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This little piggy might save your life Process of cloning pigs for transplants offers hope, questions By JOHN FAUBER of the Journal Sentinel staff Veterinarian Gail Lange checks out several transgenic cloned pigs on a rural Wisconsin farm. The pigs were developed by Infigen of DeForest and the company is continuing research and development of the pigs in hopes that someday pigs may provide organs for humans in need of organ transplants. DeForest - In a nursery pen at a secret location not far from here, a dozen piglets scamper around, cute and oblivious to their status as pioneers in modern medicine. Not only are these little porkers some of the world's first cloned pigs, but they also have a human gene inserted in their DNA, making them transgenic. Other than sheer madness, why would scientists want to add human genes to a pig? Because someday, one of the 100 million or so pigs slaughtered in this country may save your life. Researchers here at Infigen Inc. are trying to genetically alter and clone pigs to produce organs that will not result in massive organ rejection when transplanted into humans. Just how many lives are saved, extended or improved may well depend on the success of the experiments taking place at Infigen and other research sites around the country, including the University of Wisconsin-Madison. In the nextfive years, porcine hearts, kidneys, livers and even brain cells probably will be transplanted into sick, dying or injured people in hopes of giving them a new lease on life, some scientists say. The official term for when animal organs or cells are transplanted into a human is "xenotransplantation." Some scientists think that millions of people could someday benefit, and that xenotransplantation could act as a bridge to the kind of human tissue advancements that stem cell research may yield. But there are obstacles and risks. First, more work is needed to genetically alter and clone pigs to produce organs that will not be rapidly rejected by their human hosts, although many scientists now believe that day is near. Beyond that, there is unknown risk lurking. What if a hidden virus or other unknown infectious agent in pigs attacked the person who received a pig organ? Worse yet, what if that person spread the virus to large numbers of other people before scientists realized it was deadly to humans? It is believed that HIV, for example, jumped from chimpanzees to humans sometime during the first half of the 20th century, eventually leading to the worldwide AIDS epidemic. Infections from animals In their cells, nearly all pigs carry porcine endogenous retrovirus (PERV), a pathogen that has shown the ability to infect human cells, at least in a laboratory dish. The virus does not make pigs ill; its effect on humans remains unknown. But in a 1999 study of 160 people who had been exposed to living pig cells, none showed any evidence of being infected by PERV. Still, PERV is just one known virus; other animal pathogens may not have been identified yet. For example, scientists already know that pigs play a unique role in the spread of flu viruses. Most of the viruses originate in birds, then infect animals such as pigs, which can recombine the flu virus DNA in novel ways before spreading it to humans. "We don't want to unleash a pandemic on the world," said David Cooper, a professor of surgery and immunology at Harvard Medical School and president of the International Xenotransplantation Association. But the pig already may be out of the pen. Already, more than 200 experiments involving pig cells or organs have taken place. In one of the early cases, Rebecca Draeger, then a 17-year-old Iron Ridge resident, had her blood infused through pig livers at the University of Wisconsin Hospital and Clinics in Madison to keep her alive for more than a day until a human liver could be transplanted. At the time, she was less than 24 hours away from brain death, according to her doctor. A catheter was inserted into the femoral vein in her leg, near her groin. Her blood was pumped out into a mechanical oxygenator, a blood warmer and then into the main vein of the pig liver. "The liver was in a sterile container at her bedside," said UW transplant surgeon Tony D'Alessandro. As the blood circulated through the pig's liver, toxins and bile were removed, and the blood was returned through the jugular vein in her neck. When one liver reached its limit, a second was used. Today, Rebecca, 22, is married and doing fine; she gave birth to a son about a year ago. Draeger's operation was a stopgap measure, not an actual transplantation. However, much more permanent and bold experiments have been devised and tested in the last several years. Brain cells substitute In September 1999, Maribeth Cook had 30 million brain cells from a pig fetus injected into her brain. Cook, 40, of Saratoga Springs, N.Y., had suffered a debilitating stroke five years earlier, and she and her doctors hoped the neural cells from the pig fetus would take over the functions of her neural cells that died as the result of her stroke. Less than two years after the operation, Cook said she has seen noticeable improvement. Her speech and walking have improved, she said. But more important: "My cognitive thinking is better," she said. "I'm thinking clear, and I'm reading." Before the operation, she said, she remembered virtually nothing when reading. Cook is one of five stroke victims and 10 Parkinson's disease sufferers to have neural cells from pigs injected into their brains in clinical trials being conducted by Diacrin Inc., a biotech company in Charlestown, Mass. The results from those trials have been mixed. The stroke trial was stopped after two of the patients suffered seizures, even though one of them later reported a significant improvement in her condition and the cessation of seizures. In the Parkinson's trial, there was an average 28% improvement in the condition of the 10 patients. It is believed the pig neural cells can help Parkinson's patients produce dopamine, a brain chemical they lack. However, there also was a 21% improvement in a group of eight "placebo" patients who had small holes drilled in their heads - "just a little divot," according to a Diacrin official - but who received no pig brain cells. Over the next three months, Diacrin researchers will analyze the data and decide their next step, said Doug Jacoby, the company's director of research. For the rest of their lives, some of the patients also will have to be tested for signs of the porcine endogenous retrovirus. In the meantime, the company last month started a trial involving the injection of pig fetal nerve cells into the spinal cords of six paraplegics and quadriplegics. Animal experiments suggest that such a procedure may help repair the spinal cord and restore some function. However, the spinal cord study is a trial designed primarily to test the safety of the procedure. Other researchers have transplanted or scheduled trials involving the transplantation of pig pancreas cells into diabetics in hopes of helping them produce their own insulin. At one time, insulin used by humans to control their disease came from pigs. Need for organs One of the big reasons why xenotransplantation may become a necessary therapy is the vast numbers of people in need of life-saving organs. Last year, 22,827 people donated organs, but more than 75,000 people needed an organ. About 15 people die every day in the United States while waiting on an organ donation list. Pig organs are the most likely source because anatomically they are similar to human organs, and there is virtually an unlimited supply. Pigs produce large litters in a little more than three months, and the animals mature quickly. Non-human primates such as chimpanzees and baboons are not likely to provide organs for people because they take longer to raise, and some are considered endangered. As close relatives to humans, they also harbor viruses that could easily be transmitted to people. The Food and Drug Administration - with input from the National Institutes of Health and the Centers for Disease Control and Prevention - has regulatory authority over xenotransplantation experiments. Former Gov. Tommy G. Thompson, as secretary of the Department of Health and Human Services, oversees those agencies. Thompson now has an 18-member group, the Secretary's Advisory Committee on Xenotransplantation, helping him with that responsibility. The committee had its first meeting in February. Thompson said xenotransplantation offers "tantalizing" possibilities and the potential to provide a much greater supply of organs and tissues. But there are concerns, especially the risk of transmission of infectious diseases from animals to humans, he said. "As high as some of our hopes are for xenotransplantation, this is an area where care and thoroughness are especially important," he said in a statement to the Journal Sentinel. Organs made to order Permanent transplantation of whole animal organs into humans could be three to five years away, said Cooper, of Harvard Medical School and co- author of "Xeno: The Promise of Transplanting Animal Organs into Humans." In fact, xenotransplantation could become one of the greatest medical advances of the 21st century, he said. In his book, Cooper, a longtime heart and lung transplant surgeon, describes a scenario that he says could be repeated daily at "donor centers" around the country. Surgeons arrive, scrub, enter sterile rooms and begin removing organs to order. Those organs quickly are perfused with a cold saline solution, put on ice and shipped by plane. The donor centers would not be hospitals, but rather "veterinary institutions" on farms where special pigs would be bred and raised by the thousands. "The potential benefits are absolutely immense, and it could prove to be the next great medical revolution," he writes. However, science still needs to address some issues. Even organs from humans are often quickly rejected when transplanted into other people. Organs and tissue from other people are viewed as foreign by the body's immune system, which begins to attack the organs as soon as they are transplanted. In human-to-human organ transplants, doctors are able to avoid part of the problem by selecting organs from donors who are a good match to the recipient, such as those from someone with the same blood type, and by using immune-suppressing drugs, which must be taken for the rest of the recipient's life. But there is a violent, hyperacute rejection that takes place when animal organs are transplanted into people. "It is a dramatic immune attack," Cooper said. To avoid hyperacute rejection, researchers are trying to genetically alter pigs, both by adding certain human genes and by knocking out pig genes to make the organs appear more human-like to the body's immune system. Experiments abound Infigen already has succeeded in adding a human gene to the DNA of pigs and then cloning those pigs, said Michael Bishop, president of Infigen. However, the first gene that was added was done just to prove that the concept worked. It was not a gene that would make pig organs more suitable for human transplantation. Other researchers have been able to add another human gene to pig DNA as another possible means of preventing hyperacute rejection problems. Infigen also has been able to clone embryos with a "knockout" or inactivated pig gene, a development researchers hope will lead to organs that won't be rapidly rejected by humans. Piglets with the knockout gene are expected to be born in July, Bishop said. So far, more than 40 cloned pigs, including several with the human gene added, have been born at Infigen, Bishop said. "We've got so good at cloning pigs, we had to quit," Bishop said. "We had so many of them around." More genetic tampering probably will be needed to prevent other organ rejection problems. While that research is going on, better immune-suppressing drugs are being developed. Last year, UW researchers received a $1.3 million grant to test drugs designed to prevent rejection of pig kidneys transplanted into baboons. Before pig organs are transplanted into humans, they will be tested in non-human primates such as baboons. Researchers at other universities also are testing immune-suppressing drugs that can be used in xenotransplantation. Hans Sollinger, head of the UW organ transplant program, said much work still needs to be done and scientists need to be careful not to give false hope. Nevertheless, he said, xenotransplantation "looks like the only promise we have" in addressing the imbalance between the number of human organs available and the number of people needing them - at least until, or unless, stem cell research opens up new opportunities to use human tissue. "Ultimately, we will be using animal organs to transplant to humans," Sollinger said. "It will change the face of medicine." Appeared in the Milwaukee Journal Sentinel on May 6, 2001. http://www.jsonline.com/alive/news/may01/pig06050501.asp *********** ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn