Notebook

Contents Moral Might Self-Validation More Alzheimer's Progress Broader Role For Mobile DNA Preferential Hearing Special Delivery Perfect Pitch Genes Imaging Dsylexia Date: March 30, 1998 A GUIDE TO ETHICS: Eric Meslin took over leadership of the National Bioethics Advisory Commission last month. MORAL MIGHT Eric M. Meslin, 36, has taken over leadership of the National Bioethics Advisory Commission (NBAC) in Rockville, Md. Harold T. Shapiro, NBAC's chairman and president of Princeton University, named Meslin executive director of the commission after a nationwide search beginning in June 1997. Meslin succeeds acting executive director William Raub, deputy assistant secretary for science policy at the United States Department of Health and Human Services. NBAC was created in 1995 by the executive order of President Bill Clinton to ensure the protection and welfare of human research subjects. NBAC also is charged with developing recommendations on a variety of issues in bioethics, including the use of genetic information and gene patenting. Prior to his appointment, Meslin served as program director for bioethics research at the National Human Genome Research Institute (NHGRI) in Bethesda, Md. Before that, he was deputy director of the University of Toronto Joint Center for Bioethics. Meslin, who has a Ph.D. in philosophy from Georgetown University, says NBAC will continue to focus its research activities on issues of national importance in bioethics, such as the use of human biologicals in research, discrimination based on genetic information, and federal responsibilities for oversight of studies involving human subjects. He points to international research issues as next on NBAC's agenda. "Traditionally, countries have tended to look inward to understand the principles and guidelines for conducting ethical research," he explains. "But the world of research is quickly transcending national borders. This trend opens up a treasure trove of social, economic, and ethical considerations for scientists and ethicists." COLOR CODING: Out of this array of colors in water-soluble synthetic melanins, the far left tube shows John Pawalek's MelaSyn100. SELF-VALIDATION Yale University School of Medicine senior research scientist John M. Pawelek works every day in the lab with complicated questions concerning melanoma. Yet, when he walks down the hall or steps off an elevator, the most common question people ask him is, "Where have you been on vacation?" For about four years, Pawelek has been using his own skin for tanning-formula experimentation, and it has paid off. Sometime this year, his work will hit retail shelves as an instant tanning cosmetic. Pawelek recently received a patent for cosmetic melanins, and through the Yale Office of Cooperative Research, the Melasyn technology has been licensed to Vion Pharmaceuticals Inc. in New Haven, Conn., which in turn inked a worldwide manufacturing and marketing arrangement with San-Mar Laboratories of Elmsford, N.Y. Although melanin has been used for protection against ultraviolet radiation, it is insoluble in water and impractical for creams and lotions. Several years ago, Pawelek's colleague Jean Bologna commented that if melanin were really soluble, it would make a good cosmetic, and Pawelek has been working toward designing a synthetic melanin ever since. The right combination of ingredients and methods eventually turned out to be an aloe vera-based formula that, when transformed into melanin, generates a sun-block product and "a lustrous tan," he says, adding, "The tan is immediate. Right before your eyes." MORE ALZHEIMER'S PROGRESS Science advances one step at a time, and researchers at the University of Pittsburgh announced another step in learning about the pathogenesis of Alzheimer's disease (AD) in February. A team of investigators headed by Robert Ferrell, a professor of human genetics, reported (S.E. Montoya et al., Nature Genetics, 18:211, 1998) that they had found a link between the natural enzyme bleomycin hydrolase (BH) and a fourfold increased risk of developing nonfamilial AD. The only other known inherited risk factor for sporadic AD is the presence of the ApoE*4 form of the apolipoprotein gene, which is thought to promote the deposits of amyloid plaques within the brains of AD patients. A recently published study about ApoE*4 prompted the National Institute on Aging to begin setting up a new $3 million database on AD (Notebook, The Scientist, 12[6]:27, March 16, 1998). However, scientists estimate that about 40 percent of the people who develop sporadic AD do not carry ApoE*4. "Our research finding suggests a plausible role for this enzyme [BH] in processing the amyloid precursor proteins that give rise to the plaques characteristic of [AD]," Ferrell explains. The Pitt investigators, with assistance from the National Institute on Aging, researched the bleomycin gene in 357 AD patients and 320 controls obtained through Pitt's Alzheimer's Disease Research Center and the Indiana Alzheimer's Disease Center Cell Repository. The bleomycin gene has two alleles, A and G. The researchers discovered that people with two copies of the G allele (G/G) of the BH gene but no ApoE*4 gene (G/G, - ApoE*4) are four times more likely to develop AD. They estimate that would encompass about 6 percent of the affected population. BROADER ROLE FOR MOBILE DNA Transposable elements (TEs)--DNA segments that move, mutating genes they disrupt--may be more important than suggested by their reputation as "selfish" DNA, a sequence that promotes its own existence and replication. TEs may have driven large-scale evolutionary changes, proposes John F. McDonald, a professor of genetics at the University of Georgia in Athens (J.F. McDonald, Trends in Ecology and Evolution, 13:94-5, 1998). TEs have a colorful history. "Barbara McClintock inferred their existence in corn in the 1950s. They were discovered in bacteria in the 1960s, then in eukaryotes in the 1970s. In the 1980s the concept of selfish DNA arose," says McDonald. Such "jumping genes" constitute a third of the human genome yet cause only 0.2 percent of spontaneous mutations. The cell, therefore, must squelch their activity, either by burying TEs in dark-staining regions called heterochromatin or by adding methyl (CH3) groups. Heterochromatin was known to be home to many TEs, and many methylated genes were known to reside among TEs. McDonald hypothesizes that heterochromatin and methylation may have originated as a weapon against the mutation-causing ability of TEs but later became able to control expression of other genes. "It is like an arms race between host genomes and transposable elements," he says. "The host evolves repressor systems, such as methylation and heterochromatin, to respond to transposable elements. Once these systems are there, they are then exploited by the host for further genome evolution to occur." PREFERENTIAL HEARING The first documented physiological difference between heterosexual and homosexual women resides in the inner ear. A series of experiments showed that sounds the inner ear makes in response to brief clicking noises are weaker in homosexual and bisexual women than in heterosexual women (D. McFadden, E.G. Pasanen, Proceedings of the National Academy of Sciences, 95:2709-13, 1998). Dennis McFadden, a professor of experimental psychology at the University of Texas in Austin, notes that differences in the sounds, called click-evoked otoacoustic emissions (CEOAEs), had already been reported between men and women, with men having weaker CEOAEs (D. McFadden et al., Hearing Research, 97:102-19, 1996). The study compared the CEOAEs of 57 heterosexual women, 37 homosexual women, 24 bisexual women, 11 bisexual men, 51 homosexual men, and 57 heterosexual men. McFadden reports that, on average, homosexual women's CEOAE was stronger than heterosexual men's but weaker than heterosexual women's. No differences were measured between homosexual and heterosexual men. Despite the small sample size, he feels confident of his conclusions: "It's a pretty large effect." He theorizes that prenatal exposure to high levels of androgen masculinized the homosexual women's auditory systems. However, he emphasizes that sexual preference is a complicated issue. "Any human trait is bound to be a combination of genetic predisposition and environment," he says. "It would not be possible to predict someone's sexual preference knowing the strength of their otoacoustic emission." Previous studies, while controversial, demonstrated links between biology and homosexuality in males (R. Finn, The Scientist, 10[1]:13, Jan. 8, 1996). SPECIAL DELIVERY The promise of gene therapy has been hampered by the failure to effectively deliver sufficient genetic materials. A method using an RNA/DNA hybrid, which matches the target gene with the exception of one nucleotide, may have a higher success rate than viral vectors, a common method of gene therapy (B.T. Kren et al., Nature Medicine, 4:285-90, 1998). Senior author Clifford J. Steer, a professor of cell biology and neuroanatomy at the University of Minnesota Medical School in Minneapolis, notes that the RNA/DNA hybrid, termed a "chimera," causes the targeted gene to repair itself. "It targets a gene sequence in vivo, then mutates it site-specifically," Steer reports. In rats, the "chimeraplasty" yielded a 40 percent gene conversion rate--a significantly higher rate than transgenic expression caused by a successful viral vector, he notes. The molecule also has the advantage of being chemically stable, Steer adds. R. Michael Blaese, chief scientific officer of Kimeragen Inc., a Newtown, Pa.-based firm developing the technique, calls it "a quantum advance in gene therapy" because so far, experiments show it results in higher conversion of mutant genes than does the viral vector method. For now, the approach is limited to single-base mutations. PERFECT PITCH GENES People blessed with perfect pitch can sing or recognize any note without hearing another. Research from the Center for Neurobiology and Psychiatry at the University of California, San Francisco, strikingly supports the idea that perfect pitch results from an inherited predisposition nurtured by early musical training (S. Baharloo et al., American Journal of Human Genetics, 62:224-31, 1998). The study surveyed 612 musicians from exclusive conservatories and orchestras and found that 92 had perfect pitch, a whopping 15 percent. "In the general population, the rate is certainly less than 1 percent," says Peter Gregersen, chief of the division of biology and human genetics at North Shore University Hospital in Manhasset, N.Y., who wrote an accompanying editorial (P. Gregersen, Am. J. Hum. Gen., 62:221-2, 1998) and investigates perfect pitch in twins. The study found that 40 percent of those who started training before age four had perfect pitch, whereas only 3 percent of those who started after age nine did. A study that the researchers just began to track the talent to a gene is using Jewish families of Eastern European descent, the Ashkenazim. The reason is twofold. For one, modern Ashkenazim descend from only a few thousand individuals, amplifying perfect pitch genes from ancestors. "The second reason is that Jewish families cherish very early musical training. The idea is to identify individual Ashkenazim with perfect pitch, type genetic markers, and find genes that are shared by descent. Both the genetic and environmental components are readily available in this population," says Siamak Baharloo, a graduate student in the laboratory of Nelson Freimer at UC-San Francisco. FAULTY WIRING: This artist's rendering shows the deficits in posterior brain function that cause dyslexia. IMAGING DYSLEXIA Sally E. Shaywitz, codirector of the Yale Center for the Study of Learning and Attention at Yale University School of Medicine, takes pains to point out that even Nobel laureates are counted among the 15 percent to 20 percent of Americans who suffer from dyslexia. Their reading troubles have nothing to do with cognitive skills. "Dyslexics probably won't be your typical bean-counters, because they can't count the beans very well," Shaywitz notes, "but they can be visionaries." What, then, causes the condition? She and colleagues recently provided neurobiological evidence that dyslexia stems from difficulty with phonologic awareness, or breaking spoken words into their component sounds (S.E. Shaywitz et al., Proceedings of the National Academy of Sciences, 95:2636-41, 1998). Their study, funded by the National Institute of Child Health and Human Development, used functional magnetic resonance imaging (fMRI) to produce computer-generated images of subjects' brains while they performed intellectual tasks. The results showed relative underactivation in posterior brain regions of 29 dyslexic readers compared with 32 normal readers. Moreover, the dyslexics had relative overactivation in the anterior Broca's area, which apparently tries to compensate for the dysfunction in the posterior regions. The study's results confirmed evidence from previous cognitive and behavioral work. "Dyslexia is not caused by trauma, it's constitutionally based, so what we've described is not neuroanatomically or structurally evident," Shaywitz comments. "Understanding the fundamental nature of dyslexia and the process of phono-logic awareness really guides us toward educational intervention." Currently, her team is using fMRI in a developmental study that measures and tracks the reading ability of children.

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