Fetal Tissue Implanted in Experiment to Treat Diabetes

Scientists in Denver have transplanted pancreas tissue from aborted human fetuses into three diabetics within the last year, marking the first time in this country that fetal tissue has been used to treat an illness.

The trials are designed to test a highly experimental treatment for the most serious form of diabetes, which generally appears before the 20th birthday. If they work, more than a million people may reap dramatic benefits. The only established treatment tends to delay, rather than defeat, the disease’s often-deadly effects.

The researchers acknowledge that the work is in the preliminary stages. In Australia, eight of nine similar human trials conducted during the last two years have failed.

Despite these disappointing results, several diabetes researchers say, the research should continue because the fetal pancreas has inherent advantages over adult pancreas tissue, which is also being transplanted. Some scientists, including one at UCLA who helped pioneer the fetal transplant technique in rats, have suggested, however, that the human trials are premature.

The human trials will probably generate controversy, coming as they do at a time when there are no federal guidelines covering the handling and use of tissue obtained from aborted fetuses. Also, the research is partly financed by a company that plans to market cultured human fetal pancreas as a diabetes treatment.

‘Ticking Time Bomb’

“The retrieval of tissues from abortuses (aborted fetuses) is a whole ticking time bomb,” said Arthur Caplan, associate director of the Hastings Center Institute of Society, Ethics and the Life Sciences in New York. “There are a lot of people who are just crazed at the thought of using abortuses for anything.”

Diabetes, which is actually several diseases, is the third-leading cause of death in the United States and causes 25% of all kidney failure, 15% of all blindness and is the second-most-common cause of limb amputations, after accidents, according to statistics provided by the the National Institutes of Health.

Although so-called juvenile-onset, or insulin-dependent, diabetes accounts for only 10% to 15% of all cases, its symptoms are especially severe. The pancreas fails to produce adequate insulin, a hormone that controls the metabolism of blood sugar, thus leaving the daily ebb and flow of sugar in the blood unregulated.

(In adult-onset diabetes, which is the most common form and is more easily controlled, adequate insulin is produced, but its effect is somehow blocked.)

The possibility of using pancreas transplants to treat insulin-dependent diabetes has tantalized researchers for almost two decades. The only treatment until now has been daily, carefully timed injections of insulin, which often fail to stem the development of kidney damage and the other side effects.

Two Organs in One

The pancreas, the shape and size of a filet of sole, is two organs in one. The main mass of tissue produces digestive enzymes that drain into the intestine. Clusters of cells called islets of Langerhans, scattered throughout the pancreas, produce and regulate insulin, which flows into the blood.

Various transplant techniques have been tried; none has left the experimental stage.

Even with the advent of the powerful anti-rejection drug cyclosporine, transplantation of the intact adult pancreas has generally ended with rejection by the recipient’s immune system. It is almost impossible to clear the organ of certain white blood cells, called passenger leukocytes, that are especially prone to triggering rejection.

Transplantation of islets that have been isolated from an adult pancreas is a promising, but extremely difficult, technique. The islets comprise only 2% of the adult organ and must go through a complex cleansing process to remove vestiges of the other tissue and reduce the risk of rejection. The first human trials of this method occurred this year, with mixed results.

In 1973, Josiah Brown, an endocrinologist at UCLA, realized that the pancreas of a fetus might make the ideal transplant.

(Brown was interviewed for this article; UCLA announced that he died Aug. 30 while traveling in Brazil.)

Capacity for Growth

Brown had noticed that at a certain stage of development--in humans, around the 16th week of gestation--only the all-important islet cells have developed. If the pancreas is removed from the fetus at that point, the tissue contains just the islet cells. No separation of extraneous tissue is needed. Fetal tissue also has great capacity for growth, and its small size (about the dimensions of an aspirin tablet) makes it easy to store and maintain in the laboratory.

Through a decade of work, Brown and research immunologist Yoko Mullen were able to reverse diabetes in rats. The key to reducing the threat of rejection, according to Mullen, is to culture the fetal cells under special conditions that kill off any passenger leukocytes.

Other researchers followed their lead, including Kevin Lafferty, an Australian immunologist.

Lafferty moved to Denver two years ago to become research director at the Barbara Davis Center for Childhood Diabetes of the University of Colorado Health Sciences Center, where he is overseeing the human trials of the technique. Five human transplants have been approved by the human subjects committee at the university.

Two groups in Australia have performed nine human fetal pancreas transplants in the last two years. Although in several cases the tissue survived, only one transplant showed some insulin production, said Thomas Mandel, director of transplantation at Royal Melbourne Hospital, in a telephone interview.

The human transplants and related research projects at the Barbara Davis Center are taking place under a joint research agreement with Hana Biologics Inc., a Berkeley-based company that specializes in materials and methods for culturing cells in the laboratory. Lafferty is a company consultant and shareholder, said Hana Biologics’ president, Robert Berkowitz.

Lafferty, reached for comment in Australia, where he is traveling, said his finances are “a private matter.”

The goal, according to Berkowitz, is to refine the transplant technique and to develop ways to culture large amounts of insulin-producing cells from a small amount of human fetal pancreas. Available in the “equivalent of a pharmaceutical dosage,” cultured fetal pancreas would do away with the chronic shortages that are typical of other types of transplants, he said.

Obtained Through Nonprofit Group

The human fetal pancreases are obtained through the National Diabetes Research Interchange, a 5-year-old nonprofit organization based in Philadelphia that retrieves human tissue for scientific research, including kidneys that are not suitable for transplants but that can be used in research, placentas, “waste tissue” from surgery and tissue from aborted fetuses.

“We get some from hospitals, we get some from various medical clinics . . . throughout the country,” said Louise Bridges, a spokeswoman for the organization. “There’s always signed consent.”

Recent debate on the rights of the unborn in the United States has left unresolved the question of when the fetus has developed into a person whose interests cannot be represented by a consent form.

“In terms of ethical and legal considerations, I would think it reasonable to regard this procedure as dubious,” said Clifford Grobstein, professor of biological science and public policy at University of California, San Diego. “It has been argued that if the mother is going to get an abortion, there is a question as to whether or not she has the best interests of the fetus in mind.”

“It’s not as if we go out seeking abortions,” said Stephen Prowse, who also moved to the Barbara Davis Center from Australia and is an assistant professor of microbiology and immunology. “They’re going to occur whether we’re able to use the tissue or not. All we get is the tissue. We don’t know who they come from or anything about the donor.”

Although the research in Denver has not been widely publicized, the human trials in Australia provoked a strong reaction.

Because of public pressure, Mandel said, his group in Melbourne stopped using pancreas tissue from induced abortions after the third human transplant and now uses pancreases from spontaneously aborted fetuses past their 20th week of development. Under Australian law, such tissue is treated as any other donated adult organ.

The last formal inquiry into the use of tissue from dead fetuses in research took place in 1974, when the National Commission for the Protection of Human Subjects touched on the subject. According to LeRoy Walters, who was a consultant to that group and is currently director of the Center for Bioethics at Georgetown University, the commission concluded that this tissue should not be treated differently from other “pathological specimens” and is a matter for the states to regulate.

‘Kind of Netherworld’

Federal regulations on fetal research apply only to the living fetus, according to Caplan at the Hastings Center. “The NIH and other organizations technically have very little to say. If it comes from the dead, then you’re off in a funny kind of netherworld where there’s almost no regulation.”

Mullen at UCLA and other diabetes researchers agree with the Denver group that tissue from dead fetuses should not be treated differently from tissue taken from other organ donors.

Mullen said she is more concerned with the pace of Lafferty’s research. She said data from recent studies of animals that are more complex than rats indicate that more basic research is needed.

The UCLA scientist said transplants and analysis of the fetal pancreases of hybrid pigs, which are very similar in metabolism and physiology to humans, suggest that the early successes with rodents will not be repeated soon. Studies of the islets in pig and human pancreases show that these cell clusters are riddled with passenger leukocytes and that rat islets have very few of these rejection-inducing cells.

Trails Called Premature

Similarly, Olga Jonasson, chief of surgery at the Cook County Hospital in Chicago and chairman of the National Task Force on Organ Transplantation, a 21-member group convened last January by the Department of Health and Human Services, said it is her belief that it is premature to start human trials of the fetal technique.

Jonasson has worked for years with diabetic monkeys and collaborated with Lafferty when using monkey fetal pancreases, with little success.

“I happen to believe it’s got a lot of potential,” she said. “But there have really not been any successful large-animal studies.” Lafferty said the human experiments are “phase one” trials, in adult diabetics who were already scheduled to have kidney transplants. “The only questions we’re trying to answer at this stage are: Does the tissue function? How much needs to be transplanted? Where should it be transplanted? . . these sorts of things,” he said.