Researchers from Harvard University have announced the most extensively gene-edited organism ever, a line of pigs that have had more than 60 genes modified. It’s about more than just showing off, though; all these changes are aimed at creating a species compatible enough with human biology to allow transplantation of animal organs into human patients. It’s called “xenotransplantation,” and it could be a big part of the future of medicine. This study could represent a real step toward a solution for a huge proportion of the 125,000 people waiting for an organ transplant in the United States alone.
Contrary to what you may have heard from that kid who sat beside you in junior high, there are not a bunch of people out there running around with baboon hearts. The most famous semi-modern attempt at xenotransplantation of a major organ occurred in 1984, with the tragic case of “Baby Fae.” Fae was born with a congenital heart defect called hypo plastic left heart syndrome, and scientists put a baboon heart in her in a desperate attempt to preserve her life a little longer; the animal heart was only ever meant to sustain her until a human donor could be found. As with all other xenotransplantation events thus far, however, her body quickly rejected the alien tissue.
That trend has continued unbroken ever since, including several failed attempted at a xeno-liver transplant. Even much smaller things like single heart valves present problems of rejection by the immune system; immune rejection often stymies even intra-species transplantation from one human to another.
Still, clinicians have been outspoken about the need for non-human sources of organs — it’s unspeakably frustrating to watch people die while knowing just how to fix them, simply because you can’t get access to the parts needed to actually do the repair. Even the risk-averse FDA says that xenotransplantation needs to be a major priority for research. There have been some amazing breakthroughs with animal transplantation, such as a successful transplant of a pig organ into a baboon. We don’t need worry nearly as much about giving pig diseases to a baboon we’re probably going to dissect anyway, however, and in any case the organ was rejected as soon as the researchers discontinued their battery of immune-suppressing drugs.
There are really only two foreseeable solutions to the overall problem of human organ failure: either we grow fully human organs from stem cells, or we take human-enough organs out of fully non-human animals. The latter solution seems like it really ought to be the easier of the two, but the immune rejection problem means the much more complex stem cell approach has actually made more overall progress so far.
That’s what this team may have achieved: pigs with organs that do not trigger the immune response when transplanted into a human. The lead researcher on this study recently started a biotech company called eGenesis for eventual sale of human-compatible porcine tissue. If successful, it has the potential to let humanity bring its expertise in farming livestock to bear on everything from diabetes to cancer.
Yes. Why? Because pigs are simultaneously close enough and far enough from humanity to make them feasible organ donors.
Pigs have long been associated with human biology. It’s been suggested that the world’s numerous cultural and religious prohibitions against eating pork might partially stem from an alleged similarity in the tastes of pig and human meat — some cannibalistic tribes of Pacific Islanders used to refer to human flesh by a phrase that roughly translates to “long pig.”
More recently, pigs have seen extensive use as animal models for human biology; if a pig can take it, maybe a human can as well. Whether you want to test a new drug, take a stab at cryogenic suspension, or observe the effects of exposure to raw vacuum, pigs have long been the premiere, well, guinea pigs. They’re not as human-like as, say, chimpanzees, but they’re also infinitely less expensive to raise and keep. They’re also physically large enough to grow useful organs for humans, unlike baboons or similarly pint-sized species.
On the other hand, porcine evolution has not overlapped with human evolution in quite some time — much longer than for apes. This means that any latent viruses, especially retroviruses hiding in the animal’s genome, are far less likely to find purchase in the human body. Don’t forget that HIV started out as PIV — Primate Immunodeficiency Virus. That sort of species-jump is why many doctors are wary of using primate organs, since they might actually end up doing more harm than good in the long term. In its policy page on xenotransplantation, the FDA says that, “of public health concern is the potential for cross-species infection by retroviruses, which may be latent and lead to disease years after infection.”
What they’re talking about are PERVs: porcine endogenous retroviruses. In the 1990s, the discovery of these genetic maladies put a hard stop on xenotransplantation research, as studies showed that, in the lab, some piggie diseases can actually infect human cells. This Harvard study used the new but already venerable CRISPR system to make 62 inactivating changes — muck up a virus’s gene, or just cut it out entirely, and you no longer need to worry about it rearing its head after you’ve already put pig organs inside a few million of the world’s most important people.
Of course, 62 genes is a lot of genes, but until we have the results of a few decades of xenotransplantation to study, the question will always remain: did they really get them all?
The potential medical benefits of having readily available source of human-compatible organs is simply too big to reject out of such paranoia, however. The danger of someday developing a biology-hopping genetic disorder will likely be seen as very acceptable, to people facing the prospect of wide-ranging organ failure.
So. Pigs it is.
These (hopefully) PERV-less pigs are actually only half the equation, and the Harvard team is already working on the other half. It’s one thing to make pig organs safe, it’s quite another to make them compatible. Though it’s the inactivation of 62 PERV genes that has set an editing record, these are still pig organs at the end of the day, and they will need to be modified on the protein level if they’re to work properly in the human body. As we just discussed, getting to that point should be easier in pigs than just about any other candidate species.
In that spirit, the team has actually engineered two separate lines of pig embryos. The second has modifications made to more than 20 separate (and currently unpublished) genes, ones that affect cell behavior through things like cell surface proteins. These are the changes that could potentially be tailored to a particular patient’s genome, allowing us to grow highly compatible organs by mixing a small number of the patient’s own genes into defanged porcine genome.
The edited pig embryos should be perfectly viable as pigs in their own right, but we won’t know for sure until they’re actually implanted in pig mothers. Harvard has a facility all setup for their growth in isolation — they’ll breed each line separately to be able to study problems with as few confounding issues as possible. To produce a real organ transplant species, the researchers will need to combine the two groups of modifications in a single line of pigs — though since the PERV-line has theoretically lost only viral functions, that shouldn’t be the biggest obstacle in the world.
When this team eventually publishes their much more ambitious work in steering the pig genome closer to the human, you can expect a robust breakdown from ExtremeTech.
From real-world congressional rows over the potential use of human tissue to literary projections like Never Let Me Go, the popular culture has made it clear that the idea of using humans to sustain humanity makes it squeamish. Yet if we go with animals for organ growth, what new challenges might arise? Will people actually accept animal parts into their bodies, or will they reject them on religious, philosophical, or purely squeamish grounds? Can a religious Jew accept a porcine heart transplant? Will your insurance plan one day include a fee for keeping you a little piggy organ factory somewhere, should it ever be needed? Will your local hospital have to build a pig pen to receive patients’ organs, still warm and safe in their original packaging?
On the one hand, it’s hard to imagine much widespread outrage over growing pigs for medical slaughter, when we already grow them for culinary slaughter. On the other hand, how eager will we be to go on consuming pork, if one of the organs involved in digesting it is made of the very same tissue?
Until we can use a person’s own adult cells to create stem cell lines from which all fully developed organs will be grown, xenotransplantation will be an important goal for the medical community.