Notebook

OLD NEWS REBORN TRANS-ATLANTIC MEDITATION AIDS HONORS FROM THE FRYING PAN TO THE PHARMACY CHEMIST HONORED BRAIN-PROTECTING DRUGS OLD NEWS REBORN The wild spike in the stock price earlier this month of Rockville, Md.-based biotechnology company EntreMed Inc. was sparked by a few remarks over dinner, says the company's chairman, John Holaday. The comments came from Nobel laureate James Watson, director of the Cold Spring Harbor Laboratory on Long Island, N.Y. He was praising the work of M. Judah Folkman and colleagues at Children's Hospital in Boston, whose research has shown that protein inhibitors of angiogenesis, or blood vessel growth, cause a variety of tumors in mice to regress (H. Black, The Scientist, 12[9]:10, April 27, 1998). A New York Times reporter heard Watson's words and quoted him in a subsequent article as saying, "Judah is going to cure cancer in two years." EntreMed, which is developing the therapy in partnership with Bristol-Meyers Squibb Co. of New York City, responded to the resulting media flurry about a cancer "cure" by issuing a statement that both its antiangiogenesis proteins in preclinical trials, angiostatin and endostatin, are unlikely to enter clinical testing for 12 to 18 months. "We were amazingly surprised by the reaction to the Times article, particularly because this was old news," Holaday says. Indeed, Folkman's research was published late last year (T. Boehm et al., Nature, 390:404-7, 1997). "We've never given the drugs to people yet and we don't know what the potential dosages are, or what the possible toxicities are," Holaday notes. He predicts that the company's current work with thalidomide will place it among the "first wave" of angiogenesis inhibitors to hit the market, followed by the proteins. ETHICIST TRIUMPHANT: Penn bioethicist Glenn McGee is the top candidate among 900 applicants for the British government's prestigious Commonwealth FoundationAtlantic Fellowship. TRANS-ATLANTIC MEDITATION Glenn McGee, associate director for education at the Center for Bioethics at the University of Pennsylvania, may not have earned knighthood. But his selection as the top candidate among 900 applicants for the British government's Commonwealth Foundation Atlantic Fellowship is no less of an honor. McGee, whose application was ranked highest, was one of 10 candidates selected for the prestigious fellowship. It was created by the British government four years ago to commemorate the 50th anniversary of D-day and acknowledge the role of the United States in liberating Europe from Nazi control. The fellowship also was designed to promote trans-Atlantic cooperation between the United Kingdom and U.S. and improve the practice of public policy in both nations. In the months to come, McGee will conduct a study of British and American public policy on new reproductive techniques, including cloning, nuclear transfer, intra-cytoplasmic sperm injection, and in vitro fertilization. Although researchers continue to push the frontiers of reproductive medicine, health care providers and the public have been slow to adapt to the use of rapidly emerging technologies, according to McGee. "More amazing is the fact that most clergy, physicians, and nurses know very little about clinical genetics or reproductive medicine," he says. Receiving his Ph.D. in philosophy from Vanderbilt University in 1993, McGee has quickly earned a reputation for his pragmatic approach to philosophy and bioethics, where deep questions are closely connected to practices and activities of everyday life. During the fellowship, he will go beyond Anglo-American concerns and travel throughout Europe to study reproductive public policy. "In my dialogue with scientists in all parts of the world, it has become clear to me that the global nature of patenting, molecular mapping, pharmacology, research trials, and the media have made nationalism in science a colossal dinosaur," he says. PRIZE-WINNER: His discoveries concerning organization and expression of genes in animals have made Pierre Chambon this year's recipient of the $300,000 Welch Award in chemistry. AIDS HONORS The two scientists credited with identifying HIV, isolating it, and developing tests for the virus split a $100,000 award--and shared credit for what was one of the more hotly contested findings of science in the 1980s--last month. Robert C. Gallo, the director of the Institute for Human Virology in Baltimore, and Luc Montagnier, of Queens College in Flushing, N.Y., and the Institut Pasteur in Paris, received the Warren Alpert Foundation Prize April 30. In the early days of AIDS research, the two virologists had been characterized--incorrectly, both have later said--as being at odds with each other. The controversy arose over who should rightly receive credit for discovering the virus, as well as royalties for an HIV screen. Gallo's Laboratory of Tumor Cell Biology in the National Cancer Institute at the National Institutes of Health announced at a high-profile press conference in 1984 a blood test for detecting HIV antibodies. Shortly after, Montagnier and colleagues at the Institut Pasteur announced they had earlier identified a virus they called LAV and supplied Gallo's labs with isolates of the virus. Gallo called his version of the virus he grew HTLV-III. In retrospect, Gallo acknowledges he should have called a joint press conference with Montagnier and said, "We believe very strongly that [the two viruses] are the same subtype," Gallo tells The Scientist. France and the U.S. government officials eventually reached a deal to give scientists from each country equal shares of the test royalties, which, at first, were allocated disproportionately to the UnitedStates. Gallo also underwent misconduct investigations that were eventually dropped. Both scientists have been publicly generous with credit to each other since. Montagnier has said that the French scientists first isolated the virus, while Gallo's group grew it and identified it as a retrovirus (Thomas A. Bass, The Scientist, 7[24]:11, Dec. 13, 1993). Gallo has said that he had given credit to his French colleagues, but that the media sometimes ignored those statements (Franklin Hoke, The Scientist, 8[22]:12, Nov. 14, 1994). The two also co-authored a chronology of their findings (R.C. Gallo, L. Montagnier, Nature, 326:435-6, 1987). Gallo, who also received the $50,000 Nomura Prize from the Mitsuyoshi Nomura Foundation for Cancer and AIDS research in Japan this month, acknowledges that his and Montagnier's work was, by its very nature, intertwined. "We built on each other's shoulders," he reports. EGGING ON PROTEINS: By inserting specific genes into the cells, N.C. State's James N. Petitte has given researchers a way to grow chickens that will serve as virtual factories for proteins used in making drugs. FROM THE FRYING PAN TO THE PHARMACY North Carolina State University researcher James N. Petitte may not have egg on his face, but it is certainly on his mind. Petitte, an associate professor of developmental biology and biotechnology, is perfecting a process that uses undifferentiated stem cells in embryos to produce transgenic chickens. By inserting specific genes into the cells, he has given researchers a way to grow chickens that will serve as virtual factories for proteins used in the making of drugs. Currently, drug companies rely on cultured bacteria for protein. With transgenic eggs, scientists would be able to insert specific genes into hen embryos. When the chicken matures and later produces offspring, proteins could be harvested from the eggs or blood of the offspring. "You can get roughly 280 eggs per year from a laying hen," Petitte says. "If you can harness this productivity, then you have found a very effective and economical way to make pharmaceutical proteins." Other applications also are envisioned for the technology. "In agriculture, we see poultry possibly using the eggs to breed chickens with certain desirable traits," he notes. "Any time you attempt to do that through natural breeding, the progress you make tends to be undone by the expression of other traits that may not be desired. With the eggs, you eliminate this threat and substantially cut down on breeding time." Petitte and N.C. State hold two patents for the process, and Origen Therapeutics Inc., South San Francisco, Calif., has exclusive license of the technology. CHEMIST HONORED For Frenchman Pierre Chambon, this year's recipient of the $300,000 Welch Award in chemistry, the advances in his field of genetics have been both exhilarating and frustrating. "I'm amazed that things that were thought to be impossible have come into reality," he says. "But we are still very far from an understanding even of things that are relatively simple." Chambon, director of the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, has made a number of breakthrough discoveries over a 40-year career concerning the organization of genetic materials and the mechanisms that govern gene expression in the cells of higher animals. Among the first experimenters in transcription, early in the 1960s, his work led to the discovery that the transcription of messenger RNA from DNA requires three enzymes in animals, compared to just one in bacteria. His cloning experiments in the 1970s showed that animal genes are organized differently from those of bacteria. He discovered DNA enhancers and their role in controlling how genes are turned on and off. He was instrumental in isolating hormone-dependent and hormone-independent molecular markers in breast cancer. Currently, he is studying nuclear receptors for retinoic acid, which he found to be essential in all tissues and organs throughout vertebrate life. Is there a major problem he would still like to solve? "We answer one question and we raise the next," he muses. "Anyway, the biggest questions will not be answered." Chambon will receive the award from the private Welch Foundation at its annual banquet in Houston in October. BRAIN-PROTECTING DRUGS When a stroke or trauma deprives the brain of blood and oxygen, some brain cells die immediately while others undergo apoptosis, leading to cell death hours to days later. In neurons, apoptosis apparently requires the activation of one or more members of a recently discovered family of proteases known as caspases. By inhibiting caspase activity in rodents, two teams of researchers have now succeeded in lessening the brain damage that typically results from a cutoff in blood (ischemia) and/or oxygen (hypoxia). A group at Washington University School of Medicine in St. Louis administered a caspase inhibitor to newborn rats three hours after inducing cerebral hypoxia-ischemia. Injecting the inhibitor either cerebrally (into a ventricle) or systemically (into the peritoneum) reduced the loss of volume in some brain regions by more than 50 percent (Y. Cheng et al., Journal of Clinical Investigation, 101:1-8, 1998). In humans, this finding suggests ways to minimize the neurological problems, including cerebral palsy, that afflict full-term babies asphyxiated during birth as well as premature babies who have suffered hypoxia-ischemia, according to lead investigator David Holtzman, an assistant professor of neurology at Washington University. The second group, at Harvard Medical School, blocked a cerebral artery in adult mice for 30 minutes and injected two caspase inhibitors into cerebral ventricles six hours later. Treatment resulted in a decrease in infarct size and neurological deficits (M. Endres et al., Journal of Cerebral Blood Flow and Metabolism, 18:238-47, 1998). But principal investigator Michael Moskowitz, a Harvard neurology professor, cautions against drawing immediate clinical conclusions from the study. He says that peptide-based caspase inhibitors--which both his team and the Washington University group used--"don't make the best drugs because [peptides] get chopped up" inside the body.

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