Angelika Schnieke - From sheep to pigs

Kat - You're listening to the Naked Genetics podcast with me, Dr Kat Arney, reporting back from the 20th birthday symposium for Dolly the sheep, held by the Roslin Institute and the MRC Centre for Regenerative Medicine in Edinburgh. Still to come, we'll be finding out how chickens could provide us with a lot more than eggs thanks to biotechnology. But first, it's time to hear from another member of the team involved in cloning Dolly. Angelika Schnieke is now chair of livestock biotechnology at the Technical University of Munich, where her research on pigs is helping to change our understanding of human diseases.

Angelika - Based on the technology which has been developed with Dolly, we can now genetically modify the pigs. So this is mainly used at the moment for models for serious human diseases and also xenotransplantation and now, we're also getting in an area where it's also available for agricultural applications.

Kat - So, let's unpick those three different things. Let's start with the human diseases? Why are pigs a good model for human diseases? Lots of people hear about using mice as models but why pigs?

Angelika - We have been working with mice for a long time because it was actually the only species where we could do genetic modification in for a long time. But of course, it also had been shown that a lot of results from the mouse cannot be transferred into the clinic. So still, we needed some other models and probably the best would be to work with apes which is not possible. So, what else is there which is sort of in the physiology, in the size and so similar to human, and the end product was a pig.

Kat - And are we talking about big pigs or little pigs? Mini pigs seem to be very trendy now.

Angelika - Yes. The big pigs are a little bit too big because they go into several hundred kilos when they're fully grown out. So, you work with many pigs or you can also work with F1s between them and then use somewhere in the mini pigs - 60 kilos and otherwise, sort of 80, 90 kilos, so quite human.

Kat - What sort of diseases can you study in these animals?

Angelika - Principally, all sorts of diseases which you also find in humans. So people are working on models for human cancers. They're working for cardiovascular disease, they're working on diabetes so all the main killers really. Plus, on top of it now also are rare diseases.

Kat - So, how do you go about studying a disease in a pig? How do you make a model pig?

Angelika - We look what experiences already in humans so do you know what the basis is for the disease? Have also the experiments been done already in the mice? And so, with that knowledge we can then really design our pig to have exactly the same genetic difference or alteration so that they might get the same disease as what you'll find in humans.

Kat - Can you give me a good example of that that you've managed to create in your lab?

Angelika - We work on cancer models. So, one of the most common cancer models is colorectal cancer. Another very serious cancer is the pancreatic cancer. And so, we're making models for both those cells.

Kat - Do they seem to recapitulate what the disease looks like in humans?

Angelika - What we have seen so far, we also have another model for osteosarcoma. So our colorectal cancer is just what you find in humans. It is different from the mouse but the mouse differs from human. So, we find the polyps and the tumours developing in the large intestine just like in humans and the mouse with the same mutation within the small intestine. We have the same for the osteosarcomas or the bone cancer that the places where the tumours appear are the same as in humans and again, the mouse is different. So it looks like at least for the tumours, the pig is a good model.

Kat - And then presumably, when you're trying to develop new treatments, understand the disease, you've got these animals right there in front of you that you can properly investigate that you couldn't do in the same way with a human.

Angelika - That is absolutely right. So you can take samples from the tumour, you can take samples from the blood then you can also look for biomarkers to do early diagnosis. Can you see some differences in your blood samples which might indicate what is happening inside the animal in the tumours and you can do this all the way through the disease progression.

Kat - You also mentioned another application of these modified pigs is xenotransplantation which just sounds like something you find in a science fiction film. What is it and what's the role of pigs?

Angelika - So xenotransplantation means that you move organs from one species to another. In this case, it would be the porcine organs or the porcine tissues into humans. So, most people know that we have problems with diabetes. Diabetes also means that we have a lot of kidney failure. There's an absolute shortage of kidney transplantation or to cure diabetes in with islet transplantation. So if you could not take the kidneys or maybe the heart or the islets from the pig and transplant it in humans, you could cure probably the serious diseases.

Kat - But why can't we do that already if pigs are so similar to humans in so many respects? Why can't we do that just from a pig?

Angelika - Well, you know that even if you transplant from human to human, you have to make sure that it is a good match. And there are some genes in the pig which are not there in humans anymore. And so, there is a rejection of the organ which happens very quickly. Those genes which causes these very fast rejections, we have to remove from the pig. So the organ can survive, we also have to have some other pigs where there might be a small discrepancy between humans and the pig system - maybe the blood coagulation system.

Kat - So you're trying to make the pig organs look as closely like the human organs at least to the immune system.

Angelika - At least to the immune system. That's absolutely right.

Kat - How long is it going to be before we can actually have these kind of organs that you could transplant into humans? What's going to be the first step this way?

Angelika - Actually, it's already happening in some ways. You have decellularised heart valves which are either from pig or from cows and they implant it into humans. But there of course, you have destroyed most of the cells so they should not be rejected. The next will be small tissues. For example, the islet cells because you can also encapsulate them. You can place them and you could also take them out.

Kat - These are the cells from their pancreas that make insulin.

Angelika - Exactly. They are the pancreatic cells which makes insulin. So that would be already quite a step forward. You can also imagine like corneas you could use and then it will be going into whole vascularised organs. They are a bit more difficult but hearts can already survive in the baboon for almost two years.

Kat - Maybe one day soon you could be walking around with a pig liver instead of your liver.

Angelika - Well, yes. I mean, you also have to imagine that you might not need the organ for your whole life. But if you had for example, eaten some poisoned mushrooms your liver might degenerate very quickly. But it could also regenerate. But in between regeneration, you might be dead. It would not be a good outcome. So what you really want is maybe sort of an ersatz liver.

Kat - Temporary liver.

Angelika - A temporary liver for the short time that your liver has time to regenerate.

Kat - I'd like one for Friday night when I go out drinking. Borrow one! In the final application you talked about was, use in agriculture. So could we have GM pigs being used in agriculture? Is that a good idea? How does that work?

Angelika - In my opinion, it would be a good idea. But it depends of course, what is your target, what would you want to change. We talked a lot about human diseases and how you can help the humans. But of course, we also have a lot of diseases in the pigs, infectious diseases. And so, if you could find out what are the receptors for those infectious diseases, can you alter them so you don't get the infection but the pig is still healthy or is a sheep or cow, make them more resistant to diseases. So you have something which is good for the animal, something which also will have a better product because you know you can have your meat, your milk and so on from healthy animals. So yes, I would think it is a good idea.

Kat - Is that the same kind of techniques that we've seen so adding genes in to these animals or changing the genes to make them more healthy?

Angelika - The technologies would be the same. So in most cases, you would probably alter the genes which are already there. You would not necessarily have to add new genes and you have more and more new technologies coming up. Genome editing is one of them, where you can make really sort of very fine, precise alterations of the genome.

Kat - The world heard all about Dolly the sheep. She was a cloned animal cloned from an adult cell. Everyone got very excited. But then a year later, there were some other very unusual sheep born. Tell me about them.

Angelika - It was right from the beginning the reason why we were interested in the Dolly experiment is because we had cells in cell culture. And cell culture also alters the cells and cell culture was absolutely the next question necessary. And so the next experiment was to introduce transgenes, in this case it was factor 9 which is one of the factors which is important for blood coagulation and people who don't have factor 9 are haemophiliacs. And so, we wanted to make the product in the sheep, milk the sheep and then treat the humans with it. and this was in the next experiment, added the gene to the cells, use the cells to make the animals and that was then Olly, Polly, Holly, Molly.

Kat - So that carrying on with the Dolly type naming theme.

Angelika - It was. Actually, when the animals were born, they were all males. It's the time Germany won in football, but the Scottish team was not very excited to name the animals after the German football. So, they decided on Olly, Polly, Holly, Molly.

Kat - The last question really, you were one of the team that worked on Dolly the sheep 20 years ago. What in your opinion has been her impact and really, how have you seen this field develop over that time?

Angelika - If you just talk about genetic modification in livestock the way we're doing it right now, it would not have been possible without the experiment on Dolly. Without having cells in culture which we can change and then make a whole animal out of those cells which are cultured, without that, the whole field wouldn't have really developed. I think another very important point is really that it has inspired people to think differently. So, some things which looked impossible before, now they became reality. It also makes sort of, you're looking at something which can be very exciting. Science can be very frustrating but from time to time, you have these little highlights and they sort of spark an interest in science, in sort of your adventurous Geist.

Kat - Angelika Schnieke from the Technical University of Munich.