Notebook

WHAT FOLLOWS TAMOXIFEN? Warnings accompanied recent announcements from the University of Pittsburgh-based National Surgical Adjuvant Breast and Bowel Project and the National Cancer Institute in Bethesda, Md., that tamoxifen achieved a 45 percent reduction in the incidence of breast cancer compared to women who took a placebo in the Breast Cancer Prevention Trial. The 25-year-old drug still carries the risk of serious side effects for women over 50, officials said. But the overall results were a scientific boon, and the question now is, what safer compounds might follow? Genentech Inc. of South San Francisco is among several biotechnology firms working on ways to kill tumors by starving them of blood. Genentech's Dan Adelman is the lead clinician on Phase 2 clinical trials of anti-VEGF, a monoclonal antibody to block receptor binding of vascular endothelial growth factor (VEGF), which stimulates blood vessel development that can feed growing malignancies. Adelman is quick to point out, "Our compound is not intended for prevention." However, he also wonders whether the six-year tamoxifen study involving 13,388 women actually established prevention. He notes that it can take a decade for a tumor to grow to a detectable size of about one centimeter in diameter. "How many of those women already had cancers when they started this study?" he asks. "Did the tamoxifen really prevent tumors, or just slow their growth?" In any case, he cautions, anti-VEGF is still far from proving its efficacy. He will present Phase 1 trial findings during the American Society of Clinical Oncology's annual meeting, May 16-19 at the Los Angeles Convention Center. MORE ON TAMOXIFEN Choosing the most effective means to combat cancer is often a process of trial and error, in which patients who fail to respond to initial treatments receive increasingly aggressive therapy. But with a new PET (positron-emission tomography) technique developed by researchers at the Washington University Medical School in St. Louis, researchers now say they can predict whether antihormonal drugs such as tamoxifen will work in an individual with breast cancer. Generally the first course of treatment for breast cancer, tamoxifen shrinks tumors by blocking estrogen receptors on the surface of some cancer cells. However, about one-third of all breast cancers do not bear estrogen receptors, and so do not respond to tamoxifen. If oncologists knew they were dealing with such a tumor, they could immediately prescribe chemotherapeutic drugs instead of spending weeks to months on ineffective tamoxifen treatment. Thus, chemist Michael Welch and coworkers devised a tamoxifen litmus test for tumors by tagging estradiol, a natural form of estrogen with fluorine-18, a short-lived radioisotope that can be visualized using PET. More than 20 breast cancer patients received injections of the radiotracer prior to treatment with tamoxifen. Only those patients whose tumors bound the labeled estradiol--as indicated by PET scans--responded to the antiestrogen drug, Welch reported at the late March meeting of the American Chemical Society in Dallas. Kenneth Fischbeck NEUROGENETICS BRANCH AT NINDS After a year-long search, Kenneth Fischbeck, a professor of neurology at the University of Pennsylvania School of Medicine, has been named chief of the new Neurogenetics Branch at the National Institute of Neurological Disorders and Stroke (NINDS). The branch is the 12th at NINDS and the first created by the institute since 1991. Its budget could eventually total the $3 million to $5 million spent by similar branches at the institute, according to Scientific Director Story Landis. Fischbeck, who will hold a joint appointment at the National Human Genome Research Institute, implicated the connexin32 gene in the demyelinating neuropathy Charcot-Marie-Tooth disease (J. Bergoffen et al., Science, 262:2039-42, 1993). He also discovered that trinucleotide-repeat expansion, encoding multiple glutamines, caused the motor-neuron disorder Kennedy's disease (A.R. La Spada et al., Nature, 352:77-9, 1991); a similar genetic abnormality was later found to underlie several neurologic diseases, including Huntington's. While intending to perform some gene searches at NINDS, Fischbeck says research on hereditary neuromuscular and neurodegenerative diseases "has gone beyond gene discovery to working out disease mechanisms, using cell culture and animal models, and to gene therapy." He plans to recruit two junior faculty members and to start a clinical program for diagnosis and treatment. Landis says that, besides creating the Neurogenetics Branch, NINDS is "going to rebuild a new neuroimaging branch from the ground up." Fischbeck's appointment, incidentally, should not be confused with the consideration of Gerald Fischbach, chairman of the neurobiology department at Harvard Medical School, to become director of NINDS. NATURE FIGHTING AIDS Long a source of anticancer drugs, natural products derived from plants and aquatic organisms are now showing promise in combating AIDS, according to a National Cancer Institute researcher. In a presentation at the Dallas meeting of the American Chemical Society in late March, Michael Boyd, Chief of NCI's Laboratory of Drug Discovery, described several promising compounds that prevent live HIV virus from infecting and killing human cells, discovered through a screen of more than 80,000 plant and animal extracts over the past decade. Their "finds" include calanolide-A, a reverse transcriptase inhibitor from Calophyllum lanigerum, a Malaysian tree. Currently in clinical studies, the compound appears to be active against several drug-resistant HIV strains. From the blue-green algae Nostoc ellipsosporum, NCI researchers have isolated an unusually stable protein, called cyanovirin-N, which binds gp120, a viral coat protein that is also displayed on the outer surfaces of HIV-infected cells. Cyanovirin-N is being studied for use in topical medications to prevent HIV infection. Aquatic organisms have yielded several other HIV-inhibiting proteins and peptides which, although unlikely drug candidates, may help researchers find new strategies for attacking HIV, Boyd said. The NCI team's discoveries "clearly demonstrate the value of using a natural products approach to finding anti-HIV drugs," said organic chemist David Kingston of the Virginia Polytechnic Institute and State University in Blacksburg. Kingston, who has himself identified several promising antifungal and anticancer compounds in plants from the Suriname rain forest, said he is encouraged by the discovery of calanolide-A, one of the first examples of natural products to show clinical promise against HIV. Also, he added, "I like the idea of using cyanovirin-N as a biocide [to prevent HIV infection], because [unlike condoms] its use could be controlled by women." GROWN MONKEYS GROW NEURONS The dogma that adult brains don't sprout new nerve cells crumbled over the past decade as researchers detected neurogenesis in grown-up birds, rats, and other animals. Now monkeys can be added to that list (E. Gould et al., Proceedings of the National Academy of Sciences, 95:3168-71, 1998), increasing the odds that the human brain also generates new neurons--a potential boon for treating strokes and Alzheimer's disease. In the monkey study, Elizabeth Gould, an assistant professor of psychology at Princeton University, and colleagues injected three-year-old marmosets with a DNA-base analog incorporated only into dividing cells. After three weeks, the analog was present in the hippocampus, a brain region linked to learning and memory. Labeled cells resembled granule neurons and expressed a neuronal marker. When animals were stressed by being caged with unfamiliar monkeys, the number of labeled hippocampal cells dropped significantly. Gould is now seeking neurogenesis in Old World monkeys, which are closer relatives to Homo sapiens than marmosets are. "We're also interested in determining the function of these new neurons, a much trickier issue than just looking to see if neurogenesis happens," she says. One difficulty, notes Ronald McKay, chief of the laboratory of molecular biology at the National Institute of Neurological Disorders and Stroke, is that "the precursor cells giving rise to these neurons have not been identified." McKay has transplanted various precursors from one brain region to another, where they developed into neurons characteristic of their new homes. Transplants may become the therapy of choice since most of the adult brain, including the cerebral cortex, still shows no evidence of neurogenesis. Photo: Robert Neroni NEW WRINKLE: Jefferson's Jouni Uitto developed a model to study photoaging of skin. PROTECTION EXTENSION In a 4-2 vote, the Supreme Court of New Jersey on March 26 upheld a lower court ruling that effectively provides international protection of whistleblowers in the state from retaliation by employers. The court ruled that under New Jersey's Conscientious Employee Protection Act (CEPA), Myron A. Mehlman, a former toxicologist at Fairfax, Va.-based Mobil Corp., was protected from company retaliation for protesting levels of benzene in gasoline at a Japanese subsidiary of the company. Under CEPA, an employer may not take retaliatory action against an employee who objects to or protests a practice or policy of the company that is believed to be contrary to mandates concerning the public health, safety, or welfare of the environment. In 1989, Mehlman advised a subsidiary of Mobil in Japan to stop manufacturing and selling gasoline containing hazardous levels of benzene, a carcinogen (T.W. Durso, The Scientist, 10(17):1, September 2, 1996), Mehlman was fired almost immediately upon returning to his laboratory in Hopewell, N.J. Mobil alleged that he misused company resources for his private publishing company, Princeton Scientific Publishing Co. Inc. In 1994, Mehlman sued the company under CEPA and was awarded $7 million in compensatory and punitive damages by a jury for wrongful dismissal. However, the judge presiding over the case was reluctant to extend CEPA beyond the boundaries of New Jersey and threw out compensatory damages. In the decision to uphold the original award, Justice Gary S. Stein wrote, "A cause of action under CEPA exists for a New Jersey employee whose employer retaliated against him for objecting to the violation of a clear mandate of public policy that threatens to harm citizens of other states or countries. . . ." Mehlman, now an adjunct professor at Robert Wood Johnson Medical School in Piscataway, N.J., says the court's decision sends a strong ethical message to scientists: "It affirms that as a researcher I can be concerned about the welfare of citizens around the world and not fear retaliation. After all, people are the same everywhere and a carcinogen in the U.S. is a carcinogen in Japan or anywhere else." YOUNG SCIENTIST: Emily Rosa's fourth-grade science fair project--a simple test of the assumptions behind touch therapy--ended up in the pages of JAMA. JUNIOR SKEPTIC A science fair project turned into a media sensation after Emily Rosa, then a fourth-grade student from Loveland, Colo., designed and conducted an experiment to test touch therapy. Touch therapy practitioners say they can heal a variety of symptoms by realigning energy fields surrounding a patient's body without touching the patient. Emily became curious about the practice after watching a nursing training tape that Linda Rosa, Emily's mother and co-author, had playing. Emily wanted to know if the practice really worked, her mother said. After her mother told her that measurability was one key to scientific study, Emily devised a test where a barrier separated her from the practitioner. The touch therapy practitioner should theoretically be able to detect which hand the tester places near her hand, Emily reasoned. Linda recruited the 21 touch therapy practitioners for the study. "I explained that my daughter had a fourth-grade science fair project." Her mother reports that Emily thinks the practitioners complied because of Emily's age; however, "They didn't take her seriously because she was a kid." The practitioners identified the correct hand in 123 of 280 trials, a 44 percent success rate --worse than chance (L. Rosa, et al., JAMA - The Journal of the American Medical Association, 279:1005-10, April 1998). After the article was published, the Rosas were featured on network television news, CNN, "The Today Show," and in People magazine, says Stephen Barrett, chairman of the Allentown, Pa.-based Quackwatch Inc. and the study's senior author. Barrett hopes the media attention makes people reconsider undergoing touch therapy, which he says is widely practiced by nurses in holistic medicine. More information on the study can be found at the Quackwatch website: http://www.quackwatch.com. CAT AND MOUSE MODEL HUMAN SKIN AGING Transgenic mice model many types of human disease, and now a new variety is being used to evaluate photoaging of skin. Jouni Uitto, professor and chairman of the department of dermatology and cutaneous biology at Jefferson Medical College in Philadelphia, and Eric Bernstein, an associate professor in the department, have developed mice that are transgenic for the promoter for the human elastin gene. Elastin is the protein that accumulates and redistributes in aging, sun-exposed skin to cause yellowish wrinkles and sags. The promoter, instead of being attached to the elastin gene, is hooked up to a "reporter" gene that produces a detectable enzyme called CAT (chloramphenicol acetyltransferase). When exposed to light, the promoter turns on and produces CAT. "We find that the elastin promoter is activated tremendously by UVB [ultraviolet-B] and to a lesser extent by UVA [ultraviolet-A], but nevertheless, UVA does activate it," says Uitto. This information is important to manufacturers of sunscreens that predominantly shield against UVB. Reformulation to widen protection to UVA wavelengths may be necessary. "We can use this model to rank or rapidly screen sunscreens for efficacy," he adds. The transgenic photoaging mouse is a great improvement over that standard approach, hairless mice mutants that must be monitored for up to a year after UV exposure. "We look at just promoter activation, and it takes a single UV exposure. We can look at the response within 24 hours," Uitto notes.

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