No, scientists are not any closer to pig-to-human transplants than they were last week
Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.
Holtzman was the president of DNX, one of the first companies to try to use biotechnology to make pig-to-human transplants possible. He had amassed a pathogen-free porcine facility for their work and so obliged, putting some unlucky hogs on an Ohio State University plane to Duke, where one of ultimately four patients treated with the procedure survived to receive a new human liver. The results were published in the New England Journal of Medicine in 1994.
Which is why Holtzman was shocked and a little bit confused when he read reports this week that doctors at NYU had conducted a “groundbreaking” procedure by, with the family’s consent, taking a pig kidney and suturing it to the leg of a brain-dead patient for 54 hours.
It was something scientists could’ve done for years, he said. And it didn’t get them closer to actually making animal-to-human transplants possible, or addressing the field’s main goal: solving a national organ shortage that kills 20 Americans per day.
Steve Holtzman“It is hype and bullshit,” said Holtzman, who is now the chairman of a Chinese company working on xenotransplantation. “It belongs in the National Enquirer.”
Other experts within the small and largely insular world of xenotransplantation — the technical term for animal-to-human transplants — were more subdued. Pig kidneys, they said, are more difficult to engraft in a human than pig livers. And they noted Robert Montgomery, the NYU surgeon, and United Therapeutics, the company that supplied the genetically modified pig, were not the first ones to conceive of this type of procedure.
Yet while many were glad to see xenotransplantation get mainstream attention after two decades in which much of the field worked in obscurity, they struggled to see the exact research question the experiment answered or the scientific knowledge gained.
Although DNX and other 90s-era xenotransplant companies flamed out for a variety of reasons, scientists have known since the early 2000s that a single genetic edit should allow organs to survive for days, if not months, in a patient. The real question is getting pig organs to consistently survive long-term, a much higher immunologic hurdle.
The best some could say was that the work confirmed what they already knew.
Megan Sykes“The result doesn’t contain any surprises for those of us in this transplant field,” said Megan Sykes, director of Columbia’s center for translational immunology. In that sense, it was a “good first step.”
For those who missed it, on Tuesday night, USA Today published an intricate feature detailing how, in late September, with $3.2 million in funding from United Therapeutics, Montgomery connected a modified pig kidney to the leg of a 66-year-old woman who had recently been declared brain-dead.
The patient’s family was approached, with the advice of bioethicists, because they wanted to donate her organs but they weren’t fit for transplant. It offered another way to help advance medicine that could one day save lives, they explained.
The kidney began filtering her blood into urine within minutes and stayed pink and functional for just over 2 days. Crucially, Montgomery said, there was no evidence of instant rejection.
“As you all know, this is really important,” he said afterwards. “This is going to take us to the next step, which is having organs available to everyone who needs them at any time.”
The story was soon picked up by The New York Times, Economist, BBC and Al Jazeera, along with AP and Reuters reports that were reprinted widely. The procedure, the Times said, was “a scientific breakthrough that one day may yield a vast new supply of organs for severely ill patients.”
The xenotransplantation field has indeed been inching toward that goal for two decades, slowly building itself up after falling apart in the 1990s, when companies such as DNX and Novartis poured billions into engineering animals into donors. That decade, it became clear just how much modification a pig — an animal chosen because it was both close to humans and easy to mass produce — would require, while the discovery of a porcine virus vaguely reminiscent of HIV alarmed public health authorities dealing with the deadliest days of the AIDS crisis.
Since then, a handful of companies have introduced a slew of new modifications and strategies and tested the resulting organs in non-human primates, in some cases getting the monkeys to survive for years.
The field, stocked with big and competitive personalities, began to buzz about who would be the first to do it in humans. The question is whether or not Montgomery’s procedure actually helped toward the goal of doing it in a living patient who will have to be able to survive off the organ.
“People are chasing — who will be first? ‘I want to be first!’ ‘I want to be first!'” said Kaz Yamada, director of surgical research, Columbia Center for Translational Immunology. But “our goal is to cure the patient, not to say, ‘I’m first.'”
Montgomery’s procedure arose out of discussions between the transplant team at NYU and the university’s renowned bioethicist department, led by Art Caplan, who proactively outlined how, in the right conditions, a brain-dead patient could be the best first test for a xenotransplant. (They also advised against granting exclusivity to any news outlet, fearing the media frenzy that indeed ensued when NYU did so. “I don’t win all my fights,” Caplan told me.)
But the idea of using the recently deceased as a test case for xenotransplantation goes back to at least Thomas Starzl, often considered the father of the field, who first proposed it in the early 2000s, said University of Miami surgeon Joe Tector.
Joe TectorLong one of the field’s most prominent figures, Tector had considered doing it himself. But by the 2010s, it no longer seemed necessary. Although Montgomery consulted with him prior to the operation, Tector himself had lost interest.
“We knew the biology,” he said. “We weren’t as comfortable that that would give us useful information.”
A lot had changed since the early 2000s, when Starzl first proposed the idea.
Montgomery said his experiment showed that patients wouldn’t instantly reject the modified pig. But the lone genetic modification United gave the pig was first done successfully 20 years ago. And Yamada showed back in 2004 that the modification — knocking out a sugar called alpha-gal that all primates, including humans, have antibodies against — prevents primates from instantly rejecting the organs, allowing them to live in that experiment for 83 days.
That finding has been held up repeatedly, experts say, with some monkeys living for hundreds of days after receiving organs from pigs modified with that edit alone.
There’s disagreement within the xenotransplantation on how many edits will ultimately be needed: Tector’s pigs have three; eGenesis, the well-backed Harvard-spinout, and Qihan Biotech, its Chinese offshoot that Holtzman now chairs, have tested dozens; at Columbia, Yamada and Sykes use only the one edit but also transplant a pig’s thymus, alongside the kidney, to try to get long-term T cell tolerance.
The groups are now competing to get the right FDA-approved facilities and supply chains to make donations from a pig to a living patient possible, to show they can get consistent long-term survival in monkeys. All agreed that there were ample data showing humans wouldn’t reject a modified pig organ instantly, or in the 54 hours Montgomoery studied.
For Tector, it was “comforting,” he said, to now have validation in humans, even if he wouldn’t have done it himself. Others were less sanguine.
“I can’t imagine that things would be so much different in humans to think that this was really informative,” said Jim Markmann, chief of transplant at Massachusetts General. (Markmann is also a scientific advisor for eGenesis.) “I think it was more sensationalism.”
United Therapeutics, a company that has long courted both hype and secrecy, did not respond to an interview request or detailed questions. At a press conference Thursday, Montgomery said he used a pig that only had the single edit because alpha-gal is the most important knockout for preventing immediate rejection and because the FDA had already cleared pigs with the edit for consumption and some research purposes.
He argued that you could never be sure the animal results will translate into humans until it’s actually done. And he said a full peer-reviewed publication outlining the procedure and its results was coming.
“There have been many other examples of preclinical primate studies that have not translated well into what happens in humans,” he said. “We do have quite a bit of nonhuman primate data but whether we’re going to see the same things when we go to human trials is really not something that we can rely upon.”
Still, there was at least one point he and many of the outside experts agreed upon. Although Holtzman feared that the hype around the operation could detract from “people with integrity and scientific chops … who are the best hope for making this stuff happen,” Sykes and Markmann argued that it could actually help xenotransplantation, even if it contributed nothing to the science.
Making pig-to-human transplants a reality will require not only strong results in monkey studies, but also the trust of regulators and the public.
That has not always been easy to win, but knowing that nothing catastrophic happened for at least the first 54 hours might help. Sykes, asked if she would have done the experiment, said that might be not be the right question.
“I’m happy to reap the benefits of it having been done,” Sykes said. “Of people having assurance that something bad is not going to happen. I think that’s helpful.”
