by BLACKSBURG, Va. (AP) – A wide-eyed piglet rushing to check out the visitors to its unusual barn could represent the future of organ transplants – and there’s no rolling around in the mud here.
The first gene-edited pig organs ever to be transplanted into humans came from animals born on this special research farm in the Blue Ridge mountains – behind locked gates, where entry requires washing your vehicle, washing your clothes exchange for medical scrubs and enter disinfectant pubs. to clean your boots between each air-conditioned barn.
“These are precious animals,” said David Ayares of Revivicor Inc., which spent years learning how to clone pigs with the right genetic changes to allow those first experiments to stick.
Biosecurity gets tighter just a few miles away in Christiansburg, Virginia, where a new herd is being built – pigs expected to provide organs for formal animal-to-human transplant studies as early as next year.
This huge building of the first kind bears no resemblance to a farm. It is more like a pharmaceutical plant. And part of it is closed to certain carefully selected employees who take timed showers, provide company clothes and shoes, and enter an enclosure where piglets grow up.
Behind that protective barrier are some of the cleanest pigs in the world. They breathe air and drink water that is better filtered against contaminants than humans need. Even their feed is disinfected – all to prevent them from any 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, Revicicor’s parent company. “Everyone who enters this building is at risk of pathogens.”
The Associated Press got a look at what it takes to clone and raise designer pigs for their organs — including a $75 million “pathogen-free designated facility” built to meet Food and Drug Administration safety standards for with xenotransplantation.
Creating pigs to alleviate the shortage of human organs
Thousands of Americans die each year waiting for a transplant, and many experts admit there will never be enough human donors to meet the need.
Animals offer a great promise of ready supply. After years of failed attempts, companies including Revivicor, eGenesis and Makana Therapeutics are engineering pigs to be more human.
So far in the US there have been four “compassionate use” transplants, last ditch experiments on dying patients – two hearts and two kidneys. Revivicor provided both hearts and one of the kidneys. Although all four patients died within a few months, they offered valuable lessons to researchers who were ready to try again in less ill people.
Now the FDA is evaluating promising results from experiments in donated human bodies and awaiting the results of additional studies on pig organs in baboons before deciding on next steps.
They’re semi-custom organs — “these pigs are growing to the size of the recipient,” Ayares noted — that won’t show the wear and tear of aging or chronic disease like most human-donated organs.
Transplant surgeons who retrieve organs at the Revivicor farm “go, ‘Oh my god, that’s the most beautiful kidney I’ve ever seen,'” Ayares added. “The same thing when they get the heart, a happy, healthy pink heart from a young animal.”
The main challenges: how to avoid rejection and whether the animals may have some unknown risk of infection.
The process begins with modifying genes in pig skin cells in a laboratory. Revivicor first destroys a gene that produces a sugar called alpha-gal, which triggers immediate destruction by the human immune system. Then came three gene “swimmers” to remove other immune-stimulating red flags. Now the company is focusing on 10 gene arrays – pig genes are deleted and additional human genes that together reduce the risk of rejection and blood clots plus limit organ size.
They clone pigs with those changes, similar to how Dolly the sheep was created.
Twice a week, slaughterhouses send hundreds of eggs retrieved from sow ovaries to the Revivicor. Working in the dark with the light-sensitive eggs, the scientists peer through a microscope as they sniff out the mother’s DNA. Then they slip in the genetic modifications.
“Put it in nicely,” said senior researcher Lori Sorrells, pushing to the right place without breaking the egg. Mild electrical shocks fuse the new DNA and activate embryo growth.
Ayares, a molecular geneticist who leads 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 in place with a hand one and handling it with the other. The company’s first modified pig, the only GalSafe gene, is now bred instead of cloned. If xenotransplantation eventually works, there would be other pigs with the desired gene combinations, too.
Hours later, embryos are transported to the research farm in a handheld incubator and implanted into waiting sows.
Luxury accommodation for important pigs
At the research farm, Tom Petty’s “Free Fallin'” was playing in a pig barn, where music accustoms the youth to human voices. In the air-conditioned pens, the animals shouted excited greetings until it became clear that their visitors had not brought any meals. The 3-week-old babies went back to the safety of mom. Next door, older siblings settled down for a nap or checked out balls and other toys.
“Your pig is a luxury,” Ayares said. “But these are precious animals. They are very intelligent animals. I watched pigs play with balls together like soccer.”
About 300 pigs of different ages live on this farm, located in the rolling hills, their exact location not revealed for security reasons. Tags on their ears identify their genetics.
“There are certain ones that I would say hello to,” said Suyapa Ball, Revivicor’s head of pork technology and farm operations, as she rubbed the back of one pig. “You have to give them a good life. They are giving their lives for us.”
A subset of pigs used for the most important experiments—those early efforts with humans and the FDA-required baboon studies—are housed in more restricted, even cleaner, barns.
But in the Christiansburg neighborhood is the clearest sign that elder transplant is entering a new phase — the massive size of United Therapeutics’ new pathogen-free facility. Inside the 77,000-square-foot building, the company expects to produce about 125 pig organs per year, likely enough to supply clinical trials.
The company’s video shows a piglet running around behind the protective barrier, chewing on toys and snorting balls back and forth.
They were born in a piggery attached to the facility, weaned a day or two later and moved into their super clean pens for hand raising. As well as showering on site, their keepers must put on a new protective suit and mask before entering each row of pig pens – another precaution against germs.
The piggery is surrounded on all sides by security and mechanical systems that protect the animals. Outside air enters through multiple filtration systems. Huge cisterns hold backup supplies of drinking water. Standing above the pig rooms, VonEsch showed how pipes and vents were placed to allow maintenance and repair without any contact with animals.
It will take years of clinical trials to prove whether a gene transplant actually works. But if successful, United Therapeutics’ plan is for even bigger facilities, capable of producing up to 2,000 organs per year, in different parts of the country.
The field is at a point where multiple studies are “telling us that there are no train wrecks, that there is no immediate rejection,” Ayares said. “The next two to three years are going to be really exciting.”
—
The Associated Press Health and Science Section is supported by the Howard Hughes Medical Institute Science and Media Education Group. The AP is solely responsible for all matters.
