Retroviruses concealed in the DNA of pigs

We’re going to look at one of the major risks of moving intact animal organs into humans - how we safeguard against infection. Lurking in the animal’s DNA are viruses, which can reawaken in the immunosuppressed patient and begin to infect human cells with unknown consequences. Chris heard from Harvard’s George Church who has found a way to track down the genetic signatures of these viruses and remove them…

George - So, the viruses in the pig genome, these endogenous retroviruses, have been inherited since probably the dawn of mammals, if not earlier. Unfortunately, humans are not resistant to these particular pig viruses - we and others have shown that they will replicate in human cells. Now, whether that is a health risk is not known yet, but I don't feel so lucky that I would want to take a risk that one out of a hundred patients would get sick and possibly spread that virus to their family.

Chris - So, your concern would be: if we were to just put an organ from, say, a pig into a human, including an immunosuppressed human - so they're already fighting with one immune arm tied behind their back - that these viruses lurking in the pig tissue, despite not being human viruses, could nevertheless come out of the pig tissue and begin to infect the human tissue in the new host the organ is in.

George - Exactly. We've shown that these viruses will replicate in human cells. We have not yet shown that they replicate in human beings.

Chris - And how many of these viruses are there lurking inside the pig DNA?

George - They range from about 20 to 80 per genome, and we have established methods that are available to anyone to eliminate all of them. We've shown in peer-reviewed papers that we have eliminated all of them from several strains.

Chris - How do you do that?

George - We use a new method that we helped work in mammalian cells, which is called CRISPR, which is an enzyme that, when introduced into the pig cells, will edit every copy that it is directed to edit. This also works in human cells and is the basis for a variety of therapies. But, in this case, we're engineering the pig germline so that when they breed like regular pigs, from that point on all of their offspring will be virus free.

Chris - In essence, you've got gene editing tools that can go and ferret out where these viruses are in the genome and remove them. Does it remove them entirely, or does it just remove enough of them that they're no longer a threat?

George - We could remove them entirely, but they actually have some positive functions. So, what we do is we remove their ability to replicate, but we don't remove all their genes.

Chris - And is there no danger if you've left the vestige of the virus behind that something could come along and restore the bit you've taken out - so it regains the ability to grow.

George - If something came in from outside, they wouldn't have to restore it - they would already be a risk in and of themselves. But the thing that we've left behind that actually protects them from that outside invasion is a membrane protein, something that coats the pig cells, and prevents them from getting infected by other retroviruses of this category.

Chris - And there's no danger through doing the gene editing that you introduce changes that you don't foresee or plan for so you've solved one problem, but potentially left another booby trap lurking in there.

George - There is that possibility. And that's why it's nice that we're doing it in pigs before we do humans: we get to observe the pigs growing up and breeding and show that generation after generation everything's fine and only then do we transplant them into humans.

Chris - And where's this going to go next? You're in a position where you have created these pigs and they lack what could be regarded as an infectious threat were we to use their organs - are they a kind of foundation now where we can make further changes or tweaks or build on that foundation to use these as the starting stock of animals that could be donors for organ transplants?

George - Yes. We have published on pig strains that have up to 42 changes in their genome, which have all the immunological tricks that Megan told you about earlier: coagulation, they have antiviral strategies all in place, and they've been tested for hundreds of days in primates (which is much longer than any of the human trials so far), and they will be transitioning to human clinical trials very soon. So, there's no barrier to anybody doing similar things in their favourite strain of pig.

Chris - Are you optimistic?

George - Yeah, I'm very optimistic. It's not only going to help us with the organ transplant deficit thanks to the lack of adequate donors, but it will actually give us organs that are enhanced slightly relative to human organs, in that they will be resistant to certain human diseases and possibly, eventually, engineered to be cancer resistant as well.