Sano Genetics
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[00:00:00] Patrick Short: Welcome everyone to the genetics podcast. I'm really excited to be here today with Dr. Paulo Fonte who's the chief medical officer of LyGenesis. And I have to say when Paulo was recommended to me by my colleague Mun Ching Lea I was just really blown away by what they do. And we're going to be talking today about organ transplantation.

And just to give you some context and Paulo will definitely give you some more. At any one time, there are literally millions people worldwide that are waiting for an organ transplant and about 20 people die every day waiting for an organ transplant. This is really though just the tip of the iceberg. As, as we'll talk about today, an organ transplant is really a, a cascading event because it changes everything else.

It's quite literally a new lease on life for many people. And what Dr Fonte and the rest of the Genesis team have done is they figured out a way to actually use the bodies lymph nodes to basically act like a miniature bio-reactor that can grow life saving organs and it's scifi. And it's amazing. And I'm really excited to hear about it.

Um, I'm going to let Paula explain it a little bit more detail, um, but great to have you thanks so much for taking the time to be here today. 

[00:01:02] Paulo Fonte: Thank you very much. It's an honor to be talking to you. Obviously it's something that we have a big passion for. I've been working for more than 30 years. So we as always happy to share what are we doing with the public and trying to bring more awareness that what could be done to improve the life and the quality of life and the length of life of people with organ failure.

[00:01:22] Patrick Short: Absolutely. And I'd love to maybe just jump right into the origins of this lymph node bioreactor approach that I described in the intro. This seems like the kind of thing that almost could have been discovered by accident. It's so crazy. And I know I gave a very high level overview, but I'd love to hear it from you, how the initial insight came about and where you all are at.

[00:01:38] Paulo Fonte: Yeah, this is one of the fascinating things in science that it was happening without being in obscene. So my chief scientific officer, Eric Lagasse, PhD and pharm D French, we met more than 10 years ago and he was working. He wrote a beautiful paper in atrial biology, where he show for the first time that he was able to grow liver tissue, kidney tissue in and pancreatic islets into the lymph nodes.

And it was such a unique thing that the very perspective journal published this papers. And, uh, when I first met him, I was fascinated because I've been in this business for too long. And my boss, Tom stars, who is the father of transplantation and develop this field in the 1960s in Denver. He developed this concept of how celiac liver, but sometimes you have an animal or a human that will choose segments of livers in the same body and one self regulates the other one.

And when I saw what Erica was doing in this mice with TAROS dynamic disease, it resembled exactly the concept that Dr Star's head. But when I look at the histology. The tissues looked to me like a real. So the very first question in life is can you reproduce this in a large animal model that becomes clinically irrelevant because I'm also a scientist.

I publish a lot that being full professor of surgery and this, but my interesting was always the translational medicine to my patients because I lived through the disasters and the fact that sometimes you don't have an option to offer to that family, to that patient and they will die. And then for me, it was the worst.

So I always want to create a new option for somebody who was with the disease. And when I saw Eric's work, I said, well, why don't we try to build a model with this in a large animal, that would be more translation in a meaningful, we said, well, let's do it. And this is how we start this journey. 

[00:03:31] Patrick Short: And there's a number of different technology approaches to this problem over the years.

And I think you've worked across a number of those. I wonder if you could just give a little bit of a history on, on what are the different approaches we know there's a huge shortage of know kidneys, for example, livers as well. People spend, you know, months to years on the waiting list. What other Approaches have been tried. How do they work? And how has this approach that you described different? 

[00:03:54] Paulo Fonte: It's a fascinating problem that we have went up to stars initially, develop organ transplantation that you will resolve the problem of organ failure by changing that organ. It worked with the liver it worked with the kidney. Norman Shumway did it with the lungs.

Then, you know, he did also with heart somebody else got to grab the part of the heart in South Africa later, and the organs were coming along, you know, but it was clear that we were not doing enough. And then we could do more and we could open this field for cell based therapies. So communal recording, who was somebody who trained me and still were very active in this field, came to Pittsburgh in the early nineties to develop a new program in islet transplantation.

And Dr Starso allowed us to build a cell transplantation program that will, will do eyelids hepatocytes, muscle cells, bone marrow, and other cells to try to be more comprehensive in how we will create opportunities. And then through my life, as a surgeon, I started seeing. We didn't have enough Oregon. Can we use animals as source of organs.

We call this xenographs so a very complex immunological issue that we went through and I spent more than a decade of my life working full time on xenographs it's complicated, very challenging. There's a lot of ethical issues, which animal you use as a donor. If you was a pig, as you've used no prime at this issues.

And then as technology continues to evolve, we came a time. We were able to learn more about the actual cellular matrix of the organs. And we thought about, can we de-cell organs and re seed these organs with cells and create so-called artificial organs. And can we develop organoids? Can we have something that we grow outside of the body and implant this with like a microchip that we will grow with the function of an organ. One of the biggest problems in biology is every organ is blood flow through it. So if you build something outside of the body that you cannot connect with the blood flow. And for liver hearts and lungs.

It's a massive blood flow. You don't have a very safe environment. You can kill somebody doing this, that really doesn't work well. And more than that, even a logically the blood flow through vessels, the vascular should have endothelial cells that cover this and this endothelial cells are very active immunologically, for a reason.

So we don't get antigens from outside, they will invade our body. So the challenges of working with this artificial organs with 3d printer organs, with this cell orbits, I have a company on machine perfusion and all this stuff. It were amazing. And then I see this French guy say, wait a minute, stop. Why don't we use the lymph nodes, which is a well-known bio-reactor the growth, the T-cells when you need it.

Why don't we use the lymph node as the place in where you put the right cells in, and these cells will grow like a flower, like a plant that will reassemble into an organ and they are within the patient's body. And most interesting than anything, the lymph node vessels are from the patient. So the endothelial cells that cover the vasculature of the lymph nodes are not from the donor. So you were basically doing your transplant of parenchymal cells that will have a function either as a no liver, or is it a pancreatic tissue for the insulin or is the kidney or as a timeless service, but with the flow from the patient's own endothelial cells and that is a revolutionary.

And then when we develop the first large animal model and we realized that the tissue not only grows, but it assembles histologically as a normal liver. So I did this with the pathology. I did a blind test with a pathology. I show him all the biopsies of the new crops of the animals, how how do you like this liver, and he says, this is great. Why are you were showing me all this normal liver? So, well, thanks for asking. 

[00:07:54] Patrick Short: It's not as normal as you think. 

[00:07:56] Paulo Fonte: Some of this, you should, that I'm showing you. It's not a liver. I said, what is it? And when I told him what I was doing, it was blown away because he could see hepatic labials central veins. The Porto trials, the bile ducts, the sinusoids, so when he looked at me across the microscope and see and said, this is real.

So for me, it was a third party, you know, the risky thing that we got something, and obviously. To move this forward towards a real therapy. It took our CEO, Michael Hartford with 25 years of experience in drug industry to come and say, how do you build the company and translate this technology and go through the FDA.

And then there were clinical trial. So it's a long, it's a, it's a long way. 

[00:08:42] Patrick Short: Yeah, it's amazing. And just to recap, to make sure I get, and everybody else listening gets it. So . Do you take a piece of the existing liver and then seed it into the lymph node somehow? And then it basically itself organizes and grows from there? Or have I missed something. 

[00:08:57] Paulo Fonte: Yeah, this is exactly what we did initially. So as a transplant, immunologist, I said, let's do a first experiment taking immunology away. So we take the animal's own liver. So I got some pigs that I took the left segment of the liver, the left lobe. I didn't have a tech team. I took the lab isolated cells from there.

Then I did an operation that we developed in the sixties called the Porter cable shunt that Dr. Stars will do this a lot, that you basically connect the main vein that goes into the liver. You take that away and put into the cave. So three quarters of the blood flow to the liver. I've taken away. The liver cell said, are you crazy?

We're going to die. And they go to liver failure with this. So in this animal model, we got the animal cells into the lymph nodes. And one and two months later, when we did the necropsy of this animals and you open up, you look at the lymph nodes. That you transplant the cells myself. I did it present myself.

I see this many livers. I said, you gotta be kidding. I mean, this is not, this is not possible. So, so realistically is that exactly what he said first, we did the animal's own sales when Michael built the company and went to regulatory and present this to the FDA, the FDA said. This looks great. And we've seen the data from an, a rodents doing allergenic with immunosuppression.

Can you do the same in large animal models? So we did an additional work in dogs, whether we did aloe transplantation means between different animals. So they are not matched. Using immunosuppressive therapy and the same thing happened again, even when you do an immunosuppression, if you put liver cells that worked like a stem cell base, that they were grow again, because if you and I have an accident, not a week, what are we an organ donors.

If we are alive donor to one of your relatives and we take half off your liver in six weeks the liver grows back. Right. So how is it possible? So that say mechanism that drives a paddock original iteration is what drives the cells that we put into the lymph node. But we never thought that they will grow into a point that they are not only histologically normal, but Eric did this amazing work.

When we did the pig, show me that this cells can also synthesize bile acids and produce bile. Right. So you have a functional hip battle site into the lymph node that we call ectopic is a Greek name for outside of the place. It's an ectopic liver that produces bile and works and produce albumin and the things that should be doing and goes back to Dr Starso's initial idea. When, the liver that is disease is shrinking because there's too much disease going on. The liver liberates, this growth factors among them. One called hepatic growth factor, hepatocyte growth factor. HGF. This was discovered by George Michael operas, who worked with us in 1989 when he was at duke. This growth factors, go back to the tissue that your transplant and help the cells to grow. So there is a self-regulating mechanism within any mammal that you do that if you are losing liver medicine, one point and you create another place where you can grow the liver mass you go.

[00:12:05] Patrick Short: Wow. And it will, it will figure it out.

[00:12:08] Paulo Fonte: Yeah, it's nature is self-regulation that we see in some areas, biological systems the liver was built with this because it's the largest organ in the human body with 500 different functions and we can live without it. So there is a mechanism built within mammals that when you'd have this, and even with the rodents, that when you lose a portion of your liver, the liver recovers and secrete all these growth factors that help the tissue to reestablish the total liver mass.

[00:12:36] Patrick Short: And I mean, one of the most remarkable things about this, as you all are getting ready to start a phase two, A clinical trials. So you're starting to put this into humans, which is a, as everybody in industry knows, is a lot of work that needs to be done to establish that it works. Then there's a big step of, of testing that it's safe and effective in humans.

A lot of listeners will probably be generally familiar with clinical trials, but there's definitely some nuances around obviously your approach, but also organ transplantation trials compared to small molecule or biologic drug. So it'd be great if you could just walk us through, what are you trying to measure in the trial?

How many patients, how does it work? Um, and I'd also love to hear about is are patients getting transplanted with their own tissue, so to speak, or is it more of like an off the shelf type approach where you've taken one or more donor tissues effectively grown them in an external lymph node and then are going to transplant those into patients.

So I'd love if you could just talk us through what that trial looks like. 

[00:13:30] Paulo Fonte: Those are great questions. And obviously we're excited that we got this opportunity that the FDA has understood the message that we're very mindful of the unmet medical needs. As a transplant surgeon, seeing patients with cirrhosis everyday trying to treat them.

Half of the patients sent to me, they need a liver transplant, but they could not get a liver transplant because they have other medical problems, including heart to lung disease that will preclude them to have an open operation. So I have, I have to tell this patients, I have nothing to offer. They said are you kidding?

What do we do now? Well, you're going to go to a nursing home to palliative care. That's embarrassing. I mean, I was, I was, I was very upset and frustrated every week when I have to talk to the families about this. So when we solve this opportunity and we present to the FDA and the credit goes to our CEO who really designed the clinical trial and came with this regulatory pathway to the FDA, you know, most of the phase one clinical trials are done in very small studies first in humans to do pharmacodynamics pharmacokinetics, we call it PKPD and toxicity of the drugs. We are doing a biologic. It's not a drug, but it seemed like a drug. On this biologic hepatocytes have been transplanted in humans before. So this was not the first, the change of our approach was one; we are doing a hepatocyte transplant in a new location, meaning instead of the lymph node so most of the hepatocyte transplants done around the world, we're giving inside of the portal vein. The main vein that I did at Porter cave ocean. When I took that away from deliver that main vein feeding the liver the cells would put it inside and realistically.

This. It's not how they should be. It doesn't work well. The data shows that that's not the right place to put their cells and the second issue with the FDA and we develop, and we have a patent on this. We said we don't want to do an open operation. We want to do a procedure that for an outpatient awake, you do an endoscopy on the sedation.

And with this new endoscopes, with an ultrasound at the endoscopic ultrasound, then you can see the lymph nodes outside of the GI tract. You localize the lymph nodes and you go with the NATO, achieve the marrow of the lymph node, and then you inject the cells while the patient is awake. And when we present this to the FDA has said this patient.

With cirrhosis, they cannot have open operations if there's not the liver transplant because too much of a risk. So they said, we understand that. So the safety that was built in, and it was amazing. So no phase two clinical trials where you're looking for a dose response. So we told them we want to go to three sets of three cohorts of patients to do different dose.

We're not at oncology therapy, but the dose here, meaning safety. With the idea that you were putting cells like little seeds that it will grow. So how much of the sales can you put that will grow faster enough to get the function that you want without creating more problems? So this trial was mainly designed. We call this four by four open label, those escalation with the FDA, they were very meaningful that this was an important milestone for those patients. And they gave us the right to do this phase two. And then you do a cohort of patients. Then you wait for three months and then you have the DSMB that we'll look into this to see if safety is achieved and the patient is fine.

Then you go to the next cohort and you do the same. And it goes to the next. But when you're talking to people, I said, wait a minute, you're doing a cell transplant in an outpatient with endoscopy. And what cells are you using again? So this is one of the most important things of this trial, where you're using liver cells from this, that liver.

So to make the word said enough, besides not being able to treat, take care of all the patients with cirrhosis that come to the office. When I was flying around the country and it's still going to happen when we are going for the organ donors. And we do this work for several hours, sometimes days to get organs.

Close to a third of this livers, 25, 30% of those are not used for transplantation because they have issues most commonly now with Ts opioids. And then if that we have a lot of young people die from drug overdose, and there's a lot of damage close to the time that they get. So you cannot use this organs in a safe way.

So our trial is built in getting this card delivers w they're not going to be used for transplant, we're not taking away any organ from anybody that could have this. And how many of this organs we see in our country for the last decade is almost 2,500 a year. It's just insane. So, so you have a huge amount of organs.

So the trial has to ask me, is that phase two A where the cells come from, uh, allergenic, meaning that a separate donor that we will get through the OPOs we match the blood type. We do some immune matching with this organ is doing something called PRA panel reactivity antibodies, and cross-match to avoid anybody mediator, and that will damage the organs early on. So you have a safer way to do that. You use less drugs, immunosuppressive therapy, but once you get the organs, you have to take the cells, this, this organ to a GMP facility, to a lab where you basically this disassemble a live organ. So there is a method developed that you inject collagenous and you break all the connective tissue that keep the cells intact and you isolate the cells separated.

They use you go with a centrifuge and you filter this and you end up with a very small amount of cells, 50 million cells in one ML. And this is what you use to transplant. So it is crazy for the liver size. I mean, I spend my life holding the livers. It's a big organ. You end up with a little bit of the calles who are the real seeds.

And once you transfer to the endoscope into the lymph nodes and they in graft, because you give immunosuppression there, you're avoiding the issue rejection of the cells. They start to developing this cell adhesions, the site, and gaps out junctions and start growing again. And you see the cells growing it.

You see the bike ducts being formed, you see bio be produced and you see a new liver tissue being formed. 

[00:19:53] Patrick Short: Wow. And can you get multiple doses out of a single discarded liver? How many people could you treat with one of these. 

This is 

[00:20:00] Paulo Fonte: a great question. So Michael has this PowerPoint that we showed that you could transplant for each labor up to 75 patients because the liver has billions of cells.

So this question that you ask initially is very important. I am, I am glad that you asked this question. The whole industry will, would like to have, uh, a medical treatment cell-based therapy. That's off the shelf that you get an organ. You isolate the cells and then you find a way to preserve the cells in the best possible way to transplant when needed.

So there is a way to do this with cryopreservation. Then you drop the temperatures all the way to minus 80. There's some loss of the cells, but you can keep a lot of the cells alive. And with this, you can transplant people across a huge geographic area with different medical needs. If you do the right match.

We have partners from the industry that we're very keen on in us to move this technology. So we got to working out with the GMP labs and even private colleges that want to move on this cause of can the cell based therapy business. Now that is done with allergenic cells. Can you make this off the shelf as you ask so wisely, if you find a way to isolate the cells in the GMP cryo-preserved and then provide the cells to patients in different geographic regions when needed, I think we probably are going to move into this quick. 

[00:21:19] Patrick Short: And how difficult is the matching process? Obviously I know a little bit about the, and I think there was a Nobel prize awarded for the kidney national kidney registry matching process, because it is challenging if a family member, direct family members not available to find a match.

How challenging is that? If you've got, you know, if you've got a single discarded liver and a hundred patients who need a transplant, how many of those on average, could you treat with that one? 

[00:21:42] Paulo Fonte: Yeah. You know, a lot of kidney transplants and you've been through this matching and you probably know a lot about HLA and how we tie people. For livers you don't have to do a perfect six antigen HLA matching. What we done historically is doing a blood type. So you get the same blood type. So you avoid some preform antibodies, and then you do this test that I told you about this PRA and the crossmatch to make sure that you don't have preform antibodies.

And if this is okay, that cell graph will be safe to be transplanted to a person. You don't have to have a perfect match as you have in bone marrow, because for the bone marrow, you will try to replace the entire immune system. You're trying to put cells in that the patient will not reject the cells and more complicated when you have GVHD, if the cells grow and thinking that the patient is different, the cells can attack the patient and create another problem.

So we see this in Oregon's out. So the matching is not as crucial as with the bone marrow and kidneys. And you know, it will probably help this. 

[00:22:47] Patrick Short: What other disease areas or organs have you all looked at it, it clearly you started with liver and there's a huge opportunity there to help people, but there's also opportunities in I think a pretty limitless number of areas would be great to hear about where you've tried an animal models where you're thinking of trying and humans, and also just the scope of what's what's possible.

[00:23:06] Paulo Fonte: Yeah when Eric first developed this idea with hepatocytes, he has been trained by Eric Weisman, probably the most recognized stem cell biologists in the world from San Francisco.

And so Eric was very deep into this business. So when Eric saw this phenomenon happening with hepatocytes, he moved right into pancreatic islets, which I worked several years of my life. And I was part of Camilla's first clinical trial in humans. When we transmit 26 patients in Pittsburgh in 1991, I'd see, 92, you know, putting the eyelits into the liver.

It look okay. But again, it was not the right place. So Eric showed that if you put hepatocytes on the lymph node, they grow and do well. If you put islets into the lymph nodes, they grow and do well. Then Eric said, if you put sales from the thymus, which is an organ that we have early in life. And then we'll get a traffic and involute through our adult lives. So you don't see, but it does all the T cell development. If your transplant at the thymus into the lymphoma note, you got the same outcome with the function. And this is one of the things that we're thinking about aging. Can you do timeless transplanting an older person and reboot the immune system because a lot of problems that we have with aging and we become in somehow more immune compromised and we ended up dying from infection that we should.

So can you do this? And Eric also did something that was very interesting and he got fetal renal cells for the patients with renal failure. He got FITO Reno cells and grow the cells into the lymph node. And you see the same phenomenon in an amazing way because the kidney is as complex as deliberate, but have this dual debt, it's a blood filter that will secret something.

The liver produces bile that has to come out of the organ. The kidney produces urine. So Eric was able to grow this mini kidneys into lymph nodes. And you see not only the nephron, which is the filtering parts that you know this well, the nephron portion of the kidney, but the urothelial portion of the kidney forming urine.

So in our company, we have this line of investigation that we want to do down the line. If we transplant hypnotic cells, hepatocytes into the lymph nodes, close to deliver, and the buyer can be produced in going to the GI tract. Can we do the same thing with lymph nodes close to the bladder? We have plenty of them in for those close to the bladder.

Then we have the small mini kidneys. That's somebody who is leaning towards renal failure. Doesn't go to renal failure or there's a need to go on dialysis yet because you have much better filtration of the blood. With all this ectopic kidneys and for the pancreas, if you have diabetes and you transplant beta cells, pancreatic cells into the lymph nodes and they produce insulin, can they control the diabetes and give you a normal life without using insulin?

So, so all these issues around the table, we don't have enough capital to do all these things at the same time. So we are very selective, you know, Michael raised enough money to go to the first clinical trial on the liver but we have all this pipeline to be developed. It's just fascinating. 

[00:26:16] Patrick Short: Yeah. It's facinating it seems essentially limitless in terms of the impact, you can have the point you made about the thymus is a really interesting one.

I'd love to hear more about that. So what do we know? Today about the degradation of the thymus. And I guess the consequent degradation the immune system function because everyone is looking at this concept of healthy aging from really different perspectives. And this is when I haven't actually heard before some I'm really interested to hear more about the potential there.

[00:26:42] Paulo Fonte: This is actually the credit that goes to our investors to Juven essence. So when they first saw was presenting, when they saw Michael presenting this. They were very focused on the thymus because they were an aging group of comprehensive, I mean, just in essence this is just amazing what they've done. You can go on the website and see the quality of the people and how much they invested in, you know, how much driven they add on aging.

So they said, wait a minute, can we reboot the immune system by doing time was transplant with the cell based therapy, into the lymph node. And when they solved the data, they said, we want to be part of this and let's develop the first it on your pipeline which is the liver cells. To get functional thymus cells the aging is very important. As a transplant surgeon, I'd done a lot of human donors, 10 years straight doing donors almost every week. So most of the time you open an adult person, the times is not there anymore if you look the thymus was, is not there. When you operating on kids, the thymus is right there.

You can see the thymus and you know, it's, it's easy to get the thymus and even there are some kids that it's an interesting set problem. But one of the applications that we want to do is some children with cardiac disease, with congenital cardiac disease. When they have the first operation, open heart procedures, the surgeons in order to see the heart have to take the thymus out so they can operate on the heart.

And they throw the tiles away and this kids developed some problems down the line. So could we use that thymus ourselves as we are doing it right now? Could you process the cells and set up a transplantation into the lymph node? Then if you have a good match in older people like myself, then you need it.

Then you will transplant this and reconstitute some functions of your immune system. There will make you more immune competetant, so we are very much into this because aging is not just, you know, the timeframe that goes into your body, but this metabolic features that you face there's the non-medical products that you face and infection is a major issue.

And also your ability to fight against cancer when you were in somehow immune compromised you're your own system will not pick up some neoplastic cells that otherwise the immune systems says that's not us. Right and go get them. So, so if you increase the immune competence of people, can we treat infectious disease and make them less susceptible to cancer?

And the answer is most likely yes. And the therapy that we are proposing now, the biggest issue right now is to raise enough money to get this things going, because, you know, run three or four clinical trials at the same time, cost a lot of money. It is a lot of smart people to run them. It is a major effort. Yeah.

But I mean, there's definitely unmet medical needs, sitting right in front of us and the knowledge and how to do this. I think it's definitely on the table. 

[00:29:38] Patrick Short: It's amazing. I have one final question, but actually before we go to that question, there's something that I just couldn't resist because you mentioned it while we were just talking before the show.

I normally don't like to go through entire backstories of everyone because especially people like you have had such incredible career. We could probably spend a whole episode on the backstory, but you did mention that you, I think had your own lab and were doing surgeries at 19 years old. So this was too much for me to pass off.

I'd love. If you could just talk about how you caught the medical bugs, so to speak and got involved. So I think you cut it earlier than most. 

[00:30:11] Paulo Fonte: Yeah. I was very fortunate because my both parents met in a Medical training. So there were physicians. So I was exposed to the medical field early in my life. And I really had a passion when I was a teenager to 12, 13 years old.

I used to go with my father to the hospital to see. Uh, surgical procedures. I was very interested in surgery. He was doing liver surgeries and other stuff. I was, I was very interesting. So I really understood that I could go to medical school in my country. You can go to medical school right out after you finish high school. It's like in Europe, you know, it goes to go straight. So if you get a good grade on your SATs, you will qualify to a full scholarship program that you don't put a dime and you get a free education. So I went through this, I was accepted into medical school when I was 17, 18 years.

And I wrote the paper in my first year on vascular surgery that the chief of vascular surgery said did you right this. and said, yes, sir. Would you like to come to the lab? I said, yes. Would you like to do the research? I said, yes. So this guy had this unique mind as a surgeon scientist, who was interesting in coagulation.

He was very interesting in clotting and he wants to develop this arterial, this model in dogs for develop clots and use drugs. One of the drugs that he was testing was aspirin. That's how old I am. So, so, so he taught me how to operate. So with 19 years old, we have a dot model in the lab. What I could do vascular anastomoses in dogs and test these different drugs.

And for me, it was clear that the medical field was that as a surgeon, if you understand the mechanical part and you can connect vessels then you can do some other stuff and it use your mind to work on the scientific side. You can do a lot. So I was in the lab all the time from that time until now. So it's been 50 close to 50 years now.

[00:32:02] Patrick Short: Wow. Amazing. Just to close out here. I'd I'd love if you could just paint a picture of what, what the world would look like in 20 years if LyGenesis is successful. We've just gone through a number of the different options here. But if we could just think, you know, everything's going right, big picture blue skies, what what's different in 20 years, if you all are able to achieve your vision.

[00:32:22] Paulo Fonte: Yeah. I love this question because now being old enough to live through my own failures and frustrations and dreams that didn't work through. When I started doing transplants, the guys doing gene transplantation, we used to say. You're going to lose your job in five years, we're going to be able to do all this gene transfers.

We have all the vectors, we're going to train all the DNAs and then you're not going to even need me to do transplants and, you know, get another job. 30 years later, the technology has evolved a lot. We don't have the perfect type of sales. The IPSE cells. There is one good sell from Doug mountain. Now there's going to a clinical trial is working well.

We are not there yet. And there's other technologies that I mentioned. We didn't control them safe enough to tell the FDA that we're going to make this work. Sadly, a couple of weeks ago, there was a large biotech company, international big pharma that lost the four patients on a clinical trial for genetic therapy for that.

And then they stopped the trial. So I think at the cell-based therapy, we will roll with this idea that we show that the first generation is still old-fashioned. You get the cells that work, but they have the price of be different even though logically and you have to use immunosuppression. And as you asked, so why is that?

Is sometimes it can be off the shelf all the time, but if we have the right location now and the right technology with the endoscope to put the cells in the right place. And then can we get to a second generation of cells that now we control the cells in a way that we can genetically modify the cells and create the cells that we really need for the function that we need and most, most important than anything.

Can we act early on patients? Because as a transplant surgeon, my biggest frustration was I would like to see a 10 years before. Yeah, cause now you're too sick. So can we improve in preventive medicine that we can understand diseases in a better way that if we have to do any procedure or act on the patient act earlier in a meeting evasive way to have a less aggressive operation and then increase the time that they live and the quality of life, this is why, why do we really look at.

[00:34:30] Patrick Short: Absolutely. Yeah. That's an amazing vision. Thank you. I just really appreciate your time. I really enjoyed the conversation. You've got a wealth of experience and I think you communicate it in such a passionate and patient centric way. It's so clear to me talking to you that you love the science, but you even more than loving the science, you love the patients that you're impacting.

So it's so great to get the chance to speak to you. 

[00:34:50] Paulo Fonte: Yeah. As I told you already, it's a privilege and an honor. to be able to serve all these people and the families, and you live this through yourself. So you know what I'm talking about. So, so when you were sick, you need help. And it is great when you can devote your life and have people like you around you, that values human life more than anything.

And I tell people we are the same. So when we do transplants, it's very clear. There is no difference between. There's no religion. There's no ethnicity. We are the same. We are humans and we can help each other through this process. So when we focus on the patients and their families, and we want to serve them in the best possible way, and we treat them with dignity and passion, it's the best way that you can do this and how long it will take us to get all the answers.

I hope that the VC guys help us get the money that we need to build the milestones, you know, go through the FDA one by one and, you know, safety, efficacy, get approved safety and frequency. It takes time, but you know, it's a long way to go. 

[00:35:48] Patrick Short: That's right. And with the public service announcement for any investors that like the sound of this and want to get in touch with you all to, to help get there faster. I couldn't imagine a better place to put your money right now. Well, thanks everyone for listening. And as always, please share with a friend. If you'd like the episode, send us a message@podcastatsanojax.com. Leave a review on your favorite podcast player that helps other people find us.

And thanks so much for your time. See you next time.