Rohin Francis: one small step for a heart

Rohin Francis, Image courtesy of Rohin Francis

"Click here to listen to the full podcast episode"

In January of this year, surgeons performed the first ever operation to transplant a heart from a genetically modified pig into a human, a 57-year-old man called David Bennett. Mr Bennett had been suffering from severe heart failure, and as he was not eligible for a human heart transplant, he consented to this ground-breaking operation.

To find out more, I sat down with Dr Rohin Francis, a consultant cardiologist who also runs the popular science YouTube channel, MedLife Crisis. When Rohin and I spoke in early February, the patient Mr Bennett was defying expectations and had survived for a month after the operation. However, since recording this interview, he has sadly passed away, two months after receiving the new heart, and it has not been made public whether this was due to an issue with the xenotransplant itself, or a consequence of his general poor health.

This is still a remarkable scientific and medical development, so I asked Rohin how we have arrived at a place where we can use organs from animals as transplants for humans.

Rohin: This isn't the first time a xenotransplant has been attempted, but it is the first heart transplant in this modern era. There was a kidney xenotransplantation performed towards the end of last year, but that was in a brain dead recipient, and it was more a sort of experimental proof of concept, a first sort of human test with the consent of the recipient's family of course.

Sally: And presumably if the patient was brain dead, they knew that they had no chance of living. It wasn't like, we're going to give this person a kidney and that's going to bring them back.

Rohin: No

Sally: It was just a, can we put the kidney in and it doesn't get rejected?

Rohin: Exactly, it was to test a lot of the aspects of the research that have been performed so far in, in a human recipient.

But the interesting thing about the operation last month is that the recipient was fully conscious and able to give consent for himself. And he's a middle-aged gentleman who had end stage heart failure. And for reasons that haven't been made public, he was not a candidate for the conventional treatment options that are available today, which would be obviously human to human heart transplantation.

So they pitched an idea, this experimental idea of putting a pig heart as a transplant and it was a success and it's been a month down the line. So this is a really historical first because it potentially is the start of this new era where, I mean, the end goal ideally, is that nobody has to die waiting for a transplant.

The main problem with the organ donation model at present, as I'm sure everybody knows is that we simply don't have enough organs. So there's always been an interest in xenotransplantation. Trying to use animals as a resource to get these organs. And actually the first one people may be surprised to hear was attempted way back in the 1960s, which was unsurprisingly a spectacular failure because we simply didn't understand the immunology at all then.

Sally: What sort of transplant was it?

Rohin: That was a chimp heart into a man.

Sally: And they just lifted the heart out the chimp and stuck it straight in? No kind of modification, anything like that?

Rohin: Nothing at all. So I mean there's a bit of interesting story behind it because there was a little controversy at the time. And the surgeon, James Hardy, he'd been inspired by one of his colleagues who'd had some success with chimp kidneys, and they'd had a patient who'd survived a few months with a chimp kidney. And felt that there was no other options so he was going to go for this Chimp heart transplant and he'd recently acquired some research chimps, I don't know where you get them in the 1960s version of eBay or something, but he'd got some chimps and they were in the building and the temptation was too much to resist.

And the controversy was, when he was consenting the recipient's wife, because the patient was in a coma, he didn't mention that the transplant might be coming from another species.

Sally: Oh, wow.

Rohin: And so the consent form, you can still see it, just says transplant deemed appropriate by the surgeon. So I'm glad we've moved on from those days.

But then there was a bit of interest in xenotransplantation over the subsequent decades and there were attempts made from sheep from baboons, chimps, but ultimately they all failed. And the reason is, is that the immune system is the main problem. And that's a similar kind of story for our transplants in general. In those early days of transplantation, actually success rates were really poor because we just didn't have a handle on the mechanisms of rejection.

Sally: Well, this is the one thing that I know about organ transplants is they get rejected and that's even human to human. I mean, it's even a family member to family member. They can still get rejected. So surely they're even more likely to get extra rejected if it's from a completely different species.

Rohin: Yes. I mean, exactly that it's a different kind of rejection, which is very catastrophic and immediate.

 These organs that were placed between species without any kind of modification within seconds or minutes, you will see the organ start to sort of turn a dusky colour and eventually just go black and just clot off.

Sally: When you've still got the patient's chest open?

Rohin: Yeah. This is within, immediately, and the most successful were only alive for maybe about a few weeks.

Sally: What is happening when an organ gets rejected?

Rohin: Well, I mean, that's a very complex question to be honest, but there are different aspects to the immune response. In this case, it will actually activate abnormal clotting, so it will just stop blood going to the organ just to try and kind of clot it off entirely, it will create a lot of inflammation, so it sends inflammatory cells to the region. These are kind of cells that will try and attack the foreign tissue and essentially kill it. So there are different elements to the immune response, but this initial one was that the main hurdle that had to be overcome for xenotransplantation to be a viable option.

And that, to give you a sort of idea of how complex it is, has taken about three or four decades to get to the point we're at now it's been an incremental change. And they're very, very clever. They've actually genetically modified pigs and created, what's sometimes referred to as a 10 gene pig.

Sally: 10 gene pig?

Rohin: Yes. It's referring to, not the fact that the pig has 10 genes, but

Sally: I was going to say, I think the pig has more than 10 genes.

Rohin: Just a handful, but four pig genes have been knocked out, specific ones that were causing the immune response in humans.

Sally: The ones that say, hey, I'm a pig, I'm not a human.

Rohin: Exactly. The ones that express this sugar on the surface of the cells and six human genes have been incorporated into the pig DNA.

And so this is the six plus four, that's the 10 gene that they refer to. And there was essentially a shopping list put together of the kind of changes that needed to be made in order for pig organs to be useful. And sequentially they've been going through trying to modify all these genes and it's really a absolute Marvel that they've done this. And created essentially this genetically modified organism, which can potentially have organs for human use.

Sally: These are special pigs that are donating organs, not your run at the mill, going to make bacon pig.

Rohin: Exactly. And I think that's an important point to make is that it's not just going to be a case that you can just go to a farm and get one of these pigs.

These are very, very sophisticated tailor-made organisms and they essentially will lead very unusual lives. You know, they have to be kept in very sterile conditions. So one of the big risks of xenotransplantation, which we haven't mentioned so far, is the possibility of zoonosis. So, infection moving from one species to another.

Sally: Something people are even more aware of now than before.

Rohin: I don't know what you could be referring to. But, yeah, so I remember in contagion that the movie that kind of predicted all of the pandemic, pigs were intimately involved in that weren't they? In the wet markets.

Sally: Well I think we'd just had swine flu at that point.

Rohin: Yeah. Yeah, of course. And the other potential infection concerns are something called PERVs, Porcine Endogenous Retroviruses.

Sally: I'm glad you clarified that.

Rohin: Well, you can have HERVs and PERVs depending on whether it's human or porcine. And these are actually viral DNA that's inside the pig DNA. So there's potential, if you are transplanting something from another species, that these endogenous retroviruses, which we also have in our DNA, but we are obviously used to them, could cause some sort of horrendous, catastrophic infections.

Sally: Once we've got past the barrier of it being a pig and so the human body might reject parts of it. If we assume that we've gone past that, human body's not rejecting it. Surely there are differences between pig hearts and human hearts. A pig is a larger animal than a human for a start. Are there any long-term consequences that we might be able to predict of just having a different anatomy regardless of whether it gets rejected or not?

Rohin: I guess the simple answer is we won't know the long-term effects for a while. But yes, there are obviously some anatomical differences, although they're quite slight, when it comes, I can only really speak for the heart here.

Sally: Your favourite organ, no other organs exist.

Rohin: The only organ that matters, let's be honest.

So the heart anatomy of a pig is a bit different because obviously they are on all fours, and so the orientation of their heart is somewhat different in their chest. It's a bit more straight, whereas ours is slightly diagonal in the thorax.

Sally: Does that matter?

Rohin: It matters in terms of the vessels that lead into it. So they're plumbed slightly differently, but clearly that's been overcome in transplant and obviously lots of experimental work in labs had been done prior to this.

So there are subtle anatomical differences. In terms of size, actually, we're pretty comparable. So that's one of the key advantages of the pig as a model.

Sally: Okay. Because another thought I had was if we're adding human genes to pigs, does that make the pig part human and less pig?

Rohin: Yeah, technically when you have introduced another species DNA, then that is a chimera and chimeras are not new, they've been sort of bred for a long time, but the techniques by which we're creating them now are increasingly sophisticated. So, it's quite a common research tool now to have chimeric most commonly obviously mice. Chimeric animals in research with, with human DNA as part of their genome.

Sally: Because the heart, I know you love your hearts Rohin, but the heart is, is kind of, I don't want to say an inert organ, but a heart is a heart. It does one thing, regardless of the animal that is in, whereas something like a brain, if you're adding human genes to the whole pig, therefore that will also affect say the brain. Does that give human traits to the animal that we're putting it in?

Rohin: Right. Well, this is a very interesting area and there's a 2003 book by Margaret Atwood, of Handmaid's tale fame, called Oryx and Crake. Where in this dystopian future, they, they breed pigs as a source of organs for humans. But the pigs start taking on human characteristics. So they become, super-intelligent, not super intelligent, but for pigs.

Sally: Which are already pretty intelligent animals.

Rohin: Well, yeah. You know, probably similar to dogs, to be honest in terms of intelligence, however, you measured that.

But, you know, I mentioned that story somewhat facetiously, but there is the potential, when you're introducing human stem cells into another organism, you're telling them to develop into a certain organ, but there is potential that they can become any cell line. You know, that's what stem cells do.

And I don't believe there's any evidence of this occurring in any of the pig models, but there are some really interesting papers I came across in research involving mice. So they made a mouse model with human glial cells. So these are support cells within the brain, not the neurons themselves.

Sally: They're the ones that wrap around neurons as an insulator

Rohin: And they found that rapidly the human glial cells replaced all the mouse ones until it was almost a hundred percent human glial cells in this mouse and mice bred in this way had four times better memory than normal mice and they were much more rapid at maze navigation.

Sally: That's like saying I've taken my computer and I haven't changed any of the wiring connections, I've just replaced it from having a red coat of plastic on the outside of the wire to a blue and now my computer works faster. That is bizarre.

Rohin: It's probably because we are oversimplifying the model. I'm sure there is more of an interaction between glia and neurons than insulation on wires. But yes, you know, it is really quite shocking. And, you know, I hesitate to talk about some of these things when it comes to this field, because I don't want to come across like I'm being some doom monger and trying to make it sound very dramatic like we're going to have some horrendous half pig, half human.

Because I think that's getting a bit carried away and it's science fiction, but these are very interesting and important considerations to have, and you're very right when we fiddle with DNA, and I'm sure all your listeners will know this better than me is, we don't have a complete understanding of everything we're doing.

And there's always the potential for some unintended consequence down the line. These are very early stages in a nascent field, it's really at the first steps. And I don't think it's realistic that we're going to have xenotransplantation widespread in the next few years. I think it's still going to take quite a while.

But, hopefully, this is a step in the right direction. And ultimately trying to avoid, I was looking up the statistics for the UK and at the moment there are 6,000 people on the waiting list for a transplant in the UK. And a lot of them sadly, won't make it to the end of the year. So this is all with the intention of trying to prevent those avoidable deaths.