'Million-Dollar pigs' are medical marvels

By Luis Fabregas

Tribune-Review

April 9, 2006

Photo Gallery Steven Adams/Tribune-Review Steven Adams/Tribune-Review About Revivicor Revivicor was born in 2003 as a spin-off of the U.S. division of PPL Therapeutics, the Scottish biotech firm that in 1997 created Dolly, the cloned sheep. Revivicor is a privately held partnership with University of Pittsburgh Medical Center, Highmark Inc. and Fujisawa Investments for Entrepreneurship L.P. Its main focus is to make human therapeutic products from pig cells, tissues and organs. The firm initially sought to corner the market by creating animals that could produce human therapeutic proteins in the milk of dairy animals. Its cows, for example, produced human milk protein that could be used in baby formula. But despite other scientific milestones, including the creation of the world's first cloned pigs, PPL in 2000 lost one of its major financial backers, based in California. As PPL looked for new partners, it hit a grand slam: Its Virginia-based scientific team, led by Dr. Yifan Dai, created the world's first pig that lacks a sugar-making gene that is important in the rejection of pig organ transplants. That gave transplant pioneer Dr. Thomas Starzl and the University of Pittsburgh the impetus to align itself with Revivicor. Dai, who also led the PPL/Revivicor team that created a pig with both copies of the gene knocked out, is now at Pitt, trying to modify other pig genes responsible for rejection.

BLACKSBURG, Va. -- In the brave new world of medical marvels, this remote pig farm along the Blue Ridge Mountains could become the unlikely new capital of organ transplantation.

The farm, miles from town atop a dusty road, is home to 200 pigs, small and large, cute and not-so-cute. Some have received the ultimate genetic tune-up: Their DNA has been stripped of a pesky, sugar-making gene so their organs someday could be safely transplanted into humans.

"They're million-dollar pigs," says David Ayares, president and chief executive of Revivicor, a biotech firm funded by the University of Pittsburgh Medical Center, as he shows off a squealing litter of piglets.

Aware that it could be walking into a medical bonanza, UPMC, through its Revivicor alliance, has been taking quiet but aggressive steps to resurrect the highly controversial field of xenotransplantation, in which organs and cells are transplanted between different species, including humans.

"Xenotransplantation is the one thing that's most potentially proximate, closest at hand," says UPMC transplant pioneer Dr. Thomas E. Starzl, who for years has worried about finding alternatives to address a long-standing shortage of organs for transplantation.

UPMC and Revivicor are making fast progress -- and fast plans.

At seven testing facilities scattered throughout Pittsburgh, hearts from the genetically altered pigs are surviving in baboons for about three months and sometimes even longer.

That survival is expected to grow more consistently -- for up to six months -- as scientists further tweak the pigs' genetic make-up.

Revivicor also is working out agreements to sell other pig tissue and cells to several companies, including a still undisclosed deal with a Los Angeles company that will use them in an artificial liver.

If it clears government permits, Revivicor wants to set up pig organ centers across the country to distribute pig hearts to transplant centers in the 11 geographic regions set up by the United Network for Organ Sharing, the agency that allocates organs on behalf of the federal government, Ayares says.

"The advantage of this is that you don't have to wait for people to get really sick or before they go on the organ transplant list," Ayares says. "Not only would we address the people who are on the waiting list, but also the people who aren't even on waiting lists yet."

The company's plan extends well beyond the United States. There have been early discussions about setting up a pig hub in Palermo, Italy, where UPMC operates a specialized hospital, Ayares said.

If the plans succeed, UPMC and Revivicor have the potential to break scientific barriers by using pig organs in ways never done before in the U.S.

A $6 billion market

Momentum is building for two promising projects.

One is using insulin-making pig islets to bolster the insulin levels of people with type 1 diabetes, something routinely done in at least one hospital in Mexico City. In the last five years, about 40 patients at Children's Hospital of Mexico have received the pig islet transplants. Some of them have significantly reduced their insulin intake, said spokeswoman Isis Casanova.

Researchers at Children's Hospital of Pittsburgh, led by Dr. Massimo Trucco, have been testing pig islets in small monkeys since 2004.

Another project would use pig hearts in people with severe heart failure instead of mechanical pumps.

By Revivicor's own estimates, the market for pig organs could be worth at least $6 billion.

The intensity of UPMC's efforts, including discussions between Revivicor and the U.S. Food and Drug Administration, suggest UPMC is poised to begin human clinical trials within two or three years.

Starzl, who turned 80 last month, says he expects to be alive to see that happen.

"If it happens in the next five years, I'd have a crack at it," he says.

From baboons to pigs

UPMC's interest in xenotransplantation isn't new.

In 1992, under the leadership of Starzl and his protege, Dr. John J. Fung, Pitt surgeons transplanted a baboon's liver into a 35-year-old man. The man lived 70 days. A second liver was transplanted from a baboon to a human in 1993. The recipient died 26 days after the transplant because of an infection.

Those attempts were preceded by the world-famous case of a 5-pound infant known as Baby Fae. On Oct. 26, 1984, doctors at Loma Linda University Medical Center in California placed in the girl's chest the heart of a baboon.

She did well for a few days, but soon her body mounted a massive immunological attack against the organ. She died 20 days after the transplant.

Those controversial cases, bolstered by the fear of spreading animal diseases to humans, have turned xenotransplantation into a hush-hush, ethically charged topic that only a handful of scientists find worth pursuing.

"There was tremendous initial promise and people were very excited, but the field didn't deliver immediately and people's enthusiasm waned," says Dr. Christopher McGregor, a researcher at Mayo Clinic heavily involved in xenotransplantation.

At its height, at least eight companies were involved in xenotransplantation research, most of them propped up by deep-pocketed pharmaceuticals such as Novartis.

Few remain in the field, including Revivicor, which survived only because of UPMC's deep pockets and $11 million in federal grants over the last four years.

Scientists say pig organs have emerged as front-runners in the field because their size better matches the human body.

Pigs also are less controversial than monkeys or baboons, because they are widely slaughtered for meat.

"One would think society would accept them as a life-saving modality," McGregor says.

If there's an argument to support the need for xenotransplantation, it lies in the more than 90,000 people who are waiting for organ transplants across the country.

The organ network says about 6,300 people died in 2005 waiting for an organ transplant.

Recent studies suggest only about half of potential organ donors agree to a donation.

"It's pretty clear that even if you were able to get a 100 percent participation by the public, you probably still would have a shortfall with some organs, especially the kidney and certainly the heart," Starzl says. "There are real limits. So that means, the big solution is out there somewhere."

UPMC pushes forward

That somewhere could well be Revivicor's 900-acre farm.

On this sunny winter morning, a litter of hungry piglets angle for a feeding spot underneath their mother's round, hairy belly.

Just outside their metal pens, Ayares points to their flopping ears. They've been purposely notched -- the only sign their genes have been altered.

"They still smell like pigs," Ayares says with a laugh.

The piglets lack a sugar -- called alpha-1-galactose -- that causes humans to reject pig tissues and organs. Humans carry antibodies that instantly recognize this sugar, often prompting rejection within minutes.

So crucial is this genetic tune-up, that scientists have further stripped other copies of the sugar-making gene from subsequent piglets.

Starzl and others at UPMC saw this achievement as an opportunity, and in 2003 UPMC became one of three investors backing Revivicor. The hospital network first invested $1.5 million and continues to fund the biotech on an ongoing basis, Ayares said.

"UPMC was our savior, definitely," Ayares says.

Health insurer Highmark Inc. also invested $1.5 million, as part of a plan to help fund new medical treatments, said spokesman Michael Weinstein. Fujisawa Investments for Entrepreneurship L.P. also invested $500,000.

The investments already are paying off.

In September, Revivicor struck a deal with Zimmer Holdings Inc., an Indiana surgical products company, that will use pig cells to make implants to repair damaged cartilage, tendons, bone, ligaments and tissues.

The implants -- including some to repair hernias and common rotator cuff injuries -- are made from pigskin that is treated with detergents to break open its cells.

Once these cells are killed, the scaffold that remains is used to encourage the growth of the person's own cells in and around that mesh.

More potential than stem cells?

Revivicor's progress helped lure to Pittsburgh Dr. David K.C. Cooper, a xenotransplant expert who began his career alongside Dr. Christian Baarnard, the South African surgeon who performed the world's first open heart transplant in 1967.

Cooper, a London-born surgeon who last worked at Harvard, says he believes xenotransplantation has much more potential than stem cells, which scientists say can morph into any cell type in the body.

"To consider that you're going to make a whole heart or a whole kidney or a whole liver out of a stem cell -- that's, to me, the meaning of science fiction," Cooper says. "I think they may be able to do it in 50 or 100 years time, but here with the pig, we at least have the whole organ, and we know it works."

Cooper is behind an effort that is looking to test the pig hearts as a so-called bridge to transplantation.

Cooper says the pig hearts could provide temporary relief to seriously ill patients with congestive heart failure, a common ailment in which people can't pump enough blood to the body's organs.

Some of those patients are now treated with mechanical pumps that are inserted in the abdomen, then attached to the left ventricle and the main blood vessel carrying blood from the heart to the body.

Cooper says that in some instances, using pig hearts might help patients stay alive longer than when they're fitted with the artificial pumps.

In studies conducted at Pitt, six patients who died while using the pumps survived an average of just over three months.

To justify the use of a pig heart in humans, patients would need to survive longer than that -- for at least six months.

That's the recommendation of the International Society for Heart and Lung Transplantation, which has more than 2,300 members in 45 countries.

The society in 2000 said a pig heart should have to survive between three and six months in a nonhuman primate for a human clinical trial to be considered.

Some baboons with pig hearts have survived almost six months but not consistently, Cooper says.

In a study published in the November issue of the journal Transplantation, Cooper said six of eight baboons that received the hearts of genetically altered pigs survived a few days short of six months.

The baboons, however, encountered setbacks, mainly the formation of tiny clots in their small vessels. The clots worsened over time and wound up killing the animals.

Pitt scientists, led by Dr. Yifan Dai, are putting a human anticoagulant gene into their knock-out pigs to solve the problem. Scientists at Imperial College in London, working with UPMC, have successfully tested this approach in rodents.

"This anticoagulant gene prevents all of the rejection that we normally see," Cooper says.

Revivicor already has held preliminary talks with the U.S. Food and Drug Administration, Ayares said. The federal agency has asked Revivicor to screen all pigs for more than 100 viruses and bacteria that could be potentially harmful to humans.

Ayares says he has no doubt the government will be supportive of Revivicor's plans for human clinical trials, which he expects to happen in two to three years.

"There is no other way to overcome the shortage of human organs," he says.

Luis Fabregas can be reached at lfabregas@tribweb.com or (412) 320-7998.

Copyright © 2006 by The Tribune-Review Publishing Co.

This article posted May 7, 2006.