ON OCTOBER 19th, USA Today, an American newspaper, reported that surgeons in New York had successfully transplanted a pig kidney into a human subject. The organ was successfully attached for three days in an experimental procedure on a brain-dead patient. It was the culmination of years of work; scientists have dreamed of xenotransplantation, in which organs from animals are put into humans, for decades. The successful transplant shows both how far science has come in this process, and how far it still has to go.
In 2014, a firm called Synthetic Genomics in La Jolla, California, began work on a unique and radical project. The idea was to make a raft of genetic changes to pigs so that their organs would be more suitable for transplantation into humans without rejection. The purpose was to address the growing shortage of organs for transplantation. Synthetic Genomics partnered with another biotech firm, United Therapeutics Corporation, based in Silver Spring, Maryland. United Therapeutics reckons that in America alone, 1m people each year have end-stage organ disease and may need a heart, kidney, or lung transplant.
For years, attempts to take xenotransplantation forward failed, largely because of problems stemming from immune rejection of the foreign organ. But by 2014, when United Therapeutics started working with Synthetic Genomics, the growing availability of gene-editing technologies such as CRISPR seemed to bring the goal of creating a more transplantable organ within closer reach.
Martine Rothblatt, who founded United Therapeutics, has a personal stake in the outcome: her daughter has a rare and incurable lung condition, and may at some point require a transplant. Seven years ago the firm began to engineer a variety of genes into pigs with the goal of making their organs work more harmoniously when transplanted into the human body. Pigs have been the focus of most research in xenotransplantation because, among other things, their organs are the right size. Organs taken from a cow would be too large, while those from a goat would be too small.
There were a number of problems to solve—the first being rampant inflammation inside the pig organ after removal. Another is blood clots. Then there are issues with human antibody and T-cell responses, which can cause the recipient’s body to quickly reject the organ. Humans lack an enzyme called alpha 1,3-galactosyltransferase. In pigs, this enzyme places a sugar on the surfaces of their cells—something the human immune system immediately notices as foreign and rejects.
So anyone who wanted to transplant a pig’s organ into a person had to first knock out the enzyme-making genes in pigs. This problem was solved in 2003, long prior to the advent of gene-editing. A firm called Revivicor, now a unit within United Therapeutics, created the world’s first pig without those genes, now dubbed GalSafe.
Comments by a surgeon who performed the surgery yesterday suggest that the transplant involved only taking an organ from a GalSafe pig, without further genetic modification. Many questions remain. United Therapeutics declined an interview request, and this work has not been published in a journal. But if removing the enzyme-making gene is the only genetic change made to the pig that provided the kidney, this suggests that there remains much work ahead for United Therapeutics and the future of xenotransplantable organs.
The firm has been working on a “ten-gene pig”, which presumably refers to the number of modifications that have been made to the pig’s genome. One genetic change it has made is to add a human gene to pigs that produces a human protein called CD46, which moderates the action of the immune system. The firm is also inserting anticoagulant genes to prevent blood clots forming in the transplanted organ, and genes that will make organ rejection by T-cells less likely. The long-term goal is to make pig organs so compatible with the human body that the drug therapy required would be the same as is currently used for human-to-human organ transplants. Beyond this the firm is also working on more futuristic ideas, such as manufactured organs that would need no immunosuppressant use at all.
These endeavours are essential. Demand for organs is far outpacing supply. Although the news will bring hope to many on the waiting lists for an organ transplant, animal organs will not be used routinely for years to come.
Regulatory agencies would do well to focus on how these innovations should be governed. For instance, do pigs modified by CRISPR, either to disrupt pigs’ genes or insert human ones, fall within existing legal frameworks for genetically-modified organisms? In Europe these animals would likely qualify as GMOs. China has yet to put a regulatory regime in place.
The conundrums do not stop there. Koko Kwisda at the Centre for Ethics and Law in the Life Sciences, Leibniz University Hannover, and colleagues, write in Nature Biotechnology this July, “Is the pig as a whole a medical device or a medicinal product? Or is the pig merely an incubator for the organ transplant?” Just as researchers start to see a path through the quagmire of xenotransplantation, regulations may yet bog them down.
culled from The economist