Biochemist Hungers To Win Battle Against Killer Diseases

Allan Goldstein believes the thymosins he discovered can cure immune diseases, and he hopes his company and institute will prove it WASHINGTON--Science moves too slowly for biochemist Allan Goldstein. For most of his professional life, he has been trying to unravel the mysteries of the human immune system through a better understanding of a group of hormones known as thymosins. He discovered them 26 years ago, and their use in 1974 to save the life of a five-year-old girl, along with his encouraging but inconclusive research findings, have led him to believe in their curative powers in the war against cancer, hepatitis, and other killers. Goldstein has been impatient for much of his career, however, with the type of slow, steady progress that his NIH grant would permit. In 1980 the chairman of the biochemistry department of George Washington University in Washington, D.C., took out a $100,000 bank loan and founded a small biotech company to develop and market his discovery, published in 1966 (Proceedings of the National Academy of Sciences, 56:1010-1017). And last March that company, Alpha 1 Biomedicals Inc. of Washington, D.C., received permission to become the third group in the U.S. to test a potential AIDS vaccine that has a chemical structure similar to thymosins. But Goldstein's big break came five years ago when Lynn Kamins entered his life. The daughter of a wealthy Washington, D.C., family who had just lost her mother to cancer, Kamins walked into Goldstein's office in 1985, after reading a newspaper article about him. As he listened to her questions about aging and disease, Goldstein realized that her interest might be channeled into science. For her part, Kamins was convinced by Goldstein's conviction that her money could do much to advance cutting-edge research. "He's a brilliant scientist with a lot of grand ideas," says Kamins, who subsequently donated $100,000 and raised another $80,000 to help create an Institute for Advanced Studies in Immunology & Aging, located at George Washington and directed by Goldstein. Last May, the institute was host to an international scientific symposium that featured such luminaries as NIH's Robert Gallo and Anthony Fauci and polio vaccine pioneer Jonas Salk. They talked about progress in research on AIDS-- currently the best known of the maladies that kill by attacking the body's immune system. That event symbolizes Gold-stein's approach to science. It's a combination of nose-to-the-grindstone research, sharp business sense and an eagerness to rub shoulders with scientific celebrities. In an era of growing competition for limited federal dollars for basic research, Goldstein represents a new wave of scientists who welcome support from all quarters. But while many scientists turn to industry or private foundations for backing, it's the rare researcher who establishes both his own company and research institute to pursue his science goals. "What continues to drive me is to be able to accelerate the application of the thymosins," he says. "Life is so short, I really don't want to stand on the sidelines. I really would like to use every avenue possible to take advantage of every possibility of my work." Sometimes that drive pushes him temporarily beyond the facts. Granted, he holds seven patents associated with thymosins and is the author or coauthor of more than 350 papers published in well-respected journals. But in his enthusiasm for his work, colleagues say, he may, for example, exaggerate the medical implications of a clinical study. Or Goldstein is likely to see a cure for cancer in the results of one small--though significant--preliminary study of cancer patients, says one thymosin researcher with good humor. "Goldstein is famous for being too enthusiastic when, in terms of the actual data, it's not appropriate," says Stefan Gravenstein, a geriatric immunologist studying thymosins at the University of Wisconsin, Madison. But Gravenstein admits that Goldstein's advocacy serves a purpose. Noting that recent results show that people with diseased immune systems improve when given thymosins, Gravenstein is quick to give credit where he feels it is due. "Sometimes great science gets done because people like Goldstein have great vision," he says. Because of Goldstein's persistence, and because people like Gravenstein and Kamins have shown their belief in the importance of thymosin research by supporting or working with him (at least 34 graduate students, postdocs, and visiting scientists have trained under him, many going on to study thymosins on their own), thymosins have earned a place on the biomedical map. Goldstein has built a mini-empire, consisting of his academic research, his commercial company, and his nonprofit institute. And it's the institute that he hopes will give him the chance to show the world the value of thymosins. The thymus is "the master gland of the immune system," explains Allan Goldstein. Fist-sized in infancy, the gland shrinks to the size of a quarter by old age. Thymosins are the peptide messengers the gland secretes. Thymosins circulate in the blood stream, summoning disease-fighting T cells and invigorating the immune system. As a postdoc in New York in the early 1960s in the Albert Einstein Hospital laboratory of biochemist Abe White, one of the early and influential students of the immune system, Goldstein helped isolate and characterize the thymus hormones, publishing the results in 1966 in Proceedings of the National Academy of Sciences. Today, scores of scientists around the world are investigating the physiological and pharmacological properties of these half-dozen hormones. The sale of naturally occurring thymosins extracted from the calf thymus and of synthetic thymosins is a multimillion-dollar business in Italy, France, Germany, Poland, China, and the Soviet Union. Immune-damaged patients in these countries take thymosin tablets and liquids to treat everything from cancer and arthritis to multiple sclerosis and lupus. Since 1988 almost 500 papers have been published in Europe on the use of thymosins for burns, asthma, gonorrhea, tuberculosis, influenza, diabetes, and herpes. The Food and Drug Administration has not approved their use in the U.S. for treating any disease or illness. --D.M. Companies like Hoffmann-La Roche and Bristol-Myers Co., as well as Alpha 1 Biomedicals, have also donated money to buy equipment and support graduate student and postdoc researchers for the institute, which Goldstein says runs on an annual budget of $150,000. Last year, Alpha 1 gave $80,000 to the institute, and over the past five years, 10 other companies have given from several hundred dollars to $10,000. The money supports research conducted by Goldstein and others at his George Washington labs. By 1995 he envisions an annual budget of $5 million, drawn largely from pharmaceutical companies interested in his work. He would also like a separate building with laboratories dedicated to the study of immunology and aging. Kamins, by helping to bankroll his institute, is making it possible for Goldstein to reach a broader audience--both scientific and political. Goldstein hopes that by isolating and chemically synthesizing the active ingredients of the thymus gland hormones, he and other scientists can develop drugs to fight disease by boosting the immune system. Thymosins, Goldstein believes, will cure two very different kinds of diseases: those such as cancer, which are associated with a depressed immune system, as well as the autoimmune diseases, such as arthritis, lupus, and diabetes, which are caused by an overactive immune system. "Thymosins are special sorts of compounds," says Goldstein. "They have no toxicity in any of the human or animal models, and I think there is a lot of potential to help a lot of people." His belief in the therapeutic powers of thymosins has its roots in his intervention to save the life of a little girl from California. In 1974, Heather, age 5, was dying because her thymus gland would not produce white blood cells to fight off infections. Her doctors, Goldstein says, begged him for a supply of thymosin. In those days the only source was an unpurified form of the hormone, extracted directly from the thymus of a calf. It had never been tested in anything but a test tube. But in these first rough in vitro experiments, it restored the girl's missing T cells, the white blood cells that are keys to the immune system. So Goldstein rushed to get Food and Drug Administration approval and took a chance. "It probably was too early," he admits in hindsight about her treatment, which was published a year later in the New England Journal of Medicine (292:70-74, Jan. 9, 1975). "But this child was going to die, and I made the decision to do it." Eventually, Heather outgrew her need for thymosins and is now a healthy young adult. Today, Goldstein consults with 150 labs across the country that study thymosins. He says that the studies of their use with Hepatitis B, with neck cancer, and with the influenza virus look especially promising. And though the FDA has yet to okay their use in the U.S., thymus gland hormones, either chemically synthesized or extracted from animals, are used to treat various afflictions in other countries (see accompanying story). Research has been slower in the U.S. than in other countries, according to Paul Chretien, director of medical affairs for Alpha 1 Biomedicals, in part because of greater interest here in interleukins and interferons for fighting immune disorders and in part because scientists have tended to question Goldstein's work. "Allan has been faced with keeping a scientific and clinical program alive when there was no general acceptance by the scientific community. For a while pharmaceutical firms [supporting his work] and labs lost interest," Chretien says. But those attitudes are changing, says Chretien, who has published his own studies on thymosins and neck cancer treatment and who has worked with Goldstein for the past quarter century. "Now [Goldstein and his colleagues] are developing a scientific body of information that shows thymic hormones alter levels of interleukins and interferons," he says. "There is emerging a diminution of the skepticism." Researchers like Jack Battisto, an immunologist at the Cleveland Clinic Foundation, say more patient trials are needed to learn if synthetic thymosins can actually cure disease. Moreover, the clinical research also faces criticism by those who question the basic science behind the research. "What these things [thymosins] do is unclear," Battisto says. "I get too many questions I can't answer, like `Is it really a hormone?' or `What are its receptors?' " says William Ershler, a geriatric immunologist at the University of Wisconsin School of Medicine who is running his own clinical study of thymosins. "I've been pretty discouraged by the reception in the scientific community." Though Ershler and his colleagues would also like to know more about the thymus peptide, they are enthusiastic about the clinical results. Using a drug provided by Goldstein's company, Wisconsin's Gravenstein has recently been able to strengthen the immune systems of older people, enhancing their response to the flu vaccine. The National Cancer Institute voiced its doubts last year when it did not renew Goldstein's research grant after 12 years of support. Many of Goldstein's scientific goals "suffer severely from lack of focus and poorly detailed methodology," noted the NIH panel that reviewed his grant proposal. "The most disturbing aspects of this application are the rather vague aims of studying tissue and serum levels of these peptides in health and disease." Goldstein disagrees that his research needs to be more focused. "My work is nonconventional and interdisciplinary," he says. "It includes the immune deficiency of the newborn, the immune system and the brain, hepatitis, cancer and the immune system. Thymosins tie all these together, but it's hard to find funding for something so broad." Nor does Goldstein intend to slow down because of such criticism. "I've gotten a lot of flak for making too many promises and just looking at the potential," he says. "I think you have to have someone who is willing to champion a truly creative but risky idea for it to succeed." Chretien believes that, because of his enthusiasm, Goldstein "may have overextended himself scientifically." But, he adds, "if Allan Goldstein had not formed his company and institute and if he hadn't supported other people's ideas, [thymosin research] would have died. Thymosins were an incredibly important discovery, and one day a lot of lives will be saved." Meanwhile, Lynn Kamins says that she gives the institute her money--and up to 60 hours a week of her time--because she wants to "help Dr. Goldstein's dream." Whether he has a "dream" or a "messianic mission," as one colleague calls it, Goldstein is out to continue his research with whatever backing he can find.

Biochemist Hungers To Win Battle Against Killer Diseases

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