July 07, 2022

Special blood and transplants

By Conor McKechnie and Dodi Axelson

Special blood and transplants

This episode is all about special blood and transplants. We speak to Jon Adkins, co-founder of XenoTherapeutics, who walks us through their use of xenotransplantation for skin grafts and organ transplantation. We are also joined by Dr. Franck Zal, a marine biologist, CSO and CEO of Hemarina, to discuss the lugworm. His discovery, that the lugworms’ blood is compatible with human blood, means it can be used in medical applications for transplants.

Join us for this eye-opening and insightful conversation.

DODI: Conor, like me, I know that you have read and enjoyed Ishiguro, am I right?

CONOR: Yes. The Nobel laureate for literature in 2017. Yep, absolutely love his stuff.

DODI: One of my favorites is his novel 'Never Let Me Go'. I've had many a sleepless night thanks to that novel. It was also made into film a few years back.

EXCERPT FROM NEVER LET ME GO: Who told you these stories? Everybody knows them. And how do you know they're true? Of course, they're true. Who'd make up stories as horrible as that?

DODI: Spoiler alert for those of you who have not read or seen the movie, it is set in a dystopian future. Humans are being grown for organ replacement.

CONOR: Exactly. There's like this whole other group of humans kept separate from the population and they're just there as like exact spares.

DODI: And of course, Ishiguro represents all of this under the umbrella of dystopia. But I actually started wondering if there are any real-life examples of this idea maybe not particular separate human population. Maybe there's a parallel Conor and Dodi somewhere, not making a podcast but growing organs. But maybe there is an innovative way forward when it comes to transplants and helping us survive with healthy organs.

CONOR: Ah, okay, I like it. So, it's like The Matrix, but it's organ farming.

DODI: Right.

CONOR: I guess that's what matters in today's episode.

DODI: That's right. In fact, let's Never Let Me Go.

CONOR: No! She didn't.

JON ADKINS: That moment of trauma, and then the moment of needing a cure, how do we replace what is lost? What is damaged? How do we fix the problem? That becomes the foresight of our minds. And the more we can create a better supply of these things, and also in a humane and ethical way, I think that the end results justify the means.

CONOR: So, who is this talking so poetically?

DODI: Meet Jon.

JON ADKINS: My name is Jon Adkins. I'm the co-founder of XenoTherapeutics.

CONOR: Okay, so I assume Xeno with an X and not a Z. It's not a paradoxical Greek philosopher, but Xeno- as in foreign right?

DODI: That's right.

CONOR: It's transplants, its organs for humans grown in other species.

JON ADKINS: Exactly it stems from the term xenotransplantation, which is the transplantation from different species.

CONOR: How would you try and get involved with Xenotransplantation?

DODI: Well, it all started from a fascination with how the donor system works.

JON ADKINS: When individuals pass away, and they're organ donor providers, that's the first phase because organs, you know, will become necrotic very quickly. So then from that is tissues can be harvested, as well as skin, bone, cartilage, etc. And there's quite a large industry that's involved with it. But one of the things that I did see in that business was that there wasn't a whole lot of continuity in the actual donors. You know, it varied in ages and stages of the donors.

DODI: The more Jon looked into the idea of transplanting from different species, the more he thought...

JON ADKINS:...Well, this is fascinating. You know, if you could change the source of human donor tissue to something that's a genetically engineered porcine donor, that could be a complete game changer. So, we started through the process of how can we do a tech transfer with this, you know, where do these animals stem from? And we really opened up Pandora's box for all the history that was involved in it. But seeing just what I like to call the low hanging fruit, with skin and tissue, there's a real opportunity here to make something different in a live biotherapeutic product. And that's what we embarked on.

CONOR: Okay, so before we go any further, can we get a little bit of perspective here? When did xenotransplantation really first become something that, you know, we would think about?

DODI: Good point, it has been around for a while today, we're seeing a bit of a resurgence. And the reason for this can be traced back to the late 1990s when a temporary suspension of Xenotransplantation activity was enforced, because there was a big concern for safety.

JON ADKINS: You know, is there going to be an endogenous retrovirus on the heels of the HIV that was going on. Not to mention, you know, the complexity and immunological problems with both hyper acute rejection and acute rejection.

DODI: But as I said, today, people are starting to see the potential of xenotransplantation again.

JON ADKINS: With this resurgence, you know, the possibilities now become a lot more hopeful. And we're seeing it, it's actually being more accepted in terms of the medical community to take risks in doing this.

CONOR: So, the thing that strikes me here is that potentially you suddenly have this kind of unlimited supply of organs, right?

JON ADKINS: Exactly. We're looking at just the gestation of pigs, you know, three months, three weeks, three days before another litter is produced. And we can really deliver cells, tissues and organs far faster, more efficiently, and really optimize it.

DODI: We're not just talking internal organs here.

JON ADKINS: So, we're talking about transplants, skin is a transplant. Skin is the largest organ in the body. And when we're looking at burns, you know, you don't think about burns too often. And seeing it firsthand, as I mentioned, it really makes you think, and it can happen to anyone. Anything can happen, whether it's boiling water, just accidents that happen and you can wake up in the ER, and just the devastating injury that's occurring, and then the not knowing what the course of action is.

DODI: Our skin is this incredible organ, it helps regulate our temperature, it prevents infection, there are so many good reasons to say thank you to our skin.

JON ADKINS: So, when those cells are damaged or lost, we have to replace them. And that's why skin grafts are the gold standard of care in burns. So, we need to be able to provide skin grafts and by using a live biotherapeutic product that we've created with xeno-skin, from these genetically engineered animals, we can actually provide this at scale.

DODI: Jon says one of the biggest challenges here when it comes to xenotransplantation is immunity and mismatches.

JON ADKINS: You know, just animals in general, the biggest one that we found was the alpha1,3-galactosyltransferase, or α-gal that all animals have. It's a sugar moiety in their cells that we, as humans, have antibodies for. So, as soon as it's transplanted within our body, our antibodies create hyperacute rejection, and it's rejected. So, the complexity, especially with internal organs, becomes very fast.

DODI: So, as technology gets better, Jon and his team at XenoTherapeutics are aiming to get better to make better genetic edits to these animals to account for those mismatches.

JON ADKINS: And that's ultimately what we're looking to do. When you can create a universal off the shelf, you can do haplotype matching, I think even if you're staving off mortality for six months, a year, two years, what does that mean to that individual and their families? Think that's the ultimate goal.

CONOR: Okay, well, this is epic. This is like personalized medicine, personalized organ transplantation, but at massive scale.

JON ADKINS: Yes, it is. And you know, personalized it becomes a little more nuanced. You know, it can't just be me, right? You can't just manufacture another me in that sense. But I think, you know, that term of being universal or universally adaptive, is more in line with it. But yeah, I agree. And personalized medicine is going to be the medicine of the future. That, you know, when we treat an individual with a disease, we want to treat and understand what the individual is going through and what their body's reacting to, and not just throwing generic drugs or treatments that aren't necessarily going to work.

CONOR: So, what does Jon see XenoTherapeutics developing in the next 10 years? I mean, what does he need from the biotechnology industry so that they can take the next step?

JON ADKINS: And I think what we have done is starting down the course on really how do we pave that path? Regulatory speaking from everything from CVM on the FDA side of things, it's very complex, and no one really has an answer. The difference between pioneers and settlers is pioneers have arrows in their backs. So, we're taking some arrows to figure that out.

DODI: Ultimately, for Jon, this is all coming down to the exciting idea of staving off preventable mortality. So, why die early if you don't have to?

JON ADKINS: If we can create something in nature's own bio factory 'Mother Nature', and nature knows best, if we can harness Mother Nature, and adapt, and modify, and make something more optimized, then we can provide those live biotherapeutic products to patients that will actually be cured instead of just chasing symptoms and going back and forth with actually replacing what was lost, that to me is delivering on the promise of regenerative medicine.

CONOR: Okay, that is super cool. What else is out there?

DODI: Well, we're going to get a little creepy and crawly to answer that question.

DR FRANCK ZAL: Okay, go ahead.

DODI: This is Dr. Franck Zal. He's all about worms.

CONOR: Worms?

DODI: Yes. So, I know you like your garden but I'm not talking about earthworms. This is not earthworms. These are worms that prefer the seaside. Dr. Franck says the important and fascinating thing to know about worms is that they live in the sea and rivers, so they are polychaeta worms.

DR FRANCK ZAL: So, it's very interesting to find species living in different environments. And since there are 10,000 species of worm, it's very easy to work. For example, when you are very interested by respiration, to take a look at species colonizing different other environments. Instead, to try to find a solution and you just want one species.

CONOR: So, we're talking about comparative physiology, right? Other animals to understand how we work.

DODI: That's exactly right. So, one day, Dr. Zal, a marine biologist, was standing on a beach in his beloved Brittany, and he was watching the tide, low tide, high tide, low tide, high tide.

CONOR: And it happens like that every day. Amazing, isn't it!

DODI: Yeah, back, and forth, back, and forth. And he started thinking about worms. And he was looking at those little sandworms the lugworm as there were also known.

CONOR: Ah, the humble lugworm, bait of choice for the discerning angler. And a squiggly pile of poo on the beach to the rest of us. Yeah. Brilliant.

DODI: So, there was Dr. Zal on the beach, he started asking himself the question.

DR FRANCK ZAL: Sometimes, there's always a breakthrough innovation coming from basic question.

DODI: That question was, how do these sandworms breathe between low tide and high tide? This question was the beginning of it all for Dr. Zal.

DR FRANCK ZAL: I focused my attention of the blood of this animal, and I discovered a very strange respiratory pigment. We have hemoglobin inside the red blood cell. And we know that oxygenation in respiration is something which is common to all the life on Earth. And I discovered to this worm, very special molecule, which is very close to human blood, hemoglobin, but totally different because it is not included in the red blood cell.

DODI: Basically, what he realized was that unlike human, who have hemoglobin stored in red blood cells, the lugworm, with all of its intricate specifics, has hemoglobin directly dissolved in their blood. To what that means is their blood is compatible with all types of human blood.

CONOR: Okay, so now let's see the link to xenotransplantation. Yeah, we're doing it already. The lugworm is basically the grubby strangest, littlest, weirdest, universal blood donor.

DODI: Exactly!

CONOR: That's so cool. So next time, dear listener, when you are out on a beach and picking lugworms for bait think! That little critter could save your life.

DR FRANCK ZAL: There is a bunch of innovation with a common species, common animal, common invertebrate. But you just need to ask yourself other questions, like 'Yes, it's a sea urchin. Okay, are we going to eat this one? It's a starfish. Okay, no we cannot eat it.' You know, every question that human beings ask themselves, you know, I can eat it, or can it do something? My vision is you need to ask yourself why is the worm here? You know, it's just you can ask the question, but most of the people don't ask this question.

DODI: At first, perhaps not oddly, after his discovery, people in the scientific world thought that Dr. Franck was a bit mad with this talk of blood and worms.

DR FRANCK ZAL: This guy is crazy. It's not it's impossible. We know that in a medical area all blood is contained in a red blood cell. And this guy is totally crazy.

DODI: Then one day he was invited to give a talk at a hospital in Paris.

DR FRANCK ZAL: So, I was marine biologist arriving in a hospital making a talk about worms. And the people at the beginning were laughing and saying, 'what's he's going to talk about and so on?' And at the end of my talk people said, 'Are you sure? Because we have been looking for something like that for over 40 years by now.' I said yes, and that there are plenty on the beach.

DODI: And now people refer to Dr. Franck Zal's discovery as important as penicillin.

CONOR: Okay, so this is just brilliant. I'm feeling super inspired. I could just go down to my local pond now. And if I kind of knew what I was doing, I would find a cure for something. So, with that inspiration in mind, just doctors all have advice for kind of young scientists who are looking to have their own lugworm moment one day.

DR FRANCK ZAL: There is a quotation coming from a very old guy called Leonardo da Vinci. He said, 'Take inspiration from nature'. So, you know, he was the first to do that. In my point of view, it's to go back to the nature and try to learn about the nature and avoid destroying the biodiversity. It is not just for the ecology, political ecology, is just because biodiversity is the library of innovation. So, it's very easy. Go to the beach, go out, try to ask yourself questions that nobody has ever asked you about trees, about why this muscle is here, why is this bird living here? And you can find it, believe me, you can find a bunch of innovation.

CONOR: Okay, back to Leonardo, of course. It's so brilliant.

DODI: I know. Isn't it so great? We've talked about serendipity so much on this podcast, and it we've talked about curiosity, and here it is, you know, from lugworm to xenotransplantation to possibly you know, having spare parts somewhere in a lab helping us live longer.

CONOR: I know I feel a little bit like Scully but it's not that the answer is out there, but the answer is out there we just have to look in the right places and maybe stop making all of the dumb mistakes right. But those help as well.

DODI: Our beach-going executive producer is Andrea Kilin, and this podcast is produced with the help of Bethany Grace Armitt-Brewster. Editing, mixing, and music is by Tom Henley and Banda Produktions. My name is Dodi Axelson.

CONOR: And I'm Conor McKechnie, make sure you rate us on Spotify or whichever platform you use. If you're listening on Spotify, answer the poll underneath the description. We're kind of interested in what you think. We'll see you when we come back with another episode of Discovery Matters.

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