Science to Clinic Milestones
When I started graduate school in 1979, very little was known about the molecular basis of cancer compared to today. Just five years later, advances in the world of science had changed that, as had the prospects for developing new therapies for cancer as well as many other conditions where the genetic basis could be understood. New tools were invented by scientists, and then refined and commercialized by companies so they could be used broadly by all scientists. This scientific-commercial collaboration played a key role in enabling the revolution in biotechnology that followed, and its enormous impact on life science research, medicine, agriculture, and a host of other fields.
This past week we witnessed another milestone in medicine, enabled by a similar collaborative effort to move science to the clinic and improve human healthcare. For the first time a genetically engineered kidney from a pig was transplanted into a man suffering from end stage renal disease (ESRD) (see NY Times article). It’s only been a week, but in his first few days post-transplant the patient, 62 year old Richard “Rick” Slayman was doing extremely well, walking the halls, and destined for discharge one week post-transplant. A timeline fairly typical for high risk kidney recipients. Hopefully this courageous man continues to do well for many years to come. If so, the field of organ transplantation would be fundamentally changed, in the US alone positively impacting the lives of over 100,000 people currently on lists awaiting compatible organs from deceased donors, and more than 500,000 Americans enduring dialysis and not yet – if ever – able to even qualify to be listed as a candidate for transplant.
In 2013, just after I agreed to take on the CEO role at Transplant Genomics, I attended the 4th International Conference on Transplantomics and Biomarkers in Organ Transplantation held in Cambridge, UK. I didn’t know much about the science underlying transplantation at the time, but after just one day of presentations it became glaringly obvious that transplant medicine is similar to rare diseases in many ways. With only around 25,000 kidney transplants being performed annually in the US, limited by a lack of donors, it is challenging to access large numbers of patients for studies. As a consequence, presentations and publications often present shockingly low sample numbers from which conclusions are drawn. This is the only way to make progress, but it is not without risk.
In light of this situation, the clinical use of genetically engineered porcine kidneys in humans was only possible following some promising nonhuman primate (NHP) studies, and then two transplants into brain dead humans who had generously agreed to the use of their bodies for such experiments. The specific type of engineered pig kidney transplanted this past week, however, had never been used in a human before. Its use was based on the promising NHP data, the FDA’s “compassionate use program” for certain patients with a terminal condition, and the courageousness of the patient who understood the risks and benefits. Mr. Slayman believed that he had a chance of not only extending his own life, but of advancing science and medicine in the hope of one day being able to extend the lives of millions of fellow human beings.
The idea of using animal organs to make up for the shortage of human donors has been around and attempted for decades. The field is called xenotransplantation, and it has had a frustrating history. The current advances were made possible by years of incremental advances in basic research, critically enabled by the Nobel prize winning development of CRISPR technology by Jennifer Doudna and colleagues. In 2015 a company called eGenesis was founded to pursue the specific objective of using such technologies to engineer animal organs for use in human transplantation, among other things. So hats off to all of the scientists involved along the way, and the teams at eGenesis and MGH who have brought this from the lab to the clinic.
In spite of all the excitement around this major milestone, I feel compelled to manage expectations with a dose of historical reality. First, virtually every major breakthrough in transplantation has followed multiple attempts that did not yield satisfactory results. This is commonplace not just in transplant medicine, but in all of medicine – and science more broadly – even if every now and then, fortunately, there are immediate successes at the first attempt to implement a new concept. One that comes immediately to mind for me, having been involved in its initial commercialization, was the polymerase chain reaction (PCR) process invented by 1993 Nobel Prize winner Kary Mullis. However, most of the time we don’t succeed at first, and just need to learn what we can from the experience and keep trying to improve.
The other point I’d raise is that the scientists and engineers at eGenesis attempted to address all of the known risks when they made modifications to 69 genes. Some were changed to protect against a virus known to infect pigs. Others to delete certain pig genes and add human genes in an attempt to make the organs less immunogenic to human recipients.
As optimistic as I would like to be about this transplant, I’ve long understood that things don’t always go as planned, no matter the intelligence and diligence of the planners. One must always beware of the unknown and unexpected. These concerns and others are discussed in an NPR article that can be read/heard here.
I hope this milestone becomes a monumental turning point in transplant medicine. It is so sorely needed, both with the general shortage of organs for transplant, as well as the disparity in organ availability for minority patients who are disproportionately affected by ESRD. Time will tell.
***
Announcement: my new book Can’t Tame a Mongoose: Memoir of a Genomics Entrepreneur, is now available. More information at roseventures.net/book
***