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Growing New Livers to Save Lives · What's Your Problem?

0:15
Speaker 1: Pushkin. I'm Jacob Goldstein. This is What's your Problem? And
0:34
Speaker 1: my guest today is Michael Hufford. He's the co founder
0:37
Speaker 1: and CEO of a company called Ligenesis. Michael and his
0:41
Speaker 1: colleagues are working on a new kind of medical treatment.
0:45
Speaker 1: If it works, it will save lives. And I have
0:47
Speaker 1: to say the way the treatment is supposed to work
0:50
Speaker 1: is wild. It's for people with end stage liver disease
0:53
Speaker 1: who don't qualify for a liver transplant. And what le
0:57
Speaker 1: Genesis does is they take healthy liver cells, just cells,
1:01
Speaker 1: and they inject those cells into the patient's lymph nodes,
1:05
Speaker 1: and then the patient grows one or more little new
1:08
Speaker 1: liver in those lymph nodes. This has worked in experiments
1:12
Speaker 1: in animals, and now they're trying it in people. In
1:15
Speaker 1: our conversation, Michael told me about the science of why
1:19
Speaker 1: this might work. He told me what it would mean
1:21
Speaker 1: for patients if it does work, and we also talked
1:24
Speaker 1: about why it might not work. And then we talked
1:27
Speaker 1: a little bit about the future of regenerative medicine more broadly,
1:31
Speaker 1: and the possibility of a world where no one dies
1:34
Speaker 1: waiting for an organ transplant. But to start Michael told
1:38
Speaker 1: me some truly interesting facts about the liver and Greek mythology.
1:44
Speaker 2: It is remarkable because it's the only organ in the
1:47
Speaker 2: human body that will naturally regenerate. So you can lose
1:51
Speaker 2: seventy percent of your liver, and over a course of
1:55
Speaker 2: just a few weeks, you will regenerate that liver entirely.
1:58
Speaker 2: And that's true only for the liver. And ironically, it's
2:02
Speaker 2: something we've known for three thousand years, right the myth
2:04
Speaker 2: of Prometheus, if you might remember, the titan that stole
2:07
Speaker 2: fire from Zeus and gave it to a man was
2:09
Speaker 2: punished by being chained to a rock, and that eagle
2:12
Speaker 2: would come every day and eat his liver, and the
2:16
Speaker 2: punishment was eternal, because his liver would regenerate, an eagle
2:20
Speaker 2: would have more liver to feast on the next day.
2:24
Speaker 1: I I was vaguely familiar with the myth of Prometheus,
2:28
Speaker 1: but I was not familiar with the fact that the
2:30
Speaker 1: liver regenerates itself. I mean, do you infer that the
2:33
Speaker 1: Greeks knew that? Yeah?
2:35
Speaker 2: Absolutely, I think they did know that. I think probably
2:39
Speaker 2: through the experiences in battle and what have you, you
2:42
Speaker 2: could they could see that you could sustain a dramatic
2:45
Speaker 2: injury to the liver and that, unlike any other organ,
2:49
Speaker 2: it would regenerate. But at the same time, it's taken
2:51
Speaker 2: us three thousand years to get to the point that
2:54
Speaker 2: one we can successfully transplant it.
2:56
Speaker 1: Right.
2:56
Speaker 2: That was the pioneering work of doctor Tom Starzel. You know,
3:00
Speaker 2: he first attempted it in nineteen sixty three, got it
3:02
Speaker 2: to work in nineteen sixty seven. It saved tens of
3:06
Speaker 2: thousands of patients lives since then, and Nowgenesis is really
3:10
Speaker 2: standing on the shoulders of folks like doctor Starzel and
3:14
Speaker 2: now trying to regenerate the liver in other places in
3:17
Speaker 2: the body.
3:18
Speaker 1: Let me ask a nitpicky question before I ask a
3:21
Speaker 1: real question. Is the skin an organ? And does the
3:24
Speaker 1: skin regenerate itself?
3:26
Speaker 2: That's a good that's a good point. The skin has
3:29
Speaker 2: some ability to regenerate itself, for sure, And in fact,
3:32
Speaker 2: in children, if a small child loses the tip of
3:36
Speaker 2: a finger in an accident before the age of seven,
3:40
Speaker 2: you can actually regrow the tip of your finger. But
3:43
Speaker 2: we lose that that remarkable ability to regenerate as we
3:47
Speaker 2: get older, and the only organ that retains that capability
3:52
Speaker 2: is the liver.
3:54
Speaker 1: So you mentioned liver transplants, incredible life saving technology. Let's
4:01
Speaker 1: call it a technology. Why why do we need ligenesis? Like,
4:06
Speaker 1: what is the limit of liver transplants? Liver transplants?
4:10
Speaker 2: We have about nine thousand patients on the US currently
4:13
Speaker 2: for a liver transplant. Fifteen to twenty percent of those
4:17
Speaker 2: patients will die each year awaiting a liver transplant to
4:20
Speaker 2: become available. So I would say it's there's really a
4:24
Speaker 2: fundamentally a two fold problem. One is supply and demand. Today,
4:28
Speaker 2: one donated organ treats one patient using our technology, a
4:34
Speaker 2: single donated organ, because we're isolating the individual liver cells
4:38
Speaker 2: or hepatosites from that liver, a single donated organ could
4:41
Speaker 2: treat fifty patients. So one, we're kind of fixing and
4:46
Speaker 2: really up ending the supply demand calculus when it comes
4:48
Speaker 2: to you know, instead of one donated organ treating one patient,
4:51
Speaker 2: with our approach, one donated organ can treat up to
4:54
Speaker 2: fifty patients. But the other problem is is what oftentimes
4:57
Speaker 2: people aren't aware of, which is for all the you know,
5:01
Speaker 2: the understandable human drama of a liver transplant weightlist, of
5:04
Speaker 2: all the organ transplant weight lists, where people are waiting
5:07
Speaker 2: for this life save even gift of organ donation. Many
5:13
Speaker 2: patients are too ill to even make the list. So
5:16
Speaker 2: in the US you have about five million cases of
5:19
Speaker 2: in stage liver disease in one form or another. You
5:22
Speaker 2: have eighty five thousand deaths. At least fifty percent of
5:27
Speaker 2: the patients that could benefit from an organ transplant don't
5:30
Speaker 2: qualify because we know that they simply won't survive the procedure.
5:34
Speaker 1: Because it's a big, open surgery that involves a lot
5:37
Speaker 1: of trauma, and if you're very sick already, you'll probably
5:40
Speaker 1: die from the surgery. Yes. Correct, So you co founded
5:44
Speaker 1: the company with scientists with a researcher named Eric Leagas right,
5:48
Speaker 1: and it was based on research that he had done.
5:51
Speaker 1: So tell me about meeting him where you were and
5:56
Speaker 1: what was the work he had done that you found
5:58
Speaker 1: so compelling that you had to go start a company
6:00
Speaker 1: with him? Yeah, absolutely so.
6:02
Speaker 2: Eric Legass is a professor at the McGowan Institute for
6:05
Speaker 2: a Generative Medicine and Pathology at the University of Pittsburgh.
6:09
Speaker 2: At the time, I was an entrepreneur in residence at
6:11
Speaker 2: the University of Pittsburgh and I had spent twenty five
6:14
Speaker 2: years doing drug development and had been fortunate to work
6:16
Speaker 2: on a number of very innovative programs and had started
6:20
Speaker 2: and sold a number of companies. And so was working
6:22
Speaker 2: with the University of Pittsburgh because they get almost a
6:25
Speaker 2: billion dollars of NIH funding annually. It's remarkably remarkable research enterprise,
6:31
Speaker 2: both at the University of Pittsburgh and the University of
6:33
Speaker 2: Pittsburgh Medical Center or UPMC, and so they wanted to
6:37
Speaker 2: get more companies spun out as a function of that funding.
6:41
Speaker 2: And so one day a colleague of mine took me
6:42
Speaker 2: to meet Eric Lagas, and what Eric told me was
6:46
Speaker 2: a remarkable story in two ways. One, he showed me
6:49
Speaker 2: these remarkable pictures from his publication in Nature Biotechnology, showing
6:54
Speaker 2: that he could regrow organs in the lymph nodes of mice.
6:59
Speaker 2: That he could take liver cells from a mouse and
7:02
Speaker 2: graph them into the lymph node of another mouse. And
7:06
Speaker 2: these animals had a genetic liver disease, and so as
7:11
Speaker 2: a function of that liver disease, they would otherwise die
7:13
Speaker 2: from that liver disease. But when he ingrafted these hepatosites
7:17
Speaker 2: into their lymph nodes, those lymph nodes acted as living bioreactors,
7:21
Speaker 2: and they literally grew those animals miniature livers, so that
7:26
Speaker 2: instead of dying from their liver disease, one hundred percent
7:29
Speaker 2: of them were rescued from that otherwise fatal liver disease.
7:32
Speaker 2: So he had these pictures that were truly jaw dropping,
7:35
Speaker 2: you know, of these ectopic organs in places in the
7:39
Speaker 2: body that they should not otherwise be.
7:41
Speaker 1: So I just want to repeat what you just said
7:44
Speaker 1: because it is the central extraordinary fact of the thing
7:47
Speaker 1: that you are doing. Right. What Leagas did was he
7:52
Speaker 1: had put liver cells, just cells, into the lymph nodes
7:57
Speaker 1: of these mice that had liver disease, and within the
8:01
Speaker 1: lymph node there grew a teeny liver that worked, that
8:06
Speaker 1: did what the big liver needed to do, and the
8:08
Speaker 1: mice did die. Like why why should that even be true? Yeah,
8:14
Speaker 1: So two things.
8:15
Speaker 2: One, over time the lymph node disappears, the lymph node
8:18
Speaker 2: acts as a temporary bioreactor to get that ectopic organ
8:22
Speaker 2: and by ectopic we just mean in a different place
8:25
Speaker 2: in the body that ectopic liver to grow. And in fact,
8:28
Speaker 2: those ectopic livers and mice could grow to seventy percent
8:31
Speaker 2: the size of a normal liver. So he could grow
8:34
Speaker 2: really quite large ectopic livers using these lymph nodes.
8:38
Speaker 1: And that doesn't mess the mice up. It doesn't like
8:41
Speaker 1: mess up their emphatic system or something like that.
8:44
Speaker 2: Yeah, So remarkably, we've seen no untoward effects on the
8:48
Speaker 2: immune system, now, partly because let's stop and talk about
8:51
Speaker 2: lymph nodes for a second, right, So, lymph nodes in
8:54
Speaker 2: the human body, we have four hundred and fifty to
8:57
Speaker 2: seven hundred lymph nodes spread throughout our body, a majority
9:00
Speaker 2: in our gut area, right, and they've helped us as
9:04
Speaker 2: a species survive infection, right, because what a what a
9:08
Speaker 2: lymph node does, It's its primary evolutionary function is help
9:12
Speaker 2: bioreact T cells. So when you develop a cold, you
9:16
Speaker 2: have a sore throat and you feel that nodule that
9:19
Speaker 2: kind of you know marble or maybe even you know
9:22
Speaker 2: large marble underneath your jaw, that's a lymphnode that's bioreacted
9:26
Speaker 2: billions of T cells to help you fight that infection.
9:29
Speaker 1: When you say bioreact, you basically mean grow, right, it.
9:33
Speaker 2: Is it is an admittedly biotech jargon term for grow.
9:38
Speaker 1: That's exactly right. Okay, So the lymph note is a
9:41
Speaker 1: really good place for cells to grow. That's one reason
9:44
Speaker 1: it works, or it works in animals. You said there
9:47
Speaker 1: were two reasons. The what's the other reason?
9:50
Speaker 2: The other is what's special about the liver and why
9:54
Speaker 2: even the Greeks, you know, knew that it would regenerate
9:57
Speaker 2: under the right circumstances. Is the fundamental cell of the
10:02
Speaker 2: liver is the hepatocite. Hepatasites are naturally regenerative, and so
10:07
Speaker 2: Eric's fundamental s scientific discovery was that if you combine
10:12
Speaker 2: that natural regenerative potential of the hapatosite with the natural
10:16
Speaker 2: ability of the lymph node to bioreact cells, you get
10:22
Speaker 2: this remarkable effect. And you could think of it as
10:24
Speaker 2: the flip side of the cancer coin. You know, many
10:27
Speaker 2: people are aware that cancer probes the environment to form tumors,
10:32
Speaker 2: and very often cancer will grow tumors in someone's lymph nodes.
10:37
Speaker 1: Right, And in fact, that the classic sort of staging
10:39
Speaker 1: question in cancer set has it spread to the lymph nodes?
10:43
Speaker 1: And if it has in the case of cancer, that
10:46
Speaker 1: is bad.
10:47
Speaker 2: That is bad, exactly right, precisely because lymph nodes are
10:50
Speaker 2: such effective bioreactors, and they are agnostic as to what
10:54
Speaker 2: they bioreact You know, they're so good at growing cells. Yeah,
10:58
Speaker 2: exactly right. So if a cancer cell gets in there,
11:01
Speaker 2: the cancer cell thinks, man, that's a fantastic place. I
11:03
Speaker 2: have access to blood and nutrients, and I have a
11:06
Speaker 2: confined space that I can focus on growth. And what
11:10
Speaker 2: you end up are these is the spread of these tumors. Well,
11:14
Speaker 2: what Eric realized is that you could turn that biology
11:18
Speaker 2: to it to a therapeutic instead of a malignant potential.
11:22
Speaker 2: So by putting a self therapy like apatasite into a
11:26
Speaker 2: lymph node, you could generate functional tissues that exerted life
11:31
Speaker 2: saving effects. And so he showed me those first pictures
11:35
Speaker 2: from his study, and it really was jaw dropping. And
11:37
Speaker 2: I asked him that afternoon what I thought was the
11:40
Speaker 2: gotcha question, because it so often is with academic minded professors.
11:45
Speaker 2: I said, well, you know, that's great, Eric, it's incredibly impressive.
11:48
Speaker 2: What about large animals.
11:49
Speaker 1: Right, it's good news for mice. Right, you must exactly
11:53
Speaker 1: the phrase mice lie and primates exaggerate drug. I love
11:58
Speaker 1: that I had not heard that. Somebody told me that
12:01
Speaker 1: twenty five years that's fantastic. I'm going to steal it. Actually,
12:05
Speaker 1: that's wonderful.
12:06
Speaker 2: So and he said, oh yeah, Michael. And in fact,
12:10
Speaker 2: his colleague, doctor Palofontes, who was our co founder and
12:14
Speaker 2: chief medical officer, showed that the exact same principle applied
12:17
Speaker 2: in pigs. So they showed you could take a pig
12:20
Speaker 2: that would otherwise die from a fatal liver disease, and
12:23
Speaker 2: you could rescue that pig using the exact same procedure.
12:27
Speaker 2: And they even tried a different model where they surgically
12:30
Speaker 2: injure the liver. There's something called a portocable shunt where
12:33
Speaker 2: you can go in and kind of rearrange the plumbing
12:36
Speaker 2: of the liver, so to speak, to deprivate of blood flow,
12:40
Speaker 2: which was a procedure that doctor Starzeal had pioneered as
12:42
Speaker 2: a way to test and develop the procedure that would
12:45
Speaker 2: eventually become liver transplantation. And again rescued those animals. And
12:50
Speaker 2: he told me something that as a drug developer you
12:53
Speaker 2: virtually never hear. He said, Michael, I can't get this
12:55
Speaker 2: not to work. And as a drug developer, right, I'd
12:59
Speaker 2: spent my entire career and the entire industry really is
13:02
Speaker 2: focused on getting the exact right drug delivered in the
13:06
Speaker 2: exact right way to the exact right patient, exact right dose,
13:10
Speaker 2: oftentimes at the exact right time of day, and you
13:13
Speaker 2: hope for an effect. And what Eric was telling me
13:16
Speaker 2: was that nature had kind of primed this approach between
13:20
Speaker 2: the natural originative capacity of the liver the natural bioreactor
13:25
Speaker 2: capabilities of the lymph node, and that when he said
13:28
Speaker 2: he couldn't get it not to work. Quite literally, the
13:30
Speaker 2: hairs on the back of my neck stood up, and
13:33
Speaker 2: I said, Okay, let's back up and go over this
13:34
Speaker 2: whole story again, you know, And really that day was
13:39
Speaker 2: the genesis of the company.
13:42
Speaker 1: So you start the company nine years ago, is that right?
13:47
Speaker 1: Twenty seventeen?
13:49
Speaker 2: Yeah, Yeah, time's flown.
13:50
Speaker 1: Yeah yeah. I mean it takes a long time to
13:53
Speaker 1: develop new therapies, right, This is regenerative medicine, cell therapy,
13:59
Speaker 1: a hard new thing to do. So where are you
14:02
Speaker 1: now nine years later? Yeah?
14:04
Speaker 2: So we are now running a first in human phase
14:07
Speaker 2: two a clinical trial. So this is a clinical trial
14:11
Speaker 2: in patients within stage liver disease. These are patients, most
14:15
Speaker 2: of them, not all, Most are on the liver transplant
14:18
Speaker 2: wait list and they can come into the trial. They
14:22
Speaker 2: may have any number of different types of liver disease,
14:25
Speaker 2: but we're going for patients who have in stage liver
14:29
Speaker 2: disease that typically have a life expectancy of many months
14:33
Speaker 2: or a few years, okay, because we know that. We
14:36
Speaker 2: know that one limitation of our approach is that when
14:39
Speaker 2: you ingraph these cells, they do take time to organize themselves.
14:42
Speaker 2: It's not like the next day you have, you know,
14:46
Speaker 2: a fully functioning actopic liver. We know that it takes
14:48
Speaker 2: probably two to three months, is our best guess, and
14:51
Speaker 2: so we want to make sure that these patients have
14:54
Speaker 2: the time to have the potential beneficial effects of the therapy.
14:59
Speaker 2: So we've now transplanted our first cohort of patients. There
15:02
Speaker 2: were four patients, all done at the Houston Methodist Hospital.
15:07
Speaker 2: Like you typically the phrases, you start low and go slow,
15:10
Speaker 2: you start low in dose and go slow because you're
15:12
Speaker 2: not sure what the effect will be. And so the
15:15
Speaker 2: FDA had counseled us this first trial is just going
15:18
Speaker 2: to be twelve patients, so we have three different dose groups.
15:23
Speaker 2: We've completed that first dose cohort and we had a
15:26
Speaker 2: data Safety Monitoring Board meeting where they look at all
15:28
Speaker 2: the safety data and the efficacy data to date and
15:31
Speaker 2: they said, okay, you know, it's looking good. Let's let's
15:33
Speaker 2: go on and dose escalate as per the protocol. And
15:37
Speaker 2: so that's that's what we are in the midst of
15:40
Speaker 2: right now.
15:41
Speaker 1: One are you going to know if it worked, if
15:45
Speaker 1: this trial, you know, had a positive result, that will
15:48
Speaker 1: allow you to move to presumably the next bigger trial.
15:52
Speaker 2: Yeah, we should have a very good sense of that
15:54
Speaker 2: in the middle part of next year. Okay, so the
15:56
Speaker 2: middle part of twenty twenty seven, and then yeah, move
15:59
Speaker 2: on from there.
16:00
Speaker 1: So let's talk about how it works. So there's a patient,
16:03
Speaker 1: as you've said, yeah, who is you know, has liver disease,
16:09
Speaker 1: has some liver function left, but it's not looking good
16:11
Speaker 1: for them. And then there is what a donated liver.
16:15
Speaker 1: Like what actually happens.
16:17
Speaker 2: That's exactly right. When an organ becomes available, if the
16:20
Speaker 2: organ is eligible for transplant, then it's transplanted into a
16:24
Speaker 2: patient that needs it. Some organs, though, are not eligible
16:28
Speaker 2: for transplant, and that can be for any number of reasons.
16:31
Speaker 2: They may have been injured because of the cause of death,
16:36
Speaker 2: they might be a little fatty where when the transplant
16:39
Speaker 2: surgeon looks at the organ they think, ah, you know,
16:41
Speaker 2: that's not going to be a great fit for this
16:44
Speaker 2: particular patient, and so that they pass on it when
16:48
Speaker 2: they come to us. We then have a facility at
16:51
Speaker 2: Houston Methodist currently where we can take that organ and
16:55
Speaker 2: it takes us just about four or five hours. It's
16:59
Speaker 2: a seventy plus step process, but we start with the
17:03
Speaker 2: full organ and after seventy steps and about four to
17:07
Speaker 2: five hours, we've isolated and suspended those hepatocytes into a
17:11
Speaker 2: solution that we then currier over to the endoscopic ultrasound suite.
17:18
Speaker 1: And so just to be clear, it's it's when you
17:21
Speaker 1: say the patasites are in a solution, it's like a
17:24
Speaker 1: bottle full of liver cells in liquid.
17:27
Speaker 2: That's That's That's exactly what it is. Okay, It's a
17:30
Speaker 2: small syringe really because really injecting about yeah, about one
17:34
Speaker 2: about one milliliter of the cell suspension. But it's it's
17:38
Speaker 2: literally like a brown thick liquid.
17:42
Speaker 1: That's yeah, So a syringe like like what like you'd
17:44
Speaker 1: get in a shot, but instead of a vaccine, it's
17:47
Speaker 1: liver cells from a donated liver. Okay, so then you
17:49
Speaker 1: cur youer that over to go go on. Yeah.
17:52
Speaker 2: Yeah, And so the patient is put under light sedation
17:55
Speaker 2: and just the way you might have an endoscope you know,
17:58
Speaker 2: to look to see if you have an ulcer or
18:00
Speaker 2: to you know, have any number of diagnostic procedures. Yes, Basically,
18:04
Speaker 2: an endoscopius takes that into scope under sedation, down through
18:08
Speaker 2: the mouth of the patient and then threads it down
18:12
Speaker 2: their gi track kind of into their gut area. And
18:16
Speaker 2: at the end of that endoscope is an ultrasound. And
18:20
Speaker 2: so the ultrasound you can basically look adjacent to the
18:24
Speaker 2: gut wall and lymph nodes there show up. Is they
18:28
Speaker 2: almost look like bubbles to the untrained eye, right, So
18:32
Speaker 2: they kind of look like these bubbles that come into
18:35
Speaker 2: view via the ultrasound, and the endoscopist takes a five
18:40
Speaker 2: foot needle that threads down through the industry thing. Yeah,
18:44
Speaker 2: it then goes through the gut wall and punctures into
18:48
Speaker 2: the lymph node.
18:50
Speaker 1: So it's like a shot. It's like a shot, but
18:52
Speaker 1: it's going into your stomach, across the wall of your
18:57
Speaker 1: stomach and into the lymph node. That's exactly right. That's
19:00
Speaker 1: exactly right.
19:00
Speaker 2: And so this takes about ten minutes to find the
19:03
Speaker 2: lymph node and inject the cell suspension. And so we
19:07
Speaker 2: inject one millileter to that lymph node. They withdraw the
19:11
Speaker 2: needle and pull the scope out, and the procedure itself
19:15
Speaker 2: at that point is done. The cells are in the
19:17
Speaker 2: lymph node. The patients put on immune suppression.
19:21
Speaker 1: Right, the patients put on immune suppression because these are
19:24
Speaker 1: cells from somebody else. So it's just like if you
19:26
Speaker 1: get a transplant, your body's cells will be like, oh,
19:29
Speaker 1: that's foreign, I'm going to get rid of it. That's
19:32
Speaker 1: exactly right. Yeah, okay, So the patients put on immune
19:34
Speaker 1: suppression and then if it works, what happens.
19:39
Speaker 2: If it works, what happens is those cells find themselves
19:43
Speaker 2: in an environment that they find very comforting and very nourishing,
19:48
Speaker 2: and so they use that those bioreactor, you know, aspects
19:53
Speaker 2: of the lymph node begin dividing because they're natural stem cells,
19:57
Speaker 2: and they begin organizing themselves into liveral obdules, which are
20:00
Speaker 2: these little hexagonal collections of cells that are kind of
20:04
Speaker 2: the functioning filtering unit of the liver. And from all
20:09
Speaker 2: of our preclinical data in both small and large animals,
20:12
Speaker 2: that division will continue to go on and the vascularization
20:16
Speaker 2: will then occur. So the lymph nodes are well vascularized anyway.
20:20
Speaker 2: But what you find is that these ectopic organs recruit
20:27
Speaker 2: cells from the patient's body to form additional vasculature, so
20:32
Speaker 2: additional blood flow to that ectopic organ, so that over time,
20:38
Speaker 2: and again our best guess is it's over a few
20:40
Speaker 2: months of time, what you'll be left with is this
20:43
Speaker 2: functioning ectopic organs. So I'm picturing one like tiny little
20:49
Speaker 2: mini liver, like, I don't know how big is it?
20:54
Speaker 2: Is there only one?
20:55
Speaker 1: How big does it have to be or how many
20:57
Speaker 1: do there have to be for it to be clinically useful?
21:00
Speaker 2: They can get quite large. In small animals. You can
21:03
Speaker 2: get up to seventy percent of the native liver grown
21:07
Speaker 2: in a lymph node, and the larger animal was a
21:09
Speaker 2: smaller percentage. And your question about clinically meaningful. You know,
21:15
Speaker 2: when you talk to hepatologists or folks like our chief
21:18
Speaker 2: medical officer, doctor Fontes, who's treated these patients, you know,
21:21
Speaker 2: across his entire life, if you can bump the functional
21:25
Speaker 2: amount of liver for one of these patients by ten
21:28
Speaker 2: to twenty percent, you will alleviate a lot of the
21:31
Speaker 2: signs and symptoms of their in stage liver disease. And
21:34
Speaker 2: in fact, in stage liver disease is a problem because
21:37
Speaker 2: very often patients don't know that they have advanced liver
21:39
Speaker 2: disease until pretty far along, because it is a redundant system.
21:44
Speaker 2: As a species, we have very large livers to help us,
21:46
Speaker 2: you know, with the various things that we might eat
21:48
Speaker 2: and get exposed to. So it's a redundant system and
21:51
Speaker 2: by the time you know you have a problem, you
21:53
Speaker 2: know you really have a problem. And so that's why
21:57
Speaker 2: we think if we can even bump it up by
21:59
Speaker 2: ten to twenty percent, I think this will be a
22:01
Speaker 2: transformative therapy. So, you know, we envision clinically the potential
22:07
Speaker 2: both to treat patients that are never going to get
22:09
Speaker 2: an organ because they simply don't qualify for the list,
22:12
Speaker 2: but for others it may be more clinically, what you're
22:15
Speaker 2: doing is just buying them time so that an organ
22:18
Speaker 2: can become.
22:19
Speaker 1: Available for them. We're gonna take an ad break right now,
22:26
Speaker 1: and then we're gonna come back and talk about a
22:27
Speaker 1: bunch of more things, including why what Michael, and like
22:30
Speaker 1: genesis are working on might not work. I want to
22:41
Speaker 1: go back to one detail or one step you mentioned
22:46
Speaker 1: of what happens inside the body in this process, and
22:50
Speaker 1: that is, after the cells have been injected, they are
22:54
Speaker 1: just cells. They're just random liver cells floating around. And
22:58
Speaker 1: you said they organize themselves essentially into a liver, into
23:03
Speaker 1: a little liver. You didn't say into a living over
23:04
Speaker 1: but that is essentially what's happening. Yeah, that part that
23:08
Speaker 1: seems like the central shocking thing that is going on here, right,
23:13
Speaker 1: And I've talked to a couple of other people doing
23:17
Speaker 1: regenerative medicine in other way, somebody doing bones, somebody doing
23:23
Speaker 1: blood vessels, and they both use this term that I
23:27
Speaker 1: think I've seen you use elsewhere and that I'm reminded
23:29
Speaker 1: of here, and that is it's more of a phrase
23:32
Speaker 1: that is that cells are intelligent. Cells have some intelligence,
23:37
Speaker 1: which is not intuitive, but but I'm reminded of it here.
23:41
Speaker 1: Like what's going on? How does that work?
23:44
Speaker 2: It's a great question, and in fact, it's almost a
23:47
Speaker 2: testimony to why lie genesis exists. That many academic researches
23:51
Speaker 2: that never found companies can get not distracted because it's
23:55
Speaker 2: really the fundamental scientific pursuit of why and how. But
23:59
Speaker 2: to Eric's credit, when he's.
24:01
Speaker 1: So long you don't know the answer, you don't.
24:03
Speaker 2: Know, You're absolutely right. The short answer is we don't know.
24:09
Speaker 2: The longer answer is yeah, well, short answers we don't
24:14
Speaker 2: know too. I think you're right. The cells are remarkably intelligent,
24:19
Speaker 2: and we know there's those dozens of pro growth signals
24:21
Speaker 2: from the disease liver. We know they play a role,
24:25
Speaker 2: but exactly how it works, I'm thankful. Let's put it
24:28
Speaker 2: this way that Eric focused on trying to get it
24:31
Speaker 2: not to work, because he ended up finding that it
24:33
Speaker 2: was so robust, where you know, a lot of researchers
24:37
Speaker 2: would been their whole life trying to understand the why
24:39
Speaker 2: and how well.
24:40
Speaker 1: And clearly in other organs or body parts, like I
24:45
Speaker 1: remember in the case of blood vessels, and this is
24:48
Speaker 1: a classic challenge when people are trying to grow organs
24:52
Speaker 1: or mini organs, is they do a lot of work
24:55
Speaker 1: to create the scaffolding, to create the structure, right, and
24:58
Speaker 1: so the fact that in this instance it is naturally
25:02
Speaker 1: self organizing solves what seems to be the largest problem
25:06
Speaker 1: or at least a key problem.
25:08
Speaker 2: For any other organs, I would just say, yeah, it
25:12
Speaker 2: is better to be lucky than good, and that really
25:15
Speaker 2: is a case. Nature has really engineered this in a
25:20
Speaker 2: lot of respects. Right As a drug developer, so often
25:24
Speaker 2: you're trying to trick the body, right, like you're trying
25:27
Speaker 2: to trick it to do something that's unnatural and have
25:30
Speaker 2: to fight against it all along the way. I think
25:32
Speaker 2: what excites me about regenerative medicine, but like genesis in particular,
25:36
Speaker 2: is that we just have a lot of headwinds because
25:38
Speaker 2: of evolution and biology than the naturally regenerative capability of
25:44
Speaker 2: the liver, the natural ability of the lymph node to
25:47
Speaker 2: buy or react a variety of tissues. Because Eric shown
25:49
Speaker 2: that it's not just to patasites and ectopic livers, he
25:53
Speaker 2: can grow. He can put pancreatic islets and rescue animals
25:57
Speaker 2: that have diabetes by putting those islets into lymph nodes.
26:00
Speaker 2: He can put the thymus from a young animal into
26:07
Speaker 2: the lymph node of an old animal and help reboot
26:10
Speaker 2: that old animal's immune system, and in fact the whole
26:14
Speaker 2: animal starts to look more youthful physiologically as a function
26:18
Speaker 2: of that. So I think the lymph node is going
26:21
Speaker 2: to act as a platform for a variety of different tissues,
26:25
Speaker 2: and so at like genesis, where the liver is certainly
26:28
Speaker 2: the most you know, far along of the assets we have,
26:31
Speaker 2: but we also have this work on the thymus and
26:34
Speaker 2: the kidney and the pancreas, because as I said, the
26:37
Speaker 2: lymph node is it's just remarkably agnostic about the type
26:40
Speaker 2: of tissue that it bioreacts.
26:42
Speaker 1: And just to be clear that other work that is
26:45
Speaker 1: that is not yet in humans, right, that is earlier year.
26:47
Speaker 1: That's correct, That's exactly right. Yeah, so correct in the
26:51
Speaker 1: liver trial, which is the one that's the farthest along.
26:53
Speaker 1: So let's talk about that. What might go wrong? Why
26:56
Speaker 1: might it not work?
26:58
Speaker 2: In terms of what might go wrong, our body's ability
27:03
Speaker 2: to reject what's called allogenetic, which is just the medical
27:06
Speaker 2: term right for from another from another person, say, from
27:10
Speaker 2: another animal. Our body's ability to do that has been
27:15
Speaker 2: central to our success as a species. And as a result,
27:18
Speaker 2: when you try to get around it, you have to
27:21
Speaker 2: use very powerful drugs to try to convince it not
27:25
Speaker 2: to reject those cells. And so I think acute rejection,
27:29
Speaker 2: especially when you're injecting a relatively small number of cells
27:32
Speaker 2: as compared to a very large organ. I think that's
27:35
Speaker 2: one thing that you worry about.
27:37
Speaker 1: Oh, the small number of cells, because it's like easier
27:40
Speaker 1: for the body with its immune response to wipe out
27:43
Speaker 1: a small number of cells. Isn't exactly right? Yeah, dumb question.
27:48
Speaker 1: I mean I sort of know the answer. But presumably
27:51
Speaker 1: the patients with liver disease have some of their own
27:54
Speaker 1: liver cells left. Yes, what if you took some of
27:56
Speaker 1: their own liver cells and put them in the lymph node,
27:59
Speaker 1: you wouldn't have the rejection problem.
28:01
Speaker 2: That's a great question, and we get that a lot
28:04
Speaker 2: for the patients that were targeting within stage's liver disease.
28:07
Speaker 2: The liver is also grown to potentially catastrophic bleeding risk,
28:12
Speaker 2: and so the notion of biopsing a fibrotic liver is
28:17
Speaker 2: one that has, you know, very significant medical risks associated
28:21
Speaker 2: with it.
28:21
Speaker 1: Okay, another one. I'm just good. I'm this one. I'm
28:23
Speaker 1: just making up. Can you do like induced pluripotent stem
28:30
Speaker 1: cells from the patient and turn them into liver cells.
28:33
Speaker 2: That's that is exactly our vision actually for our for
28:36
Speaker 2: our second generation therapy. So our first generation therapy is
28:39
Speaker 2: going to be these allogenetic cells. The second generation will
28:42
Speaker 2: be exactly that, the hope, and there are labs around
28:45
Speaker 2: the world working on this. No one's solved it yet.
28:48
Speaker 2: But induced pluripotent stem cells where you take a skin
28:51
Speaker 2: cell and you push it back to a more embryonic
28:54
Speaker 2: like state and then bring it forward as a different
28:56
Speaker 2: cell type. You know, we've had tremendous success in a
28:59
Speaker 2: variety of cell types to have a fully mature human
29:03
Speaker 2: hepatocide is something that no one's been able to do yet.
29:06
Speaker 1: Nobody's been able to get a stem cell to turn
29:09
Speaker 1: into a mature human liver cell. Oh exactly, So okay,
29:13
Speaker 1: So immune rejection that's one problem. What else?
29:17
Speaker 2: You know, one thing that we didn't worry a lot about,
29:20
Speaker 2: but just because we had endoscopic colleagues that assured us
29:24
Speaker 2: this was a very safe procedure. But you know, I've
29:26
Speaker 2: taken several drugs first into human you always worry, and
29:29
Speaker 2: so with patients with bleeding risk, you know, the the
29:32
Speaker 2: indoscopic ultrasound is something that you want to make sure
29:36
Speaker 2: goes well. But again we're using incredibly talented endoscopist. They
29:40
Speaker 2: do the same procedure to look for patients who've been
29:43
Speaker 2: newly diagnosed with pancreatic cancer. The good news is we're
29:47
Speaker 2: asking endoscopists to do something they're very familiar with, using
29:51
Speaker 2: equipment they're very familiar with. But still you always worry
29:53
Speaker 2: about you know, you're going through the gut wall with
29:56
Speaker 2: a needle and into a lymph node, and you know
29:58
Speaker 2: you always want that to go well. And at this
30:00
Speaker 2: point we've had no serious adverse events from the administration itself,
30:05
Speaker 2: but that's something you know, that's why you start low
30:07
Speaker 2: and go slow, as they say, right in these first
30:09
Speaker 2: and human trials.
30:10
Speaker 1: And then so these are the sort of technical risks
30:15
Speaker 1: or medical risks. Is there like running out of money?
30:19
Speaker 1: I mean a biotech company with no product, Like, how's
30:22
Speaker 1: how's that part of it?
30:24
Speaker 2: Sure? Yeah, there's always business risk.
30:26
Speaker 1: You know.
30:26
Speaker 2: I was told a long time ago that the the
30:28
Speaker 2: definition of a biotech is a company unencumbered with revenues.
30:33
Speaker 1: And you know you don't have to worry about the
30:35
Speaker 1: profit loss exactly only half.
30:38
Speaker 2: You and l is very yeah, we only have half
30:40
Speaker 2: of it. So I will say that, Yeah, you always
30:43
Speaker 2: worry about running out of money. Drug development always takes
30:45
Speaker 2: longer and costs more than you hope it will, even
30:48
Speaker 2: when you've done it a long time, there's always surprising challenges.
30:51
Speaker 2: I will say, you know, we're fortunate to have wonderful
30:54
Speaker 2: investors that are patient with us despite the inevitable setbacks
30:58
Speaker 2: as we push forward. As a drug developer, you're always
31:02
Speaker 2: taught that great drugs are killed at least three times
31:04
Speaker 2: right before they actually make it over the finish line.
31:07
Speaker 2: So we have we have folks that are with us
31:10
Speaker 2: and supporting us, and we've tried to be very cappully efficient.
31:12
Speaker 2: Like Genesis is just half a dozen people. We've raised
31:16
Speaker 2: under forty million dollars to date, where when you look
31:18
Speaker 2: at the typical cost to get an investigational new drug
31:21
Speaker 2: clearance by the FDA or a IP that usually costs
31:25
Speaker 2: hundreds of millions of dollars, and just you know, we've
31:28
Speaker 2: been fortunate to not need a staggering amount of capital
31:32
Speaker 2: to get to where we are, which is in the clinic,
31:35
Speaker 2: in part because of the NIH funding that Eric Leagas
31:38
Speaker 2: had at the University of Pittsburgh. And it really is
31:41
Speaker 2: why the NIH cuts that we've seen happen really are
31:44
Speaker 2: undermining the kind of future potential of so many new
31:49
Speaker 2: therapies and technologies that you're simply not going to hear
31:52
Speaker 2: about because the funding wasn't available for them to move forward.
31:55
Speaker 2: But thankfully Eric's work was very well funded by the
31:58
Speaker 2: NIH and so we've we've been able to take it forward.
32:03
Speaker 1: So I just want to talk for a minute more
32:05
Speaker 1: broadly about straight to such should we talk about cellular
32:10
Speaker 1: therapy or regenerative medicine? Right, you're kind of both. Yeah,
32:14
Speaker 1: we're sort of reading the world, right, but I'm not sure.
32:17
Speaker 1: I mean, I recognize that what you were doing is
32:19
Speaker 1: distinct and particular, but it does seem like there is
32:23
Speaker 1: this broader landscape that you were part of, where people
32:26
Speaker 1: are using cells to treat disease, and people are thinking
32:31
Speaker 1: about how to create new versions of skin and of
32:35
Speaker 1: blood vessels, and are working on new ways of thinking
32:38
Speaker 1: about organs and transplantation. I mean, what does the broader
32:42
Speaker 1: landscape look like from your point of view and where
32:45
Speaker 1: do you fit into it? And like what are the
32:46
Speaker 1: big shifts, Like what do you expect to see in
32:49
Speaker 1: the next five tenures?
32:52
Speaker 2: Look, I think in ten years there is the realistic
32:55
Speaker 2: possibility that at least in some cases like a liver transplant,
32:59
Speaker 2: that those are relegated to medical history books, that the
33:04
Speaker 2: notion of being on a wait list for an organ
33:08
Speaker 2: will hopefully seem as foreign and strange to our children
33:12
Speaker 2: and grandchildren. Like you talk to a grandparent, you're like, wait,
33:14
Speaker 2: there were these sanatoriums with iron lungs everywhere. So I
33:19
Speaker 2: think there's this opportunity that we really are going to
33:22
Speaker 2: be turning the page from a medical history perspective, and
33:26
Speaker 2: that there is the potential that in the really foreseeable future,
33:30
Speaker 2: you're going to be the source of your own medicine.
33:33
Speaker 2: You're going to be able to engineer your own cells
33:36
Speaker 2: to avoid the problems of immune suppression and use them
33:39
Speaker 2: in ways to induce remarkable regenerative outcomes, both in terms
33:44
Speaker 2: of organ regeneration potentially in terms of lem regeneration, and
33:48
Speaker 2: do things that again seem like science fiction today. Now
33:53
Speaker 2: things always take longer and cost more than you hope.
33:55
Speaker 2: But I do think when you look broad brushstrokes, we
33:58
Speaker 2: really are on the cusp of a very exciting time.
34:01
Speaker 1: That way, we'll be back in a minute with the
34:09
Speaker 1: lighting round, and now we are going to finish with
34:20
Speaker 1: the lightning round. You were a practicing clinical psychologist before
34:28
Speaker 1: you got into the drug development business. Briefly, how did
34:32
Speaker 1: that happen? Briefly?
34:35
Speaker 2: I was very fortunate to work on some research methodologies
34:38
Speaker 2: that were used widely in clinical psych but had a
34:41
Speaker 2: lot of applicability and drug development, and so got involved
34:45
Speaker 2: in consulting in that kind of niche area of research design,
34:50
Speaker 2: and really just love the intersection of science and business
34:54
Speaker 2: because you saw how much more rapidly you could you
34:57
Speaker 2: could make progress, and how many more lives you could
35:00
Speaker 2: affect than just writing publications. So and I'll also say
35:04
Speaker 2: when you meet with the FDA, having those group psychotherapy
35:06
Speaker 2: skills can come in remarkably helpful.
35:09
Speaker 1: I feel like you're not joking when you say that.
35:11
Speaker 1: It plays a joke, but.
35:15
Speaker 2: You're you're right on that you kind of joke about
35:18
Speaker 2: the skills of a clinical psychologist, but those key skills
35:21
Speaker 2: in business settings being able to kind of take the
35:23
Speaker 2: perspective of other people very rapidly and pick up on
35:26
Speaker 2: concerns they may have that actually ends up being you know,
35:29
Speaker 2: incredibly essential and regulatory interactions.
35:34
Speaker 1: So you did research on smoking cessation in your previous
35:38
Speaker 1: professional life. What's one thing that you learned about addiction
35:42
Speaker 1: in your research.
35:44
Speaker 2: You know that when you're trying to understand why some
35:46
Speaker 2: people return to substance use, so much of it can
35:50
Speaker 2: come down to momentary decisions and small slips and how
35:55
Speaker 2: a single slip can lead to a full blown relapse,
35:57
Speaker 2: but from that single slip people can recover and rebound,
36:02
Speaker 2: and finding out how these fleeting life stressors can play
36:05
Speaker 2: an incredibly large role in just kind of that chaos
36:09
Speaker 2: of life that kind of pushes us on different trajectories
36:13
Speaker 2: that ends up, you know, making you a smoker or
36:16
Speaker 2: a non smoker or so is it just random?
36:20
Speaker 1: I mean, what what do I what is the inference
36:22
Speaker 1: from that? Like? What does that mean?
36:24
Speaker 2: Yeah, well, you know, some of my work was actually
36:26
Speaker 2: in something called catastrophe modeling, which was a subset of
36:30
Speaker 2: chaos theory that kind of fundamental of the butterfly wings
36:34
Speaker 2: causing the tornado, right, that these very small changes in
36:37
Speaker 2: life can have this outsized impact, and it was it
36:41
Speaker 2: was hard to avoid that conclusion when you look at
36:44
Speaker 2: real time monitoring of folks trying to quit smoking.
36:48
Speaker 1: So I understand you also run a nonprofit called Harm
36:52
Speaker 1: Reduction Therapeutics that brought to market a generic over the
36:56
Speaker 1: counter version of noloxone.
36:58
Speaker 2: That's correct.
36:59
Speaker 1: Briefly, how'd that happen? There was a huge.
37:04
Speaker 2: Unmet need, as you know, as the opioid crisis unfolded.
37:07
Speaker 2: Noloxone had been FDA proof since seventy one, it'd been
37:10
Speaker 2: off patents since eighty five. It was an incredibly effective,
37:14
Speaker 2: incredibly safe opioid overdose andidote, but for profit companies were
37:19
Speaker 2: refusing to take their products over the counter because they
37:23
Speaker 2: were making such high margins on them as prescription products.
37:27
Speaker 2: Got extraordinarily frustrated with that set of circumstances when you
37:30
Speaker 2: had over one hundred thousand Americans dying annually of opioid overdose.
37:34
Speaker 2: So my colleague John pinion I formed a five oh
37:37
Speaker 2: one C three nonprofit pharmaceutical company and ended up bringing
37:42
Speaker 2: in over the counter three milligram Naloxo nasal spray and
37:46
Speaker 2: doing it as a nonprofit. We entered the market at
37:49
Speaker 2: about thirty six dollars worth thirty three dollars now at
37:53
Speaker 2: the time Narcan was one hundred and forty dollars and
37:56
Speaker 2: lo and behold, you can buy them now for about
37:59
Speaker 2: mid thirty dollars per pack. So the hand of the
38:01
Speaker 2: market did its job, you know, So we forced other
38:05
Speaker 2: folks to go over the counter with their product, forced
38:07
Speaker 2: them to lower their price. And yeah, that's something that
38:11
Speaker 2: I was a very satisfying professional accomplishment to kind of
38:14
Speaker 2: help the whole field move forward. So our product, Revive
38:18
Speaker 2: is now this FDA approved over the counter three milligram
38:22
Speaker 2: internasal noloxo nasal spray for emergency treatment of opioid overdose.
38:27
Speaker 1: Last one, you've written that if you're running a startup,
38:31
Speaker 1: you can only have three out of the following five things. Family, friends, sleep, exercise,
38:38
Speaker 1: and hobbies. Which are your three? Oh?
38:42
Speaker 2: Man, I'm very fortunate to have a family that I
38:47
Speaker 2: adore and cannot spend enough time with, so I would
38:49
Speaker 2: say family. I do exercise regularly. Oh I was so,
38:55
Speaker 2: Hold on, what were.
38:56
Speaker 1: The So you have to choose now one from the
38:59
Speaker 1: following three? Friends, sleep, or hobbies.
39:04
Speaker 2: I don't see near as much of my friends as
39:07
Speaker 2: I would like, so I guess I would say hobbies
39:11
Speaker 2: are the other thing that keep me grounded.
39:14
Speaker 1: Also, you don't sleep. Unfashionable it's suddenly fashionable?
39:19
Speaker 2: Yeah, exactly, exactly.
39:21
Speaker 1: Not as much as i'd like. What's the hobby.
39:24
Speaker 2: Amateur musician, so you know, kind of singer songwriter and yeah,
39:29
Speaker 2: so amateur musician in my very spare time.
39:33
Speaker 1: Is there a song of yours we should play under
39:35
Speaker 1: the credits of today's show? Can you play us out?
39:40
Speaker 2: I'll think about it. Sure, I'll send you something you
39:42
Speaker 2: can play out.
39:42
Speaker 1: Okay. It was delightful to talk with you. Thank you
39:46
Speaker 1: for your time, Jacob. It was really, really nice.
39:49
Speaker 2: These were wonderful questions. I actually really enjoyed the conversation.
39:56
Speaker 1: Michael Hufford is the co founder and CEO of Like Genesis.
40:00
Speaker 1: Today's show was produced by Gabriel Hunter Chang, edited by
40:03
Speaker 1: Lydia Jean Kott, and engineered by Sarah Bruguer. I'm Jacob Goldstein.
40:08
Speaker 1: Will be in the next couple of weeks off and
40:11
Speaker 1: then we'll be back in the meantime. You can email
40:14
Speaker 1: us at problem at pushkin dot fm, or you can
40:17
Speaker 1: find me on LinkedIn or on x I'm at Jacob Goldstein.
40:21
Speaker 1: Thanks for listening. We'll be back in a few weeks.
40:25
Speaker 1: Oh sick, Oh sick.