The Future of Animal-to-Human Organ Transplants
Could a genetically engineered pig heart one day function in a person?
On a farm in Virginia, a company called Revivicor is breeding pigs that have some genetic similarities to humans. The scientists call them GalSafe pigs, and they have added five human genes to the pigs' livers, kidneys and hearts. The hope is that the organs can be harvested and used for transplants, and that human bodies won’t reject them.
It sounds like science fiction, but it’s sort of working. Revivicor (started by the British company PPL Therapeutics that produced Dolly the cloned sheep) is making strides in the slowly growing field of xenotransplantation, or the transplanting of non-human organs or cells into a human body. The first step has been to make transplants from one animal species to another a reality.
Last month, surgeons at the National Heart, Lung, and Blood Institute, in Bethesda, Maryland, managed to keep one of Revivicor's genetically modified pig hearts alive inside a baboon's stomach for 945 days. They were testing the baboon's immune response to the foreign organ, not the pig heart's ability to function as the animal's heart. Humans share more than 90 percent of their DNA with baboons, so transplanting a pig organ into the primate is a step in the right direction.
There’s a shortage of human organs for transplants—an average of 21 people die each day in the United States because they don’t get transplants in time. Lungs or hearts can only stay functional on ice for a few hours, and so they often aren’t used before they expire. Revivicor thinks pig organs can fill that void, and create a much more accessible and plentiful supply of transplantable organs, if only scientists can get our bodies to accept them.
Pigs are genetically distant from humans, but their organs are of a similar size and they’re easy to breed, which is why they’ve been a target for xenotransplantation. Pig valves are already used successfully in heart transplants.
Human-to-human organ transplantation has only been around since the 1950s, and scientists have been working on animal-to-human transplants for almost that long. In the '60s, Keith Reemtsma experimented with transplanting chimpanzee kidneys into humans. Most of them failed within a few weeks, but one woman lived for nine months. Most other attempted xenotransplantations, especially hearts and lungs, have had similar degrees of success. In 1984, in one of the most famous cross-species transplantations, Leonard Bailey transplanted a baboon heart into a infant, Baby Fae. The heart failed after 20 days, but it became a gateway for the first pediatric human-to-human heart transplant a year later. Recently, with genetic engineering, scientists have kept, in addition to the pig heart, a pig kidney alive and functioning in a baboon for 136 days.
So far, cross-species transplantations have been impossible to sustain indefinitely, because the human immune system is built to reject foreign organs. In lab trials, troubles occur when human blood pumps through pig organs. According to Revivicor, the immune response is triggered by natural antibodies directed against the galactose epitope, or the part of the pig cells that determines whether antibodies can attach themselves or not. So the company is working to modify that epitope by adding human thrombomodulin, the protein that coats those epitopes, to the pig’s genome. That makes them seem more human, and, therefore, it is less likely for the body to reject them.
The challenge is to target the genes that human bodies reject and then find ways to edit them. The baboon that survived with the heart transplant was on a heavy course of immunosuppressant drugs and died when it was taken off the regimen. But scientists are still hopeful about the next experiment—actually replacing a baboon's heart with a pig heart.
"Based on the data from long-term surviving grafts, we are hopeful that we will be able to repeat our results in the life-supporting model. This has potential for paving the way for the use of animal organs for transplantation into humans," Muhammad M. Mohiuddin, of the National Heart, Lung, and Blood Institute, told the American Association for Thoracic Surgery.
Part of Revivicor's push for pig organs is personal. Martine Rothblatt, founder of Revivicor's current parent company United Therapeutics, has a daughter with pulmonary arterial hypertension, a lung condition that is usually fatal. The only way to treat it is with a transplant, so she’s sunk time and money into organ transplants and tissue engineering. Revivicor is focusing on hearts and livers before lungs, because lungs are more influenced by the immune system. They've said they want to do the first complete pig-to-human organ transplant within a decade.
Rothblatt's dream for Revivicor to become an assembly line for new organs, so that there’s never a shortage, is just that, a dream. Although there’s been significant progress in how the organs maintain their integrity, direct pig-to-human transplants are still a long ways off.
"The immunological and pathophysiological problems associated with pig xenotransplantation...are significant and probably reflect the fact that it has been 80 million years since the pig and human diverged on the evolutionary scale," wrote David K.C. Cooper, a surgeon at the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh Medical Center, in a 2012 paper about xenotransplantation. "Therefore, in the words of [German scientist] Claus Hammer, what we are trying to do is to 'outwit evolution.'"
In addition to bodies rejecting the organs, there’s fear about cross-species infection, like swine flu, because humans don't have immunity to viruses that originate in animals. These infections would be especially dangerous, because patients would have to be on immunosuppressants to prevent organ rejection. There’s also tricky moral ground to cross. Bailey's heart transplant is still controversial, and there's worry about both informed consent from the patient's side and animal welfare. Animal rights groups, as you might expect, are opposed to raising animals for the purpose of harvesting their organs.
Anyone doing xenotransplantation in the U.S. has to get clearance from the Food and Drug Administration. The FDA's guidelines on the risks of animal-to-human disease transmission, informed consent and animal welfare are perpetually updated, and they are due for a revision in March 2016.
According to MIT Technology Review, “The last time a doctor transplanted a pig heart into a person, in India in 1996, he was arrested for murder.”