Pig organs could soon be transplanted into patients after Harvard University scientists discovered a way to genetically modify pig DNA so it is more compatible with humans. Scientists have spent decades trying to engineer pig tissue so that it would not be rejected by the human body, but the immune system has always prevented success. A major hurdle in transplanting pig organs into humans has been overcome by the scientists.
All pig DNA carries the porcine endogenous retrovirus which infects human cells and makes transplantation impossible. Now Professor George Church and colleagues have used a ground-breaking technology called Crispr to snip away the retrovirus’ genetic code. In tests on early pig embryos, Prof Church was able to eliminate all 62 copies of the retrovirus from the pig cells which would have been spotted by the human immune system. The edited cells were 1,000 times less likely to infect kidney cells when transplanted in the lab. The team are hoping to create retrovirus-free pig clones whose organs can be harvested.
Although researchers still need to get over the hurdle of the immune rejection, Prof Church said the discovery opens the door for animal organs in people, a practice known as xenotransplantation. Prof Church, who part-owns a company that wants to develop modified pigs to grow organs, said: “It was kind of cool from two stand points. “One is it set a record for Crispr or for any genetic modification of an animal, and it took away what was considered the most perplexing problem to be solved in the xenotransplantation field. “With immune tolerance, that completely changes the landscape as well. “These two things, immune tolerance and now getting rid of all the retroviruses, means we have a clear path.”
The concept of xenotransplantation, which is the transplant of an organ from one species to another, is nothing new. Researchers and clinicians have long hoped that one of the major challenges facing patients suffering from organ failure, which is the lack of available organs in the United States and worldwide, could be alleviated through the availability of suitable animal organs for transplant. Pigs in particular have been especially promising candidates due to their similar size and physiology to humans. In fact, pig heart valves are already commonly sterilized and de–cellularized for use repairing or replacing human heart valves. But the transplant of whole, functional organs comprised of living cells and tissue constructs has presented a unique set of challenges for scientists. One of the primary problems has been the fact that most mammals including pigs contain repetitive, latent retrovirus fragments in their genomes.
“The presence of this type of virus found in pigs known as porcine endogenous retroviruses or PERVs , brought over a billion of dollars of pharmaceutical industry investments into developing xenotransplant methods to a standstill by the early 2000s,” said Church. “PERVs and the lack of ability to remove them from pig DNA was a real showstopper on what had been a promising stage set for xenotransplantation.” Now, using CRISPR–Cas9 like a pair of molecular scissors ,Church and his team have inactivated all 62 repetitive genes containing a PERV in pig DNA, surpassing a significant obstacle on the path to bringing xenotransplantation to clinical reality. With more than 120,000 patients currently in the United States awaiting transplant and less than 30,000 transplants on average occurring annually, xenotransplantation could give patients and clinicians an alternative in the future.
“Pig kidneys can already function experimentally for months in baboons, but concern about the potential risks of PERVs has posed a problem for the field of xenotransplantation for many years,” said David H. Sachs, M.D., Director of the TBRC Laboratories at Massachusetts General Hospital, Paul S. Russell Professor of Surgery Emeritus at Harvard Medical School, and Professor of Surgical Sciences at Columbia University’s Center for Translational Immunology. Sachs has been developing special pigs for xenotransplantation for more than 30 years and is currently collaborating with Church on further genetic modifications of his pigs. “If Church and his team are able to produce pigs from genetically engineered embryos lacking PERVs by the use of CRISPR-Cas9, they would eliminate an important potential safety concern facing this field.”
Yang says the team hopes eventually they can completely eliminate the risk that PERVs could cause disease in clinical xenotransplantation by using modified pig cells to clone a line of pigs that would have their PERV genes inactivated. Scientists in Britain said the research, which was published in the journal Science, was a major step forward in the field of animal transplantation. Dr Sarah Chan, of the University of Edinburgh, said: “Of course, there is still a long way to go to overcome other problems associated with pig xenotransplants, notably immune compatibility, and even once the scientific and safety issues have been addressed, we should be mindful of the possible cultural concerns and societal impacts associated with more widespread use of pig organs for human transplantation. “Nonetheless, the results of the study are valuable both as a proof of principle and a potential step towards therapeutic advances in this area of much-needed research. “
Prof Bruce Whitelaw, Professor of Animal Biotechnology, Roslin Institute, University of Edinburgh, added: “This study experimentally addresses a challenge for xenotransplantation and, if replicated in animals, could be another step towards this biomedical goal. “This advance overcomes a major hurdle that has until now halted the progress of xenotransplantation research and development,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences. “The real value and potential impact is in the number of lives that could be saved if we can one day use xenotransplants to close the huge gap between the number of available functional organs and the number of people who desperately need them.” The remarkable and newly demonstrated capability for CRISPR to edit tens of repetitive genes such as PERVs will also unlock new ways for scientists to study and understand repetitive regions in the genome, which has been estimated to comprise more than two–thirds of our own human genome.
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