Gene editing animals for organ transplants to humans

Dr Chantal Babb de Villiers discusses gene editing animals for organ transplants to humans, otherwise known as xenotransplantation.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.

In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.

You can read Chantal's briefing on xenotransplantation here.

If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

If you have any further questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: 0:12

Welcome to 'Making science work for health', the PHG Foundation's podcast, exploring developments in genomics and related emerging health technologies. Social media and the many digital news outlets now mean more of us than ever are aware of the progress being made by teams of intrepid scientists and researchers around the world. Many of the latest advances feature genomics and 'omics related technologies, the field in which the PHG Foundation has 25 years of experience helping policy makers get to grips with practical on the ground delivery. 'Making science work for health' aims to strip away the gloss and explain what new science means for patients, health professionals, and members of society. My name is Ofori Canacoo, part of the communications team at the PHG Foundation and host of 'Making science work for health'. For this episode, we are talking about new developments in technologies that could enable the use of animal organs and tissues to supplement or even replace some human-to-human medical transplants. The use of animal organs and tissues in humans called xenotransplantation raises many ethical questions and is the subject of considerable debate. Ethical and societal implications of innovations in healthcare are at the heart of our work at PHG, however, for this episode, we are focusing on the state of the science, which is moving rapidly. Joining me for this episode is Dr. Chantal Babb de Villiers, senior policy analyst at the PHG Foundation. Hello, Chantal.

Chantal: 1:37

Hi.

Ofori: 1:38

How are you?

Chantal: 1:39

Good, thanks. And you?

Ofori: 1:40

Yes. Good, thank you. So firstly, would you like to tell us a little bit about yourself?

Chantal: 1:44

Sure. So, I'm a senior policy analyst at the PHG Foundation. I'm originally from South Africa, but I have a background in genetics and I am particularly interested in how genomics is being used in healthcare and improving the health of people and patients. Part of my work here at PHG Foundation, we do innovation in sciences and we look at how new innovation is being used in healthcare. As part of my role, I looked at xenotransplantation, which is what we are going to be talking about today.

Ofori: 2:15

And xenotransplantation is the process of grafting or transplanting tissue or organs from one species to another. This isn't a particularly new idea, is it?

Chantal: 2:25

No it isn't. They've been trying to do this for years. Back in the nineties, there was significant research happening around this topic, and actually they were even doing research a hundred years ago, looking at the chances of transplanting from one animal to humans and contributing towards different aspects of transplantation that needed to be tackled. So, in the nineties, they were mainly using non-human primates, which was baboons and chimpanzees. But there was a number of concerns around using these as source animals for this type of activity. So, at the same time, research was being done and they discovered there was a risk of infection, so zoonosis, where the disease would jump from one animal to another animal. So, research slowed down significantly within the nineties, but it's always been there and there's always been an interest in trying to figure out how to do xenotransplantion.

Ofori: 3:20

What problem is xenotransplantation aimed at resolving?

Chantal: 3:24

So, the main issue is related to the shortage of organs. There are large waiting lists for individuals waiting to receive an organ due to organ failure. So, we know of all the waiting lists that are out there for people who need organs, such as kidneys, hearts, lungs, and livers. But we do not have enough organs for these individuals and every year, thousands of people are dying while they are waiting for an organ.

Ofori: 3:51

How big are the waiting lists generally then?

Chantal: 3:53

If you look at the EU in 2019, over a hundred thousand people were on the waiting list. In the United States, it's a very similar number, and daily, within the US, seventeen people are dying while they're on the waiting list, waiting for an organ. We know that these are probably the minimal numbers as well, because there's very stringent criteria to be included onto an organ waiting list, and there's going to be a lot more people out there who would benefit from getting a new organ.

Ofori: 4:22

So, for this episode, we are going to focus on the state of the science of xenotransplantation and genetic engineering is one of the key technologies. What are the advances that are behind this renewed interest?

Chantal: 4:35

So, you're right, there's many ethical questions that need to be asked around genetic engineering, but for, for our purposes, we are just gonna focus on the science that has allowed us to reach the stage where xenotransplantation might be an option. So the advances that have recently taken place is that the genetic engineering technology has changed quite a bit. They've been looking at this for years, but they were using techniques and methodologies that would take a significant amount of time to be able to get a single change into the genome. Whereas now using advanced techniques, which is CRISPR, they're able to do this much quicker and they're able to do a number of different changes in one go. So, due to these advances, they've now been able to genetically engineer a pig a lot quicker and allowed for preclinical trials to take place in a much shorter timeframe, that it's now advanced significantly that we can start considering xenotransplantation. It's not only gene editing. There's been a number of other things alongside this that has allowed it to happen, but genetic engineering itself has been a significant contribut- contributor to allowing this to happen.

Ofori: 5:48

Could you briefly explain what CRISPR is for us?

Chantal: 5:52

So, genome editing, also known as gene editing, is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or changed at particular locations in the genome. Several approaches to genome editing have been developed. A well-known one is called CRISPR, which is short for "Clustered Regularly Interspaced Short Palindromic Repeats". It was adapted from a natural occurring genome editing system that bacteria use as an immune defense to viruses and researchers have adapted the system to edit DNA. The process involves generating a new genetic sequence and attaching it to a protein enzyme. The most commonly used enzyme is Cas9. This enzyme scans DNA strands until it locates the target sequence, which we'll then cut, which is mirroring the process that we see in bacteria. Once the DNA is cut, researchers use the cell's own DNA repair mechanisms to add or delete pieces of genetic material. It kind of works like a biological version of a word processer's "cut and replace". It allows for faster, cheaper, more accurate and more efficient genome editing than a lot of the other methodologies that are out there.

Ofori: 7:10

So, you've mentioned pigs as being the subject of genetic engineering for xenotransplantation. Is there a reason they've been focused on instead of non-human primates as you previously discussed?

Chantal: 7:21

So, the choice of the pig as a donor species is for a number of reasons. The physiology for many of their organs is similar to humans as the shape and the size, so it makes it quite compatible. They're easy to obtain and their care is well understood through farming. Pigs can be cloned and their genomes can be edited, and any genetic changes that are introduced are heritable. So, it's also seen that they're less likely than non-human primates to transmit pathogens because they are more distinctly related from humans. They also have a very short gestation period and produce large litters, which make them suitable as a sustainable source for xenotransplantation. And their tissues, such as heart valves and skin grafts, have been successfully used in clinics already, meaning to some extent they are likely to be acceptable, although this still needs to be determined when we're considering whole organs.

Ofori: 8:18

Are there specific organs or tissues of interest, and is that focus driven by need or by the science indicating those organs that are more amenable to transplantion?

Chantal: 8:29

It's a little bit of both. So they're definitely focusing on organs where there's high demand, which is... kidneys are number one, followed by heart, lungs, and liver. So, that is the main focus areas because there is such a demand for these organs, but there's also the limitations within the science. Hearts and kidneys are showing a lot of promise in preclinical trials. They are progressing a lot easier than with liver and lungs. Why that is is still not completely clear. They might not be as amenable to being xenotransplanted, but there's work happening and they're trying to solve it, but it definitely looks like hearts and kidneys are the organs where we are seeing progress.

Ofori: 9:18

How do they tackle the issue of rejection?

Chantal: 9:21

This is where genetic engineering definitely comes into play. So, the majority of genes that are being focused on are the ones related to rejection. Whenever a foreign object is transplanted or found within our bodies, our immune system responds to that and will attack it and try to remove it. This happens when we have organ transplants taking place. Rejection is the biggest concern and problem; that the organ will be rejected by our immune system. So to tackle this, they're looking at the different genes, not only within the pig genome, but also within the human genome. They're trying to identify what is causing this immune response and then removing the proteins, so the genes that produce those proteins from the pig genome. But then they're also introducing human genes. So, transgenes, where the organ from the pig can look more human-like. Which means once it's placed within a human, the immune system thinks it's part of the body and won't necessarily attack it and reject it. To do this, they've actually looked at over 40 different genes, and there's a variety of different combinations that are being looked at to see what the optimal combination is to reduce rejection. On top of that, immunosuppressants, so the use of drugs, is also being a significant contributor because we've advanced the therapies that are available to combat rejection as well. So these are being used in normal day-to-day transplants that are taking place as well, so they're contributing to avoiding rejection as well.

Ofori: 10:57

From a technical perspective, how close are we to seeing animal organs being used for patients in need of, say, a new heart, lung, or kidney?

Chantal: 11:05

In the last year, there's already been a transplant of a pig heart into a human. It was a compassionate use case where the individual had run out of traditional healthcare options. The pig heart allowed him to live for an additional two months, which is a significant amount of time considering that this has never been done before. So the heart is looking promising, and so are kidneys. Kidneys have reached a stage where they're doing preclinical trials in brain dead individuals. So, in these situations they are checking that the organs aren't rejected, but also to check some of the organ functions. So for example, can they handle the blood pressure from a human body because the organ is being transferred from a quadruped to a biped, and research needs to be done to determine whether organs from one animal into humans can cope with some of these changes.

Ofori: 11:53

Setting aside the ethics, there is also a big question around the public health implications and concerns for people who interact with a xenotransplant recipient. Could you tell us a bit more about that?

Chantal: 12:03

One of the main concerns is the risk of zoonosis, which is the transfer of infectious agents from one species to another. So, in this case, transfer of pathogens from a pig organ to the human who receives it. The person who receives the organ is the most likely at risk of getting one of these infectious agents, but they may also become a carrier or a vector for the infection, so they may not get sick themselves, but pass the infection onto people who are in close proximity to them. This of course, is a big concern and it is not just the person who receives the organ who would be at risk, and although the real risk of this occurring is still not known, it is a major concern that it could happen. And this is why there are guidelines in place that include the monitoring of close contacts for such infections, and close contacts will need to be part of any monitoring that is done on xenotransplant patients.

Ofori: 13:00

Are there alternatives to xenotransplantation on the near horizon?

Chantal: 13:03

I'm glad you asked this because it is important to realize there are alternatives to xenotransplantation that are being looked at. Unfortunately though, none of these are on the near horizon and they're all at very early stages of research. They include things such as 3D-bioprinting, tissue and organ regeneration, tissue engineering, and the use of people's stem-cells to regenerate organs. There are also mechanical solutions that are being looked at, but these and other options are in very early stages, so that's why xenotransplantation is suggested to be a bridge until these technologies become available. Not only until the research of these technologies has advanced enough, but also they're thinking of xenotransplantation as a bridge between when people need an organ now and a human organ becoming available. So receiving a xenotransplant until a human...a suitable human organ is available for them.

Ofori: 14:00

What's the global involvement at the moment and who's leading the research?

Chantal: 14:04

There are a number of different groups who are interested in this globally, and the interest of course stems from organ shortages. The research is primarily being led by the US, China, and a group in Germany. A number of research groups in these countries have made significant advances and have their own breeding and research facilities. They provide a lot of the preclinical trial evidence and animal trials to show that the organs they are producing are going to be viable and useful. It has now reached a point where they are proposing that we move towards clinical trials. The UK, however, has not been very active in this area for some time. Particularly when we look at the regulation aspects, and the last time the UK did any updates on this was in 2007. However, globally, the World Health Organization has set out very clear guidelines on how xenotransplantation and the clinical trials should be regulated. In the US, the FDA is also leading the way in establishing guidelines, so there are guidelines in place that can be followed and used globally.

Ofori: 15:06

What are the next steps in this field of research?

Chantal: 15:09

There is a lot of ongoing effort and continued research already taking place. Preclinical trials are continuing with animal study, xenotransplantations being done between pigs and non-human primates. And this is being done to understand where there might be possible issues and to examine where the rejection is something that we've been able to overcome with genetic engineering. From a research perspective, there is important groundwork that has been laid and these preclinical trials are important for this. They demonstrate that the organs are functional, that there is reproducibility, and predict the safety and durable efficiency of these organs. Although there are limitations to these studies as there is only so much that a study in a non-human primate can tell about organs intended for use within humans. There are other important areas of research ongoing. Trying to figure out exactly which gene edits are most vital to prevent rejection taking place, and also what combination of gene edits and with which immunosuppressants they are most optimal to use. There are reasons for caution though, including the scientific, ethical and social challenges, as well as hidden dangers that could have public health consequences. It is also impossible for xenotransplantation to completely solve the demand for organs in the short term, even with the continuous accumulation of scientific understanding and technological progress, it'll only be one option among many for a considerable period of time in the future.

Ofori: 16:38

You mentioned regulations, so just briefly, could we touch upon that and the ethical considerations?

Chantal: 16:45

Sure. As well as understanding the science, we will need to understand the ethical issues that occur from xenotransplantation becoming a recognized practice, particularly as we move towards clinical trials. Research and conversations will need to take place to establish what this means for society and the individual. So when we reach clinical trials, questions will need to be asked on how the trials will be conducted, how patients might be recruited, and how would we monitor those who come in close contact with a patient who has received a pig organ. Particularly, are we discussing patients that have run out of options? Is there a freedom of choice? Also, the risk of zoonosis and the monitoring of patients mean that the right to withdraw from a study may not be an option, and the list of concerns can just go on and on and on. This is very novel technology. Then of course there will be the societal considerations. So would society agree with xenotransplantation? Is this an acceptable thing to do? There is already some research on these matters because we already have tissues and cells transplanted from pigs to humans. But organs could be something else that needs to be addressed and considered when we are looking at societal, ethical, and legal issues.

Ofori: 18:00

Thank you, Chantal. Just lastly, could you tell us what you are working on next?

Chantal: 18:04

Certainly. So, there is a number of different projects. I have a particular interest in pharmacogenomics and how that's being implemented within healthcare, but I'm also looking at different biomarkers for cardiovascular disease and how that can play a role in prevention of cardiovascular disease. Polygenic scores is a key area that we are focused on within the PHG Foundation and I've just completed a report looking at polygenic scores and the potential role they have in cancer management, and we do hope to continue that work.

Ofori: 18:38

Great stuff. Thank you, Chantel.

Chantal: 18:40

Thank you for today.

Ofori: 18:44

Well, that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org, and if you have any further questions about the topic, then you can email us at intelligence@phfoundation.org. Thank you for listening. My name is Ofori Canacoo and I look forward to bringing you a new topic in the next episode.