Xenotransplantation Breakthroughs, And The Odd Case Of New Zealand's Island Pigs
No natural predators
The pigs have no natural predators, and over time, they have wrought destruction upon Auckland Island’s flora and fauna. Government conservationists now want them gone — but there’s a twist: These once domesticated farm animals have evolved into ultra-resilient, disease-free pigs that have caught the eye of scientists who study xenotransplantation, a type of medical procedure in which cells, tissues, or organs from one species are transferred into another species.
Last year, for the first time, surgeons transplanted pig hearts and pig kidneys into humans. Such procedures have not yet been tested in clinical trials, and they are not approved by the U.S. Food and Drug Administration or regulatory agencies in New Zealand.
But researchers say that xenotransplantation could eventually prove effective at treating a range of conditions and may alleviate the huge global need for donor organs. The Auckland Island pigs, with their unique genetics, may be especially well-suited for this purpose.
Some of the hardy quadrupeds are now housed in a research facility on the New Zealand mainland. Meanwhile, conservation authorities are preparing a massive effort to eradicate those left in the wild.
A special place
The first European ship to reach the Auckland Islands (known as Maukahuka or Motu Maha in the Māori language) was the whaler Ocean, in 1806. The ship’s captain returned the following year to drop off a team of seal hunters. During this visit, pigs were first released as a food source. Subsequent introductions continued, and in the late 1800s, with the tales of shipwreck and survival piling up, the New Zealand and Australian governments got involved, releasing additional pigs for the castaways.
The archipelago is “an immensely special place."
The pigs, which were of mostly European and Asian origin, had to learn to live with the persistent cold, rain, and wind — far from ideal conditions for animals bred for sheltered barnyards. But because pigs produce up to two litters each year, they can adapt relatively quickly, said Michael Willis, of the Rare Breeds Conservation Society of New Zealand. Soon, Auckland Island’s pigs formed one unique strain.
In the winter, they survived by eating the island’s endemic plants and scavenging carrion. In the summer, their fortunes changed, and they gorged on plump albatross chicks and protein-filled penguin eggs. Twenty-five species of seabird breed on the Auckland Islands, but after two centuries of pig predation, their numbers have fallen. New Zealand conservationists are increasingly wary of the porcine prowlers.
The archipelago is “an immensely special place,” said Stephen Horn, a project manager at New Zealand’s Department of Conservation. It’s the biggest remaining stronghold of the yellow-eyed penguin, the world’s rarest penguin species, and the Gibson’s wandering albatross, which breeds there exclusively. (Currently, said Horn, seabirds on Auckland Island nest only on the precipitous edges of the land, where even the most tenacious pig won’t venture.)
The pigs have also taken a toll on the spectacular flowering plants known as megaherbs, which are now “almost non-existent” on Auckland Island, Horn said. “They’re absent until you get to the extremely steep cliff areas. Then you can see patches of green that are out of reach” of the pigs.
Horn believes there are between 700 and 1,500 pigs on the island, with the population fluctuating widely. Survival to breeding age, he said, is low. Those that do make it have to be tough and adaptable. “On one hand, super admirable,” he said, “the way they’re able to adapt and survive in those conditions.” And on the other hand, incredibly damaging. “They use the coastline pretty heavily,” he said. “They’ll eat anything that turns up, scavenging things like dead whales and seals or even krill and squid.”
Eradication as a solution
Mindful of the Department of Conservation’s long-held wish to eradicate the pigs, the Rare Breeds Conservation Society sent a team to retrieve some in 1999. Using dogs, they managed to catch 17. “Hunger appeared to be the pigs’ constant companion,” wrote team member Peter Jackson for New Zealand Geographic. “The suckling sows had only two or three teats producing milk, which told how few piglets survived.”
The team loaded the pigs on a boat and brought them back to the southern New Zealand town of Invercargill. There, the animals were put into a quarantine facility, intended to protect the country’s domestic pig herd from potential diseases.
Keeping the pigs in quarantine required money the Society didn’t have, so they prevailed upon Invercargill’s then-mayor, Tim Shadbolt, a colorful former left-wing activist, who dipped into his contingency fund for the approximately 2,300 in today’s New Zealand dollars, or $1,400, needed to feed them.
During the first year of quarantine, the pig population ballooned. “They dined on porridge and swedes and they became raging sexual beasts, producing larger litters than they did on the Auckland Islands,” Shadbolt recalled in a 2008 article in the Otago Daily Times. The pig’s food bill increased tenfold — an expenditure that whipped up a political storm in Invercargill, with councilors and constituents railing against what they characterized as a scandalous waste of public money. Shadbolt was unceremoniously stripped of his contingency fund.
The mayor, though, would be vindicated. These pigs from a previous century soon found an unlikely home in the futuristic world of xenotransplantation.
On Auckland Island, a pig roots near a white-capped mollymawk colony. Currently, Horn said, seabirds on the island are successfully breeding only on the precipitous edges of the land, where even the most tenacious pig won’t venture.
Paul Sagar/New Zealand National Institute of Water and Atmospheric Research
A controversial method
Globally, the demand for transplant organs is overwhelming. Every year, thousands of people die waiting for a new heart, liver, kidney, or lung that never arrives. In the United States alone, around 17 people on the organ waiting list die every day. For decades, xenotransplantation has been seen as a possibility to bridge this shortfall.
Since the 1960s, surgeons have transplanted chimpanzee and baboon parts into a small number of humans with life-threatening conditions, but these efforts have had little success. The biggest challenge is getting the human body’s immune system to accept the new organ.
Xenotransplantation carries many risks of infection.
The use of non-human primates for biomedical research is controversial, so over time, researchers looked to pigs. “Their organs, their tissues, and their physiology are sufficiently close to humans,” said Paul Tan, founder and CEO of New Zealand xenotransplantation research company NZeno. “Their cells function in a manner that is very close to humans. So their blood sugar levels and our blood sugar levels are pretty close.”
Islet cells are found in the pancreas and produce insulin, but in Type-1 diabetes patients, are destroyed by the immune system. Trial transplants of human islet cells had met with mixed results, and in any case, with millions of Type-1 diabetes sufferers globally, there were nowhere near enough human donors to meet demand.
Diatranz aimed to surgically implant pig islet cells, encapsulated in a seaweed-derived polymer that shielded them from the human immune system, into the pancreases of diabetes patients. In the 1990s, though, the work stalled amid fears of disease.
Xenotransplantation, of both cells or organs, carries the risk of bacterial or viral infections crossing from the donor animal into humans. Pigs are not as closely related to humans as apes and baboons, a circumstance that makes transplanted pig parts less likely to spread disease to humans. Still, the risk persists.
While common diseases might be eliminated with medicines, a more serious risk was thought to come from viruses that essentially gatecrash the genetic material of the host animal. These are called retroviruses; they include HIV as well as viruses that cause certain cancers.
Some retroviruses, called endogenous retroviruses, have, in the deep past, even insinuated themselves into the DNA of sperm and egg cells — they are therefore part of the animal’s genetic makeup, replicated in every cell in the body and passed down through generations. There is currently no medication to eliminate retroviruses.
The concern was that pig tissues could secrete infectious particles of a porcine endogenous retrovirus, or PERV, which could then infect human cells to create a new, transmissible human disease. In the worst-case scenario, it was feared, such an event could trigger a global pandemic.
In the late 1990s, a London-based research team confirmed that, in a laboratory setting at least, PERVs could infect human cells.
The discovery, for a time, “killed xenotransplantation,” said Björn Petersen, a xenotransplantation researcher with the Friedrich Loeffler Institute, the German government’s animal-disease research center. “Pharmaceutical companies withdrew their money from the research.”
Around the world, the hunt was on for pigs that were as disease-free as possible.
Years of research
In 1998, Diatranz partner Olga Garkavenko turned on her radio and got wind of Invercargill’s new arrivals. She decided to investigate.
The company obtained tissue samples from the quarantined pigs for analysis. The islands’ harsh conditions, it seemed, had been tough on disease.
The animals were suddenly reputed to be worth hundreds of thousands of dollars each.
“They remained isolated and therefore they remained free of a lot of common infections that you have in pigs,” said Tan. “The pigs that were weak were probably wiped out. Only the fittest survived.”
The pigs also have an unusually low number of retrovirus copies in their genome. Petersen noted that the population is also completely free of a type of PERV called PERV-C, which may pose the biggest risk to human transplant recipients. This was possible “because they were isolated for a long time and they never had contact with other pigs.”
Joachim Denner, a xenotransplantation researcher from the Free University of Berlin, said the Auckland Island pigs had another major advantage over other pig breeds — their small stature. At around 90 pounds in weight, he said, “they are the right size for transplantation.” A domestic pig weighs 300 to 700 pounds, and its organs, he added, are too large.
In 2004, Elliott, Tan, and others set up a company called Living Cell Technologies, or LCT, which absorbed Diatranz and took over the pigs’ care, building an expensive facility near Invercargill to keep them in medical-grade isolation while they were selectively bred for xenotransplantation.
The animals housed in quarantine were suddenly reputed to be worth hundreds of thousands of dollars each, much to then-Mayor Shadbolt’s barely-concealed glee.
The project brought jobs and millions of dollars of investment to Invercargill. “It has all come to fruition,” Shadbolt said in the 2008 Otago Daily Times article. “I rub it into those people who didn’t support me at every opportunity.”
First successful transplant?
By the 2010s, concerns around PERVs were lessening, as multiple clinical trials of cell transplants suggested not only that pig cells could be effective in treating diabetes, but also that PERVs weren’t passing to humans. New gene-editing technology also meant that retrovirus genes could be rendered non-functional before an animal was born.
Their cells have already been used in humans for years.
With these advancements, the race to successfully implant pig organs in humans has gathered pace. Groups around the world now breed pigs for this purpose. It’s big business — a recent report estimated the global xenotransplantation market could be worth $24.5 billion by 2029.
In January 2022, a University of Maryland group, using a pig organ from the U.S. company Revivicor, conducted the first successful transplant of a pig heart into a living patient. The patient survived for two months. While the cause of his death is still being examined, evidence of a disease called porcine cytomegalovirus was found during the autopsy. The pig used in the transplant, said Tan, would have been rigorously screened for the virus, which, he added, shows the importance of breeding pigs that are genuinely free from such diseases.
Paul Tan now runs NZeno, which has taken over the breeding and keeping of the Auckland Island pigs. LCT, meanwhile, has switched its focus to Parkinson’s disease and recently began clinical trials of a treatment that involves inserting capsules containing pig brain cells into the human brain to repair nerve damage.
NZeno supplies pig cells to LCT and is also trying to establish itself as a major player in the organ game. “We like to think that our strain of pigs, derived from the Auckland Islands, further developed at Nzeno, would be the ideal pig strain for human organ xenotransplantation,” said Tan. Their cells, he noted, have already been used in humans for years, and have a very good track record of safety. The small number of retrovirus copies in the pigs’ genomes, he said, also require less gene editing compared to other breeds.
NZeno recently provided its pig cells to a team at Ludwig Maximilian University in Munich, which aims to have a genetically-modified pig ready for a pig-human heart transplant by 2025. NZeno is also working with another xenotransplantation group in China that aims to develop kidneys for transplant.
Petersen agreed that there is a solid rationale for minimizing gene editing. “The more genetic modifications you do,” he said, “the more side effects you can maybe expect.” But, he added, there may be cases in which it doesn’t make sense to prioritize the minimization of gene editing. For example, “if you want to have a universal donor” — an animal that can supply a variety of suitable organs or cells for human transplant — “then you need to have a pig with more genetic modifications right from the beginning.”
Denner said the Auckland Island pigs, which he describes as the most disease-free pigs in the world, may yet prove their true worth. But he cautioned against viewing them — or any pig — as a silver bullet. “All these studies have limitations,” he said. “The real effect of PERVs on humans, we will see when we perform the first transplants of organs.”
Undoing the damage
For now, wild Auckland Island pigs continue to run free in their storm-battered home, but the clock is ticking. Over the last five years, New Zealand’s Department of Conservation has been preparing for eradication.
Stephen Horn leads the team charged with this enormous task. Previous work attached GPS trackers to pigs, trying to learn their movements, and Horn’s team has trialed various methods of killing them. The plan is to wipe out the pigs using a combination of traps, poisoning, and hunters shooting from helicopters and on foot.
“The approach is really high intensity, as quickly as possible,” said Horn, “and try to keep the population as naive as possible.
“You need a suite of tools,” he continued, “because pigs are smart. Not every pig is going to be vulnerable to the same technique.”
There are major hurdles to overcome.
Compounding the difficulty is the island’s size and isolation. It is several days’ dangerous sail from the mainland and, aside from a few uninhabitable hut shelters, the islands have no infrastructure to support human life. Once ashore, movement through the dense undergrowth and shoulder-high grasses is extraordinarily difficult.
“It’s rugged, remote, and massive,” said Horn. “It’s pretty overwhelming when you’re looking at it through a lens of animal pest control.”
Not everyone is thrilled at the prospect of the pigs’ demise. The animals are “very much part of our heritage,” said Willis of the Rare Breeds Conservation Society. The organization argues more effort should be made to preserve at least some of them. Perhaps the pigs could be fenced off, so as not to disrupt the entire island, said Willis. Or some could be relocated to another island, where they might not pose as much of a problem. As far as he is aware, however, these options are not being considered.
Paul Tan said he would also jump at the chance to retrieve more pigs.
The Department of Conservation, said Horn, has fielded inquiries about recovering pigs, but the logistics of retrieving them from the Auckland Islands, as well as the enormous costs involved in quarantine, are major hurdles to overcome.
Horn said that while staff are actively discussing options for retrieving pigs, their focus is eradication. With a plan in place, the department just needs to secure enough funding to make it happen, he said, “to undo some of the damage that was done by people, on what is an extremely fragile, but important place.”
File:水火同源.JPG - Wikimedia Commons
