In the midst of all the controversy surrounding the science of healthcare, certain technologies continue to progress in the background, with the promise of transforming the practice of medicine. One of them is the development of genetically modified animals as a source for organ transplants.
I most recently wrote about this earlier this year, specifically about an experiment to transplant a pig heart into a baboon infant. The goal is to provide a bridge until the infant is old enough to receive a permanent heart transplant. Now Chinese surgeons have transplanted a pig lung into a brain-dead patient as a preliminary exploration of the viability of this approach.
The ability to transplant organs from a living or dead human donor into a human patient was transformative for modern medicine. Since 1988, in the US alone, about 800,000 people have had their lives saved or significantly improved (such as coming off of dialysis) with organ donation. But the technology still faces significant challenges.
The biggest medical challenge is rejection. Organs have to be carefully matched between donor and recipient in order to minimize the attack by the host’s immune system against the “foreign” tissue that has been transplanted. This often requires a lifetime of anti-rejection medication, which contributes to a major practical limitation of organ transplantation – it’s very expensive. Another significant practical limitation is the availability of organs for transplant. There simply is not enough to go around, and many people die on the waiting list for an available organ.
In my opinion, the best high tech solution to these challenges is genetically modifying animals to be human organ donors. Pigs are good candidates for many organs because their size and anatomy is very compatible with humans. A transplant from another species is called a xenograft, and these are especially challenging because the immune attack (without modification) would be very robust and lead to certain failure. As I discussed in my last article, other options, such as 3D printing organs, growing organs outside of animals, and mechanical organs, are very far away from realization.
Genetically modifying animals, which still has a way to go scientifically, is the best hope for creating an almost limitless supply of transplantable organs. Not only would this meet the need of those on the existing waiting list, it could allow for the lowering of the threshold for who gets on the list. If supply were not an issue, we could use transplants to treat more and more diseases and conditions. Your organ is causing you some trouble? Here’s a new one.
The technology leverages our rapidly advancing genetics knowledge and techniques. CRISPR and other techniques allow for rapid and relatively cheap genetic modification and experimentation. The main goal of research is to identify all the genes that would need to be modified so that the organ recipient’s immune system does not detect the donated organ as foreign.
In the current study, for example, six genes were edited in the pig donor to limit rejection. The recipient was monitored for 216 hours, during which time:
“Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9. Immunosuppression included rabbit anti-thymocyte globulin, basiliximab, rituximab, eculizumab, tofacitinib, tacrolimus, mycophenolate mofetil and tapering steroids, with adjustments made during the postoperative period based on assessments of immune status.”
So there was some early signs of rejection, with partial recovery by the end of the monitoring period. And- the recipient was also receiving a heavy dose of anti-rejection drugs. This was definitely a preliminary study, really just paving the way for more details experiments. Two other details worth noting:
Lungs are the most difficult organ to transplant from an immune perspective. This is because lungs have robust immune responses because they are constantly exposed to the outside world. Obviously many invading organisms gain entry through the lungs, so it is often a first line of immune defense. Immune incompatibilities can therefore be a special problem.
Second, this study did not evaluate the function of the lung. Only one lobe was transplanted, and the other lobe was left intact, so the researchers did not determine if the transplanted lung functioned and could sustain the host. So again – this is very preliminary. At most this study tells us that the organ was not immediately rejected, nor cause significant graft vs host disease. This likely means that the modified genes had some impact.
Let’s say this technology reaches its ultimate goal, what would that world look like? That would mean that scientists have identified all the genes necessary to prevent any form of immune rejection in either direction (the host rejecting the transplant and the transplant attacking the host).
I also have to point out that genetic modification like this has two basic forms. First, the genetic change can render the pig an immune blank slate, meaning that they are a universal donor, without any of the proteins or targets that would provoke an immune attack. The second would be to match the animal’s immune system to the specific intended recipient. Likely we would see some combination of these strategies – genetic changes to humanize the pig’s immune factors, perhaps tailored to specific types (such as blood type), and if necessary with specific changes to align with an intended recipient.
Also, this kind of modification is not an all-or-nothing situation. The more thorough and successful the genetic modification, the lower the risk of rejection and the lower the need for anti-rejection drugs. Ideally, we could achieve zero rejection with no need for any immune suppressing drugs. j
In that ideal situation, organ transplantation might become far more routine. Not only would there be essentially no waiting list (transplants on demand), but the list of conditions for which transplants make sense would grow. This could significantly extend life expectancy and quality of life. It might also significantly reduce healthcare costs, by eliminating the need for lifelong treatments and costly hospitalizations.
It is hard to know how long it will take and how close we will get to this ideal situation. But this is definitely a technology to watch. There is no theoretical reason why such an ideal organ supply is not possible. Genetic technology continues to advance at a rapid pace, and all we need is incremental advances to achieve this goal. There are no fundamental breakthroughs or brand new technologies needed, just continued improvements in existing tech.
