:19:31,556 Speaker 2: to try to keep pathogens out. So we're actively managing 348 00:19:31,876 --> 00:19:35,436 Speaker 2: the environment that those animals are raised in. And on 349 00:19:35,516 --> 00:19:39,516 Speaker 2: top of all of that, we're doing very robust path 350 00:19:39,676 --> 00:19:44,516 Speaker 2: consistent pathogen testing, so we're constantly monitoring all the animals 351 00:19:44,556 --> 00:19:46,956 Speaker 2: for any potential pathogens or disease. 352 00:19:47,276 --> 00:19:50,756 Speaker 1: Right, I mean presumably some kind of like jumping the 353 00:19:50,836 --> 00:19:53,876 Speaker 1: species barrier or transfer would be one of the like 354 00:19:54,916 --> 00:19:57,036 Speaker 1: nightmarishly bad outcomes, right. 355 00:19:57,116 --> 00:19:59,676 Speaker 2: Yes, I mean one of the reasons that we selected 356 00:20:00,236 --> 00:20:03,276 Speaker 2: pigs as the species is one we've co you know, 357 00:20:03,396 --> 00:20:06,196 Speaker 2: existed with these animals for thousands of years and we 358 00:20:06,276 --> 00:20:09,556 Speaker 2: haven't seen that you know, that particular that type of 359 00:20:09,596 --> 00:20:12,676 Speaker 2: disease transmission, and then we can edit, and then we 360 00:20:12,716 --> 00:20:15,596 Speaker 2: also know how to grow animals at scale. But yes, 361 00:20:15,636 --> 00:20:17,196 Speaker 2: we're always on the lookout and I think this is 362 00:20:17,236 --> 00:20:20,476 Speaker 2: part of surveillance that we'll do for the foreseeable future, 363 00:20:21,036 --> 00:20:23,716 Speaker 2: is on the lookout for things that we aren't paying 364 00:20:23,716 --> 00:20:24,756 Speaker 2: attention for. Right. 365 00:20:25,276 --> 00:20:27,716 Speaker 1: So let's talk about the first patient. Let's talk about 366 00:20:27,756 --> 00:20:30,556 Speaker 1: Richard slam and the first person ever to be walking 367 00:20:30,596 --> 00:20:34,956 Speaker 1: the earth with a pig kidney as far as we know, probably. 368 00:20:37,316 --> 00:20:37,916 Speaker 2: Why him? 369 00:20:38,076 --> 00:20:40,076 Speaker 1: What was it about his case that made him the 370 00:20:40,156 --> 00:20:40,796 Speaker 1: right patient? 371 00:20:40,956 --> 00:20:43,236 Speaker 2: Yeah, So it's a great question, and part of it 372 00:20:43,276 --> 00:20:45,836 Speaker 2: was inspired by the work that was done at the 373 00:20:45,916 --> 00:20:49,316 Speaker 2: University of Maryland in the first heart transplants, right, so 374 00:20:49,356 --> 00:20:52,356 Speaker 2: we refer to those as the Bennett and Fossett transplants. 375 00:20:51,836 --> 00:20:55,676 Speaker 1: The first pig heart pig heart, Yeah, which just happened. 376 00:20:55,676 --> 00:20:59,356 Speaker 1: That was like a different project, right, but it just 377 00:20:59,356 --> 00:21:01,436 Speaker 1: happened in the last year or so, right now, the. 378 00:21:01,476 --> 00:21:03,836 Speaker 2: Last two years two years, Yeah, absolutely. And there was 379 00:21:03,836 --> 00:21:05,996 Speaker 2: always this debate in the field of zeno is what 380 00:21:06,036 --> 00:21:09,556 Speaker 2: patients would constitute the right patient population to go into 381 00:21:09,716 --> 00:21:12,276 Speaker 2: And the team at Maryland really showed us that there's 382 00:21:12,316 --> 00:21:14,636 Speaker 2: a case for compassionate use. There's a case for patients 383 00:21:14,636 --> 00:21:17,076 Speaker 2: who have reached the end of the treatment options and 384 00:21:17,116 --> 00:21:20,036 Speaker 2: really they're facing imminent death and we have a technology 385 00:21:20,036 --> 00:21:23,476 Speaker 2: that could save their life, so shouldn't we try now. Unfortunately, 386 00:21:23,556 --> 00:21:27,356 Speaker 2: you know, those gentlemen passed away within forty or fifty 387 00:21:27,436 --> 00:21:31,316 Speaker 2: days post transplant. But it showed us that the regulatory 388 00:21:31,316 --> 00:21:34,556 Speaker 2: agencies were open to the discussion, and we just need 389 00:21:34,596 --> 00:21:37,156 Speaker 2: to define what is the right patient population in the 390 00:21:37,196 --> 00:21:39,836 Speaker 2: case of kidney and so we had a discussion with 391 00:21:39,876 --> 00:21:43,036 Speaker 2: the FDA back in twenty twenty two about what would 392 00:21:43,076 --> 00:21:45,676 Speaker 2: be the right patient population for a formal phase one 393 00:21:45,716 --> 00:21:49,916 Speaker 2: clinical study, and we'd come to agreement on patients over fifty, 394 00:21:50,436 --> 00:21:53,796 Speaker 2: patients on the transplant weightlist, and patients that had failed 395 00:21:53,836 --> 00:21:56,316 Speaker 2: a previous alo transplant, right, so they'd had a human 396 00:21:56,396 --> 00:21:58,996 Speaker 2: kidney before, and they had it for a certain duration 397 00:21:59,036 --> 00:22:01,516 Speaker 2: of time and eventually that kidney fails and you find 398 00:22:01,516 --> 00:22:04,436 Speaker 2: yourself back on the transplant weightlist. And why that patient 399 00:22:04,476 --> 00:22:07,916 Speaker 2: population made sense is because those patients have a very 400 00:22:07,956 --> 00:22:12,036 Speaker 2: low likelihood if you're over fifty with that profile of 401 00:22:12,076 --> 00:22:15,036 Speaker 2: getting a second kidney. Now, in the case of mister Slamon, 402 00:22:15,036 --> 00:22:18,636 Speaker 2: are patients like him. He was also losing access to dialysis, 403 00:22:19,596 --> 00:22:24,396 Speaker 2: so he had a kidney transplant in twenty eighteen. He 404 00:22:24,436 --> 00:22:27,316 Speaker 2: had been on dialysis for seven years, got a kidney transplant, 405 00:22:27,596 --> 00:22:30,236 Speaker 2: the kidney function for five years, and then he lost 406 00:22:30,276 --> 00:22:34,236 Speaker 2: the kidney stop functioning. In twenty twenty three, Okay, he 407 00:22:34,276 --> 00:22:37,236 Speaker 2: found himself back on dialysis, but he was having trouble 408 00:22:37,276 --> 00:22:40,396 Speaker 2: with vascular access, so he had to go through multiple 409 00:22:40,396 --> 00:22:43,756 Speaker 2: surgeries to create access so he could go on dialysis. 410 00:22:43,956 --> 00:22:46,916 Speaker 1: And just to be clear, dialysis is when your kidneys 411 00:22:46,916 --> 00:22:48,596 Speaker 1: don't work. There is a machine and they hook you 412 00:22:48,676 --> 00:22:50,476 Speaker 1: up to the machine and it cleans your blood. It 413 00:22:50,516 --> 00:22:51,276 Speaker 1: does the work of the kids. 414 00:22:51,356 --> 00:22:53,316 Speaker 2: Yeah. Usually, you know, the typical schedule would be three 415 00:22:53,316 --> 00:22:54,876 Speaker 2: times a week, four hours each time. 416 00:22:54,956 --> 00:22:58,196 Speaker 1: Okay, And so Richard Slaman, you were saying dialysis just 417 00:22:58,596 --> 00:23:00,116 Speaker 1: wasn't working for him anymore. 418 00:23:00,156 --> 00:23:02,276 Speaker 2: In some patchion it was just very hard to do. 419 00:23:02,556 --> 00:23:04,316 Speaker 2: It was working, but he would have to have these 420 00:23:04,396 --> 00:23:08,556 Speaker 2: vascular access surgery so his blood vessels would acclude and 421 00:23:08,636 --> 00:23:10,796 Speaker 2: prevent the ability to do dialysis. So we'd have to 422 00:23:10,796 --> 00:23:13,956 Speaker 2: go through a relatively painful procedure to allow him to 423 00:23:13,956 --> 00:23:16,516 Speaker 2: get dialysis. And I think, you know, he was and 424 00:23:16,636 --> 00:23:20,396 Speaker 2: I think his neuprologist, when Williams put it really well, 425 00:23:20,396 --> 00:23:23,396 Speaker 2: he was kind of losing faith, losing hope, like, huh, 426 00:23:23,556 --> 00:23:25,716 Speaker 2: is this my life? Is this my future? Like, I'm 427 00:23:25,716 --> 00:23:28,236 Speaker 2: just going to have to keep doing this and I 428 00:23:28,276 --> 00:23:30,476 Speaker 2: have no chance of getting a transplant because he had 429 00:23:30,516 --> 00:23:32,836 Speaker 2: had a transplant for five years, so he knew what 430 00:23:32,916 --> 00:23:36,316 Speaker 2: that was and now he finds himself on dallasis. So, 431 00:23:36,316 --> 00:23:39,956 Speaker 2: so we knew at some point mister Sliman would lose 432 00:23:39,956 --> 00:23:42,716 Speaker 2: access to dialysis and without a transplant, he would he 433 00:23:42,716 --> 00:23:45,596 Speaker 2: would go to hospice. And so he was a patient 434 00:23:45,636 --> 00:23:49,596 Speaker 2: that we felt was a good candidate for trying. And 435 00:23:49,676 --> 00:23:52,956 Speaker 2: so the team at Mass General approached mister Slaman with 436 00:23:52,996 --> 00:23:55,876 Speaker 2: this idea of he could participate and be the first 437 00:23:55,876 --> 00:23:58,396 Speaker 2: patient to try this, and this is what we knew, 438 00:23:58,716 --> 00:24:01,116 Speaker 2: and these were the risks, and I think that's part 439 00:24:01,156 --> 00:24:04,076 Speaker 2: of one of the biggest challenges, kind of articulating what 440 00:24:04,116 --> 00:24:06,516 Speaker 2: we know and then articulately what we don't know and 441 00:24:06,556 --> 00:24:10,076 Speaker 2: how this could go. But much to mister slam his credit, right, 442 00:24:10,316 --> 00:24:12,036 Speaker 2: he was the one that raised his hand and said 443 00:24:12,036 --> 00:24:14,396 Speaker 2: he would go first. And then we took it to 444 00:24:14,396 --> 00:24:16,716 Speaker 2: the FDA and we laid out the case to the 445 00:24:16,756 --> 00:24:20,356 Speaker 2: FDA that you know mister Slamon's story and kind of 446 00:24:20,356 --> 00:24:22,716 Speaker 2: where he found himself in his treatment. What we had 447 00:24:22,756 --> 00:24:25,676 Speaker 2: been doing are non human primate data, all the data 448 00:24:25,716 --> 00:24:29,076 Speaker 2: on the characterization of our donors. And after a few 449 00:24:29,116 --> 00:24:32,916 Speaker 2: weeks of discussion, the FDA said, we agree and you 450 00:24:32,956 --> 00:24:34,436 Speaker 2: guys can try. 451 00:24:35,356 --> 00:24:39,716 Speaker 1: So what is the path for you for your fore genesis? 452 00:24:39,756 --> 00:24:42,876 Speaker 2: From here, we believe that there's the opportunity to treat 453 00:24:42,916 --> 00:24:46,516 Speaker 2: more patients like mister Slimon. He's not unfortunately, he's not 454 00:24:46,716 --> 00:24:48,596 Speaker 2: unique in this space, and there are other patients that 455 00:24:48,636 --> 00:24:51,996 Speaker 2: are suffering very similar fate with continued success. Our intention 456 00:24:52,156 --> 00:24:56,076 Speaker 2: is to do more of these expanded access requests and 457 00:24:56,116 --> 00:25:00,756 Speaker 2: transplants while we prepare for a formal trial, right so 458 00:25:01,156 --> 00:25:04,116 Speaker 2: in patients that may be facing less risk than patients 459 00:25:04,156 --> 00:25:08,196 Speaker 2: like mister Slamon, patients earlier in their dialysis journey, earlier 460 00:25:08,236 --> 00:25:12,436 Speaker 2: in their their kidney failure progression. But that will come, 461 00:25:12,636 --> 00:25:14,596 Speaker 2: you know. Our intention is to file something like that 462 00:25:14,636 --> 00:25:18,076 Speaker 2: at the end of twenty twenty five. Beyond that, you know, 463 00:25:18,116 --> 00:25:21,396 Speaker 2: we are also exploring patients that are suffering from liver 464 00:25:21,436 --> 00:25:25,556 Speaker 2: failure as well as heart failure. This past December, we 465 00:25:25,596 --> 00:25:30,156 Speaker 2: did the longest liver perfusions on liver perfusion in a 466 00:25:30,196 --> 00:25:34,556 Speaker 2: decedent patient. Ever, we did three days of continuous perfusion. 467 00:25:35,036 --> 00:25:36,916 Speaker 2: The idea there is you take a patient who may 468 00:25:36,916 --> 00:25:40,916 Speaker 2: be suffering from liver failure and perfuse them through a 469 00:25:40,956 --> 00:25:44,436 Speaker 2: pig liver to allow their own liver to recover again. 470 00:25:44,476 --> 00:25:48,116 Speaker 2: This was something that was demonstrated in the nineties to work. 471 00:25:48,156 --> 00:25:51,636 Speaker 2: So they took fourteen patients with acute liver failure perfused 472 00:25:51,636 --> 00:25:55,676 Speaker 2: them through pig livers. All fourteen patients improved. Seven patients 473 00:25:55,676 --> 00:25:57,516 Speaker 2: were successfully bridged to transplant. 474 00:25:58,196 --> 00:26:00,516 Speaker 1: So just to unpack that for a sec the pig 475 00:26:00,516 --> 00:26:02,076 Speaker 1: liver is kind of like when people get put on 476 00:26:02,116 --> 00:26:05,236 Speaker 1: those like external artificial hearts or something like the outside 477 00:26:05,276 --> 00:26:06,636 Speaker 1: the body, and it's like or. 478 00:26:06,596 --> 00:26:10,396 Speaker 2: What you know when think about kidney disease is akin 479 00:26:10,436 --> 00:26:13,436 Speaker 2: to dialsis right? You hooked up to a machine. In 480 00:26:13,476 --> 00:26:15,116 Speaker 2: this case, in the machine is a big. 481 00:26:14,916 --> 00:26:16,756 Speaker 1: Liver, and like, is it in a box? 482 00:26:17,036 --> 00:26:21,116 Speaker 2: Like yeah, yeah, So it's in a plastic container on 483 00:26:21,196 --> 00:26:22,156 Speaker 2: a perfusion device. 484 00:26:22,316 --> 00:26:25,036 Speaker 1: So the pig's liver is doing the work of the 485 00:26:25,076 --> 00:26:28,756 Speaker 1: liver for the patient while the patient is waiting for 486 00:26:28,876 --> 00:26:31,996 Speaker 1: a human donor exactly. Like, let me ask the dumb question, 487 00:26:32,276 --> 00:26:34,836 Speaker 1: why not just put the pigs liver in the person. 488 00:26:35,556 --> 00:26:39,716 Speaker 2: Because the incompatibilities between a pig liver and the person 489 00:26:39,716 --> 00:26:43,476 Speaker 2: are still too great. OK, So we could I think 490 00:26:43,476 --> 00:26:45,876 Speaker 2: we're only going to get a week or two before 491 00:26:45,916 --> 00:26:46,836 Speaker 2: that gets rejected. 492 00:26:47,316 --> 00:26:50,476 Speaker 1: And so similarly, does the perfusion just last for a 493 00:26:50,476 --> 00:26:52,756 Speaker 1: week or two it's just like an emergency bridge. 494 00:26:52,916 --> 00:26:55,356 Speaker 2: Yeah, so it's a great question, and we started out 495 00:26:55,396 --> 00:26:57,636 Speaker 2: with a goal of greater than twenty four hours of perfusion. 496 00:26:58,116 --> 00:27:00,716 Speaker 2: The pen study went for three days. Looking at the 497 00:27:00,756 --> 00:27:02,436 Speaker 2: histology at the end of the study, we believe it 498 00:27:02,436 --> 00:27:05,076 Speaker 2: can go for about a week. So we're continuing to 499 00:27:05,076 --> 00:27:05,836 Speaker 2: push the duration. 500 00:27:06,036 --> 00:27:08,996 Speaker 1: So that's like a that feels like much more of 501 00:27:08,996 --> 00:27:11,396 Speaker 1: a kind of edge case than the kidney case. 502 00:27:11,876 --> 00:27:13,796 Speaker 2: Well, this is the thing. We think there's actually much 503 00:27:13,836 --> 00:27:17,036 Speaker 2: greater unmet need and liver failure than there even is 504 00:27:17,036 --> 00:27:20,516 Speaker 2: in kidney failure because these patients, because there is no 505 00:27:20,796 --> 00:27:24,236 Speaker 2: equivalent of dialysis, they either recover on their own, which 506 00:27:24,276 --> 00:27:27,076 Speaker 2: is a little bit of like ICU time and hope, 507 00:27:27,356 --> 00:27:29,916 Speaker 2: or they get transplanted. So we're hoping that we can 508 00:27:29,956 --> 00:27:33,516 Speaker 2: provide liver support through a poresigne liver, we can bridge 509 00:27:33,556 --> 00:27:35,276 Speaker 2: more patients to recovery. 510 00:27:34,876 --> 00:27:38,356 Speaker 1: Okay, and then you're and then hearts. 511 00:27:38,476 --> 00:27:40,996 Speaker 2: Yeah. So the third setting, again is inspired by the 512 00:27:40,996 --> 00:27:44,676 Speaker 2: work done at Maryland, but instead of looking at adult 513 00:27:44,716 --> 00:27:47,916 Speaker 2: patients where the heart has to and heart has to 514 00:27:47,956 --> 00:27:51,756 Speaker 2: function continuously or the patient passes away, we're focused in 515 00:27:51,756 --> 00:27:55,236 Speaker 2: the pediatric population. So children who need a heart transplant 516 00:27:55,316 --> 00:27:57,636 Speaker 2: currently have poor standard of care to bridge them to 517 00:27:57,716 --> 00:27:58,596 Speaker 2: human heart transplant. 518 00:27:58,676 --> 00:28:02,076 Speaker 1: And so this is like typically like babies born with 519 00:28:02,196 --> 00:28:04,156 Speaker 1: genetic anomalies. 520 00:28:03,596 --> 00:28:06,516 Speaker 2: Yeah, typically children under two is kind of where the 521 00:28:06,516 --> 00:28:09,716 Speaker 2: focus is and the current support of care. About fifty 522 00:28:09,716 --> 00:28:13,276 Speaker 2: percent of these children die waiting for a human heart transplant. 523 00:28:14,476 --> 00:28:16,556 Speaker 1: That is a brutal one. Is a brutal That would 524 00:28:17,036 --> 00:28:18,996 Speaker 1: be a good one too, Yeah, that would be a 525 00:28:18,996 --> 00:28:19,916 Speaker 1: good one to tve. 526 00:28:20,156 --> 00:28:22,356 Speaker 2: And so the idea is if we can simply create 527 00:28:22,396 --> 00:28:26,076 Speaker 2: one hundred to two hundred day bridge using a Poresigne heart, 528 00:28:26,076 --> 00:28:28,076 Speaker 2: then at the end of that or sometime in the middle, 529 00:28:28,196 --> 00:28:30,916 Speaker 2: when the human heart became available, the child would simply 530 00:28:30,956 --> 00:28:33,836 Speaker 2: get the human heart. So we call that a bridging strategy. 531 00:28:34,356 --> 00:28:37,076 Speaker 1: And so in that instance, is it a transplant or 532 00:28:37,156 --> 00:28:38,876 Speaker 1: is it external It's a transplant. 533 00:28:38,996 --> 00:28:42,196 Speaker 2: Yeah, So the intention is to do the por signed 534 00:28:42,196 --> 00:28:45,036 Speaker 2: heart transplant allow the patient to go home. They can 535 00:28:45,076 --> 00:28:47,156 Speaker 2: wait at home right now, they would have to wait 536 00:28:47,196 --> 00:28:49,236 Speaker 2: in the hospital, but they could wait at home until 537 00:28:49,236 --> 00:28:50,556 Speaker 2: the human heart becomes available. 538 00:28:51,076 --> 00:28:56,436 Speaker 1: Okay, So so those are two other organs. When do 539 00:28:56,476 --> 00:28:57,516 Speaker 1: you think you're going to do those? 540 00:28:58,076 --> 00:29:00,116 Speaker 2: So the intention, the intention is to do all that 541 00:29:00,196 --> 00:29:02,276 Speaker 2: this year, right, So, we believe we have the not 542 00:29:02,316 --> 00:29:04,996 Speaker 2: what we call non clinical data or the primate data 543 00:29:05,716 --> 00:29:07,836 Speaker 2: to support moving into the clinic. And I do think 544 00:29:08,156 --> 00:29:10,916 Speaker 2: mister the success so far with mister Slaman's transplant is 545 00:29:10,956 --> 00:29:13,716 Speaker 2: helpful because the emune of suppression that we plan to 546 00:29:13,916 --> 00:29:17,276 Speaker 2: use in the pediatric heart setting is very similar to 547 00:29:17,316 --> 00:29:20,356 Speaker 2: what we're using in mister Slaman's transplant. So we do 548 00:29:20,436 --> 00:29:24,716 Speaker 2: think that continued success in the kidney transplant will help 549 00:29:24,716 --> 00:29:26,676 Speaker 2: inform what we're going to be doing at heart. 550 00:29:27,596 --> 00:29:31,996 Speaker 1: And is it the same set of genetic changes? 551 00:29:32,476 --> 00:29:35,156 Speaker 2: Yeah, so it's the same genetics of the donor. So 552 00:29:35,196 --> 00:29:37,436 Speaker 2: the current plan is to use the same donor for 553 00:29:37,516 --> 00:29:41,356 Speaker 2: both kidney, hearts and livers. 554 00:29:41,396 --> 00:29:46,876 Speaker 1: And how does how does the immune response to a 555 00:29:46,916 --> 00:29:50,956 Speaker 1: pig organ compare to the immune response to an organ 556 00:29:50,996 --> 00:29:52,116 Speaker 1: from another human? 557 00:29:52,636 --> 00:29:54,516 Speaker 2: Yeah, it's definitely more robust. 558 00:29:55,036 --> 00:29:57,716 Speaker 1: More robust meaning worse in this concept, it's. 559 00:29:57,556 --> 00:29:59,916 Speaker 2: Probably going to require you know, we already are using 560 00:29:59,956 --> 00:30:01,556 Speaker 2: more evenie suppression. Yeah. 561 00:30:01,596 --> 00:30:06,516 Speaker 1: And is there some medium to long term future where 562 00:30:06,556 --> 00:30:12,516 Speaker 1: you do more gene editing in order to make that 563 00:30:12,556 --> 00:30:15,316 Speaker 1: piece of it easier, where you make the pig kidney 564 00:30:15,356 --> 00:30:16,436 Speaker 1: more like a human kidney. 565 00:30:16,516 --> 00:30:18,556 Speaker 2: Yeah. Absolutely. The long term vision here is to produce 566 00:30:18,676 --> 00:30:21,396 Speaker 2: organs that don't require immuno suppression, party. 567 00:30:21,276 --> 00:30:22,396 Speaker 1: That don't require it at. 568 00:30:22,316 --> 00:30:24,596 Speaker 2: All at all. I mean, that's the ultimate that's the vision. 569 00:30:24,636 --> 00:30:26,556 Speaker 1: I mean, if you could do that. Just to be clear, 570 00:30:27,116 --> 00:30:30,676 Speaker 1: like that vision is a pig kidney is better than 571 00:30:30,716 --> 00:30:32,196 Speaker 1: a kidney from another human. 572 00:30:32,036 --> 00:30:35,556 Speaker 2: Right, I mean it sounds like you've been talking to George. Wow. 573 00:30:36,276 --> 00:30:38,636 Speaker 1: I appreciate that you were skeptical. You were supposed to 574 00:30:38,636 --> 00:30:40,956 Speaker 1: be high picking up and I'm supposed to be skeptical. No. 575 00:30:41,036 --> 00:30:43,596 Speaker 1: But if you say, like, is that even plausible? I 576 00:30:43,596 --> 00:30:45,396 Speaker 1: appreciate that you're skeptical of it. That's good. 577 00:30:45,476 --> 00:30:47,556 Speaker 2: Yeah, do it might work for me. I think one 578 00:30:47,596 --> 00:30:49,276 Speaker 2: of the things that transplant World has taught us over 579 00:30:49,276 --> 00:30:51,636 Speaker 2: the past fifty years is things that we thought were 580 00:30:51,676 --> 00:30:54,836 Speaker 2: impossible are actually now routine, right, So I think it's 581 00:30:54,836 --> 00:30:58,156 Speaker 2: a matter of time, effort, and work. I think we 582 00:30:58,196 --> 00:31:01,356 Speaker 2: can get there, right. I think this initial transplant into 583 00:31:01,596 --> 00:31:04,556 Speaker 2: patients is a really important step because for us to 584 00:31:04,716 --> 00:31:06,396 Speaker 2: be informed about what we need to do from an 585 00:31:06,436 --> 00:31:09,596 Speaker 2: engineering perspective, it is very helpful to have data from 586 00:31:09,676 --> 00:31:12,996 Speaker 2: humans to feedback into that loop, so we can do 587 00:31:13,356 --> 00:31:16,396 Speaker 2: lots of things from an engineering perspective. The question is 588 00:31:16,396 --> 00:31:18,516 Speaker 2: what to do next, and I think the results that 589 00:31:18,796 --> 00:31:21,916 Speaker 2: will achieve with mister Slayman and patients like him will 590 00:31:21,956 --> 00:31:24,916 Speaker 2: help inform what else we need to do to really 591 00:31:24,916 --> 00:31:27,916 Speaker 2: realize this big vision, which is organs that don't require suppression. 592 00:31:28,356 --> 00:31:33,076 Speaker 1: Organs that don't require suppression, is wildly ambitious, right do you? 593 00:31:33,156 --> 00:31:37,076 Speaker 1: I mean it seems like, not knowing basically anything about it, 594 00:31:37,076 --> 00:31:42,076 Speaker 1: it would be a kind of incremental, maybe even as symptotic, like, ah, 595 00:31:42,116 --> 00:31:44,316 Speaker 1: this will get us to less, This will get us 596 00:31:44,316 --> 00:31:47,436 Speaker 1: to less as opposed to some binary breakthrough. Does that 597 00:31:47,436 --> 00:31:47,956 Speaker 1: seem right? 598 00:31:48,156 --> 00:31:50,996 Speaker 2: Yeah? I think it's incremental. But what we're starting to 599 00:31:51,036 --> 00:31:56,756 Speaker 2: see is kind of multiplex editing in a way that 600 00:31:56,796 --> 00:31:59,196 Speaker 2: we couldn't even before Christper, we couldn't conceive of making 601 00:31:59,196 --> 00:32:02,076 Speaker 2: fifty nine edits for GENO. Okay, now we're conceiving of 602 00:32:02,796 --> 00:32:05,036 Speaker 2: how would you make a thousand edits to geno? What 603 00:32:05,076 --> 00:32:07,196 Speaker 2: does that actually look like? And I think that's what's 604 00:32:07,236 --> 00:32:08,116 Speaker 2: going to be required. Huh. 605 00:32:08,436 --> 00:32:11,036 Speaker 1: I mean, do you get weird like structural like three 606 00:32:11,156 --> 00:32:13,876 Speaker 1: D structural problems once you start doing that, like is 607 00:32:13,916 --> 00:32:15,836 Speaker 1: it even gonna yes work? 608 00:32:16,076 --> 00:32:18,156 Speaker 2: So there's definitely a lot to solve, right, So how 609 00:32:18,196 --> 00:32:19,796 Speaker 2: do you make you know, how do you make that 610 00:32:19,876 --> 00:32:23,436 Speaker 2: many changes without totally destroying the geno? We thought that 611 00:32:23,516 --> 00:32:27,196 Speaker 2: originally with Crisper and the first retroviolent activation, they thought 612 00:32:27,196 --> 00:32:28,676 Speaker 2: you would never be able to make that many at it. 613 00:32:28,716 --> 00:32:30,756 Speaker 2: So we did that. We just have to figure out 614 00:32:30,796 --> 00:32:32,836 Speaker 2: how to do it. And you know, we don't know 615 00:32:32,876 --> 00:32:35,236 Speaker 2: how to do it right now, but I do think 616 00:32:35,236 --> 00:32:36,236 Speaker 2: we'll figure out how to do it. 617 00:32:38,716 --> 00:32:54,756 Speaker 1: We'll be back in a minute with the lightning. Let's 618 00:32:54,756 --> 00:32:56,756 Speaker 1: finish with a lightning ground. I won't take much more 619 00:32:56,756 --> 00:32:57,156 Speaker 1: of your time. 620 00:32:57,436 --> 00:33:00,116 Speaker 2: Okay, Okay, what's one. 621 00:32:59,956 --> 00:33:03,596 Speaker 1: Thing that that we don't understand about the human body 622 00:33:03,636 --> 00:33:11,956 Speaker 1: that you wish we understood? 623 00:33:12,876 --> 00:33:15,796 Speaker 2: I think, coming from the neuroscience world, I think we 624 00:33:15,836 --> 00:33:22,116 Speaker 2: have a really poor understanding of mental health and what 625 00:33:22,156 --> 00:33:25,356 Speaker 2: to do about depression, and because I think those are 626 00:33:25,396 --> 00:33:30,076 Speaker 2: just paralyzing diseases that we are a long way from 627 00:33:30,196 --> 00:33:33,716 Speaker 2: really understanding why they exist and actually how to effectively 628 00:33:33,756 --> 00:33:36,156 Speaker 2: treat them. So if you could generalize that as brain, 629 00:33:36,236 --> 00:33:40,476 Speaker 2: we still don't really understand in the way we need to, 630 00:33:40,636 --> 00:33:42,436 Speaker 2: you know, how the brain actually works and what we 631 00:33:42,476 --> 00:33:44,876 Speaker 2: can do to improve diseases of the brain. 632 00:33:46,596 --> 00:33:50,156 Speaker 1: Well, I know you worked in pharmaceuticals for decades, right, 633 00:33:50,196 --> 00:33:53,676 Speaker 1: I don't point on it, Yeah, and so you know 634 00:33:53,796 --> 00:33:57,236 Speaker 1: it's a famously hard industry. Most drugs fail, right, I'm 635 00:33:57,276 --> 00:34:01,356 Speaker 1: curious if you have any any tips for dealing with failure. 636 00:34:02,676 --> 00:34:04,876 Speaker 2: I think you go in with the best hypothesis, you 637 00:34:04,956 --> 00:34:07,596 Speaker 2: run the most efficient studies you can, and then you 638 00:34:07,636 --> 00:34:10,956 Speaker 2: pick yourself up and go again, because I think you 639 00:34:10,996 --> 00:34:13,556 Speaker 2: can't let failure bring you down, right, And we know 640 00:34:13,636 --> 00:34:15,916 Speaker 2: we're going to fail, and often we learned a tremendous 641 00:34:15,956 --> 00:34:18,356 Speaker 2: amount from those failures and we just have to build 642 00:34:18,356 --> 00:34:20,156 Speaker 2: on them. The worst thing you can do is stop. 643 00:34:20,676 --> 00:34:22,316 Speaker 2: I think you have to always keep going. 644 00:34:23,276 --> 00:34:25,316 Speaker 1: So if you look back over the thirty years that 645 00:34:25,356 --> 00:34:27,356 Speaker 1: you worked in the drug industry, I'm curious, like, if 646 00:34:27,356 --> 00:34:29,156 Speaker 1: you think about when you were getting into the field. 647 00:34:30,516 --> 00:34:34,036 Speaker 1: What is something that has happened since then, like a breakthrough, 648 00:34:34,076 --> 00:34:37,356 Speaker 1: a change that you wouldn't have expected that's surprising to you. 649 00:34:41,836 --> 00:34:45,316 Speaker 2: I think this whole field of genetic medicines, you know 650 00:34:45,356 --> 00:34:47,996 Speaker 2: the fact that we're now producing potential cures for sickle cell, 651 00:34:48,636 --> 00:34:51,796 Speaker 2: cures for beta thalsemia. I think those were all visions 652 00:34:52,236 --> 00:34:54,756 Speaker 2: that we had, you know, fifty sixty one hundred years ago, 653 00:34:55,036 --> 00:34:58,356 Speaker 2: like could we actually cure diseases that we're now literally 654 00:34:58,356 --> 00:35:00,636 Speaker 2: on the shelf have cures for. And I think that 655 00:35:00,916 --> 00:35:02,836 Speaker 2: no one ever thought we would get there, and here 656 00:35:02,876 --> 00:35:03,356 Speaker 2: we are. 657 00:35:03,236 --> 00:35:07,796 Speaker 1: So conversely, so that's the happy surprise. Is there something 658 00:35:07,836 --> 00:35:11,116 Speaker 1: when you got into the field that you fought like, 659 00:35:11,236 --> 00:35:14,516 Speaker 1: surely we'll figure this out, Surely this will be solved 660 00:35:14,556 --> 00:35:15,516 Speaker 1: that we haven't figured out. 661 00:35:15,676 --> 00:35:19,276 Speaker 2: I mean, our inability to really effectively fight viral infection is, 662 00:35:19,836 --> 00:35:23,356 Speaker 2: you know, our infectious disease broadly. We really haven't evolved 663 00:35:23,996 --> 00:35:27,716 Speaker 2: our armamentarium against infectious disease very much. I think there 664 00:35:27,836 --> 00:35:31,476 Speaker 2: we've way under invested and focused on infectious disease. I 665 00:35:31,476 --> 00:35:35,436 Speaker 2: don't think the current way we fund drug development doesn't 666 00:35:35,476 --> 00:35:38,636 Speaker 2: support active work there. I think it's the one. It's 667 00:35:38,636 --> 00:35:40,316 Speaker 2: a blind spot for us, and I think we saw it, 668 00:35:40,596 --> 00:35:41,396 Speaker 2: you know, during COVID. 669 00:35:41,476 --> 00:35:43,196 Speaker 1: Yeah, right, so. 670 00:35:45,036 --> 00:35:46,956 Speaker 2: And it's still a blind spot. What's really sad is 671 00:35:46,956 --> 00:35:49,196 Speaker 2: I don't think COVID. Actually, I don't think we've done 672 00:35:49,236 --> 00:35:50,956 Speaker 2: much different than we were. 673 00:35:50,796 --> 00:35:56,996 Speaker 3: Doing that that that hurts, but I think it's true. 674 00:35:58,236 --> 00:36:02,836 Speaker 1: Mike Curtis is the CEO of E Genesis. Today's show 675 00:36:02,996 --> 00:36:06,236 Speaker 1: was produced by Gabriel Hunter Chang. It was edited by 676 00:36:06,276 --> 00:36:10,356 Speaker 1: Lydia jene Kott and engineered by Sarah. You can email 677 00:36:10,436 --> 00:36:14,356 Speaker 1: us at problem at Pushkin dot FM. I'm Jacob Goldstein 678 00:36:14,396 --> 00:36:16,636 Speaker 1: and we'll be back next week with another episode of 679 00:36:16,636 --> 00:36:17,396 Speaker 1: What's Your Problem.