Gene edits move pig organs closer to human transplantation

Benjamin Thompson

Welcome back to the Nature Podcast. This week, making pig organs more compatible for human transplantation.

Shamini Bundell

And why our brains find it harder to count more than four objects. I'm Shamini Bundell...

Benjamin Thompson

...and I'm Benjamin Thompson.

Benjamin Thompson

Organ transplantation from donors or recipients is an established clinical practice. But around the world, there is a chronic shortage of available organs. This leaves many people on transplant waiting lists who run the risk of dying while they wait to receive a suitable organ. One long-sought solution to make up this shortfall is the use of animal organs. But it's been a struggle to get animal-to-human transplants known as xenotransplants into a clinical setting due to the rejection issues caused by things like the complexities of the human immune system, and concerns about the potential for disease transmission. However, in the past couple of years, there have been huge strides in things like gene editing, and the first pig-to-human heart transplant, which happened in early 2022. Spurring the field on. And this week in Nature, there's a paper that reports on the successful transplantation of kidneys from pigs to monkeys. These kidneys have been engineered to be closer to their human counterparts, and this research could help overcome some of the hurdles associated with xenotransplantation and may have important implications for future human trials. Nature reporter Max Kozlov has been following the story and he joins me now. Max, how're you doing?

Max Kozlov

I'm good. How are you?

Benjamin Thompson

Yeah doing okay. Thank you so much for joining me today. So we've got a story then about xenotransplantation. So transplanting organs from one species to another. And this is something that's been talked about and researched for decades, I think it's fair to say, but it's been getting a lot of attention recently, what's the state of the field at the moment?

Max Kozlov

Yeah, so the reason why a lot of researchers and clinicians are excited about this is there's an enormous waiting list for organs. And specifically, pigs have been a species that researchers have honed in on. And that's because the organs are roughly a similar size to human organs. We know a lot about the pig genome, so it's easy to edit it, and they don't take a very long time to grow, their gestation period isn't very long. So all of those things make pigs an ideal species to be doing xenotransplantation research on.

Benjamin Thompson

And there's been a couple of stories recently of hearts being transplanted from pigs into humans. Although in one case, the person receiving the organ did pass away a few months after the operation. So it seems like that's not the end of the story there's a lot more complications just yet.

Max Kozlov

There have been a few one-off cases in that they're not being studied in a systematic way, in the context of a randomised control trial. So researchers and clinicians and regulators are all gearing up toward starting phase I trials where we can start to evaluate this in a systematic way.

Benjamin Thompson

But getting to those phase I human trials requires, of course, a lot of background research. And this week, there's a paper that showed that engineered pig kidneys can be implanted into non-human primates, and can last in some cases a very long time. But before we get to that, and the results, maybe we can talk a little bit about the pigs that are used in this research.

Max Kozlov

Yeah, they used miniature pigs so they're much smaller than normal pigs. And not only are the pigs smaller, but the organs are smaller too. And one of the problems is when you take these organs and put them in a larger animal, say a monkey, the organs will grow with the animal. And sometimes you don't want the organs to grow that much. And so one technique has been to knock-out a gene that is responsible for a growth hormone. So that kind of tamps down the growth of the organs, but it can lead to some other unwanted side effects. So instead of doing that, their technique here was to use a smaller pig species. And because it's a smaller pig species, the organs just naturally grow at a slower pace. So it was kind of a clever way to get around the problem.

Benjamin Thompson

And these pigs then had had their genomes engineered, and this work sort of pulled together a bunch of different strands of research.

Max Kozlov

Yes, and they edited 69 different genes in the pig genome, the bulk edit out this kind of virus, they're called Porcine Endogenous Retroviruses, and they linger in the pig genome and under the right circumstances could kick back up again and potentially cause damage to the organ or patient receiving it, it's still unclear to what extent that's actually a problem. But again, the bulk of those edits were to lower the possibility of those reactivating. And then they also moved some human genes into the porcine genome. These help protect the cells that line the blood vessels and prevent the blood from clotting when you don't want it to. And then on top of that, there are certain antigens, they're basically these molecules that the immune system recognises as foreign and starts to attack them, it basically removed the genes that encode the enzymes that produce them, lowering the chances that the immune system will go haywire if these organs are transplanted into humans, or non-human primates.

Benjamin Thompson

And so that's what's happened here. And these kidneys from these engineered pigs have been transplanted into a type of monkey, the cynomolgus monkey, what happened?

Max Kozlov

What they found was when they transplanted these kidneys into the primates, some of them were able to survive more than a year and one even survived more than two years, which is, I think, the longest survival of a nonhuman primate with a pig derived organ. But there are some that didn't make it to a year. And that's one of the things that the lead researcher pointed out is there was more variation than they were expecting in how long these primates were surviving. I've talked to other researchers in the field who weren't surprised by that result. And that's because in this study, that used human trans gene, not non human primate trans genes. So it's not a surprise, necessarily that, you know, these genes aren't optimised for use in these specific species. But regulators want to see that you have tried every single gene edit that you want to put in humans in a nonhuman primate or an animal model. And that's part of the reason they needed to still test them, even if they weren't optimised for the non-human primates.

Benjamin Thompson

And one thing that stood out to me then Max is that the monkeys also still had to take immunosuppression drugs, which suggests that even though the kidneys were engineered to remove these antigens and these molecules that the immune system attacks, there's more to understand about potential rejection say.

Max Kozlov

Yeah, you're right. So some researchers are very optimistic that one day we'll find the specific gene edits necessary to prevent all immunosuppressive drugs altogether. And that would be huge because we use immunosuppression, and it works to prevent rejection. But it also leaves your body very vulnerable to other potential pathogens, and can take a toll on the body as well. So that is their ultimate goal. But in this study, they still did use immunosuppressive drugs.

Benjamin Thompson

As we discussed, there's a lot that still needs to be figured out about this, you know, technical hurdles to overcome and ethical discussions to be had, as well. What are the researchers you've spoken to hope for this field and where it's going to progress to?

Max Kozlov

I mean, they're very encouraged by these results. And I think that this is one step closer to human trials. I mean, I think a lot of the researchers I talked to are itching to start human trials, because it's been instructive to do this in non-human primates, but some of the things that they need to iron out need to be done in humans. And so they're saying that, you know, at a certain point because people are dying, not getting the organs that they need. At a certain point, if we know that this technique is, you know, xenotransplantation, has a reasonable likelihood of success, that is almost an ethical imperative to begin trials is what they're saying. Whether or not regulators agree, you know, I think that this will be a conversation in the next couple of years. But I think researchers are hopeful that by the end of the decade, this will be something that is being tested seriously in humans.

Benjamin Thompso

That was Nature's Max Kozlov there. To read his story about the new paper look out for a link in the shownotes.

Shamini Bundell

Coming up, the neurons that help us count things. Before then though, it's time for the Research Highlights with Noah Baker.

Noah Baker

New research is getting to the bottom of how the littlest children are able to combat SARS-CoV-2. A pandemic's worth of research has painted an increasingly clear picture of how the immune system of adults and older children respond to the virus, but much less is known about the response in babies. To plug the gap a team in the US tracked immune responses in 54 young children, most of whom had been infected with SARS-CoV-2 before the age of two. In adults and older children, antibody levels in the blood spiked after infection and then plummet. By contrast, whilst babies saw no drop in antibodies for nearly a year. The level of antibodies they produced tended to be lower, as did the size of the T-cell response. However, the researchers also found unusually strong immune responses in the noses of babies. This will give them the ability to stop SARS-CoV-2 in its tracks in the upper airways, which the researchers say could explain why babies tend to have milder infections. You can find that paper in Cell.

Noah Baker

A new 3D printing technique is allowing scientists to build miniscule objects using a sort of molecular glue, opening the door to new materials that were previously off limits. Conventional 3D printing works best with metals and plastics because atoms in these materials effortlessly form chemical bonds with each other. But a team of researchers in China set out to expand this repertoire. They use nanometer-scale crystals of various semiconductors, metal oxides and metals to make liquid inks mixed with a chemical additive. Then they fired short laser pulses at the mixture, which caused the additive to form reactive atoms. These behave like a glue binding together molecules found on the surface of the nanocrystals and causing the liquid ink to solidify wherever the laser beam was focused. By guiding this laser through the liquid, the authors could create complex structures, such as a model of the Eiffel Tower, they were even able to print objects from a mixture of materials, paving the way for the printing of complete electronic devices. You can find more on that in Science.

Benjamin Thompson

Finally, on the show, it's time for the Briefing Chat, the part of the show where we discuss a couple of stories highlighted in the Nature Briefing. And Shamini why don't you go first this week? What have you got?

Shamini Bundell

Okay, so I've been learning to count this week, we're back to basics its a news article in Nature, Human Behaviour. And yeah, it's all about how our brains count things, and particularly why it's harder to very quickly estimate a large number of things compared to if there's any very few things. I was trying to sort of think of a suitable example and it's just before lunch today, so I'm a bit peckish. So my example is going to be cupcakes. You walk past the tray of cupcakes at a conference, you glance at it and someone says, oh, how many cupcakes are there left? If there's three or four cupcakes, you could probably at a quick glance, really quickly, just know the number of cupcakes that were left on that tray–

Benjamin Thompson

–Yeah–

Shamini Bundell

–when it gets to more even five? Oh, what do you think, Ben? Do you recognise that sort of just having to spend slightly longer counting as it goes higher up? Maybe even from five, six?

Benjamin Thompson

Yeah, I mean, I guess so with those smaller numbers, you've got that kind of instantaneous, okay, there's three of those there. Right. But when there's more, I suppose yeah, it does take a bit of time. So what's going on there, then?

Shamini Bundell

The question has always been, is it just that it gets harder the higher numbers? If you see, you know, 20 cupcakes or a tray that's gonna take you a little while and your estimate is gonna be a bit rough probably, versus if there are four of them. Or is there actually something different going on in our heads, when we count a small number of things versus a big number of things?

Benjamin Thompson

And so researchers didn't know this then?

Shamini Bundell

It's the neuronal basis of it all that we don't know. So you can observe the behaviour. And you can measure how long it takes people to, you know, count dots on a screen and see this sort of slight disparity in times and see that increasing as you get longer. But yeah, is it sort of continuous? Is it the same process in our brains that's counting any numbers or the other theory, are there two different mechanisms, neuronal mechanisms that we're using to assess the numbers?

Benjamin Thompson

Right, and this is what the researchers have figured out in this new paper, which of the two it is.

Shamini Bundell

Exactly so they've done some previous research showing that you've got neurons in your head that respond to particular numbers of things. And in this new research, they wanted to dive into that further. So what they did was they had patients with microelectrodes in their heads already due to getting some surgery for seizures. And then they showed them screens with series of dots on, they sort of flashed it up for half a second, anywhere from zero to nine dots, and then said was that an odd number of dots, or an even number of dots.

Benjamin Thompson

Okay.

Shamini Bundell

And as you'd expect, they were better when it was four or fewer dots, much more precise answers, tended to be a little less precise, occasionally got it wrong when it was five or more. And then the key thing was, let's look at the neuronal activity, which neurons are firing when you're looking at these different numbers? And yes, what they found was, the answer to that question seems to be this two slightly different mechanisms at play here.

Benjamin Thompson

So there's the small number, neuronal system and the big number, neuronal system.

Shamini Bundell

Yeah, and it seems when you've got these neurons that are like it's three, it's four, as you go higher up in the counting, those neurons are less selective. So if you have a neuron that responds to three, it'll only respond to three it'll only fire when it sees three of something and the same for all the other three neurons. But if you have neurons that respond to eight, they might also fire on seven on nine, they're a little bit less specifically selective to one number. And that's why people then make more mistakes when they're trying to count a large number of objects. And they haven't sort of elucidated the full system exactly what's going on where. But it does suggest these two distinct number systems, which one of the authors says he was actually quite surprised by, he'd been one of the people who thought, you know, there's only one mechanism. He said, "I had a hard time believing that there's really this dividing line, but based on this data, I must accept it."

Benjamin Thompson

Well, that certainly is a neat one and one that I will keep in mind next time, I'm trying to work out how many cupcakes left on a tray. But let's move on to the second story this week. And I identified that number very quickly. But it couldn't be more different and something I read about in Nature and it's about the European Space Agency's Euclid Space Observatory, which has been, well, performing some unexpected pirouettes in space, which have threatened the craft's ability to do what it was launched to do.

Shamini Bundell

That sounds a bit worrying, like ESA have launched a craft that's just sort of spinning off through space uncontrollably.

Benjamin Thompson

Well, thankfully not uncontrollably. It has to be said. But there were some subtleties that had to be looked at. Now, Euclid was launched into space on the first of July this year. And it currently is 1.5 million kilometres away from Earth, right. And it's up there to help researchers understand why the universe's expansion is accelerating, okay. And the way they plan to do this is to map the positions of 1.5 billion galaxies in three dimensions looking beyond the Milky Way, right. But to do this, it's going to have to photograph some of the darkest patches of the sky, and it's got really faint stars. And to make sure it's pointing the right way. It has to use known positions of these stars, which were taken from a previous mission, and then adjust its position accordingly.

Shamini Bundell

Okay, so it is very important when looking at these distant stars that it is pointing at the right stars.

Benjamin Thompson

Yeah, exactly right. So it has to be pointing the right way. And there's actually quite a hard thing to do right requires some quite high-precision manoeuvres for more than 10 minutes at a time what it takes its images. But this hasn't exactly gone according to plan. So initial tests showed that in some cases, the telescope was wobbling, okay–

Shamini Bundell

–oh, no–

Benjamin Thompson

–it couldn't stay stable, which of these pirouettes, okay–

Shamini Bundell

–yeah–

Benjamin Thompson

–and this was leading to test images with these kind of loopy trails of stars, right, you imagine a long-exposure photograph–

Shamini Bundell

–oh right yeah–

Benjamin Thompson

–to the point where it kind of gets smeared across the photo, right? Like a child's scribble, I guess. And these pictures they took are kind of beautiful, really. And if you look for a link in the show notes, you can see one, but obviously, if you're trying to do precision measurements of where galaxies are, that is not ideal.

Shamini Bundell

Yeah, not so good. Loopy little motion-blurs do sound pretty though, do they know why it's failing to sort of stabilise?

Benjamin Thompson

Well, actually, yes. And thankfully, it's been fixed as well. So the team behind the spacecraft sprung into action, right to diagnose what was going on. And it turned out that these sensors in the pointing system, right, which made it point the right way, these take periodic two-second exposures, right. And they match it to the previous map to make sure it's like constantly facing the right way. But the sensors are also absolutely bombarded by energetic particles, things like cosmic rays, okay–

Shamini Bundell

–oh–

Benjamin Thompson

–and very quickly, the software on this spacecraft in like less than 100 milliseconds has to filter these out. So it can make sure it's only looking at the real stars, not these other artefacts, and it was getting confused, and it was losing the guiding stars and mistaking this cosmic noise for faint stars and dark patches of sky.

Shamini Bundell

Oh, okay. So like a really noisy image full of lots of random lights. And you have to figure out which one's the one that you're looking for, basically.

Benjamin Thompson

Yeah. And what they've done is in this case, they've updated the system. So it can filter these out appropriately. And it does seem to be working. But there's actually more to this story, they fixed another problem as well. In early test images, tiny amounts of stray light, were getting into the telescope for an unknown reason, because this telescope is shielded has got a sunshield, and it's got multiple layers of insulation. And it turned out that there's a thruster sitting on the side of the spacecraft that's not protected by the sunshields. And when it was facing at certain angles, sunlight was bouncing off a one centimetre squared patch of this thruster that wasn't painted black, bouncing off the sunshield and making its way to the side of the telescope, where the super-sensitive cameras were picking it up. And it turns out that just really slightly tilting the spacecraft 2.5 degrees adjustment has meant that this problem has gone away. So the levels of precision we're talking a million-and-a-half kilometres away from Earth is staggering, really.

Shamini Bundell

And it's lucky that they were able to fix both of those because I guess the first one, it's the software, isn't it? So it's not something physically wrong so they can then update how it's filtering and then the second one, yeah, thank goodness that the slight tweak fixes the light-bouncing issue and doesn't break something else because it's a bit late to go back and paint your one centimetre patch black.

Benjamin Thompson

It's going to be a tricky one right? One of the researchers quoted in the article was saying that we heard about these problems and it sounded like these things were going to work out. But it's always an immense relief when it does, which I can certainly imagine and so testing can now be restarted and scientific work is due to start potentially in November. And the first results are expected in 2025. And a little bit later for the kind of the full 3D map. And hopefully it'll tell researchers more about sort of dark energy and dark matter which researchers don't know much about, which could help maybe explain why the universe's expansion, as I say, is accelerating.

Shamini Bundell

Wow, mysterious dark matter and the expanding universe sounds like the kind of things we shall undoubtedly be reporting on here on the Nature Podcast. And in the meantime, you can check out the links to these particular stories in the show notes. And also you can sign up to the Nature Briefing and find out where we get all these cool stories from.

Benjamin Thompson

And that's all for this week. As always, you can keep in touch with us on X we're @naturepodcast, or you can send an email to podcast@nature.com. I'm Benjamin Thompson...

Shamini Bundell

...and I'm Shamini Bundell. Thanks for listening.