Wide-eyed piglets rushing to check out the visitors to their unusual barn just might represent the future of organ transplantation 害羞草研究所� and there害羞草研究所檚 no rolling around in the mud here.

The first gene-edited pig organs ever transplanted into people came from animals born on this special research farm in the Blue Ridge mountains 害羞草研究所� behind locked gates, where entry requires washing down your vehicle, swapping your clothes for medical scrubs and stepping into tubs of disinfectant to clean your boots between each air-conditioned barn.

害羞草研究所淭hese are precious animals,害羞草研究所� said David Ayares of Revivicor Inc., who spent decades learning to clone pigs with just the right genetic changes to allow those first audacious experiments.

The biosecurity gets even tighter just a few miles away in Christiansburg, Virginia, where a new herd is being raised 害羞草研究所� pigs expected to supply organs for formal studies of animal-to-human transplantation as soon as next year.

This massive first-of-its-kind building bears no resemblance to a farm. It害羞草研究所檚 more like a pharmaceutical plant. And part of it is closed to all but certain carefully chosen employees who take a timed shower, don company-provided clothes and shoes, and then enter an enclave where piglets are growing up.

Behind that protective barrier are some of the world害羞草研究所檚 cleanest pigs. They breathe air and drink water that害羞草研究所檚 better filtered against contaminants than what害羞草研究所檚 required for people. Even their feed gets disinfected 害羞草研究所� all to prevent them from picking up any possible infections that might ultimately harm a transplant recipient.

害羞草研究所淲e designed this facility to protect the pigs against contamination from the environment and from people,害羞草研究所� said Matthew VonEsch of United Therapeutics, Revivicor害羞草研究所檚 parent company. 害羞草研究所淓very person that enters this building is a possible pathogen risk.害羞草研究所�

The Associated Press got a peek at what it takes to clone and raise designer pigs for their organs 害羞草研究所� including a $75 million 害羞草研究所渄esignated pathogen-free facility害羞草研究所� built to meet Food and Drug Administration safety standards for xenotransplantation.

Creating pigs to ease the shortage of human organs

Thousands of Americans each year die waiting for a transplant, and many experts acknowledge there never will be enough human donors to meet the need.

Animals offer the tantalizing promise of a ready-made supply. After decades of failed attempts, companies including Revivicor, eGenesis and Makana Therapeutics are engineering pigs to be more humanlike.

So far in the U.S. there have been four 害羞草研究所渃ompassionate use害羞草研究所� transplants, last-ditch experiments into dying patients 害羞草研究所� two hearts and two kidneys. Revivicor provided both hearts and one of the kidneys. While the four patients died within a few months, they offered valuable lessons for researchers ready to try again in people who aren害羞草研究所檛 quite as sick.

Now the FDA is evaluating promising results from experiments in donated human bodies and awaiting results of additional studies of pig organs in baboons before deciding next steps.

They害羞草研究所檙e semi-custom organs 害羞草研究所� 害羞草研究所渨e害羞草研究所檙e growing these pigs to the size of the recipient,害羞草研究所� Ayares noted 害羞草研究所� that won害羞草研究所檛 show the wear-and-tear of aging or chronic disease like most organs donated by people.

Transplant surgeons who害羞草研究所檝e retrieved organs on Revivicor害羞草研究所檚 farm 害羞草研究所済o, 害羞草研究所極h my god that害羞草研究所檚 the most beautiful kidney I害羞草研究所檝e ever seen,害羞草研究所櫤π卟菅芯克鶟 Ayares added. 害羞草研究所淪ame thing when they get the heart, a pink healthy happy heart from a young animal.害羞草研究所�

The main challenges: how to avoid rejection and whether the animals might carry some unknown infection risk.

The process starts with modifying genes in pig skin cells in a lab. Revivicor initially deleted a gene that produces a sugar named alpha-gal, which triggers immediate destruction from the human immune system. Next came three-gene 害羞草研究所渒nockouts,害羞草研究所� to remove other immune-triggering red flags. Now the company is focusing on 10 gene edits 害羞草研究所� deleted pig genes and added human ones that together lessen risk of rejection and blood clots plus limit organ size.

They clone pigs with those alterations, similar to how Dolly the sheep was created.

Twice a week, slaughterhouses ship Revivicor hundreds of eggs retrieved from sow ovaries. Working in the dark with the light-sensitive eggs, scientists peer through a microscope while suctioning out the maternal DNA. Then they slip in the genetic modifications.

害羞草研究所淭uck it in nice and smooth,害羞草研究所� murmurs senior researcher Lori Sorrells, pushing to just the right spot without rupturing the egg. Mild electric shocks fuse in the new DNA and activate embryo growth.

Ayares, a molecular geneticist who heads Revivicor and helped create the world害羞草研究所檚 first cloned pigs in 2000, says the technique is 害羞草研究所渓ike playing two video games at the same time,害羞草研究所� holding the egg in place with one hand and manipulating it with the other. The company害羞草研究所檚 first modified pig, the GalSafe single gene knockout, now is bred instead of cloned. If xenotransplantation eventually works, other pigs with the desired gene combinations would be, too.

Hours later, embryos are carried to the research farm in a handheld incubator and implanted into waiting sows.

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Luxury accomodations for important pigs

On the research farm, Tom Petty害羞草研究所檚 害羞草研究所淔ree Fallin害羞草研究所櫤π卟菅芯克鶟 was serenading a piglet barn, where music acclimates the youngsters to human voices. In air-conditioned pens, the animals grunted excited greetings until it害羞草研究所檚 obvious their visitors brought no treats. The 3-week-olds darted back to the security of mom. Next door, older siblings laid down for a nap or checked out balls and other toys.

害羞草研究所淚t is luxury for a pig,害羞草研究所� Ayares said. 害羞草研究所淏ut these are very valuable animals. They害羞草研究所檙e very smart animals. I害羞草研究所檝e watched piglets play with balls together like soccer.害羞草研究所�

About 300 pigs of different ages live on this farm, nestled in rolling hills, its exact location undisclosed for security reasons. Tags on their ears identify their genetics.

害羞草研究所淭here are certain ones I say hi to,害羞草研究所� said Suyapa Ball, Revivicor害羞草研究所檚 head of porcine technology and farm operations, as she rubbed one pig害羞草研究所檚 back. 害羞草研究所淵ou have to give them a good life. They害羞草研究所檙e giving their lives for us.害羞草研究所�

A subset of pigs used for the most critical experiments 害羞草研究所� those early attempts with people and the FDA-required baboon studies 害羞草研究所� are housed in more restricted, even cleaner barns.

But in neighboring Christiansburg is the clearest signal that xenotransplantation is entering a new phase 害羞草研究所� the sheer size of United Therapeutics害羞草研究所� new pathogen-free facility. Inside the 77,000-square-foot building, the company expects to produce about 125 pig organs a year, likely enough to supply clinical trials.

Company video shows piglets running around behind the protective barrier, chewing on toys and nosing balls back and forth.

They were born in sort of a porcine birthing center connected to the facility, weaned a day or two later and moved into their super-clean pens to be hand-raised. In addition to the on-site shower, their caretakers must put on a new protective suit and mask before entering each suite of pig pens 害羞草研究所� another precaution against germs.

The pig zone is surrounded on all sides by security and mechanical systems that shield the animals. Outside air enters through multiple filtration systems. Giant vats hold backup supplies of drinking water. Standing over the pig rooms, VonEsch showed how pipes and vents were placed to allow maintenance and repair without any animal contact.

It will take years of clinical trials to prove whether xenotransplantation really could work. But if it succeeds, United Therapeutics害羞草研究所� plan is for even larger facilities, capable of producing up to 2,000 organs a year, in several places around the country.

The field is at a point where multiple kinds of studies 害羞草研究所渁re telling us that there害羞草研究所檚 no train wrecks, that there害羞草研究所檚 no immediate rejection,害羞草研究所� Ayares said. 害羞草研究所淭he next two or three years are going to be super exciting.害羞草研究所�

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The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute害羞草研究所檚 Science and Educational Media Group. The AP is solely responsible for all content.

Lauran Neergaard, The Associated Press