The public is mostly numb to claims for “scientific breakthroughs” because the term is so highly overused. Every incremental advance is deemed a breakthrough, and often false claims of breakthroughs are used to market highly dubious products and treatments. It is also often difficult to know when an advance is truly a breakthrough, meaning that it will change the world in some significant way. We can only really know in retrospect. But I am going to go out on a limb and declare this incremental step at least a significant milestone, if not a genuine breakthrough.
On January 7, David Bennett, 57, received a heart transplant from a bioengineered pig. This is a technology that we have been anticipating for years, and it is not ready for prime time yet, but the first such bioengineered xenotransplant in a living recipient definitely crosses an important line. There is a high probability, in my opinion, that this is a first “test-tube baby”-type moment.
The pig heart was provided by a company called Revivicor. They made news last summer when they provided a slightly genetically engineered pig kidney (one gene was altered) to connect to a human recipient. In this case the recipient was braindead and the kidney was just hooked up to their blood supply, not implanted. This is best considered a pre-clinical study, mainly to determine if the kidney would be immediately rejected. It wasn’t, and it seemed to work, filtering blood and making urine. But this safety test lasted only 54 hours.
The pig heart that Revivicor supplied to David Bennett has had ten genetic modifications: four genes were silenced, three to reduce rejection and one to limit growth after transplantation, and six human genes were inserted, all to reduce rejection. The modifications essentially are used to make the pig’s immune system more like a human’s, so that the organ recipient’s body will not vigorously reject them. The strength of immune rejection depends greatly on how close a genetic match the donor and recipient are. Even within the human species, genetic matching is critical. Crossing the line to a different species (the definition of xenotransplantation) is guaranteed rapid rejection. With these genetic modifications, the goal is to at least make the pig donor’s immune markers closer to that of a human.
Bennett, however, also is receiving an experimental anti-rejection drug which will suppress the part of his immune system responsible for rejection. The drug was developed by Kiniksa Pharmaceuticals, co-developed by Muhammad Mohiuddin, M.D., director of the University of Maryland School of Medicine’s cardiac xenotransplantation program, who did the surgery. Further, Bartley P. Griffith did the surgery and had to develop the technique of adapting the pig heart anatomy to the human vascular system. So this one operation is a triple experiment – testing the viability of the genetically modified pig heart, a new anti-rejection drug, and the surgical techniques used to adapt a pig heart to a human. The FDA gave emergency use authorization for the entire procedure based on their compassionate use program on December 30st.
Part of the reason the FDA cleared the experimental treatment is that Bennett had a terminal cardiac arrhythmia and was being kept alive on a heart machine. He had exhausted his treatment options and is not a candidate for a human donor, so his options were this experimental procedure or death. What does his treatment, if successful, mean for the future of xenotransplantations?
This research is being done because there is a great unmet need for organ transplants. In the US alone more than 100,000 people are on the waiting list for an organ, and 17 of them will die every day before they can get that organ. The ability to simply make or grow organs, therefore, would be a game-changing technology. Of all the possibilities, such as mechanical hearts, 3D printed organs, and cloning, the technology that seems to have the greatest chance of success is bioengineering non-human donors. Several companies are working on this technology, not just Revivicor. For example, Harvard geneticist George Church cofounded a company, eGensisis, also developing bioengineered pigs for organ transplantation, although they are apparently not as far along as Revivicor.
And obviously this technology is still highly experimental, but the learning curve is steep. CRISPR and other genetic modification technology allows this research to be done many times more rapidly than even in the recent past. The heart that Bennett received is just “pig heart 1.0” and it is likely we will see more elaborately engineered non-human organs in the future, further reducing organ rejection. It’s even theoretically possible that such genetic tinkering can go beyond making humanized donors, to tweaking the genetics to be a match for a specific donor. In the end bioengineered organs may be superior to human donated organs.
For now such transplants will remain in the realm of experimental use, like in cases such as Bennett where all other options have been exhausted. But once the technology is established well enough (which will take years of research) they will likely be approved for general use. That will be the day that this technology completely changes the world of organ transplantation. From there incremental improvements will only make the technology better. Essentially, the approach of bioengineering non-human organ donors allows transplantation science to ride the wave of rapidly advancing genetic technology.
There will likely be the usual pushback from predictable ideological groups. Some will question the ethics of growing animals as donors. But we already grow over 100 million pigs every year to slaughter for food, growing even a million extra to save lives hardly feels like an ethical line. There will also likely be the usual luddite response that such treatments are not “natural” or violate some natural code. I predict these objections will have as much of an effect as protests against in-vitro fertilization. Once xenografts start literally saving lives, demand for this technology will overwhelm criticism.
