BLACKSBURG, Va. – Wide-eyed piglets running to see visitors to their unusual barn may represent the future of organ transplantation – and here there is no way to roll in the mud.
O first genetically edited pig organs already transplanted into people came from animals born on this special research farm in the Blue Ridge Mountains – behind locked gates, where entry requires washing your vehicle, changing out of your clothes for medical scrubs, and stepping into tubs of disinfectant to clean your boots between each breath. conditioned barn.
“These are precious animals,” said David Ayares of Revivicor Inc., who has spent decades learning how to clone pigs with the right genetic changes to allow those first audacious experiences.
Biosecurity becomes even stricter a few kilometers away, in Christiansburg, Virginia, where a new herd is being created – pigs that are expected to provide organs for formal animal-to-human transplant studies next year.
This huge, unprecedented building bears no resemblance to a farm. It’s more like a pharmaceutical factory. And part of it is closed to everyone except a few carefully chosen employees who take timed showers, don company-supplied clothes and shoes, and then enter an enclave where piglets are growing.
Behind this protective barrier are some of the cleanest pigs in the world. They breathe air and drink water that is better filtered against contaminants than is needed by people. Even their food is disinfected – all to prevent them from contracting possible infections that could harm the transplant recipient.
“We designed this facility to protect pigs from contamination from the environment and people,” said Matthew VonEsch of United Therapeutics, Revivicor’s parent company. “Every person who enters this building poses a potential pathogen risk.”
The Associated Press took a look at what it takes to clone and breed engineered pigs for their organs — including a $75 million “designated pathogen-free facility” built to meet Food and Drug Administration safety standards for xenotransplants.
Thousands of Americans every year die waiting for a transplant, and many experts recognize that there will never be enough human donors to meet the need.
Animals offer the tantalizing promise of a ready supply. After decades of failed attempts, companies like Revivicor, eGenesis and Makana Therapeutics are pigs designed to be more humane.
So far in the US, there have been four “compassionate use” transplants, last-minute experiments on dying patients – two hearts and two kidneys. Revvivicor provided hearts and one of the kidneys. Although the four patients died within months, they offered valuable lessons for researchers ready to try again in people who weren’t as sick.
Now, the FDA is evaluating promising results from experiments on donated human bodies and awaiting results from additional studies of pig organs in baboons before deciding next steps.
They are semi-customized organs – “we are growing these pigs to recipient size,” Ayares noted – that do not show the wear and tear of aging or chronic disease like most organs donated by people.
Transplant surgeons who have recovered organs at the Revivicor farm “say, ‘My God, that’s the most beautiful kidney I’ve ever seen,’” Ayares added. “The same thing when they get the heart, a healthy, happy, pink heart from a young animal.”
The main challenges: how to avoid rejection and whether animals can carry something unknown risk of infection.
The process begins with modifying genes in pig skin cells in the laboratory. Revvivicor initially deleted a gene that produces a sugar called alpha-gal, which triggers the immediate destruction of the human immune system. Next came three-gene “knockouts” to remove other warning signals that trigger the immune system. Now, the company is focusing on 10 gene edits – deleted pig genes and added human genes that together lower the risk of rejection and blood clots, as well as limiting organ size.
They clone pigs with these changes, similar to how Dolly the sheep was created.
Twice a week, slaughterhouses send hundreds of eggs taken from sows’ ovaries to Revivicor. Working in the dark with the light-sensitive eggs, scientists watch through a microscope as they aspirate the maternal DNA. Then they introduce genetic modifications.
“Put it in nice and gently,” coos senior researcher Lori Sorrells, pushing it into place without breaking the egg. Mild electrical shocks fuse the new DNA and activate the embryo’s 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 the same time”, holding the egg in place with one hand and manipulating it with the other. The company’s first modified pig, the GalSafe single gene knockout, is now created rather than cloned. If xenotransplantation eventually works, other pigs with the desired genetic combinations would also work.
Hours later, the embryos are transported to the research farm in a portable incubator and implanted into waiting sows.
At the research farm, Tom Petty’s “Free Fallin’” serenaded a piglet barn, where the music accustomed the youngsters to human voices. In air-conditioned pens, the animals grunted enthusiastic greetings until it became obvious that their visitors had brought no treats. The 3-week-olds ran back to their mother’s safety. Next door, older siblings lay down for a nap or checked out balls and other toys.
“It’s a luxury for a pig,” said Ayares. “But these are very valuable animals. They are very intelligent animals. I’ve seen piglets play with balls together, like football.”
Around 300 pigs of different ages live on this farm, situated on hills, the exact location of which has not been revealed for security reasons. Tags on the ears identify your genetics.
“There are some I say hi to,” said Suyapa Ball, head of swine technology and agricultural operations at Revivicor, as she rubbed a pig’s back. “You have to give them a good life. They are giving their lives for us.”
A subset of pigs used for the most critical experiments—the first trials on people and the FDA-required baboon studies—are housed in more restricted and even cleaner barns.
But in nearby Christiansburg there is the clearest sign that xenotransplantation is entering a new phase – the size of United Therapeutics’ new pathogen-free facility. Inside the 7,000-square-foot building, the company expects to produce about 125 pig organs a year, likely enough to power clinical trials.
The company’s video shows piglets running behind the protective barrier, chewing toys and sniffing balls back and forth.
They were born in a sort of swine birthing center connected to the facility, were weaned a day or two later, and were moved to their super-clean pens to be hand raised. In addition to the on-site shower, your caregivers must don a new protective suit and mask before entering each set of pig pens – another germ precaution.
The pig area is surrounded on all sides by mechanical and safety systems that protect the animals. Outside air enters through several filtration systems. Giant tanks store reserves of drinking water. Standing over the pig rooms, VonEsch showed how pipes and vents were placed to allow maintenance and repairs without any contact with the animals.
It will take years of clinical trials to prove whether xenotransplantation could actually work. But if successful, United Therapeutics’ plan is to create even larger facilities, capable of producing up to 2,000 organs per year, in multiple locations across the country.
The field is at a point where various types of studies “are telling us that there are no train accidents, that there is no immediate rejection,” Ayares said. “The next two or three years are going to be super exciting.”
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The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. AP is solely responsible for all content.
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