Notebook

Table of Contents Fisher Case Is Settled Loaded Questions Malaria Immunity Scientific Immigration Slips Terminating Telomerase Getting Tough With E.Coli Hospitable Merger `No Confidence' Vote For Confide Mendel's Mighty Midgets Bullish on Cloning Research 'A VICTORY': Bernard Fisher accepted a favorable settlement in a long-running dispute with the government and the University of Pittsburgh. Showered with praise, apology, and a financial settlement, cancer surgeon Bernard Fisher has triumphed in a three-year struggle to defend his reputation. In 1994, the University of Pittsburgh acceded to demands by the National Cancer Institute (NCI) to remove Fisher after 27 years as chairman and principal investigator of the federally funded National Surgical Adjuvant Breast and Bowel Project (NSABP). Earlier, Fisher had told NCI that an NSABP investigator in Canada had falsified records of women in a study. The Office of Research Integrity later filed charges of scientific misconduct against Fisher. He responded by initiating a lawsuit against the government and the university, which was due for court on September 2 (S. Benowitz, The Scientist, March 31, 1997, page 1). Among the terms of the settlement, announced August 27, was $300,000 from the government toward legal fees and a statement of Fisher's scientific contributions that extols him as "a dominant force in the study of breast cancer for the last 40 years." The university, which issued a statement of "sincere regret," has not disclosed financial settlement details. "This reaffirms the fact that we had no wrongdoing at any time, in any way," says Fisher, currently scientific director of the NSABP and distinguished service professor in the University of Pittsburgh School of Medicine's surgery department. "I would look upon this as a victory for scientists, not just for me." Clinical trials and statistical analyses are needed to answer questions concerning the therapeutic utility of smoked marijuana, concluded a panel of eight scientists after sifting through evidence presented last February at a National Institutes of Health workshop. "To the extent that the NIH can facilitate the development of a scientifically rigorous and relevant database, the NIH should do so," the group recommended in a report released August 8. Paul Armentano, director of publications at Washington, D.C.-based National Organization for the Reform of Marijuana Laws (NORML), praises the panel's declarations that marijuana should not be held to more stringent Food and Drug Administration approval standards than other drugs, and that inhaling the smoke might be acceptable therapy for some patients. The most likely uses are for appetite stimulation, movement disorders, analgesia, and glaucoma, the report said. NORML remains wary of a federal government that has not supplied marijuana for research on its therapeutic effects in recent years, even though 34 states now have legislation permitting such studies (P. Gwynne, The Scientist, Nov. 27, 1995, page 1; P. Gwynne, The Scientist, March 31, 1997, page 1). Armentano says Massachusetts and Washington's state governments have been waiting all year for a National Institute on Drug Abuse response to their marijuana research protocols. "I think the workshop panel was sincere about wanting scientists to address these questions," he adds, "and not politicians." NIH is studying the report. The worldwide fight against malaria may have a powerful new weapon-a vaccine that can create a lifelong "immunologic memory" in animals against the human parasite Plasmodium falciparum. One injection into immune system cells of an engineered plasmid DNA induces antibodies in mice, researchers at the Medical Center of the University of California, San Diego, have shown. Their results, published this month in two companion pieces (S. Xiong et al., Nature Biotechnology, 15 :876-81, 882-6, 1997), demonstrate that engineered DNA prompts the modified immune system cells to replicate the pathogen, without actually causing infection. This "replicating phenomenon" can be recalled throughout the mouse's life, says senior author Maurizio Zanetti, a professor of medicine at UC-San Diego School of Medicine. However, he cautions, "I don't foresee any work of a clinical nature within the next three years." And the new method has been tested on only one of four human malarial parasites. "No one could make a vaccine that would work for every species of malaria," he notes. Nevertheless, he thinks the new technique, dubbed "somatic transgene immunization," also might be useful in developing vaccines against HIV or against diseases for which an infectious component is not immediately evident, such as cancer. His team already has begun research in those areas. Recently released data compiled from Immigration and Naturalization Service reports show a 26 percent decline in the number of immigrants employed as scientists and engineers in the United States. The number dropped from 23,534 in 1993 to 17,403 in 1994, according to a "data brief" from the National Science Foundation. The decline ends a brief boom in immigration from 1990- 93 and marks a return to stable 1980s levels. "We have seen this decline because the full effect of certain reforms has been reached," Joanne Streeter, a survey operations specialist at NSF, explains. "There was a boom because under the 1990 Immigration Act and the 1992 Chinese Student Protection Act many aliens readjusted their status here." The 1990 act allowed for highly skilled and educated workers to enter the U.S. on permanent visas if labor-certified. The 1992 act was passed in the wake of the Tiananmen Square incident and allowed Chinese students to adjust their status to permanent resident. Barry R. Chiswick, a professor of economics at the University of Illinois at Chicago, argues that the decline really shows that the 1990 act did little to stimulate immigration. "Overall, there has been a continuing strong demand for science professionals." Chiswick says. "The return to 1980s levels could show that labor certification has had almost no effect in increasing the attractiveness of immigrants to employers. The policy puts a mountain of paperwork between the company and the foreign scientist." Photo: Donna Coveney/MIT CANCER DRUGS: Robert Weinberg of the Whitehead Institute hopes that the anti-telomerase drugs of the future will help impede the proliferation of cancerous cells. Two teams of scientists may have found a new target for cancer drug design. Groups led by Nobel laureate Thomas Cech, a professor of chemistry and biochemistry at the University Colorado Boulder and a Howard Hughes Medical Institute investigator (T. Nakamura et al., Science, 277 :955-9, 1997), and Robert A. Weinberg, a member of the Whitehead Institute for Biomedical Research and a professor of biology at the Massachusetts Institute of Technology (M. Meyerson et al., Cell, 90 :785-95, 1997), independently converged on the same discovery: a gene called hEST2 (human ever shorter telomerase 2), the catalytic subunit of human telomerase. The telomerase molecule helps maintain the ends of chromosomes in reproductive cells and certain immature progenitor cells by replacing the DNA that chromosomes lose each time a cell divides. Most mature cells lack the telomerase enzyme, and as a result, their telomeres-the ends of their chromosomes-grow shorter with each round of cell division. Eventually the shortening process reaches a critical stage, the chromosomes become unstable, and any further cell division leads to cell death. By contrast, continued telomerase activity allows cancerous cells to divide indefinitely. "In principle, if one were able to inhibit that enzyme [telomerase], one might deprive cancer cells of their immortal growth," says Weinberg. And scientists may have a bit of a head start in finding a drug that could do just that: The three known catalytic subunits of telomerase belong to the same family of molecules as the reverse transcriptase enzyme produced by the HIV virus. "It's plausible that inhibitors of reverse transcriptases [drugs such as AZT] . . . might also act to inhibit telomerase," explains Weinberg. Yale University researchers have scored a victory in the ongoing war between disease and medicine by successfully restored antibiotic sensitivity to resistant strains of E. coli bacteria (C. Guerrier-Takada et al., Proceedings of the National Academy of Sciences, 94 :8468-72, 1997). The team, which was led by Nobel laureate and biology professor Sidney Altman, included senior researcher Cecilia Guerrier-Takada and postdoctoral fellow Reza Salavati. The researchers delivered RNA nucleotides called external guide sequences (EGS) into the bacteria. Once inside, the EGS attached to and destroyed messenger RNA associated with drug-resistant traits. The EGS technique of overcoming drug resistance could prove to be more cost-effective than the development of new antibiotics, according to Altman. "Our method is much more economical both in terms of time for designing a new antibiotic and dollars for initial lab testing than are most 'classical' approaches to antibiotic development," he says. Innovir Laboratories Inc. hopes to take the research to the marketplace. The New York company is developing EGS molecules that target hepatitis B, hepatitis C, and psoriasis viruses. So far, EGS has been effective against hepatitis B in animal experiments at company laboratories. Altman's breakthrough comes at a time when the problem of drug-resistant diseases like strep throat and tuberculosis is increasing, according to Stephen Heyse, a bacteria specialist at the National Center for Infectious Diseases. In an age of hostile takeovers and unholy divorce, two of America's largest medical organizations have proved that reunion and reconciliation indeed exist. The Philadelphia-based American College of Physicians (ACP) and the American Society for Internal Medicine (ASIM) in Washington, D.C., agreed in August to a merger. Merger discussions between ACP and ASIM began two years at the bidding of rank-and-file membership who saw the overlapping efforts of each organization, according to Harold J. Fallon, chairman of the board of regents of ACP. "Over the years, the missions of the ACP and ASIM grew closer together," Fallon explains. "Two-thirds of the members of the ASIM also held membership in the ACP. So, the time seemed right to strengthen and widen the scope of each organization through the merger." ASIM was founded 41 years ago when a group splintered from ACP to form an internal medicine organization devoted to social, economic, and political issues. "Twenty-five years ago I was a member of the ASIM," Fallon says. "Their strength was practical and political issues and the ACP focused on the education of the postgraduate internist. The merger brings the two together into a single, powerful voice for internal medicine." The proposed merger will be submitted to a final vote by the governing bodies of each organization this fall. If approved, the merged ACP-ASIM will be headquartered in Philadelphia and maintain offices in Washington, D.C. Johnson and Johnson has pulled the plugs on its home HIV test, Confide. Toll-free hot lines fell silent August 29 as the company ended its test result and counseling services. The New Brunswick, N.J.-based health care products manufacturer cited low consumer interest for its decision to end production of Confide in June. The Home Access Health Corp.'s HIV-1 Test System now stands alone in the "telemedicine" HIV-test market. Richard A. Quattrocchi, president of Hoffman Estates, Ill.-based Home Access, surmises that other corporations now may attempt to enter the growing home diagnostics market. Revenues in home diagnostics have increased to $1.07 billion in 1995 from $746.8 million in 1992, according to Frost and Sullivan Consulting, a Mountain View, Calif.-based market analysis firm. But Quattrocchi warns speculators who might want to stake a claim, "Telemedicine is not like manufacturing. You need expertise in medicine, telephony, computers, laboratories, customer service, client service, and counseling. Knowing how to put a bandage in a box is not a enough to make it." DYNAMITE DWARFS: Oregon State University's Bill Proebsting helped clone the gene responsible for dwarfism in pea plants. Researchers recently put the finishing touches on one of the most famous experiments in the history of genetics. In a recent paper (D.N. Martin et al., Proceedings of the National Academy of Sciences, 94 :8907-11, 1997), Bill Proebsting and David Martin, professors of horticulture at the Oregon State University Agriculture Experiment Station, and Peter Hedden, a professor of agriculture at the University of Bristol, announced the cloning of the gene responsible for dwarfism in pea plants, one of the seven plant traits Gregor Mendel studied in his revolutionary experiments more than 130 years ago. First described by Mendel as the Le, or length, locus, the dwarfism gene controls the final step in the production of gibberellins, plant hormones that control not only stem height, but also seed dormancy, seed germination, photoperiod responses, and flowering. The researchers attributed dwarfed plants' lack of gibberellin production and resulting stunted growth to a single genetic mutation not found in tall plants. Proebsting terms the discovery "the most recent event in the evolution of knowledge about the gene that [Mendel] worked with." He also suggests that the findings may have more practical implications.Because dwarfed plants produce more seed or fruit and less stem than tall plants and because they remain upright, allowing for easier harvest, dwarfed plants are considered more productive than tall ones. According to Martin, the isolation of the dwarfism gene will enable genetic engineers "to genetically alter its effects in order to reduce gibberellin and produce a smaller plant." In an announcement reminiscent of Jane Smiley's 1995 novel Moo (New York, Fawcett Columbine), researchers at DeForest, Wis.-based ABS Global Inc. announced last month that they had cloned a bull calf from a single cell grown in a lab. The calf, named Gene, was born February 6. ABS simultaneously announced the formation of a subsidiary, Infigen Inc., to commercialize applications of cloning technologies in cattle breeding, xenotransplantation, and the pharmaceutical and nutraceutical industries.

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September 1997

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