Frontlines

Despite some success, reproductive cloning in mammals is still a tricky feat. University of Pennsylvania School of Veterinary Medicine researchers, by tracking the gene Oct4 in mice, have shown how its routine failure to reprogram after nuclear transplant commonly prevents the successful development of mammalian embryos (M. Boiani et al., "Oct4 distribution and level in mouse clones: consequences for pluripotency," Genes & Development, 6[10]:1209-19, May 15, 2002). Producing a clone requires that the donor nucleus abort its current genetic program and express that of an embryonic nucleus. Oct4, which is not expressed in adult somatic cells, encodes a transcription factor essential to embryonic development and viability. "Without its expression," says Hans Schöler, director of Penn's Center for Animal Transgenesis and Germ Cell Research, "you can't set aside the pluripotent stem cells." Schöler and colleagues tracked Oct4 expression in the inner cell mass (ICM), the embryonic stem cell gold mine that ultimately gives rise to fetal tissue. Only 34% of the cloned embryos expressed Oct4 in the ICM, and of those, many did not express the gene at normal levels. By demonstrating what goes wrong at the very beginning of the cloning process, Sch’ler says his research undermines the argument that reproductive cloning could become commonplace. "We've seen how many attempts you have to make before you're successful, and there still remains the risk of problems occurring later."

The National Human Genome Research Institute is producing bacterial artificial chromosome (BAC) large-insert DNA libraries for numerous mammals, birds, and other creatures. "In order to make meaningful biological comparisons [between species], you want to have a wide range of species: ones that are closely related and ones that are much more distantly related," says Chris Amemiya, of the Virginia Mason Research Center in Seattle, Wash. Amemiya's lab is one of three in the US making the BAC libraries for National Institutes of Health-selected species. Libraries for the duck-billed platypus, zebra finch, orangutan, echidna (spiny anteater), galago (bush-baby), gibbon, gorilla, acorn worm, and nearly a dozen other species are in progress. The NIH's committee that reviewed white paper proposals for species has ranked the African elephant, brown bat, nine-banded armadillo, and European common shrew as high priorities, but further justification is needed before their DNA can be cloned into BAC libraries. The BAC clones are "routinely being used as reagents for DNA sequencing," says Amemiya. Moreover, "BACs permit investigations into underlying mechanisms of gene regulation during development that may ultimately play a role in disease manifestation." The next white paper deadline to propose additional species is June 10, 2002.

In one of the first studies that examines the neural correlates of the placebo effect, investigators demonstrated that the sugar pill can not only be effective in treating depression, but may share neurological mechanisms with medication. (H.S. Mayberg et al., "The functional neuroanatomy of the placebo effect," American Journal of Psychiatry, 159:728-37, May 2002) Actual medication did appear to activate additional potentially key areas of the brain that may maintain response to treatment, however. Researchers at the University of Texas Health Science Center in San Antonio used positron emission tomography (PET) to scan the brains of 17 male patients with depression. As part of the randomized, double-blind trial, subjects received either placebo or fluoxetine (Prozac). Four placebo patients improved, as did four fluoxetine patients. Both groups exhibited increased activity in the cortex and decreased activity in limbic regions, but only patients given fluoxetine experienced changes in brainstem, striatum, and hippocampus. These changes might help explain the well-documented clinical observation that, compared with those receiving placebo, patients treated long-term with active drugs are less likely to relapse, according to lead author Helen Mayberg, professor of psychiatry and neurology at the University of Toronto. She suggests such studies may help narrow the search by identifying those brain regions most critical for recovery.

Mark Fishman, a Harvard University professor with a hankering for zebrafish research, got an unexpected telephone call that would transform his life and, he predicts, alter the face of pharmaceutical discovery. The call came from Daniel Vasella, CEO of the Basel, Switzerland-based Novartis. Vasella had a vision: to direct global drug discovery from a future Novartis Institute of Biomedical Research (NIBR) in Cambridge, Mass. Fishman would head that center. "The [company directors] were evolving to realize that this would involve a major rethinking of the way to do science, and I was evolving to see that this was an opportunity that would never occur again—to put this new culture together in Boston," says Fishman, director of the Cardiovascular Research Center at Massachusetts General Hospital. The physician-scientist will not only guide the company through the region's academic manses, but also lead the hunt for new heart medicines, says Paul Herrling, head of global research at Novartis. "That was a special aspect that we would like to strengthen very much, our cardiovascular research," Herrling adds. Novartis, which plans to employ 400 in the new facility, is one of many global pharmaceutical powerhouses, including Merck, Wyeth, AstraZeneca, Abbott Labs, and Pfizer with research centers in Massachusetts. "Having a physical presence here, being side-by-side with the opinion leaders, will [give the company] a realistic view of what matters here," says Katherine Arnold, a pharmaceutical company analyst at Bernstein in Manhattan. The first NBIR recruits? Fishman's zebrafish.

The National Institutes of Health has awarded four grants totaling $3.5 million (US) for human embryonic stem cell (HESC) research, the first such grants to be made-and accepted-under revised federal guidelines announced by President George W. Bush last summer. The new grants are directed to four institutions already producing HESC lines certified for government-supported research. The two-year funding is designed to aid in the expansion, testing, quality assurance, and distribution to other researchers of 17 stem cell lines. "This area holds so much promise that we wanted to be sure that the sources of HESC listed on our registry would really be able to meet the needs of the scientific community," says Wendy Baldwin, deputy NIH director for extramural research. The grant recipients are: Cellsaurus, the Athens, Ga., subsidiary of BresaGen, based in Australia and the United States; ES Cell International, of Melbourne; the University of California, San Francisco; and the Wisconsin Alumni Research Foundation, the tech-transfer arm of the University of Wisconsin, Madison.

Using a new microscopic technique, neuroscientists at Johns Hopkins University measured for the first time how sound waves become electrical signals in the cochlea—that is, how sounds are heard by the brain. The advance provides insight into the basic mechanisms of the inner ear and opens the possibility for a better understanding of hearing disorders such as Meneire's disease. The researchers discovered that hair cells continuously signal the presence of sounds by bombarding nerve fibers with multiple chemical packets at high frequencies. This is surprising, say authors, because nerve cells typically function by sending a single packet of chemical transmitters at a time (E. Glowatzki et al., "Transmitter release at the hair cell ribbon synapse," Nature Neuroscience 5[2]:147-54, February 2002). "The hair cell looks like a kind of 'super synapse' compared to how this process takes place throughout most of the nervous system," says lead investigator Elisabeth Glowatzki of the Center for Hearing and Balance at Johns Hopkins. Continuous signaling may help hair cells smoothly transmit the wide range of sound frequency and volume, she adds. The technical advancement that allowed the authors to record excitatory postsynaptic currents in the nerve fibers of rat cochlear hair cells may eventually lead to improvements in the design and programming of hearing aids and cochlear implants, according to Glowatzki.