Piglets rushing into their unusual stable with wide eyes to inspect the visitors could be the Future organ transplantation – and there is no rolling around in the mud here.
The first gene-edited pig organs The most transplanted animals ever into humans came from animals born on this special research farm in the Blue Ridge Mountains – behind locked gates where, to get in, you have to wash your car between air-conditioned stalls, change your clothes into medical scrubs, and step into tubs of disinfectant to clean your boots.
“These are valuable animals,” said David Ayares of Revivicor Inc., who has spent decades learning how to clone pigs with just the right genetic changes to these first bold experiments.
Just a few miles away in Christiansburg, Virginia, biosecurity regulations are being tightened even further. A new herd of pigs is being raised there that is expected to provide organs for official animal-to-human transplant studies as early as next year.
This massive building, the first of its kind, has nothing to do with a farm. It’s more like a pharmaceutical factory. And part of it is off-limits to all but a few carefully selected employees who, on a time limit, shower, put on company-provided clothing and shoes, and then enter an enclave where piglets are raised.
Behind this protective barrier live some of the cleanest pigs in the world. They breathe air and drink water that is better filtered against contaminants than that prescribed for humans. Even their food is disinfected – all to prevent them from catching any possible infections that could ultimately harm a transplant recipient.
“We designed this facility to protect the pigs from environmental and human contamination,” said Matthew VonEsch of United Therapeutics, Revivicor’s parent company. “Every person who enters this building poses a potential pathogen risk.”
The Associated Press got a glimpse of what it takes to clone designer pigs and breed them for their organs, including a $75 million “designated pathogen-free facility” built to meet Food and Drug Administration safety standards for xenotransplantation.
Breeding pigs to alleviate the shortage of human organs
Thousands of Americans every year die wait for a transplant, and many experts admit that there will never be enough human donors to meet the need.
Animals offer the tantalizing promise of ready-made care. After decades of failed attempts, companies like Revivicor, eGenesis and Makana Therapeutics are breeding pigs to make them more human-like.
So far, four compassionate use transplants, final attempts on dying patients – two hearts and two kidneys – have been performed in the United States. Revivicor provided both hearts and one of the kidneys. Although the four patients died within a few months, they provided valuable insights for researchers willing to try again in people who are not quite as sick.
The FDA is currently evaluating promising results from experiments using donated human bodies and awaiting the results of additional studies using pig organs in baboons before deciding on next steps.
They are semi-customized organs – “we breed these pigs to the size of the recipient,” Ayares says – that, unlike most organs donated by humans, do not show signs of age-related wear and tear or chronic disease.
Transplant surgeons who have removed organs at Revivicor’s farm “said, ‘Oh my God, this is the most beautiful kidney I’ve ever seen,'” Ayares added. “The same is true when they remove the heart, a pink, healthy, happy heart from a young animal.”
The biggest challenges: How to avoid rejections and whether the animals may have unknown Infection risk.
The process begins with modifying genes in pig skin cells in the laboratory. Revivicor first deleted a gene that produces a sugar called Alpha Galwhich triggers immediate destruction of the human immune system. Next came three gene “knockouts” to remove more immune-triggering red flags. Now the company is focusing on 10 gene edits – deleting pig genes and adding human genes that together reduce the risk of rejection and blood clots and limit organ size.
They clone pigs with these changes, similar to how Dolly the sheep was created.
Twice a week, slaughterhouses ship hundreds of eggs taken from sows’ ovaries to Revivicor. Scientists work with the light-sensitive eggs in the dark, looking through a microscope as they extract the maternal DNA. Then they insert the genetic changes.
“Put it in nice and smooth,” murmurs lead researcher Lori Sorrells, pressing in just the right place without tearing the egg. Mild electric shocks fuse the new DNA and activate embryo growth.
Ayares, a molecular geneticist who runs Revivicor and helped create the world’s first cloned pigs in 2000, says the technique is “like playing two video games at once,” holding the egg with one hand and manipulating it with the other. The company’s first modified pig, the GalSafeSingle gene knockout, is now bred instead of cloned. If xenotransplantation eventually works, other pigs could also be bred with the desired gene combinations.
A few hours later, the embryos are brought to the research farm in a portable incubator and implanted into waiting sows.
Luxury accommodation for important pigs
At the research farm, Tom Petty’s “Free Fallin'” was played in a piglet pen, where the little ones get used to human voices through music. In air-conditioned pens, the animals grunted excitedly in greeting until it became obvious that their visitors had brought no treats. The three-week-olds scurried back to the safety of their mother. Next door, the older siblings lay down for a nap or looked at balls and other toys.
“It’s a luxury for a pig,” said Ayares. “But they are very valuable animals. They are very smart. I have seen piglets playing with balls together as if they were playing soccer.”
Nestled in rolling hills, this farm is home to about 300 pigs of various ages. Their exact location is not disclosed for security reasons. Marks on their ears indicate their genetics.
“I say hello to some of the pigs,” said Suyapa Ball, Revivicor’s director of pig technology and farm operations, as she stroked a pig’s back. “You have to give them a good life. They give their lives for us.”
A subset of the pigs used in the most important experiments — those early human trials and the baboon studies required by the FDA — are housed in more restricted, even cleaner barns.
But neighboring Christiansburg is the clearest sign that xenotransplantation is entering a new phase – the sheer size of United Therapeutics’ new pathogen-free facility. In the 7,000-square-foot building, the company plans to produce about 125 pig organs annually, likely enough to fund clinical trials.
A company video shows piglets running around behind the protective barrier, chewing on toys and throwing balls back and forth.
They were born in a sort of pig birthing center connected to the facility, weaned a day or two later, and taken to their super-clean pens to be hand-reared. In addition to the on-site shower, their caretakers must put on a new protective suit and mask before entering each pig pen—another precaution against germs.
The pig area is surrounded on all sides by security and mechanical systems that shield the animals. Outside air enters the barn through several filter systems. Huge vats contain reserve supplies of drinking water. Standing above the pig pens, VonEsch showed how pipes and ventilation openings have been placed so that maintenance and repair work can be carried out without contact with the animals.
It will take years of clinical trials to prove whether xenotransplantation really works. But if it’s successful, United Therapeutics plans even larger facilities that can produce up to 2,000 organs a year in multiple locations across the country.
The field has reached a point where various studies “tell us that there are no train wrecks, that there is no immediate rejection,” Ayares said. “The next two or three years are going to be super exciting.”