Scientists have used CRISPR technology to develop a new generation of gene-edited pigs that may one day provide much-needed donor organs for people. The genetically engineered animals are described in a new paper published on 19 December in BioRxiv (1). So-called xenotransplantation — the use of non-human organs for transplant, in this case, pigs — could provide a viable alternative to human donor shortages, thanks to genetic engineering.
Pigs are widely consumed around the world, so breeding them for replacement body parts presents much less of a moral dilemma than other animals with organs similar to humans, like say monkeys. Pigs also reach adulthood in just six short months and the anatomy of pig organs are quite close to those of human organs.
The main hurdles to overcome are the risk of spreading animal diseases to humans — in particular, the porcine endogenous retrovirus (PERV) — and rejection of the foreign organ by the recipient – species-specific molecules in pigs can trigger the human immune system.
Tissues from gene-edited pigs are already being testing in humans, including pancreatic cells to treat diabetes, replacement corneas, and gene-edited skin. But organs like the heart and lungs pose a much bigger challenge. Indeed, a rejected heart or liver could be a life or death situation.
With advances in genetic engineering, the idea of transplanting pig organs into humans is becoming a not-so-distant reality. By genetically modifying the organs of pigs, scientists can make them more likely to be accepted by the human body.
Now several companies around the world are working hard to decode just the right mix of gene edits to make this possible. In other words, which genes will cause an organ from a different species to be rejected. And ideally, using the fewest modifications possible, which will make it easier to control and measure the effects.
In an effort to meet this challenge, the team of from Chinese startup Qihan Bio and US biotech company eGenesis, have unveiled the most extensively genetically engineered pigs to date, which they claim can be used for safe and successful transplant of virtually any organ into humans.
In the recent study, the researchers present their prototype pigs, which have a total of 13 modified genes — the largest number of edits to date — including PERV “knockouts” with several other changes to prevent immune rejection: three genes associated with the immune response and six that inhibit human immune responses, and three to prevent blood coagulation, which is another part of the rejection response. The modified pigs appear healthy and fertile with functioning organs, according to the authors.
So far, the researchers have only tested cells from the pigs in the lab and showed that the modified pig cells survived quite well aside human cells and bound to 90 per cent less human antibodies compared to normal pig cells.
The next step towards use in humans — transplanting the organs into nonhuman primates — has also begun and the company is hoping to begin testing in humans within five years.
(1) Yue, Y. et al. Extensive Mammalian Germline Genome Engineering. BioRxiv (2019). DOI: 10.1101/2019.12.17.876862