March 19, 2026 • 40 mins
Michael Hufford is the co-founder and CEO of LyGenesis, a company working on a new treatment for end stage liver disease. Michael’s problem is this: How do grow a new liver inside the body of a sick patient?
In this episode, Michael explains:
- The liver's unique power of regeneration
- The organ transplant crisis and how regeneration can help
- The science behind using lymph nodes to grow new organs
- The status of LyGenesis’ human trials
- The future of regenerative medicine
Learn more:
- Check out LyGenesis’ website
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:15):
Pushkin. I'm Jacob Goldstein. This is What's your Problem? And
my guest today is Michael Hufford. He's the co founder
(00:37):
and CEO of a company called Ligenesis. Michael and his
colleagues are working on a new kind of medical treatment.
If it works, it will save lives. And I have
to say the way the treatment is supposed to work
is wild. It's for people with end stage liver disease
who don't qualify for a liver transplant. And what le
Genesis does is they take healthy liver cells, just cells,
(01:01):
and they inject those cells into the patient's lymph nodes,
and then the patient grows one or more little new
liver in those lymph nodes. This has worked in experiments
in animals, and now they're trying it in people. In
our conversation, Michael told me about the science of why
this might work. He told me what it would mean
(01:21):
for patients if it does work, and we also talked
about why it might not work. And then we talked
a little bit about the future of regenerative medicine more broadly,
and the possibility of a world where no one dies
waiting for an organ transplant. But to start Michael told
me some truly interesting facts about the liver and Greek mythology.
Speaker 2 (01:44):
It is remarkable because it's the only organ in the
human body that will naturally regenerate. So you can lose
seventy percent of your liver, and over a course of
just a few weeks, you will regenerate that liver entirely.
And that's true only for the liver. And ironically, it's
something we've known for three thousand years, right the myth
of Prometheus, if you might remember, the titan that stole
(02:07):
fire from Zeus and gave it to a man was
punished by being chained to a rock, and that eagle
would come every day and eat his liver, and the
punishment was eternal, because his liver would regenerate, an eagle
would have more liver to feast on the next day.
Speaker 1 (02:24):
I I was vaguely familiar with the myth of Prometheus,
but I was not familiar with the fact that the
liver regenerates itself. I mean, do you infer that the
Greeks knew that? Yeah?
Speaker 2 (02:35):
Absolutely, I think they did know that. I think probably
through the experiences in battle and what have you, you
could they could see that you could sustain a dramatic
injury to the liver and that, unlike any other organ,
it would regenerate. But at the same time, it's taken
us three thousand years to get to the point that
one we can successfully transplant it.
Speaker 1 (02:56):
Right.
Speaker 2 (02:56):
That was the pioneering work of doctor Tom Starzel. You know,
he first attempted it in nineteen sixty three, got it
to work in nineteen sixty seven. It saved tens of
thousands of patients lives since then, and Nowgenesis is really
standing on the shoulders of folks like doctor Starzel and
now trying to regenerate the liver in other places in
(03:17):
the body.
Speaker 1 (03:18):
Let me ask a nitpicky question before I ask a
real question. Is the skin an organ? And does the
skin regenerate itself?
Speaker 2 (03:26):
That's a good that's a good point. The skin has
some ability to regenerate itself, for sure, And in fact,
in children, if a small child loses the tip of
a finger in an accident before the age of seven,
you can actually regrow the tip of your finger. But
we lose that that remarkable ability to regenerate as we
(03:47):
get older, and the only organ that retains that capability
is the liver.
Speaker 1 (03:54):
So you mentioned liver transplants, incredible life saving technology. Let's
call it a technology. Why why do we need ligenesis? Like,
what is the limit of liver transplants? Liver transplants?
Speaker 2 (04:10):
We have about nine thousand patients on the US currently
for a liver transplant. Fifteen to twenty percent of those
patients will die each year awaiting a liver transplant to
become available. So I would say it's there's really a
fundamentally a two fold problem. One is supply and demand. Today,
one donated organ treats one patient using our technology, a
(04:34):
single donated organ, because we're isolating the individual liver cells
or hepatosites from that liver, a single donated organ could
treat fifty patients. So one, we're kind of fixing and
really up ending the supply demand calculus when it comes
to you know, instead of one donated organ treating one patient,
with our approach, one donated organ can treat up to
fifty patients. But the other problem is is what oftentimes
(04:57):
people aren't aware of, which is for all the you know,
the understandable human drama of a liver transplant weightlist, of
all the organ transplant weight lists, where people are waiting
for this life save even gift of organ donation. Many
patients are too ill to even make the list. So
in the US you have about five million cases of
(05:19):
in stage liver disease in one form or another. You
have eighty five thousand deaths. At least fifty percent of
the patients that could benefit from an organ transplant don't
qualify because we know that they simply won't survive the procedure.
Speaker 1 (05:34):
Because it's a big, open surgery that involves a lot
of trauma, and if you're very sick already, you'll probably
die from the surgery. Yes. Correct, So you co founded
the company with scientists with a researcher named Eric Leagas right,
and it was based on research that he had done.
So tell me about meeting him where you were and
(05:56):
what was the work he had done that you found
so compelling that you had to go start a company
with him? Yeah, absolutely so.
Speaker 2 (06:02):
Eric Legass is a professor at the McGowan Institute for
a Generative Medicine and Pathology at the University of Pittsburgh.
At the time, I was an entrepreneur in residence at
the University of Pittsburgh and I had spent twenty five
years doing drug development and had been fortunate to work
on a number of very innovative programs and had started
and sold a number of companies. And so was working
(06:22):
with the University of Pittsburgh because they get almost a
billion dollars of NIH funding annually. It's remarkably remarkable research enterprise,
both at the University of Pittsburgh and the University of
Pittsburgh Medical Center or UPMC, and so they wanted to
get more companies spun out as a function of that funding.
And so one day a colleague of mine took me
to meet Eric Lagas, and what Eric told me was
(06:46):
a remarkable story in two ways. One, he showed me
these remarkable pictures from his publication in Nature Biotechnology, showing
that he could regrow organs in the lymph nodes of mice.
That he could take liver cells from a mouse and
graph them into the lymph node of another mouse. And
(07:06):
these animals had a genetic liver disease, and so as
a function of that liver disease, they would otherwise die
from that liver disease. But when he ingrafted these hepatosites
into their lymph nodes, those lymph nodes acted as living bioreactors,
and they literally grew those animals miniature livers, so that
instead of dying from their liver disease, one hundred percent
(07:29):
of them were rescued from that otherwise fatal liver disease.
So he had these pictures that were truly jaw dropping,
you know, of these ectopic organs in places in the
body that they should not otherwise be.
Speaker 1 (07:41):
So I just want to repeat what you just said
because it is the central extraordinary fact of the thing
that you are doing. Right. What Leagas did was he
had put liver cells, just cells, into the lymph nodes
of these mice that had liver disease, and within the
lymph node there grew a teeny liver that worked, that
(08:06):
did what the big liver needed to do, and the
mice did die. Like why why should that even be true? Yeah,
So two things.
Speaker 2 (08:15):
One, over time the lymph node disappears, the lymph node
acts as a temporary bioreactor to get that ectopic organ
and by ectopic we just mean in a different place
in the body that ectopic liver to grow. And in fact,
those ectopic livers and mice could grow to seventy percent
the size of a normal liver. So he could grow
really quite large ectopic livers using these lymph nodes.
Speaker 1 (08:38):
And that doesn't mess the mice up. It doesn't like
mess up their emphatic system or something like that.
Speaker 2 (08:44):
Yeah, So remarkably, we've seen no untoward effects on the
immune system, now, partly because let's stop and talk about
lymph nodes for a second, right, So, lymph nodes in
the human body, we have four hundred and fifty to
seven hundred lymph nodes spread throughout our body, a majority
in our gut area, right, and they've helped us as
(09:04):
a species survive infection, right, because what a what a
lymph node does, It's its primary evolutionary function is help
bioreact T cells. So when you develop a cold, you
have a sore throat and you feel that nodule that
kind of you know marble or maybe even you know
large marble underneath your jaw, that's a lymphnode that's bioreacted
(09:26):
billions of T cells to help you fight that infection.
Speaker 1 (09:29):
When you say bioreact, you basically mean grow, right, it.
Speaker 2 (09:33):
Is it is an admittedly biotech jargon term for grow.
Speaker 1 (09:38):
That's exactly right. Okay, So the lymph note is a
really good place for cells to grow. That's one reason
it works, or it works in animals. You said there
were two reasons. The what's the other reason?
Speaker 2 (09:50):
The other is what's special about the liver and why
even the Greeks, you know, knew that it would regenerate
under the right circumstances. Is the fundamental cell of the
liver is the hepatocite. Hepatasites are naturally regenerative, and so
Eric's fundamental s scientific discovery was that if you combine
(10:12):
that natural regenerative potential of the hapatosite with the natural
ability of the lymph node to bioreact cells, you get
this remarkable effect. And you could think of it as
the flip side of the cancer coin. You know, many
people are aware that cancer probes the environment to form tumors,
(10:32):
and very often cancer will grow tumors in someone's lymph nodes.
Speaker 1 (10:37):
Right, And in fact, that the classic sort of staging
question in cancer set has it spread to the lymph nodes?
And if it has in the case of cancer, that
is bad.
Speaker 2 (10:47):
That is bad, exactly right, precisely because lymph nodes are
such effective bioreactors, and they are agnostic as to what
they bioreact You know, they're so good at growing cells. Yeah,
exactly right. So if a cancer cell gets in there,
the cancer cell thinks, man, that's a fantastic place. I
have access to blood and nutrients, and I have a
confined space that I can focus on growth. And what
(11:10):
you end up are these is the spread of these tumors. Well,
what Eric realized is that you could turn that biology
to it to a therapeutic instead of a malignant potential.
So by putting a self therapy like apatasite into a
lymph node, you could generate functional tissues that exerted life
(11:31):
saving effects. And so he showed me those first pictures
from his study, and it really was jaw dropping. And
I asked him that afternoon what I thought was the
gotcha question, because it so often is with academic minded professors.
I said, well, you know, that's great, Eric, it's incredibly impressive.
What about large animals.
Speaker 1 (11:49):
Right, it's good news for mice. Right, you must exactly
the phrase mice lie and primates exaggerate drug. I love
that I had not heard that. Somebody told me that
twenty five years that's fantastic. I'm going to steal it. Actually,
that's wonderful.
Speaker 2 (12:06):
So and he said, oh yeah, Michael. And in fact,
his colleague, doctor Palofontes, who was our co founder and
chief medical officer, showed that the exact same principle applied
in pigs. So they showed you could take a pig
that would otherwise die from a fatal liver disease, and
you could rescue that pig using the exact same procedure.
(12:27):
And they even tried a different model where they surgically
injure the liver. There's something called a portocable shunt where
you can go in and kind of rearrange the plumbing
of the liver, so to speak, to deprivate of blood flow,
which was a procedure that doctor Starzeal had pioneered as
a way to test and develop the procedure that would
eventually become liver transplantation. And again rescued those animals. And
(12:50):
he told me something that as a drug developer you
virtually never hear. He said, Michael, I can't get this
not to work. And as a drug developer, right, I'd
spent my entire career and the entire industry really is
focused on getting the exact right drug delivered in the
exact right way to the exact right patient, exact right dose,
(13:10):
oftentimes at the exact right time of day, and you
hope for an effect. And what Eric was telling me
was that nature had kind of primed this approach between
the natural originative capacity of the liver the natural bioreactor
capabilities of the lymph node, and that when he said
he couldn't get it not to work. Quite literally, the
hairs on the back of my neck stood up, and
(13:33):
I said, Okay, let's back up and go over this
whole story again, you know, And really that day was
the genesis of the company.
Speaker 1 (13:42):
So you start the company nine years ago, is that right?
Twenty seventeen?
Speaker 2 (13:49):
Yeah, Yeah, time's flown.
Speaker 1 (13:50):
Yeah yeah. I mean it takes a long time to
develop new therapies, right, This is regenerative medicine, cell therapy,
a hard new thing to do. So where are you
now nine years later? Yeah?
Speaker 2 (14:04):
So we are now running a first in human phase
two a clinical trial. So this is a clinical trial
in patients within stage liver disease. These are patients, most
of them, not all, Most are on the liver transplant
wait list and they can come into the trial. They
may have any number of different types of liver disease,
(14:25):
but we're going for patients who have in stage liver
disease that typically have a life expectancy of many months
or a few years, okay, because we know that. We
know that one limitation of our approach is that when
you ingraph these cells, they do take time to organize themselves.
It's not like the next day you have, you know,
(14:46):
a fully functioning actopic liver. We know that it takes
probably two to three months, is our best guess, and
so we want to make sure that these patients have
the time to have the potential beneficial effects of the therapy.
So we've now transplanted our first cohort of patients. There
were four patients, all done at the Houston Methodist Hospital.
(15:07):
Like you typically the phrases, you start low and go slow,
you start low in dose and go slow because you're
not sure what the effect will be. And so the
FDA had counseled us this first trial is just going
to be twelve patients, so we have three different dose groups.
We've completed that first dose cohort and we had a
data Safety Monitoring Board meeting where they look at all
(15:28):
the safety data and the efficacy data to date and
they said, okay, you know, it's looking good. Let's let's
go on and dose escalate as per the protocol. And
so that's that's what we are in the midst of
right now.
Speaker 1 (15:41):
One are you going to know if it worked, if
this trial, you know, had a positive result, that will
allow you to move to presumably the next bigger trial.
Speaker 2 (15:52):
Yeah, we should have a very good sense of that
in the middle part of next year. Okay, so the
middle part of twenty twenty seven, and then yeah, move
on from there.
Speaker 1 (16:00):
So let's talk about how it works. So there's a patient,
as you've said, yeah, who is you know, has liver disease,
has some liver function left, but it's not looking good
for them. And then there is what a donated liver.
Like what actually happens.
Speaker 2 (16:17):
That's exactly right. When an organ becomes available, if the
organ is eligible for transplant, then it's transplanted into a
patient that needs it. Some organs, though, are not eligible
for transplant, and that can be for any number of reasons.
They may have been injured because of the cause of death,
they might be a little fatty where when the transplant
(16:39):
surgeon looks at the organ they think, ah, you know,
that's not going to be a great fit for this
particular patient, and so that they pass on it when
they come to us. We then have a facility at
Houston Methodist currently where we can take that organ and
it takes us just about four or five hours. It's
(16:59):
a seventy plus step process, but we start with the
full organ and after seventy steps and about four to
five hours, we've isolated and suspended those hepatocytes into a
solution that we then currier over to the endoscopic ultrasound suite.
Speaker 1 (17:18):
And so just to be clear, it's it's when you
say the patasites are in a solution, it's like a
bottle full of liver cells in liquid.
Speaker 2 (17:27):
That's That's That's exactly what it is. Okay, It's a
small syringe really because really injecting about yeah, about one
about one milliliter of the cell suspension. But it's it's
literally like a brown thick liquid.
Speaker 1 (17:42):
That's yeah, So a syringe like like what like you'd
get in a shot, but instead of a vaccine, it's
liver cells from a donated liver. Okay, so then you
cur youer that over to go go on. Yeah.
Speaker 2 (17:52):
Yeah, And so the patient is put under light sedation
and just the way you might have an endoscope you know,
to look to see if you have an ulcer or
to you know, have any number of diagnostic procedures. Yes, Basically,
an endoscopius takes that into scope under sedation, down through
the mouth of the patient and then threads it down
(18:12):
their gi track kind of into their gut area. And
at the end of that endoscope is an ultrasound. And
so the ultrasound you can basically look adjacent to the
gut wall and lymph nodes there show up. Is they
almost look like bubbles to the untrained eye, right, So
they kind of look like these bubbles that come into
(18:35):
view via the ultrasound, and the endoscopist takes a five
foot needle that threads down through the industry thing. Yeah,
it then goes through the gut wall and punctures into
the lymph node.
Speaker 1 (18:50):
So it's like a shot. It's like a shot, but
it's going into your stomach, across the wall of your
stomach and into the lymph node. That's exactly right. That's
exactly right.
Speaker 2 (19:00):
And so this takes about ten minutes to find the
lymph node and inject the cell suspension. And so we
inject one millileter to that lymph node. They withdraw the
needle and pull the scope out, and the procedure itself
at that point is done. The cells are in the
lymph node. The patients put on immune suppression.
Speaker 1 (19:21):
Right, the patients put on immune suppression because these are
cells from somebody else. So it's just like if you
get a transplant, your body's cells will be like, oh,
that's foreign, I'm going to get rid of it. That's
exactly right. Yeah, okay, So the patients put on immune
suppression and then if it works, what happens.
Speaker 2 (19:39):
If it works, what happens is those cells find themselves
in an environment that they find very comforting and very nourishing,
and so they use that those bioreactor, you know, aspects
of the lymph node begin dividing because they're natural stem cells,
and they begin organizing themselves into liveral obdules, which are
(20:00):
these little hexagonal collections of cells that are kind of
the functioning filtering unit of the liver. And from all
of our preclinical data in both small and large animals,
that division will continue to go on and the vascularization
will then occur. So the lymph nodes are well vascularized anyway.
But what you find is that these ectopic organs recruit
(20:27):
cells from the patient's body to form additional vasculature, so
additional blood flow to that ectopic organ, so that over time,
and again our best guess is it's over a few
months of time, what you'll be left with is this
functioning ectopic organs. So I'm picturing one like tiny little
(20:49):
mini liver, like, I don't know how big is it?
Is there only one?
Speaker 1 (20:55):
How big does it have to be or how many
do there have to be for it to be clinically useful?
Speaker 2 (21:00):
They can get quite large. In small animals. You can
get up to seventy percent of the native liver grown
in a lymph node, and the larger animal was a
smaller percentage. And your question about clinically meaningful. You know,
when you talk to hepatologists or folks like our chief
medical officer, doctor Fontes, who's treated these patients, you know,
(21:21):
across his entire life, if you can bump the functional
amount of liver for one of these patients by ten
to twenty percent, you will alleviate a lot of the
signs and symptoms of their in stage liver disease. And
in fact, in stage liver disease is a problem because
very often patients don't know that they have advanced liver
disease until pretty far along, because it is a redundant system.
(21:44):
As a species, we have very large livers to help us,
you know, with the various things that we might eat
and get exposed to. So it's a redundant system and
by the time you know you have a problem, you
know you really have a problem. And so that's why
we think if we can even bump it up by
ten to twenty percent, I think this will be a
transformative therapy. So, you know, we envision clinically the potential
(22:07):
both to treat patients that are never going to get
an organ because they simply don't qualify for the list,
but for others it may be more clinically, what you're
doing is just buying them time so that an organ
can become.
Speaker 1 (22:19):
Available for them. We're gonna take an ad break right now,
and then we're gonna come back and talk about a
bunch of more things, including why what Michael, and like
genesis are working on might not work. I want to
(22:41):
go back to one detail or one step you mentioned
of what happens inside the body in this process, and
that is, after the cells have been injected, they are
just cells. They're just random liver cells floating around. And
you said they organize themselves essentially into a liver, into
(23:03):
a little liver. You didn't say into a living over
but that is essentially what's happening. Yeah, that part that
seems like the central shocking thing that is going on here, right,
And I've talked to a couple of other people doing
regenerative medicine in other way, somebody doing bones, somebody doing
(23:23):
blood vessels, and they both use this term that I
think I've seen you use elsewhere and that I'm reminded
of here, and that is it's more of a phrase
that is that cells are intelligent. Cells have some intelligence,
which is not intuitive, but but I'm reminded of it here.
Like what's going on? How does that work?
Speaker 2 (23:44):
It's a great question, and in fact, it's almost a
testimony to why lie genesis exists. That many academic researches
that never found companies can get not distracted because it's
really the fundamental scientific pursuit of why and how. But
to Eric's credit, when he's.
Speaker 1 (24:01):
So long you don't know the answer, you don't.
Speaker 2 (24:03):
Know, You're absolutely right. The short answer is we don't know.
The longer answer is yeah, well, short answers we don't
know too. I think you're right. The cells are remarkably intelligent,
and we know there's those dozens of pro growth signals
from the disease liver. We know they play a role,
(24:25):
but exactly how it works, I'm thankful. Let's put it
this way that Eric focused on trying to get it
not to work, because he ended up finding that it
was so robust, where you know, a lot of researchers
would been their whole life trying to understand the why
and how well.
Speaker 1 (24:40):
And clearly in other organs or body parts, like I
remember in the case of blood vessels, and this is
a classic challenge when people are trying to grow organs
or mini organs, is they do a lot of work
to create the scaffolding, to create the structure, right, and
so the fact that in this instance it is naturally
(25:02):
self organizing solves what seems to be the largest problem
or at least a key problem.
Speaker 2 (25:08):
For any other organs, I would just say, yeah, it
is better to be lucky than good, and that really
is a case. Nature has really engineered this in a
lot of respects. Right As a drug developer, so often
you're trying to trick the body, right, like you're trying
to trick it to do something that's unnatural and have
(25:30):
to fight against it all along the way. I think
what excites me about regenerative medicine, but like genesis in particular,
is that we just have a lot of headwinds because
of evolution and biology than the naturally regenerative capability of
the liver, the natural ability of the lymph node to
buy or react a variety of tissues. Because Eric shown
that it's not just to patasites and ectopic livers, he
(25:53):
can grow. He can put pancreatic islets and rescue animals
that have diabetes by putting those islets into lymph nodes.
He can put the thymus from a young animal into
the lymph node of an old animal and help reboot
that old animal's immune system, and in fact the whole
(26:14):
animal starts to look more youthful physiologically as a function
of that. So I think the lymph node is going
to act as a platform for a variety of different tissues,
and so at like genesis, where the liver is certainly
the most you know, far along of the assets we have,
but we also have this work on the thymus and
(26:34):
the kidney and the pancreas, because as I said, the
lymph node is it's just remarkably agnostic about the type
of tissue that it bioreacts.
Speaker 1 (26:42):
And just to be clear that other work that is
that is not yet in humans, right, that is earlier year.
That's correct, That's exactly right. Yeah, so correct in the
liver trial, which is the one that's the farthest along.
So let's talk about that. What might go wrong? Why
might it not work?
Speaker 2 (26:58):
In terms of what might go wrong, our body's ability
to reject what's called allogenetic, which is just the medical
term right for from another from another person, say, from
another animal. Our body's ability to do that has been
central to our success as a species. And as a result,
(27:18):
when you try to get around it, you have to
use very powerful drugs to try to convince it not
to reject those cells. And so I think acute rejection,
especially when you're injecting a relatively small number of cells
as compared to a very large organ. I think that's
one thing that you worry about.
Speaker 1 (27:37):
Oh, the small number of cells, because it's like easier
for the body with its immune response to wipe out
a small number of cells. Isn't exactly right? Yeah, dumb question.
I mean I sort of know the answer. But presumably
the patients with liver disease have some of their own
liver cells left. Yes, what if you took some of
their own liver cells and put them in the lymph node,
(27:59):
you wouldn't have the rejection problem.
Speaker 2 (28:01):
That's a great question, and we get that a lot
for the patients that were targeting within stage's liver disease.
The liver is also grown to potentially catastrophic bleeding risk,
and so the notion of biopsing a fibrotic liver is
one that has, you know, very significant medical risks associated
with it.
Speaker 1 (28:21):
Okay, another one. I'm just good. I'm this one. I'm
just making up. Can you do like induced pluripotent stem
cells from the patient and turn them into liver cells.
Speaker 2 (28:33):
That's that is exactly our vision actually for our for
our second generation therapy. So our first generation therapy is
going to be these allogenetic cells. The second generation will
be exactly that, the hope, and there are labs around
the world working on this. No one's solved it yet.
But induced pluripotent stem cells where you take a skin
cell and you push it back to a more embryonic
(28:54):
like state and then bring it forward as a different
cell type. You know, we've had tremendous success in a
variety of cell types to have a fully mature human
hepatocide is something that no one's been able to do yet.
Speaker 1 (29:06):
Nobody's been able to get a stem cell to turn
into a mature human liver cell. Oh exactly, So okay,
So immune rejection that's one problem. What else?
Speaker 2 (29:17):
You know, one thing that we didn't worry a lot about,
but just because we had endoscopic colleagues that assured us
this was a very safe procedure. But you know, I've
taken several drugs first into human you always worry, and
so with patients with bleeding risk, you know, the the
indoscopic ultrasound is something that you want to make sure
goes well. But again we're using incredibly talented endoscopist. They
(29:40):
do the same procedure to look for patients who've been
newly diagnosed with pancreatic cancer. The good news is we're
asking endoscopists to do something they're very familiar with, using
equipment they're very familiar with. But still you always worry
about you know, you're going through the gut wall with
a needle and into a lymph node, and you know
you always want that to go well. And at this
point we've had no serious adverse events from the administration itself,
(30:05):
but that's something you know, that's why you start low
and go slow, as they say, right in these first
and human trials.
Speaker 1 (30:10):
And then so these are the sort of technical risks
or medical risks. Is there like running out of money?
I mean a biotech company with no product, Like, how's
how's that part of it?
Speaker 2 (30:24):
Sure? Yeah, there's always business risk.
Speaker 1 (30:26):
You know.
Speaker 2 (30:26):
I was told a long time ago that the the
definition of a biotech is a company unencumbered with revenues.
Speaker 1 (30:33):
And you know you don't have to worry about the
profit loss exactly only half.
Speaker 2 (30:38):
You and l is very yeah, we only have half
of it. So I will say that, Yeah, you always
worry about running out of money. Drug development always takes
longer and costs more than you hope it will, even
when you've done it a long time, there's always surprising challenges.
I will say, you know, we're fortunate to have wonderful
investors that are patient with us despite the inevitable setbacks
(30:58):
as we push forward. As a drug developer, you're always
taught that great drugs are killed at least three times
right before they actually make it over the finish line.
So we have we have folks that are with us
and supporting us, and we've tried to be very cappully efficient.
Like Genesis is just half a dozen people. We've raised
under forty million dollars to date, where when you look
(31:18):
at the typical cost to get an investigational new drug
clearance by the FDA or a IP that usually costs
hundreds of millions of dollars, and just you know, we've
been fortunate to not need a staggering amount of capital
to get to where we are, which is in the clinic,
in part because of the NIH funding that Eric Leagas
had at the University of Pittsburgh. And it really is
(31:41):
why the NIH cuts that we've seen happen really are
undermining the kind of future potential of so many new
therapies and technologies that you're simply not going to hear
about because the funding wasn't available for them to move forward.
But thankfully Eric's work was very well funded by the
NIH and so we've we've been able to take it forward.
Speaker 1 (32:03):
So I just want to talk for a minute more
broadly about straight to such should we talk about cellular
therapy or regenerative medicine? Right, you're kind of both. Yeah,
we're sort of reading the world, right, but I'm not sure.
I mean, I recognize that what you were doing is
distinct and particular, but it does seem like there is
this broader landscape that you were part of, where people
(32:26):
are using cells to treat disease, and people are thinking
about how to create new versions of skin and of
blood vessels, and are working on new ways of thinking
about organs and transplantation. I mean, what does the broader
landscape look like from your point of view and where
do you fit into it? And like what are the
(32:46):
big shifts, Like what do you expect to see in
the next five tenures?
Speaker 2 (32:52):
Look, I think in ten years there is the realistic
possibility that at least in some cases like a liver transplant,
that those are relegated to medical history books, that the
notion of being on a wait list for an organ
will hopefully seem as foreign and strange to our children
and grandchildren. Like you talk to a grandparent, you're like, wait,
(33:14):
there were these sanatoriums with iron lungs everywhere. So I
think there's this opportunity that we really are going to
be turning the page from a medical history perspective, and
that there is the potential that in the really foreseeable future,
you're going to be the source of your own medicine.
You're going to be able to engineer your own cells
(33:36):
to avoid the problems of immune suppression and use them
in ways to induce remarkable regenerative outcomes, both in terms
of organ regeneration potentially in terms of lem regeneration, and
do things that again seem like science fiction today. Now
things always take longer and cost more than you hope.
But I do think when you look broad brushstrokes, we
(33:58):
really are on the cusp of a very exciting time.
Speaker 1 (34:01):
That way, we'll be back in a minute with the
lighting round, and now we are going to finish with
the lightning round. You were a practicing clinical psychologist before
(34:28):
you got into the drug development business. Briefly, how did
that happen? Briefly?
Speaker 2 (34:35):
I was very fortunate to work on some research methodologies
that were used widely in clinical psych but had a
lot of applicability and drug development, and so got involved
in consulting in that kind of niche area of research design,
and really just love the intersection of science and business
because you saw how much more rapidly you could you
(34:57):
could make progress, and how many more lives you could
affect than just writing publications. So and I'll also say
when you meet with the FDA, having those group psychotherapy
skills can come in remarkably helpful.
Speaker 1 (35:09):
I feel like you're not joking when you say that.
It plays a joke, but.
Speaker 2 (35:15):
You're you're right on that you kind of joke about
the skills of a clinical psychologist, but those key skills
in business settings being able to kind of take the
perspective of other people very rapidly and pick up on
concerns they may have that actually ends up being you know,
incredibly essential and regulatory interactions.
Speaker 1 (35:34):
So you did research on smoking cessation in your previous
professional life. What's one thing that you learned about addiction
in your research.
Speaker 2 (35:44):
You know that when you're trying to understand why some
people return to substance use, so much of it can
come down to momentary decisions and small slips and how
a single slip can lead to a full blown relapse,
but from that single slip people can recover and rebound,
and finding out how these fleeting life stressors can play
(36:05):
an incredibly large role in just kind of that chaos
of life that kind of pushes us on different trajectories
that ends up, you know, making you a smoker or
a non smoker or so is it just random?
Speaker 1 (36:20):
I mean, what what do I what is the inference
from that? Like? What does that mean?
Speaker 2 (36:24):
Yeah, well, you know, some of my work was actually
in something called catastrophe modeling, which was a subset of
chaos theory that kind of fundamental of the butterfly wings
causing the tornado, right, that these very small changes in
life can have this outsized impact, and it was it
was hard to avoid that conclusion when you look at
(36:44):
real time monitoring of folks trying to quit smoking.
Speaker 1 (36:48):
So I understand you also run a nonprofit called Harm
Reduction Therapeutics that brought to market a generic over the
counter version of noloxone.
Speaker 2 (36:58):
That's correct.
Speaker 1 (36:59):
Briefly, how'd that happen? There was a huge.
Speaker 2 (37:04):
Unmet need, as you know, as the opioid crisis unfolded.
Noloxone had been FDA proof since seventy one, it'd been
off patents since eighty five. It was an incredibly effective,
incredibly safe opioid overdose andidote, but for profit companies were
refusing to take their products over the counter because they
were making such high margins on them as prescription products.
(37:27):
Got extraordinarily frustrated with that set of circumstances when you
had over one hundred thousand Americans dying annually of opioid overdose.
So my colleague John pinion I formed a five oh
one C three nonprofit pharmaceutical company and ended up bringing
in over the counter three milligram Naloxo nasal spray and
doing it as a nonprofit. We entered the market at
(37:49):
about thirty six dollars worth thirty three dollars now at
the time Narcan was one hundred and forty dollars and
lo and behold, you can buy them now for about
mid thirty dollars per pack. So the hand of the
market did its job, you know, So we forced other
folks to go over the counter with their product, forced
them to lower their price. And yeah, that's something that
(38:11):
I was a very satisfying professional accomplishment to kind of
help the whole field move forward. So our product, Revive
is now this FDA approved over the counter three milligram
internasal noloxo nasal spray for emergency treatment of opioid overdose.
Speaker 1 (38:27):
Last one, you've written that if you're running a startup,
you can only have three out of the following five things. Family, friends, sleep, exercise,
and hobbies. Which are your three? Oh?
Speaker 2 (38:42):
Man, I'm very fortunate to have a family that I
adore and cannot spend enough time with, so I would
say family. I do exercise regularly. Oh I was so,
Hold on, what were.
Speaker 1 (38:56):
The So you have to choose now one from the
following three? Friends, sleep, or hobbies.
Speaker 2 (39:04):
I don't see near as much of my friends as
I would like, so I guess I would say hobbies
are the other thing that keep me grounded.
Speaker 1 (39:14):
Also, you don't sleep. Unfashionable it's suddenly fashionable?
Speaker 2 (39:19):
Yeah, exactly, exactly.
Speaker 1 (39:21):
Not as much as i'd like. What's the hobby.
Speaker 2 (39:24):
Amateur musician, so you know, kind of singer songwriter and yeah,
so amateur musician in my very spare time.
Speaker 1 (39:33):
Is there a song of yours we should play under
the credits of today's show? Can you play us out?
Speaker 2 (39:40):
I'll think about it. Sure, I'll send you something you
can play out.
Speaker 1 (39:42):
Okay. It was delightful to talk with you. Thank you
for your time, Jacob. It was really, really nice.
Speaker 2 (39:49):
These were wonderful questions. I actually really enjoyed the conversation.
Speaker 1 (39:56):
Michael Hufford is the co founder and CEO of Like Genesis.
Today's show was produced by Gabriel Hunter Chang, edited by
Lydia Jean Kott, and engineered by Sarah Bruguer. I'm Jacob Goldstein.
Will be in the next couple of weeks off and
then we'll be back in the meantime. You can email
us at problem at pushkin dot fm, or you can
(40:17):
find me on LinkedIn or on x I'm at Jacob Goldstein.
Thanks for listening. We'll be back in a few weeks.
Oh sick, Oh sick.
Pushkin. I'm Jacob Goldstein. This is What's your Problem? And
my guest today is Michael Hufford. He's the co founder
(00:37):
and CEO of a company called Ligenesis. Michael and his
colleagues are working on a new kind of medical treatment.
If it works, it will save lives. And I have
to say the way the treatment is supposed to work
is wild. It's for people with end stage liver disease
who don't qualify for a liver transplant. And what le
Genesis does is they take healthy liver cells, just cells,
(01:01):
and they inject those cells into the patient's lymph nodes,
and then the patient grows one or more little new
liver in those lymph nodes. This has worked in experiments
in animals, and now they're trying it in people. In
our conversation, Michael told me about the science of why
this might work. He told me what it would mean
(01:21):
for patients if it does work, and we also talked
about why it might not work. And then we talked
a little bit about the future of regenerative medicine more broadly,
and the possibility of a world where no one dies
waiting for an organ transplant. But to start Michael told
me some truly interesting facts about the liver and Greek mythology.
Speaker 2 (01:44):
It is remarkable because it's the only organ in the
human body that will naturally regenerate. So you can lose
seventy percent of your liver, and over a course of
just a few weeks, you will regenerate that liver entirely.
And that's true only for the liver. And ironically, it's
something we've known for three thousand years, right the myth
of Prometheus, if you might remember, the titan that stole
(02:07):
fire from Zeus and gave it to a man was
punished by being chained to a rock, and that eagle
would come every day and eat his liver, and the
punishment was eternal, because his liver would regenerate, an eagle
would have more liver to feast on the next day.
Speaker 1 (02:24):
I I was vaguely familiar with the myth of Prometheus,
but I was not familiar with the fact that the
liver regenerates itself. I mean, do you infer that the
Greeks knew that? Yeah?
Speaker 2 (02:35):
Absolutely, I think they did know that. I think probably
through the experiences in battle and what have you, you
could they could see that you could sustain a dramatic
injury to the liver and that, unlike any other organ,
it would regenerate. But at the same time, it's taken
us three thousand years to get to the point that
one we can successfully transplant it.
Speaker 1 (02:56):
Right.
Speaker 2 (02:56):
That was the pioneering work of doctor Tom Starzel. You know,
he first attempted it in nineteen sixty three, got it
to work in nineteen sixty seven. It saved tens of
thousands of patients lives since then, and Nowgenesis is really
standing on the shoulders of folks like doctor Starzel and
now trying to regenerate the liver in other places in
(03:17):
the body.
Speaker 1 (03:18):
Let me ask a nitpicky question before I ask a
real question. Is the skin an organ? And does the
skin regenerate itself?
Speaker 2 (03:26):
That's a good that's a good point. The skin has
some ability to regenerate itself, for sure, And in fact,
in children, if a small child loses the tip of
a finger in an accident before the age of seven,
you can actually regrow the tip of your finger. But
we lose that that remarkable ability to regenerate as we
(03:47):
get older, and the only organ that retains that capability
is the liver.
Speaker 1 (03:54):
So you mentioned liver transplants, incredible life saving technology. Let's
call it a technology. Why why do we need ligenesis? Like,
what is the limit of liver transplants? Liver transplants?
Speaker 2 (04:10):
We have about nine thousand patients on the US currently
for a liver transplant. Fifteen to twenty percent of those
patients will die each year awaiting a liver transplant to
become available. So I would say it's there's really a
fundamentally a two fold problem. One is supply and demand. Today,
one donated organ treats one patient using our technology, a
(04:34):
single donated organ, because we're isolating the individual liver cells
or hepatosites from that liver, a single donated organ could
treat fifty patients. So one, we're kind of fixing and
really up ending the supply demand calculus when it comes
to you know, instead of one donated organ treating one patient,
with our approach, one donated organ can treat up to
fifty patients. But the other problem is is what oftentimes
(04:57):
people aren't aware of, which is for all the you know,
the understandable human drama of a liver transplant weightlist, of
all the organ transplant weight lists, where people are waiting
for this life save even gift of organ donation. Many
patients are too ill to even make the list. So
in the US you have about five million cases of
(05:19):
in stage liver disease in one form or another. You
have eighty five thousand deaths. At least fifty percent of
the patients that could benefit from an organ transplant don't
qualify because we know that they simply won't survive the procedure.
Speaker 1 (05:34):
Because it's a big, open surgery that involves a lot
of trauma, and if you're very sick already, you'll probably
die from the surgery. Yes. Correct, So you co founded
the company with scientists with a researcher named Eric Leagas right,
and it was based on research that he had done.
So tell me about meeting him where you were and
(05:56):
what was the work he had done that you found
so compelling that you had to go start a company
with him? Yeah, absolutely so.
Speaker 2 (06:02):
Eric Legass is a professor at the McGowan Institute for
a Generative Medicine and Pathology at the University of Pittsburgh.
At the time, I was an entrepreneur in residence at
the University of Pittsburgh and I had spent twenty five
years doing drug development and had been fortunate to work
on a number of very innovative programs and had started
and sold a number of companies. And so was working
(06:22):
with the University of Pittsburgh because they get almost a
billion dollars of NIH funding annually. It's remarkably remarkable research enterprise,
both at the University of Pittsburgh and the University of
Pittsburgh Medical Center or UPMC, and so they wanted to
get more companies spun out as a function of that funding.
And so one day a colleague of mine took me
to meet Eric Lagas, and what Eric told me was
(06:46):
a remarkable story in two ways. One, he showed me
these remarkable pictures from his publication in Nature Biotechnology, showing
that he could regrow organs in the lymph nodes of mice.
That he could take liver cells from a mouse and
graph them into the lymph node of another mouse. And
(07:06):
these animals had a genetic liver disease, and so as
a function of that liver disease, they would otherwise die
from that liver disease. But when he ingrafted these hepatosites
into their lymph nodes, those lymph nodes acted as living bioreactors,
and they literally grew those animals miniature livers, so that
instead of dying from their liver disease, one hundred percent
(07:29):
of them were rescued from that otherwise fatal liver disease.
So he had these pictures that were truly jaw dropping,
you know, of these ectopic organs in places in the
body that they should not otherwise be.
Speaker 1 (07:41):
So I just want to repeat what you just said
because it is the central extraordinary fact of the thing
that you are doing. Right. What Leagas did was he
had put liver cells, just cells, into the lymph nodes
of these mice that had liver disease, and within the
lymph node there grew a teeny liver that worked, that
(08:06):
did what the big liver needed to do, and the
mice did die. Like why why should that even be true? Yeah,
So two things.
Speaker 2 (08:15):
One, over time the lymph node disappears, the lymph node
acts as a temporary bioreactor to get that ectopic organ
and by ectopic we just mean in a different place
in the body that ectopic liver to grow. And in fact,
those ectopic livers and mice could grow to seventy percent
the size of a normal liver. So he could grow
really quite large ectopic livers using these lymph nodes.
Speaker 1 (08:38):
And that doesn't mess the mice up. It doesn't like
mess up their emphatic system or something like that.
Speaker 2 (08:44):
Yeah, So remarkably, we've seen no untoward effects on the
immune system, now, partly because let's stop and talk about
lymph nodes for a second, right, So, lymph nodes in
the human body, we have four hundred and fifty to
seven hundred lymph nodes spread throughout our body, a majority
in our gut area, right, and they've helped us as
(09:04):
a species survive infection, right, because what a what a
lymph node does, It's its primary evolutionary function is help
bioreact T cells. So when you develop a cold, you
have a sore throat and you feel that nodule that
kind of you know marble or maybe even you know
large marble underneath your jaw, that's a lymphnode that's bioreacted
(09:26):
billions of T cells to help you fight that infection.
Speaker 1 (09:29):
When you say bioreact, you basically mean grow, right, it.
Speaker 2 (09:33):
Is it is an admittedly biotech jargon term for grow.
Speaker 1 (09:38):
That's exactly right. Okay, So the lymph note is a
really good place for cells to grow. That's one reason
it works, or it works in animals. You said there
were two reasons. The what's the other reason?
Speaker 2 (09:50):
The other is what's special about the liver and why
even the Greeks, you know, knew that it would regenerate
under the right circumstances. Is the fundamental cell of the
liver is the hepatocite. Hepatasites are naturally regenerative, and so
Eric's fundamental s scientific discovery was that if you combine
(10:12):
that natural regenerative potential of the hapatosite with the natural
ability of the lymph node to bioreact cells, you get
this remarkable effect. And you could think of it as
the flip side of the cancer coin. You know, many
people are aware that cancer probes the environment to form tumors,
(10:32):
and very often cancer will grow tumors in someone's lymph nodes.
Speaker 1 (10:37):
Right, And in fact, that the classic sort of staging
question in cancer set has it spread to the lymph nodes?
And if it has in the case of cancer, that
is bad.
Speaker 2 (10:47):
That is bad, exactly right, precisely because lymph nodes are
such effective bioreactors, and they are agnostic as to what
they bioreact You know, they're so good at growing cells. Yeah,
exactly right. So if a cancer cell gets in there,
the cancer cell thinks, man, that's a fantastic place. I
have access to blood and nutrients, and I have a
confined space that I can focus on growth. And what
(11:10):
you end up are these is the spread of these tumors. Well,
what Eric realized is that you could turn that biology
to it to a therapeutic instead of a malignant potential.
So by putting a self therapy like apatasite into a
lymph node, you could generate functional tissues that exerted life
(11:31):
saving effects. And so he showed me those first pictures
from his study, and it really was jaw dropping. And
I asked him that afternoon what I thought was the
gotcha question, because it so often is with academic minded professors.
I said, well, you know, that's great, Eric, it's incredibly impressive.
What about large animals.
Speaker 1 (11:49):
Right, it's good news for mice. Right, you must exactly
the phrase mice lie and primates exaggerate drug. I love
that I had not heard that. Somebody told me that
twenty five years that's fantastic. I'm going to steal it. Actually,
that's wonderful.
Speaker 2 (12:06):
So and he said, oh yeah, Michael. And in fact,
his colleague, doctor Palofontes, who was our co founder and
chief medical officer, showed that the exact same principle applied
in pigs. So they showed you could take a pig
that would otherwise die from a fatal liver disease, and
you could rescue that pig using the exact same procedure.
(12:27):
And they even tried a different model where they surgically
injure the liver. There's something called a portocable shunt where
you can go in and kind of rearrange the plumbing
of the liver, so to speak, to deprivate of blood flow,
which was a procedure that doctor Starzeal had pioneered as
a way to test and develop the procedure that would
eventually become liver transplantation. And again rescued those animals. And
(12:50):
he told me something that as a drug developer you
virtually never hear. He said, Michael, I can't get this
not to work. And as a drug developer, right, I'd
spent my entire career and the entire industry really is
focused on getting the exact right drug delivered in the
exact right way to the exact right patient, exact right dose,
(13:10):
oftentimes at the exact right time of day, and you
hope for an effect. And what Eric was telling me
was that nature had kind of primed this approach between
the natural originative capacity of the liver the natural bioreactor
capabilities of the lymph node, and that when he said
he couldn't get it not to work. Quite literally, the
hairs on the back of my neck stood up, and
(13:33):
I said, Okay, let's back up and go over this
whole story again, you know, And really that day was
the genesis of the company.
Speaker 1 (13:42):
So you start the company nine years ago, is that right?
Twenty seventeen?
Speaker 2 (13:49):
Yeah, Yeah, time's flown.
Speaker 1 (13:50):
Yeah yeah. I mean it takes a long time to
develop new therapies, right, This is regenerative medicine, cell therapy,
a hard new thing to do. So where are you
now nine years later? Yeah?
Speaker 2 (14:04):
So we are now running a first in human phase
two a clinical trial. So this is a clinical trial
in patients within stage liver disease. These are patients, most
of them, not all, Most are on the liver transplant
wait list and they can come into the trial. They
may have any number of different types of liver disease,
(14:25):
but we're going for patients who have in stage liver
disease that typically have a life expectancy of many months
or a few years, okay, because we know that. We
know that one limitation of our approach is that when
you ingraph these cells, they do take time to organize themselves.
It's not like the next day you have, you know,
(14:46):
a fully functioning actopic liver. We know that it takes
probably two to three months, is our best guess, and
so we want to make sure that these patients have
the time to have the potential beneficial effects of the therapy.
So we've now transplanted our first cohort of patients. There
were four patients, all done at the Houston Methodist Hospital.
(15:07):
Like you typically the phrases, you start low and go slow,
you start low in dose and go slow because you're
not sure what the effect will be. And so the
FDA had counseled us this first trial is just going
to be twelve patients, so we have three different dose groups.
We've completed that first dose cohort and we had a
data Safety Monitoring Board meeting where they look at all
(15:28):
the safety data and the efficacy data to date and
they said, okay, you know, it's looking good. Let's let's
go on and dose escalate as per the protocol. And
so that's that's what we are in the midst of
right now.
Speaker 1 (15:41):
One are you going to know if it worked, if
this trial, you know, had a positive result, that will
allow you to move to presumably the next bigger trial.
Speaker 2 (15:52):
Yeah, we should have a very good sense of that
in the middle part of next year. Okay, so the
middle part of twenty twenty seven, and then yeah, move
on from there.
Speaker 1 (16:00):
So let's talk about how it works. So there's a patient,
as you've said, yeah, who is you know, has liver disease,
has some liver function left, but it's not looking good
for them. And then there is what a donated liver.
Like what actually happens.
Speaker 2 (16:17):
That's exactly right. When an organ becomes available, if the
organ is eligible for transplant, then it's transplanted into a
patient that needs it. Some organs, though, are not eligible
for transplant, and that can be for any number of reasons.
They may have been injured because of the cause of death,
they might be a little fatty where when the transplant
(16:39):
surgeon looks at the organ they think, ah, you know,
that's not going to be a great fit for this
particular patient, and so that they pass on it when
they come to us. We then have a facility at
Houston Methodist currently where we can take that organ and
it takes us just about four or five hours. It's
(16:59):
a seventy plus step process, but we start with the
full organ and after seventy steps and about four to
five hours, we've isolated and suspended those hepatocytes into a
solution that we then currier over to the endoscopic ultrasound suite.
Speaker 1 (17:18):
And so just to be clear, it's it's when you
say the patasites are in a solution, it's like a
bottle full of liver cells in liquid.
Speaker 2 (17:27):
That's That's That's exactly what it is. Okay, It's a
small syringe really because really injecting about yeah, about one
about one milliliter of the cell suspension. But it's it's
literally like a brown thick liquid.
Speaker 1 (17:42):
That's yeah, So a syringe like like what like you'd
get in a shot, but instead of a vaccine, it's
liver cells from a donated liver. Okay, so then you
cur youer that over to go go on. Yeah.
Speaker 2 (17:52):
Yeah, And so the patient is put under light sedation
and just the way you might have an endoscope you know,
to look to see if you have an ulcer or
to you know, have any number of diagnostic procedures. Yes, Basically,
an endoscopius takes that into scope under sedation, down through
the mouth of the patient and then threads it down
(18:12):
their gi track kind of into their gut area. And
at the end of that endoscope is an ultrasound. And
so the ultrasound you can basically look adjacent to the
gut wall and lymph nodes there show up. Is they
almost look like bubbles to the untrained eye, right, So
they kind of look like these bubbles that come into
(18:35):
view via the ultrasound, and the endoscopist takes a five
foot needle that threads down through the industry thing. Yeah,
it then goes through the gut wall and punctures into
the lymph node.
Speaker 1 (18:50):
So it's like a shot. It's like a shot, but
it's going into your stomach, across the wall of your
stomach and into the lymph node. That's exactly right. That's
exactly right.
Speaker 2 (19:00):
And so this takes about ten minutes to find the
lymph node and inject the cell suspension. And so we
inject one millileter to that lymph node. They withdraw the
needle and pull the scope out, and the procedure itself
at that point is done. The cells are in the
lymph node. The patients put on immune suppression.
Speaker 1 (19:21):
Right, the patients put on immune suppression because these are
cells from somebody else. So it's just like if you
get a transplant, your body's cells will be like, oh,
that's foreign, I'm going to get rid of it. That's
exactly right. Yeah, okay, So the patients put on immune
suppression and then if it works, what happens.
Speaker 2 (19:39):
If it works, what happens is those cells find themselves
in an environment that they find very comforting and very nourishing,
and so they use that those bioreactor, you know, aspects
of the lymph node begin dividing because they're natural stem cells,
and they begin organizing themselves into liveral obdules, which are
(20:00):
these little hexagonal collections of cells that are kind of
the functioning filtering unit of the liver. And from all
of our preclinical data in both small and large animals,
that division will continue to go on and the vascularization
will then occur. So the lymph nodes are well vascularized anyway.
But what you find is that these ectopic organs recruit
(20:27):
cells from the patient's body to form additional vasculature, so
additional blood flow to that ectopic organ, so that over time,
and again our best guess is it's over a few
months of time, what you'll be left with is this
functioning ectopic organs. So I'm picturing one like tiny little
(20:49):
mini liver, like, I don't know how big is it?
Is there only one?
Speaker 1 (20:55):
How big does it have to be or how many
do there have to be for it to be clinically useful?
Speaker 2 (21:00):
They can get quite large. In small animals. You can
get up to seventy percent of the native liver grown
in a lymph node, and the larger animal was a
smaller percentage. And your question about clinically meaningful. You know,
when you talk to hepatologists or folks like our chief
medical officer, doctor Fontes, who's treated these patients, you know,
(21:21):
across his entire life, if you can bump the functional
amount of liver for one of these patients by ten
to twenty percent, you will alleviate a lot of the
signs and symptoms of their in stage liver disease. And
in fact, in stage liver disease is a problem because
very often patients don't know that they have advanced liver
disease until pretty far along, because it is a redundant system.
(21:44):
As a species, we have very large livers to help us,
you know, with the various things that we might eat
and get exposed to. So it's a redundant system and
by the time you know you have a problem, you
know you really have a problem. And so that's why
we think if we can even bump it up by
ten to twenty percent, I think this will be a
transformative therapy. So, you know, we envision clinically the potential
(22:07):
both to treat patients that are never going to get
an organ because they simply don't qualify for the list,
but for others it may be more clinically, what you're
doing is just buying them time so that an organ
can become.
Speaker 1 (22:19):
Available for them. We're gonna take an ad break right now,
and then we're gonna come back and talk about a
bunch of more things, including why what Michael, and like
genesis are working on might not work. I want to
(22:41):
go back to one detail or one step you mentioned
of what happens inside the body in this process, and
that is, after the cells have been injected, they are
just cells. They're just random liver cells floating around. And
you said they organize themselves essentially into a liver, into
(23:03):
a little liver. You didn't say into a living over
but that is essentially what's happening. Yeah, that part that
seems like the central shocking thing that is going on here, right,
And I've talked to a couple of other people doing
regenerative medicine in other way, somebody doing bones, somebody doing
(23:23):
blood vessels, and they both use this term that I
think I've seen you use elsewhere and that I'm reminded
of here, and that is it's more of a phrase
that is that cells are intelligent. Cells have some intelligence,
which is not intuitive, but but I'm reminded of it here.
Like what's going on? How does that work?
Speaker 2 (23:44):
It's a great question, and in fact, it's almost a
testimony to why lie genesis exists. That many academic researches
that never found companies can get not distracted because it's
really the fundamental scientific pursuit of why and how. But
to Eric's credit, when he's.
Speaker 1 (24:01):
So long you don't know the answer, you don't.
Speaker 2 (24:03):
Know, You're absolutely right. The short answer is we don't know.
The longer answer is yeah, well, short answers we don't
know too. I think you're right. The cells are remarkably intelligent,
and we know there's those dozens of pro growth signals
from the disease liver. We know they play a role,
(24:25):
but exactly how it works, I'm thankful. Let's put it
this way that Eric focused on trying to get it
not to work, because he ended up finding that it
was so robust, where you know, a lot of researchers
would been their whole life trying to understand the why
and how well.
Speaker 1 (24:40):
And clearly in other organs or body parts, like I
remember in the case of blood vessels, and this is
a classic challenge when people are trying to grow organs
or mini organs, is they do a lot of work
to create the scaffolding, to create the structure, right, and
so the fact that in this instance it is naturally
(25:02):
self organizing solves what seems to be the largest problem
or at least a key problem.
Speaker 2 (25:08):
For any other organs, I would just say, yeah, it
is better to be lucky than good, and that really
is a case. Nature has really engineered this in a
lot of respects. Right As a drug developer, so often
you're trying to trick the body, right, like you're trying
to trick it to do something that's unnatural and have
(25:30):
to fight against it all along the way. I think
what excites me about regenerative medicine, but like genesis in particular,
is that we just have a lot of headwinds because
of evolution and biology than the naturally regenerative capability of
the liver, the natural ability of the lymph node to
buy or react a variety of tissues. Because Eric shown
that it's not just to patasites and ectopic livers, he
(25:53):
can grow. He can put pancreatic islets and rescue animals
that have diabetes by putting those islets into lymph nodes.
He can put the thymus from a young animal into
the lymph node of an old animal and help reboot
that old animal's immune system, and in fact the whole
(26:14):
animal starts to look more youthful physiologically as a function
of that. So I think the lymph node is going
to act as a platform for a variety of different tissues,
and so at like genesis, where the liver is certainly
the most you know, far along of the assets we have,
but we also have this work on the thymus and
(26:34):
the kidney and the pancreas, because as I said, the
lymph node is it's just remarkably agnostic about the type
of tissue that it bioreacts.
Speaker 1 (26:42):
And just to be clear that other work that is
that is not yet in humans, right, that is earlier year.
That's correct, That's exactly right. Yeah, so correct in the
liver trial, which is the one that's the farthest along.
So let's talk about that. What might go wrong? Why
might it not work?
Speaker 2 (26:58):
In terms of what might go wrong, our body's ability
to reject what's called allogenetic, which is just the medical
term right for from another from another person, say, from
another animal. Our body's ability to do that has been
central to our success as a species. And as a result,
(27:18):
when you try to get around it, you have to
use very powerful drugs to try to convince it not
to reject those cells. And so I think acute rejection,
especially when you're injecting a relatively small number of cells
as compared to a very large organ. I think that's
one thing that you worry about.
Speaker 1 (27:37):
Oh, the small number of cells, because it's like easier
for the body with its immune response to wipe out
a small number of cells. Isn't exactly right? Yeah, dumb question.
I mean I sort of know the answer. But presumably
the patients with liver disease have some of their own
liver cells left. Yes, what if you took some of
their own liver cells and put them in the lymph node,
(27:59):
you wouldn't have the rejection problem.
Speaker 2 (28:01):
That's a great question, and we get that a lot
for the patients that were targeting within stage's liver disease.
The liver is also grown to potentially catastrophic bleeding risk,
and so the notion of biopsing a fibrotic liver is
one that has, you know, very significant medical risks associated
with it.
Speaker 1 (28:21):
Okay, another one. I'm just good. I'm this one. I'm
just making up. Can you do like induced pluripotent stem
cells from the patient and turn them into liver cells.
Speaker 2 (28:33):
That's that is exactly our vision actually for our for
our second generation therapy. So our first generation therapy is
going to be these allogenetic cells. The second generation will
be exactly that, the hope, and there are labs around
the world working on this. No one's solved it yet.
But induced pluripotent stem cells where you take a skin
cell and you push it back to a more embryonic
(28:54):
like state and then bring it forward as a different
cell type. You know, we've had tremendous success in a
variety of cell types to have a fully mature human
hepatocide is something that no one's been able to do yet.
Speaker 1 (29:06):
Nobody's been able to get a stem cell to turn
into a mature human liver cell. Oh exactly, So okay,
So immune rejection that's one problem. What else?
Speaker 2 (29:17):
You know, one thing that we didn't worry a lot about,
but just because we had endoscopic colleagues that assured us
this was a very safe procedure. But you know, I've
taken several drugs first into human you always worry, and
so with patients with bleeding risk, you know, the the
indoscopic ultrasound is something that you want to make sure
goes well. But again we're using incredibly talented endoscopist. They
(29:40):
do the same procedure to look for patients who've been
newly diagnosed with pancreatic cancer. The good news is we're
asking endoscopists to do something they're very familiar with, using
equipment they're very familiar with. But still you always worry
about you know, you're going through the gut wall with
a needle and into a lymph node, and you know
you always want that to go well. And at this
point we've had no serious adverse events from the administration itself,
(30:05):
but that's something you know, that's why you start low
and go slow, as they say, right in these first
and human trials.
Speaker 1 (30:10):
And then so these are the sort of technical risks
or medical risks. Is there like running out of money?
I mean a biotech company with no product, Like, how's
how's that part of it?
Speaker 2 (30:24):
Sure? Yeah, there's always business risk.
Speaker 1 (30:26):
You know.
Speaker 2 (30:26):
I was told a long time ago that the the
definition of a biotech is a company unencumbered with revenues.
Speaker 1 (30:33):
And you know you don't have to worry about the
profit loss exactly only half.
Speaker 2 (30:38):
You and l is very yeah, we only have half
of it. So I will say that, Yeah, you always
worry about running out of money. Drug development always takes
longer and costs more than you hope it will, even
when you've done it a long time, there's always surprising challenges.
I will say, you know, we're fortunate to have wonderful
investors that are patient with us despite the inevitable setbacks
(30:58):
as we push forward. As a drug developer, you're always
taught that great drugs are killed at least three times
right before they actually make it over the finish line.
So we have we have folks that are with us
and supporting us, and we've tried to be very cappully efficient.
Like Genesis is just half a dozen people. We've raised
under forty million dollars to date, where when you look
(31:18):
at the typical cost to get an investigational new drug
clearance by the FDA or a IP that usually costs
hundreds of millions of dollars, and just you know, we've
been fortunate to not need a staggering amount of capital
to get to where we are, which is in the clinic,
in part because of the NIH funding that Eric Leagas
had at the University of Pittsburgh. And it really is
(31:41):
why the NIH cuts that we've seen happen really are
undermining the kind of future potential of so many new
therapies and technologies that you're simply not going to hear
about because the funding wasn't available for them to move forward.
But thankfully Eric's work was very well funded by the
NIH and so we've we've been able to take it forward.
Speaker 1 (32:03):
So I just want to talk for a minute more
broadly about straight to such should we talk about cellular
therapy or regenerative medicine? Right, you're kind of both. Yeah,
we're sort of reading the world, right, but I'm not sure.
I mean, I recognize that what you were doing is
distinct and particular, but it does seem like there is
this broader landscape that you were part of, where people
(32:26):
are using cells to treat disease, and people are thinking
about how to create new versions of skin and of
blood vessels, and are working on new ways of thinking
about organs and transplantation. I mean, what does the broader
landscape look like from your point of view and where
do you fit into it? And like what are the
(32:46):
big shifts, Like what do you expect to see in
the next five tenures?
Speaker 2 (32:52):
Look, I think in ten years there is the realistic
possibility that at least in some cases like a liver transplant,
that those are relegated to medical history books, that the
notion of being on a wait list for an organ
will hopefully seem as foreign and strange to our children
and grandchildren. Like you talk to a grandparent, you're like, wait,
(33:14):
there were these sanatoriums with iron lungs everywhere. So I
think there's this opportunity that we really are going to
be turning the page from a medical history perspective, and
that there is the potential that in the really foreseeable future,
you're going to be the source of your own medicine.
You're going to be able to engineer your own cells
(33:36):
to avoid the problems of immune suppression and use them
in ways to induce remarkable regenerative outcomes, both in terms
of organ regeneration potentially in terms of lem regeneration, and
do things that again seem like science fiction today. Now
things always take longer and cost more than you hope.
But I do think when you look broad brushstrokes, we
(33:58):
really are on the cusp of a very exciting time.
Speaker 1 (34:01):
That way, we'll be back in a minute with the
lighting round, and now we are going to finish with
the lightning round. You were a practicing clinical psychologist before
(34:28):
you got into the drug development business. Briefly, how did
that happen? Briefly?
Speaker 2 (34:35):
I was very fortunate to work on some research methodologies
that were used widely in clinical psych but had a
lot of applicability and drug development, and so got involved
in consulting in that kind of niche area of research design,
and really just love the intersection of science and business
because you saw how much more rapidly you could you
(34:57):
could make progress, and how many more lives you could
affect than just writing publications. So and I'll also say
when you meet with the FDA, having those group psychotherapy
skills can come in remarkably helpful.
Speaker 1 (35:09):
I feel like you're not joking when you say that.
It plays a joke, but.
Speaker 2 (35:15):
You're you're right on that you kind of joke about
the skills of a clinical psychologist, but those key skills
in business settings being able to kind of take the
perspective of other people very rapidly and pick up on
concerns they may have that actually ends up being you know,
incredibly essential and regulatory interactions.
Speaker 1 (35:34):
So you did research on smoking cessation in your previous
professional life. What's one thing that you learned about addiction
in your research.
Speaker 2 (35:44):
You know that when you're trying to understand why some
people return to substance use, so much of it can
come down to momentary decisions and small slips and how
a single slip can lead to a full blown relapse,
but from that single slip people can recover and rebound,
and finding out how these fleeting life stressors can play
(36:05):
an incredibly large role in just kind of that chaos
of life that kind of pushes us on different trajectories
that ends up, you know, making you a smoker or
a non smoker or so is it just random?
Speaker 1 (36:20):
I mean, what what do I what is the inference
from that? Like? What does that mean?
Speaker 2 (36:24):
Yeah, well, you know, some of my work was actually
in something called catastrophe modeling, which was a subset of
chaos theory that kind of fundamental of the butterfly wings
causing the tornado, right, that these very small changes in
life can have this outsized impact, and it was it
was hard to avoid that conclusion when you look at
(36:44):
real time monitoring of folks trying to quit smoking.
Speaker 1 (36:48):
So I understand you also run a nonprofit called Harm
Reduction Therapeutics that brought to market a generic over the
counter version of noloxone.
Speaker 2 (36:58):
That's correct.
Speaker 1 (36:59):
Briefly, how'd that happen? There was a huge.
Speaker 2 (37:04):
Unmet need, as you know, as the opioid crisis unfolded.
Noloxone had been FDA proof since seventy one, it'd been
off patents since eighty five. It was an incredibly effective,
incredibly safe opioid overdose andidote, but for profit companies were
refusing to take their products over the counter because they
were making such high margins on them as prescription products.
(37:27):
Got extraordinarily frustrated with that set of circumstances when you
had over one hundred thousand Americans dying annually of opioid overdose.
So my colleague John pinion I formed a five oh
one C three nonprofit pharmaceutical company and ended up bringing
in over the counter three milligram Naloxo nasal spray and
doing it as a nonprofit. We entered the market at
(37:49):
about thirty six dollars worth thirty three dollars now at
the time Narcan was one hundred and forty dollars and
lo and behold, you can buy them now for about
mid thirty dollars per pack. So the hand of the
market did its job, you know, So we forced other
folks to go over the counter with their product, forced
them to lower their price. And yeah, that's something that
(38:11):
I was a very satisfying professional accomplishment to kind of
help the whole field move forward. So our product, Revive
is now this FDA approved over the counter three milligram
internasal noloxo nasal spray for emergency treatment of opioid overdose.
Speaker 1 (38:27):
Last one, you've written that if you're running a startup,
you can only have three out of the following five things. Family, friends, sleep, exercise,
and hobbies. Which are your three? Oh?
Speaker 2 (38:42):
Man, I'm very fortunate to have a family that I
adore and cannot spend enough time with, so I would
say family. I do exercise regularly. Oh I was so,
Hold on, what were.
Speaker 1 (38:56):
The So you have to choose now one from the
following three? Friends, sleep, or hobbies.
Speaker 2 (39:04):
I don't see near as much of my friends as
I would like, so I guess I would say hobbies
are the other thing that keep me grounded.
Speaker 1 (39:14):
Also, you don't sleep. Unfashionable it's suddenly fashionable?
Speaker 2 (39:19):
Yeah, exactly, exactly.
Speaker 1 (39:21):
Not as much as i'd like. What's the hobby.
Speaker 2 (39:24):
Amateur musician, so you know, kind of singer songwriter and yeah,
so amateur musician in my very spare time.
Speaker 1 (39:33):
Is there a song of yours we should play under
the credits of today's show? Can you play us out?
Speaker 2 (39:40):
I'll think about it. Sure, I'll send you something you
can play out.
Speaker 1 (39:42):
Okay. It was delightful to talk with you. Thank you
for your time, Jacob. It was really, really nice.
Speaker 2 (39:49):
These were wonderful questions. I actually really enjoyed the conversation.
Speaker 1 (39:56):
Michael Hufford is the co founder and CEO of Like Genesis.
Today's show was produced by Gabriel Hunter Chang, edited by
Lydia Jean Kott, and engineered by Sarah Bruguer. I'm Jacob Goldstein.
Will be in the next couple of weeks off and
then we'll be back in the meantime. You can email
us at problem at pushkin dot fm, or you can
(40:17):
find me on LinkedIn or on x I'm at Jacob Goldstein.
Thanks for listening. We'll be back in a few weeks.
Oh sick, Oh sick.
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