How Gene Editing And Pig Organs Can End The Human Transplant Shortage

If animal-to-human transplants can be achieved successfully, it would create a sustainable organ supply. Thanks to gene editing, this may be possible in the future. REUTERS

Each year, some 30,000 patients undergo transplant surgery to receive an organ from a donor. Transplant medicine saves lives, but not enough people are willing to donate. Patients can't rely on the generosity of fellow humans to replace a heart, kidney or lungs. According to the United Network for Organ Sharing (UNOS), one patient is added to the U.S. transplant waiting list every 10 minutes, and 20 people on the national list die each day.

For decades, scientists have been hoping to address the organ shortage in more innovative ways, namely by tweaking the innards of other mammals to make them compatible with humans. Successful animal-to-human transplants (also known as xenotransplantation) would create a sustainable organ supply.

Pigs are the strongest contender for xenotransplantation because they have organs similar in size and physiological function to those found in humans. But pig organs on their own aren't suitable for transplant. Human immune systems would most definitely reject pig organs. But an even greater challenge is the risk of animal viruses infecting humans. Pigs carry active porcine endogenous retrovirus, and it remains unclear whether these viruses could be communicable or fatal in humans. PERV infection would be dangerous because transplant recipients are routinely put on immunosuppressant drugs that make it difficult to fight off any bacteria or viruses.

Now a team of researchers affiliated with Harvard Medical School appear to have solved one of these problems. Not only have these scientists made a controversial possibility—animal organs in humans—more likely, but they've done so using a controversial technology: CRISPR-Cas9 gene editing.

Through gene editing, the team eliminated all traces of the PERV virus from the cell line and conducted in vitro fertilization. There are 25 strains of PERV, which is the only known active retrovirus found in pigs. In the study, published Thursday in the journal Science, biologist Luhan Yang and her team implanted the PERV-free embryos into surrogates. The fetuses did not become reinfected with the virus, and the newborn piglets are the first animals born without PERV. Yang—who founded eGenesis a few years ago to harness advances in CRISPR-Cas9 for the worldwide organ shortage—will now monitor the animals for any long-term effects.

"I'm a strong believer that science can help us improve health care if we look holistically for a solution," says Yang, lead author on the paper and chief science officer of eGenesis, the biotechnology company funding advancements in the research. "Because there are millions of patients who suffer from end-stage organ failure, their life could potentially be saved, or largely improved, by this potential organ resource."

CRISPR-Cas9, or CRISPR (pronounced "crisper") for short, is an experimental biomedical technique. The technology utilizes snippets of certain bacteria that allow for selective modifications of DNA segments, such as changing the "misspellings" of a gene that contribute to mutations. Since CRISPR was identified several years ago, scientists have been using it in the laboratory to alter the genetic codes of living organisms. The new technology is already leading advances once considered the stuff of science fiction. In a study published last week in Nature, scientists eliminated a genetic abnormality in a human embryo.

Yang has been determined to use gene editing to solve the organ shortage problem for several years. In 2013, she and her team published the first paper showing CRISPR could be used to accurately and effectively alter the immune system. In 2015, she eradicated 62 copies of the PERV virus from a pig cancer cell line, which she says is a world record for researchers using CRISPR. The next step, she says, is to tweak the porcine genome further to prove the organs can be compatible with the human immune system.

Resurrecting a Scientific Vision

For decades, xenotransplantation research seemed impossibly dangerous and financially risky both for small biomedical companies and large pharmaceutical companies. In the early 2000s, Novartis stopped funding xenotransplantation research. The U.S. Food Administration, fearing a public health disaster, began placing regulations on research facilities, which made studies even more challenging. The projects were costly and too complicated, and animal rights activists frequently targeted the scientists. But CRISPR is reviving the area of research once again, says Yang.

Transgenic PERV-free pigs could provide a source for solid organs as well as islet cells, which are tiny cells scattered throughout the pancreas that secrete insulin. Some successful pilot studies looked at porcine islet cell transfusions as a potential treatment for diabetes.

Dixon Kaufman, president-elect of the American Society of Transplant Surgeons and a transplant surgeon at the University of Wisconsin School of Medicine and Public Health, says it's only a matter of time—probably a few years—before xenotransplant studies are open to patients. "I think it is a realistic, almost palpable opportunity," he says. "Anything that will improve safety, such as deleting this risk of the PERV infection, makes this more viable."

Kaufman thinks kidneys and pancreases will be the first solid animal organs transplanted into humans. Because these are non-vital organs, failure wouldn't necessarily lead to death. Patients who need a kidney could still receive dialysis, and those who need a pancreas could still access insulin.

These advances are a boon for transplant surgeons like Kaufman, who regularly have to tell patients they will probably die before a donated organ becomes available. He doesn't think a pig organ would be a hard sell to most of these patients, who are otherwise facing certain death.

"The field is inherently sort of risky to begin with, and I think a lot of patients have already processed that," he says. "I tell patients in the grand design we were not meant to swap body parts between ourselves."