Surgeons Are Transplanting Genetically Engineered Pig Skin Onto Humans

It’s a key first step toward using pigs to solve the world’s donor organ shortage

Credit: Minipigs/Wikimedia Commons

InIn a pathogen-free facility in Grafton, Massachusetts, a small town about 40 miles west of Boston, genetically engineered miniature pigs are being bred to donate their skin to humans.

Their skin, which looks remarkably similar to the human variety and is referred to as Xeno-Skin, will be transplanted by surgeons at Massachusetts General Hospital to a small group of burn victims in an attempt to speed up the healing process. It’s the first experiment approved by the U.S. Food and Drug Administration to use genetically engineered animal tissue in humans, a necessary step toward someday transferring entire organs grown in animals to people who need them — a process known as xenotransplantation.

The need for such organs is dire. Each day, 20 people die waiting for an organ transplant. More than 113,000 people in the United States are currently waiting for one, while only 36,528 transplants were performed in 2018, according to government data. Every year, the waiting list grows, greatly outpacing the number of available organs. For decades, researchers looked to animal donors as a way to ease this chronic shortage, but transplants from animals have often failed.

“As humans, we’re just a bag of fluids and our skin is the plastic bag.”

Xeno-Skin, developed by Boston-based biotech company XenoTherapeutics, shows promise. So far, one patient has received the genetically engineered pig skin graft, and five more burn victims are slated to receive it. The grafts are meant to be temporary and will be removed once the patients’ own skin has grown back. Doctors involved in the trial say the donor tissue appears to be healing as well as a human skin graft, which was transplanted next to the pig skin for side-by-side comparison. The process also hasn’t caused negative reactions like provoking an immune response or transmitting animal viruses, two major issues in xenotransplantation. “We’re trying to replicate exactly the same mechanisms that are used in the standard of care, or the gold standard treatment, for severe and extensive burns,” Paul Holzer, CEO of XenoTherapeutics, tells OneZero.

Typically, severe second- and third-degree burns are treated with allografts, or skin from human cadavers. Allografts help protect wounds from infection, prevent fluid loss from the body, and stabilize patients while their own skin grows back. “The skin is a really important barrier to all the things in the world,” says Dr. Curtis Cetrulo, a plastic and reconstructive surgeon at Massachusetts General Hospital who previously served as president of XenoTherapeutics’ board of directors. “As humans, we’re just a bag of fluids, and our skin is the plastic bag.”

Skin stays alive for some time after death, which is why it can be preserved from both humans and pigs. But like other organs, cadaver skin is expensive and can be difficult to acquire from national skin banks because there aren’t enough donors. Skin banks have strict criteria and can’t accept skin from donors with cancer or viral infections like HIV and hepatitis because of the potential to transmit those diseases to graft recipients. Some banks also have age restrictions on skin donors.

Pig skin could be an alternative when cadaver skin is scarce, especially on the battlefield and in developing countries, says Holzer. Skin from pigs and other animals is already used for wound dressings, but these are first treated with chemicals or radiation and essentially dried out so their cells are no longer alive. “It’s basically a piece of leather,” says Cetrulo. “It’s dead, processed tissue.”

Pig heart valves have also been used in people for decades, but the tissue is “fixed” using chemicals so that the cells are no longer alive.

Xeno-Skin is made of living tissue and is intended to promote blood flow, or vascularization, a key step in the healing process that helps fight off infections. The first patient received a five-by-five-centimeter piece of Xeno-Skin, but subsequent patients will receive larger grafts. Five days after the first patient’s transplant, surgeons removed both the pig and cadaver grafts, replacing them with permanent grafts taken from the patient’s thigh. The patient is healing and is expected to return to work soon.

Temporarily grafting pig skin onto burns is much less complicated than transplanting pig organs into humans for the long term, but Dr. Abbas Ardehali, a heart and lung transplant surgeon at the University of California, Los Angeles, who is not involved in the Xeno-Skin trial, says trying it transiently makes sense from a safety perspective. “I think the benefit of that approach is that if worst comes to worst, the pig skin fails and you’re back to square one. It’s not like you’ve undergone a major operation like a heart or lung transplant to find that the patient dies as a result.”

XXeno-Skin is the latest experiment in a long line of attempts by scientists to transplant animal organs to humans. In the 1960s, U.S. surgeon Keith Reemtsma transplanted chimpanzee kidneys into humans, but most failed within a few weeks because the organs were rejected or became infected. In 1984, an infant dubbed “Baby Fae” famously received a heart transplant from a baboon but died within a month of the procedure.

Although apes and monkeys are our closest genetic relatives, scientists now consider pigs to be the ideal donors for humans. The reasons are largely practical: For one, pigs take only months to grow to a size suitable for organ donation, unlike monkeys, which require 10 to 15 years. Pig organs are also closer in size to human ones. Meanwhile, the National Institutes of Health has ended research on chimpanzees. Scientists think the public might find it more ethically permissible to use pigs as organ donors rather than monkeys given that pigs are already raised for agriculture.

Biological differences between pigs and humans, however, make transplant rejection a serious issue that scientists are using genetic engineering to solve. In the 1990s, Dr. David Sachs at Massachusetts General Hospital used genetic engineering to eliminate a molecule found in pigs called alpha-gal, which would trigger an immune system reaction in the human body. This single modification might be enough to prevent the human body from rejecting small, temporary pig skin grafts. But to make sure whole swine organs can survive in people for potentially many years, researchers might need to make more alterations to the pig genome and develop new immunosuppressive drugs for transplant recipients.

In 2016, researchers at NIH led by Dr. Muhammad Mohiuddin reported that they had kept hearts from genetically modified pigs alive in baboon bodies for more than a year on average. One baboon stayed alive for more than two-and-a-half years, shattering previous records of pig-to-primate heart transplants.

It will likely be years before the first pig organs are transplanted into humans.

The gene-editing tool CRISPR is also making it easier to modify animals for xenotransplantation. In 2017, a startup called eGenesis announced it had successfully removed a group of viruses found only in pigs that have long been considered an infection risk for humans receiving pig transplants. These porcine endogenous retroviruses (PERVs) are considered another major hurdle for moving pig-to-human organ transplants forward, although no PERV infections in humans have occurred as a result of transplants, and lab studies have been inconclusive.

“Most people in the xenotransplantation community have said for some time now that the risk is manageable,” says Dr. Megan Sykes, director of the Center for Translational Immunology at Columbia University. “The fact that the FDA allowed this [pig skin] trial reflects that thought as well.”

LLike their predecessors, the pigs being used for the Xeno-Skin study are genetically engineered to prevent transplant rejection. But it will likely be years before the first pig organs are transplanted into humans.

“We have to make sure that skin transplantation or other non-vital tissues work first,” Ardehali says. “We could try a kidney next. If a kidney fails, the person can go on dialysis. If the heart or lung fails, you don’t have that luxury.”

But even if the technical issues are surmounted, convincing the public to accept pig transplants may present an even greater obstacle. Despite the clear need for more organ donors and the great potential of xenotransplantation, Mohiuddin, who is now director of the cardiac transplantation program at the University of Maryland School of Medicine, says changing public perception could be a challenge.

“If you tell someone, ‘We want to put a pig heart in you,’ there would probably be quite an uproar,” says Mohiuddin. “If this trial is successful, that will pave the way for other types of transplantations, like kidneys, hearts, lungs, or livers.”

One of the first uses of organ xenotransplantation might be for so-called bridge transplants, in which patients need an organ to stay alive for a period of time, such as a few weeks or even months, until they can get a suitable organ from a human donor. “But I believe once we have an ideal pig available and it survives for a longer period of time, there will not be a need to replace that organ,” Mohiuddin says.

In the meantime, XenoTherapeutics is also developing nerves grown in the genetically engineered pigs that could be transplanted into people with nerve damage from car accidents, falls, or other injuries. The company hopes to begin a clinical trial for that approach in 2020.

Ardehali says it’s unlikely that people in need of organ transplants will regularly be getting pig hearts or lungs in the next five or 10 years, but he does think the field is getting closer.

“We’ve had this high level of enthusiasm for many years and yet it hasn’t materialized,” he says. “Are we about to embark on a new chapter? I don’t know the answer to that. This requires a significant leap of faith.”

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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