Organ transplants get lift
In cloned piglet, firm sees hope for human applications
By Naomi Aoki, Globe Staff, 1/12/2003
Immerge BioTherapeutics is expected to announce today that it has successfully cloned a piglet lacking both copies of a gene responsible for triggering a violent immune response in humans, taking another step in advancing long-held hopes for growing a supply of organs for transplant to people.
The Charlestown firm's scientists said the 2-month-old piglet, named Goldie, weighs about 81/2 pounds and is developing normally. Unlike her porcine peers, however, Goldie's DNA has been altered to ''knock out'' the alpha-1-galactose genes, which produce a sugar that causes the human immune system to reject pig tissue and organs.
The announcement comes nearly five months after another company, PPL Therapeutics, reported it had cloned the first such ''double knockout'' pig. The two firms have been neck-and-neck in the race to create a safe pool of donor organs from pigs. Immerge became the first to clone a pig with one of the two genes knocked out in September 2001. Within months of that breakthrough, PPL matched Immerge's feat.
''Those in the field debate the importance of this sugar as a barrier to pig-to-human transplants,'' said Dr. Jeffrey L. Platt, head of transplantation biology at the Mayo Clinic in Minnesota. ''I myself think it is just one of many immunological barriers. I don't think its removal will prevent the rejection of pig organs. Nonetheless, this is a tremendously important achievement because it shows that you can take a gene away if you need to, that this approach can be used to address those other barriers.''
For nearly two decades, scientists have been studying pigs as a potential source of organs to replace those that are failing in humans. Surprisingly, pigs are biologically similar to people and carry fewer deadly diseases than most primates. But the research has been riddled with setbacks. Chief among them has been the powerful attack mounted by the body's immune system against foreign invaders - a natural defense that causes an almost immediate rejection of animal organs.
Scientific advances in recent years, however, have breathed new life into the field, known as xenotransplantation. Analysts predict the market could generate billions of dollars for companies that succeed in the quest. Nearly 80,000 people are on waiting lists for human organs, thousands more with ailing organs don't make the lists, and 16,000 people die each year in the United States while they wait.
''We have to have another source of organs,'' said Dr. David K.C. Cooper, an immunologist at the Transplantation Biology Research Center at Massachusetts General Hospital in Boston. ''We've tried to make the public fully aware of the need for organs. But we will never get enough human organs that way.''
Researchers said many issues must be resolved before the promise of transplanting pig organs becomes a reality. They predict it will be at least two or three years before the transplants can be tested in humans, and then only if they can show that the transplanted organs survive in primates for more than six months without requiring such severe suppression of the immune system as to pose a danger to patients.
When Goldie is older, Immerge scientists will study her organs and tissues. Before they begin transplanting organs into primates, however, they must produce more piglets like Goldie - something they plan to accomplish through breeding of the single-knockout pigs as well as cloning Goldie.
The availability of pig organs free of the problem-causing sugar promises to catapult xenotransplantation forward. The immune response to the sugar is so violent that researchers have been unable to keep transplanted organs alive for more than a few hours without almost eliminating a primate's ability to mount an immune defense. The reaction has not only prevented xenotransplantation from becoming a reality, but it has also hampered researchers' ability to identify and study other potential barriers, including transmission of disease, other immune responses, and the ability of the organ to develop once it is transplanted.
''The immune response to this sugar has been the major problem facing us for the last 10 years,'' Cooper said. ''Despite our best efforts, it's not been possible to get over it completely. Now it is.''
Normal piglets inherit one copy of the alpha-1-galactose gene from their mother and another from their father. The first group of altered swine were missing only one of the twin genes. To prevent the immune response, however, both copies had to be removed. Goldie was created using cells taken from the ear of one of the single-knockout pigs. The scientific team, which included collaborators from the University of Missouri-Columbia, then turned off the remaining functional copy of the alpha-1-galactose gene.
Like the earlier pigs, Goldie descends from a highly inbred species of miniature swine designed to create a pool of potential organs as genetically similar as possible. The pigs, whose whereabouts are kept secret for security reasons, grow to about 250 pounds each and have been screened for more than two dozen viruses and infectious diseases. Studies have shown that their cells do not infect human cells with a potentially harmful virus, known as porcine endogenous retrovirus, another major barrier to xenotransplantation.
Julia Greenstein, Immerge's president and chief executive, said those qualities make its pigs more suitable donors than the pigs produced by PPL, the US branch of the British firm that helped clone Dolly the sheep in 1997. Since PPL's pigs are domestic swine that grow to be three times as large as their miniature counterparts, Greenstein said, organs would need to be plucked from them before they were fully grown to be appropriate for humans. She also said that PPL's pigs have not been inbred to create a consistent pool of organs and tissues or tested to determine whether they can pass the porcine retrovirus to human cells.
Immerge, which employs 18 people, was formed in 2000 as a joint venture between Swiss pharmaceutical giant Novartis Pharma and Charlestown-based BioTransplant. The company's research focuses on medical therapies, including organ and cell transplants, based on xenotransplantation as well as developing the immune-related treatments that will be needed to successfully transplant organs from pigs to humans.
But the science is unclear on whether those advantages will prove to be important in treating patients, Platt said. The similarity from one Immerge pig to another may prove to be a medical advantage. But the fact that PPL's pigs are not inbred means they are less likely to fall victim to genetic weaknesses, which may ultimately give PPL the edge. Likewise, the size of the organs may or may not prove to be important because the organs could stop growing once they are transplanted in people.
''We don't know,'' Platt said. ''We just don't know the answers to many of these questions. But this technology for the first time allows us to address them definitively.''
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