Notebook

Table of Contents Gene Genies Nuclear Mass All in the Family Presenilin Problems Scientists Recast Stymied Stem Cells Plants on the Wild Side Deadeye Death Gene HUMAN ENHANCEMENT: Gene-shopping could be a future consumer craze, if the predictions in a book about science in the year 2025 are correct. The year 2025 will be no time for traditionalists, if the three authors of a new book on future science are on the mark. In the book 2025: Scenarios of U.S. and Global Society Reshaped by Science and Technology (Greensboro, N.C., Oakhill Press, 1997), Joseph F. Coates, John B. Mahaffie, and Andy Hines portray a world in which geneticists will affect virtually every major aspect of life, including health, behavior, plants and animals, food, manufacturing and materials, and information technology. The greatest genetic challenge, they say in an article adapted from the book for the current issue of The Futurist (J. Coates et al., September-October 1997, page 18) will be "human enhancement": genetic shopping for math skills, artistry, even charm or talent. A frightening prospect? "I think that's right," says Mahaffie. "A lot of the issues surrounding science and technology are worthy questions and we tried to answer as many as we could, but no matter what you do, you'll get the response, 'Sounds like Big Brother; why do we want that?'" The book was a pro-technology exercise, he explains, which grew from a project for 17 primarily corporate clients by the "futures research" consultancy Coates & Jarratt Inc. of Washington, D.C. Coates is president, Mahaffie an associate, and Hines a former associate. "There's no philosophical approach in the book," Mahaffie notes. "We looked at future technology without putting the brakes on too soon." The mechanism behind the cause of a number of neurodegenerative diseases, including Huntington's disease and several forms of inherited ataxia, appears close to discovery. Researchers led by Randall N. Pittman, an associate professor of pharmacology at the University of Pennsylvania Medical Center, have shown that excessive encoding of the amino acid glutamine, which is known to cause these disorders, occurs in the nuclei of selected neurons in affected regions of the human brain. Moreover, fragments of this expanded glutamine-containing protein form an insoluble aggregate that could endanger critical nuclear processes. The study (H. Paulson et al., Neuron, 19:333-44, 1997) was of deceased patients who had spinocerebellar ataxia type 3, also known as Machado-Joseph disease, one of the glutamine expansion disorders. Similar findings in mice afflicted with Huntington's disease were reported this month (G. Bates et al., Cell, 9:537-48), and Pittman reports that colleagues studying Huntington's disease have told him that they, too, have now found glutamine-containing aggregates in human brain tissue. Prion diseases, including Creutzfeldt-Jakob disease, also have a protein aggregation. "There are two big questions now," says Pittman. "Are there other, normal cellular proteins being recruited into these aggregates, and what is the link between that aggregate protein and a dead cell?" 'A WEIRD CASE': Harvard's Frank McKeon notes that "we can't apply the standard paradigm" to the p73 gene. Scientists recently discovered that the well-known gene p53, a tumor suppressor that's mutated in 60 percent of all human cancers, has a cousin of sorts (M. Kaghad et al., Cell, 90:1-20, 1997). Called p73, the gene resides on the very tip of chromosome 1, an area of the genome known to be a veritable hotbed of tumor suppressor genes and an area missing in many people with cancer. Researchers from Harvard Medical School and from Sanofi Recherche, a pharmaceutical company in Labege, France, serendipitously discovered p73, which evolved from the same primitive gene as p53, while doing a screen search for the IL-4 and IL-13 type receptors. In the case of p53 and other common tumor suppressors, cancerous tissue results from a deletion in one copy of the cell's chromosome 1 and a mutation in the remaining copy. However, p73 is expressed on one chromosome only. As a result, although a normal copy of the gene may reside on the "unused" chromosome of the pair, cancerous tissue will still develop if the "used" copy contains a mutation. Awakening this silenced gene has been the focus of current research. "This is just a weird case where we can't apply the standard paradigm to this gene," explains Frank McKeon, an associate professor of cell biology at Harvard Medical School. "There are clearly different RNAs and proteins and methylation events involved in [the way in which genes are silenced]. People now understand how to prevent some of these methylation events and in some cases can awaken these genes." 'NEW INSIGHT': Harvard researcher Huntington Potter's work "opens up a whole new approach for Alzheimer's disease therapies." Faulty chromosome segregation may be a leading cause of Alzheimer's disease, according to a recent Harvard Medical School study (J. Li et al., Cell, 90:917-27, 1997). Although most cases of the familial form of the disease have been linked to mutations in either of the two related genes presenilin 1 and 2, the precise role of the presenilin proteins is not fully understood. Associate professor of neurobiology Huntington Potter and his colleagues have discovered that the presenilin proteins are located in the cell's nuclear membrane and on its kinetochores and centrosomes, which are specialized structures that play a vital role in chromosome segregation during mitosis. If, as their presence suggests, presenilin proteins are involved in mitosis, then mutant forms could cause problems with chromosome segregation and produce some cells with an irregular number of chromosomes. Potter has hypothesized that Alzheimer's disease is due to a patient's having three copies of chromosome 21 (trisomy 21) in some cells, the same abnormality that, when present in all cells, causes Down's syndrome (Notebook, The Scientist, Sept. 1, 1997, page 30). People with Down's syndrome not only always contract Alzheimer's if they survive into their 30s and 40s, but also have two symptoms necessary for the onset of Alzheimer's: abnormal brain inflammation and elevated levels of amyloid precursor protein (APP), a protein coded for on chromosome 21. "The thing that's interesting, beyond our excitement about this new insight into the mechanism of the disease," says Potter, "is that the finding opens up a whole new approach for Alzheimer's disease therapies." When the New York City-based Alfred P. Sloan Foundation decided to inaugurate grants to film schools this year to develop screenplays and pictures that give science a fair shake, a stipulation was that the budding filmmakers had to meet real scientists. "The film department at UCLA [University of California at Los Angeles] normally has very little to do with the science department, so it was like, 'Who are these guys?'" says program director Doron Weber. "But it turned out to be very successful." UCLA was one of four schools chosen for the almost $800,000 in funding. The others were New York University's Tisch School of the Arts, the American Film Institute's Center for Advanced Film and Television Studies, and the University of Southern California. The objective, Weber explains, was to encourage promising student filmmakers to avoid cinematic stereotypes of scientists, who according to Sloan Foundation research were often depicted as evil and mad or merely nerds. The winning applicants, to be announced this month in film industry trade journal advertisements, may develop scripts or produce projects intended for television or cinema. "Targeting the students is an ambitious, long-term program," Weber observes. "We may have an influence years from now that is indirect." Meanwhile, the grants will continue. STEMMING CANCER: Studies by Duke's Haifan Lin of a stem cell component called the spectrosome can lead to better diagnosis and treatment of cancer. Malfunctioning of stem cells, unspecialized cells that give rise to differential cells, is considered the leading cause of all types of cancer. In an effort to better understand how these cells operate, Duke University Medical Center scientists have described the function of a cell component present within germ- line stem cells of Drosophila that appears to help those cells to both self-renew and make mature differentiated cells. Although researchers first discovered this organelle, dubbed the spectrosome, in 1994 (H. Lin, Development, 120:947-56, 1994), they hadn't investigated its function in detail until recently (W. Deng et al., Developmental Biology, 188:1-16, 1997). Spectrosomes, spheres of membrane skeletal proteins, appear to direct and help determine which cells remain stem cells and which become mature eggs. Like a sort of magnetic pole, spectrosomes orchestrate the orientation of cells during division. When researchers eliminated the gene that codes for the proteins that make the spectrosome, stem cell divisions became randomly oriented and the stem cells could no longer make eggs. The Drosophila spectrosomes are believed to act much like their human counterparts. "In order to understand how to treat a cancer, one needs to understand, first of all, how cancer formation occurs," says Duke cell biologist Haifan Lin. The function of the spectrosome is "an important mechanism for stem cell division." According to Lin, a better understanding of the role of the spectrosome in stem cell division could lead to better diagnoses and better treatments for patients with cancers caused by abnormal stem cells. CROSS PURPOSES: A plant breeding study coauthored by Cornell's Susan McCouch uses meiosis rather than bioengineering. Genes from wild plants can help boost the productivity of domesticated crops, according to a study published last spring by Cornell University scientists (S.D. Tanksley et al., Science, 277:1063-6, 1997). Modern plant breeding, which involves the repeated crossing of close relatives, reduces genetic variation. Disastrous crop diseases linked to genetic relatedness have spurred governments worldwide to establish gene banks, living seed collections of species closely related to crop plants, in order to preserve genetic variation. Using molecular markers, Cornell professor of plant breeding Steven D. Tanksley and assistant professor of plant breeding Susan R. McCouch identified productivity-boosting genes known as quantitative trait loci, or QTLs, in wild varieties of rice and tomato plants obtained from one such gene bank. Through classical breeding, or meiotic recombination, researchers combined these genes with genes from domesticated plant species. Yields increased 48 percent in tomato plants and up to 17 percent in rice plants. "Geneticists have long known that the success of breeding would depend on having ample sources of genetic diversity," says McCouch, referring to the 700 seed collections worldwide. "We have these vast reservoirs of germplasm, we spend millions and millions of dollars to maintain them . . . and [yet] they're very underutilized." McCouch points out that her study also highlights a breeding strategy that doesn't involve bioengineering (see "Political Controversy Puts Ag Biotech In Spotlight" on page 1). "We can do this through meiosis, which I think the public is happy about," she suggests. "And what we're discovering are equally novel and interesting sources of genetic variation for the breeding community." SMART BOMB: Michael Parmacek's armed and guided adenovirus could improve the safety of gene therapy. A University of Chicago research team has armed gene-loaded viruses with a guidance system that improves the safety of gene therapy. Michael S. Parmacek, an assistant professor of medicine and director of the study, says the researchers were able to limit expression of the therapeutic gene to smooth muscle cells by attaching "on-off" gene expression switches. In a small animal model, researchers used an adenovirus to deliver the therapeutic genes. The "on-off" switches, or gene promoters, prevented the virus, which infects many cells, from delivering the gene to healthy cells (S. Kim et al., Journal of Clinical Investigation, 100:1006-14, 1997). "We were able to deliver a death gene with fine precision and restrict expression of the gene to particular cells," Parmacek explains. "If we can continue to do this, we can begin to treat a variety of diseases because the safety of gene therapy is optimized." Researchers have hesitated to use adenovirus for gene delivery in humans because the virus attacks virtually all cells in the body, causing mutagenesis and a massive immune system response, according to Parmacek. The proliferation of smooth muscle cells, which regulate vascular contraction and expansion, contributes to atherosclerosis after vessel injury and the reobstruction of arteries after angioplasty. With hazards associated with gene therapy reduced, researchers could begin to treat these and other diseases like diabetes and asthma, Parmacek notes. The research team included Steven Kim, Hua Lin, Eliav Barr, Lien Chu, and Jeffrey Leiden of the departments of medicine and pathology at Chicago. Parmacek expects to continue testing on a larger animal model within two months and hopes human trials could begin in two years.

Notebook

The Scientist Staff

Interested in reading more?

Become a Member of