How genetically modified pigs could end the shortage of organs for transplants

NEAR BLACKSBURG, Va. — It's a crisp, clear winter day as I drive down a winding two-lane road through the foothills of the Blue Ridge Mountains in southwest Virginia and turn onto an unmarked gravel driveway.

At the end of the drive, I meet David Ayares, who runs Revivicor Inc., a biotech company based in Blacksburg, Virginia.

Ayares has invited me to be the first journalist to tour the company's research farm, which is on the forefront of trying to realize a long-sought goal: using cloned farm animals to provide kidneys, hearts, livers and other organs to save thousands of people who need transplants.

"It's exciting. We've been working on this for more than 20 years. And it's no longer a science fiction experiment," Ayares says. "It's actually a reality."

The experiments hold promise for alleviating the chronic shortage of organs for transplantation. But the research is also stirring concerns about the ethics of using farm animals for their organs and the risks of spreading animal viruses to people.

A hidden farm for research

Ayares asks me not to disclose the exact location of Revivicor's farm because of security concerns. He leads me up a hill to give me an overview of the facility.

"We have 22 buildings and a census of pigs — around 300 pigs — all for research purposes," he says, as we look out over yellow, one-story rectangular modular buildings clustered out of sight below us.

Next, Ayares takes me into one of the buildings to change into hospital scrubs.

"It's a barrier facility. So we're trying to protect the pigs, not us," says Ayares, explaining that wearing sterile clothes is just one precaution the company takes to make sure visitors don't infect the pigs with pathogens.

After changing, we climb into a truck and drive though what looks like a one-car outdoor car wash to disinfect the vehicle, and we then pass through a locked security gate in a tall chain-link fence.

We head into another building by stepping through a metal tub filled with disinfecting fluid to sterilize our boots.

Inside, the air is filled with the sound of snorting, grunting, squealing pigs and piglets. We find seven adult females in separate pens. Four of the pigs are pregnant with cloned pig embryos that were genetically modified. The other three are suckling litters of modified piglets.

"This is the farrowing facility where the newborn piglets are born," Ayares says. "All of these piglets are genetically modified."

How the pigs' genes are modified in the lab

Earlier in the day, Ayares took me through Revivicor's research labs in Blacksburg to show me how the company creates the genetically modified cloned animals.

Inside a brick and glass building in an office park, scientists start by using the latest genetic engineering techniques to edit the DNA in pig skin cells. Next, the scientists use a technique similar to that used to create the first cloned mammal — Dolly the sheep — to make cloned pig embryos. (Revivicor created the world's first cloned pigs.)

During my visit, four scientists methodically remove most of the genes from hundreds of pig eggs. They do it by gingerly piercing the egg with a tiny pipette under a microscope to suction out the DNA. Later that day, the scientists inject the edited pig skin cells inside the eggs' outer membrane. Finally, the scientists zap the combination of cells with two electric shocks to get the edited cells to fuse with the emptied eggs and then start cell division to create an embryo.

The resulting embryos are surgically implanted into the wombs of adult female pigs. Four months later, cloned piglets are born with 10 genetic modifications designed to make sure their organs don't grow too big, won't cause complications like blood clots and won't be rejected by the human immune system.

Back on the farm

"Every cell in the body of this animal has those same genetic modifications. And when we procure an organ from them, like every other cell, it's carrying the desired genetic modification that will be used for organ transplant," Ayares says back on the farm. "Their hearts, their kidneys, their lungs, their livers — all have the 10 genetic modifications so that they'll be compatible for transplant."

Several other companies, including eGenesis in Cambridge, Mass., are pursuing similar research. eGenesis is doing even more extensive genetic modification in the hope of helping the animal organs work even better for transplantation.

Ayares asks whether I'd like to hold one of Revivicor's cloned piglets.

"These pigs are bred to be heavily muscled and very efficient. So you'll be surprised at how dense they are," he says as he hands me one.

I try to comfort the baby pig as it squeals and squirms in my arms. It does feel very solid, but soft too. After a couple of minutes, I return the 3-week-old piglet to his mother to continue nursing with his littermates.

Next, Ayares leads me into an adjacent nursery barn, where the baby pigs are moved when they're old enough to be weaned from their mothers. Dozens of young pigs are sniffing, sleeping or playing.

"They have hanging toys. They have balls that they like to play with. Some of them at times will even play soccer with each other. You can roll the ball to them. They'll roll it back to you. They're very smart, interactive animals," Ayares says.

Each has its own unique personality, Ayares adds.

"Some of them are grouchy. Some of them are very friendly. Some like to be scratched behind their ears. Others on their back or on their tails," he says.

A network of farms could supply organs nationwide

Once the pigs are old enough, clones are bred with other clones to produce more litters of identically modified animals that could be sacrificed when they're almost a year old for research or to provide organs for transplants.

"Those litters will allow us to do multiple organ procurements. From one animal, for example, we can get two kidneys and a heart. The holy grail would be to get all the organs that you need for human transplant from one donor animal," he says.

More than 100,000 people are on the waiting list for transplants in the U.S., and about 17 a day die without getting one because there aren't enough human organs available.

So Ayares envisions a day not too far off when Revivicor will run commercial farms scattered around the country to breed these modified cloned pigs for desperate organ recipients.

"There will be multiple facilities coast to coast in order to produce enough organs for transplant," he says.

Revivicor has already built a bigger and even more secure farm nearby to produce pigs for a study that the company hopes to start in people soon to provide the necessary data to get the modified pig organs approved by the Food and Drug Administration.

Ethical concerns temper hope

But the prospect of using animal organs for human transplant is unsettling to some.

"The risks could really be catastrophic from the introduction of a novel mutated virus that might infect a human," says L. Syd Johnson, a bioethicist at SUNY Upstate Medical University in Syracuse, New York.

In addition to the potential risks to people, Johnson and others also question creating, breeding and sacrificing thousands of pigs every year to harvest their genetically manipulated organs for transplantation into people.

"They're treated like machines for the sole purpose of being disassembled to provide spare parts for humans," Johnson says. "I think the hubris of this kind of human intervention — and the radical exploitation of a human-created, built-for-purpose anima — should really give us pause."

But Ayares says that the company treats the animals humanely and that it is taking extra steps to ensure all the animals are free of any diseases. And, he notes, Americans sacrifice millions of pigs each year for food.

"These pigs are being cloned and bred for a higher purpose: to provide organs for transplant," he says. "I believe that's probably a higher goal than to be using them for meat. These pigs have the opportunity to transform medicine and save a lot of lives."

To get FDA approval to start a formal study in humans on the organ waiting list, Revivicor is first studying the pig organs in baboons and in the bodies of people who have been declared brain-dead.

Revivicor has so far sponsored eight such "decedent" procedures, involving hearts and kidneys, at NYU Langone Health in New York and the University of Alabama at Birmingham. More tests are planned as more body donors are found.

A liver procedure using a cloned, modified eGenesis animal was recently announced at the University of Pennsylvania in Philadelphia. Livers could be used as temporary bridges to transplantation with a human organ, researchers say.

In addition, surgeons at the University of Maryland in Baltimore implanted gene-edited pig hearts into two men who had run out of other options. Those volunteers survived only a few weeks. But Ayares says the men provided invaluable information about using organs from genetically modified cloned pigs in people. For example, researchers found evidence of a pig virus in one of the heart recipients, prompting Revivicor to add additional testing to ensure the animals are free from that risk.

"We're trying to solve the organ shortage crisis," Ayares says. "These people are heroes."

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