Notebook

ALZHEIMER'S VACCINE It's the classic vaccine approach: Get protection against a disease by training the body's immune system, using a bit of the disease itself, to respond to infection in force. Typically applied to infectious diseases such as smallpox or polio, immune system-boosting treatments have more recently been aimed at cancerous tumors. Now a recent paper suggests that Alzheimer's disease (AD) might be effectively treated by priming the immune system with a form of the damaging, neuron-suffocating amyloid plaques observed in the brains of AD patients. (D. Schenk et al., "Immunization with amyloid-ß attenuates Alzheimer-disease-like pathology in the PDAPP mouse," Nature, 400 :173-7, July 8, 1999). Using a synthetic form of ß-amyloid (Aß), the peptide the plaques are composed of, researchers at Elan Pharmaceuticals of South San Francisco, Calif., showed that the synthetic peptide, called AN-1792, could both prevent and arrest plaque formation in a mouse model genetically engineered to exhibit AD-like pathology. In the first experiment, young, plaque-free mice immunized regularly from age 6 weeks to 13 months exhibited neither plaque deposition nor abnormal nerve cell damage or brain inflammation. In the second experiment, plaque buildup was stymied in older mice with advanced AD-like symptoms that had been vaccinated from the ages of 11 months to 18 months. Although the vaccine's precise biochemical mechanism is still not well understood, one possibility, say Elan researchers, is that AN-1792 activates antibodies in the blood, a fraction of which get through the blood-brain barrier and signal white blood cells to engulf and destroy the plaques. Researchers plan to submit an investigational new drug (IND) application to the FDA in the next few months and hope to start Phase I safety trials by the end of the year. "If we see anything resembling what we see in our mice in patients with Alzheimer's disease," remarks Ivan Lieberburg, senior vice president of research at Elan Pharmaceuticals. "It will be a truly remarkable result and will completely revolutionize therapies for Alzheimer's disease." And even if the study doesn't eventually lead to an effective AD treatment in humans, it might help answer a central question in the field of AD research: Are plaques a cause or a by-product of the disease? "Even a negative trial, it seems to me, ... is terribly important," says William Thies, vice president of medical and scientific affairs at the Alzheimer's Association. --Eugene Russo CHIMERA CONTROVERSY Stuart Newman, professor of cell biology and anatomy at New York Medical College and a longstanding member of the Council for Responsible Genetics, took a bold step by applying for a controversial patent a year and a half ago (D. Dickson, "Legal fight looms over patent bid on human/animal chimaeras," Nature, 392 :423-4, April 2, 1998). The application describes three separate techniques for creating biologically viable chimeras between human and nonhuman species. One or more of these techniques could in principle be used to produce chimeric embryos that would have important applications in biomedical research. Recently Newman was informed that his application was rejected. Undeterred by the verdict, Newman and Jeremy Rifkin, coapplicant on the patent, promptly filed a revised application. However, Newman is not interested in creating human/animal chimeras. Instead the application is a challenge to create boundaries between what is considered human and nonhuman at a time when genetic research is progressing in leaps and bounds. A precedent for patenting living organisms was set in 1980 when the U.S. Supreme Court approved a patent on a microorganism that had been modified to help clean up oil spills. Then in 1988 a patent was issued for the first genetically modified mammal, a type of mouse used in cancer research, "oncomouse." Currently there is no legal consensus on the boundary between the types of life forms that can and cannot be patented. Newman feels the rejection of his patent on the basis that it "embraces human being" may mean progress. "Maybe the patent office is waking up and seeing what [recent biotechnology research] can lead to." Newman and Rifkin are hoping Congress will get involved with creating some definitions. In the meantime, Carl Feldbaum, president of the Biotechnology Industry Organization, criticizes Newman's actions as irresponsible and feels this attempt may interfere with valuable medical research. --Nadia S. Halim Above is a transverse section of a renal tubule co-stained with markers for the thick ascending limb of Henle (in red) and the newly discovered tight junction protein Paracellin-1 (PCLN-1) (in green). PCLN-1 appears to be localized at intercellular junctions. FUNCTION AT THE JUNCTION To prevent unwanted leakage of extracellular fluid between tissue layers, the membranes of neighboring cells are attached at connections called tight junctions. These cell sealers are the gatekeepers of tissue barriers--preventing, for example, bacteria in the mouth and intestinal tract from getting into the bloodstream, as well as maintaining the proper ion composition on either side of cell layers in the gut, kidneys, and blood vessels. Although scientists have, for a long time, known how tissues allow certain selected ions, nutrients, or cells to move through cells by using mechanisms such as ion channels, they know very little about the specific mediators at tight junctions that allow selective passage of these constituents in between cells--a process called paracellular transport. A recent paper reports the first identification of a tight junction protein with a specific function--the paracellular transport of magnesium ions (D.B. Simon et al., "Paracellin-1, a renal tight junction protein required for paracellular Mg 2+ resorption," Science, 285 :103-6, July 2, 1999). Yale University researchers identified the associated gene, called paracellin-1 (PCLN-1), by doing a positional cloning study based on the genes of individuals who have a rare disease called renal hypomagnesemia, a disorder characterized by excessive losses of magnesium and calcium. The malfunction of PCLN-1 appears to contribute to disease onset. Its tight junction protein product, PCLN-1, localizes to a segment of the kidney called the thick ascending limb of Henle--a previously known site of magnesium reabsorption. "The inference is that [paracellin's] gene product is involved, we think, in creating the pore that selectively allows magnesium to pass in between cells," explains senior author Richard P. Lifton, chairman of genetics at Yale University. Lifton's team now plans to reconstitute this system in vitro. They'd also like to use the PCLN-1 data to elucidate the as-yet-unknown function of a recently discovered tight junction protein family called the claudins. --Eugene Russo View inside the eyeball as seen through the left pupil of a 44-year-old patient affected by RP1. The characteristic findings of retinitis pigmentosa include attenuated retinal blood vessels, waxy pallor of the optic nerve, and intraretinal bone-spicule deposits. SEEING THE LIGHT Retinitis pigmentosa refers to a group of common inherited eye diseases that result in progressive loss of vision. For 20 years the position of the gene that causes one form of the autosomal dominant disease when mutated has eluded scientists. Now two groups have independently identified mutations that cause the RP1 form of retinitis pigmentosa in a gene encoding a photoreceptor protein (E.A. Pierce et al., "Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa," Nature Genetics, 22 :248-54, July 1999; and L.S. Sullivan et al., "Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa," Nature Genetics, 22 :255-9, July 1999). The Sullivan group conducted linkage studies on a large Kentucky family with many members who had retinitis pigmentosa and then located the RP1 gene on chromosome 8 using a positional cloning approach. On the other hand, the Pierce group was using a mouse model to look for proteins whose expression might be altered by decreased oxygen levels in the retina. In the process, they identified a novel gene that was only expressed in retinal photoreceptor cells and mapped it to the RP1 locus on chromosome 8. They recognized the gene as a good disease candidate, and further investigation of the Kentucky family identified the gene as RP1. "Identifying the RP1 gene and its mutations will potentially allow individuals who carry a mutation but have not exhibited symptoms to be identified. This will have an impact when a treatment or cure is discovered," explains Lori Sullivan of the University of Texas Health Science Center in Houston. Eric Pierce of the University of Pennsylvania adds, "If we understand the role of the RP1 protein in vision and how mutations lead to dysfunction, we may be able to develop drugs or treatments that prevent loss of vision." --Nadia S. Halim REFACTORING GROWTH The answer to whether growth hormone replacement (GH) is advisable to treat aging-related diseases has come a step closer with new studies concerning liver-derived insulinlike growth factor (IGF-I), production of which is stimulated by GH. It is known that many elderly people have deficiencies in GH/IGF-I in their immune systems, the latter of which can be improved by GH replacement. But other work suggests that IGF-I can play an important role in tumor development. In the 1950s, a hypothesis arose that body growth is controlled by the concentration in the blood of IGF-I, produced in the liver. In the 1980s, researchers demonstrated that IGF-I also can be produced in nonliver tissues. Now mice developed at the National Institutes of Health that are missing the igf1 gene in their livers have shown dramatic reductions of circulating IGF-I, but they have no signs of reduced body growth (S. Yakar et al., "Normal growth and development in the absence of hepatic insulin-like growth factor I," Proceedings of the National Academy of Sciences, 96 :7324-9, June 22, 1999). Senior author Derek LeRoith, chief of the molecular and cellular endocrinology branch in the National Institute of Diabetes and Digestive and Kidney Diseases, says these findings, corroborated by a Swedish study using the NIH mice, may lead to "an understanding of what replacement therapy could or couldn't do." Among questions LeRoith and his group now are examining is, "What do circulating levels of IGF-I have to do with anything?" --Steve Bunk SMALLPOX REVISITED? In the 20th century alone, smallpox took 500 million lives, more than all the wars and epidemics combined. Smallpox claimed its last U.S. victim 50 years ago. Believing the disease to be eradicated, the United States stopped inoculating citizens routinely in 1972. In 1980 the World Health Organization proclaimed the world free of smallpox. Despite its complete eradication, scientists now fear that smallpox could strike again sometime in the future, unleashed by war or terrorism. A recent book and intelligence efforts suggesting the possibility of biological warfare using smallpox virus have prompted U.S. officials to maintain laboratory samples and find new vaccines for the dreaded disease. On April 22 U.S. officials announced a delay in the intended June destruction of the country's smallpox repository for three years. Living samples might aid the development of new treatments and antidotes. Quality-control problems have damaged the stoppers on vials of stored smallpox vaccine. Scientists and health experts are calling for a federal program to produce new vaccines to protect up to 100 million people in the United States. American and Russian scientists are attempting to better understand the genetic basis of smallpox in an effort to perfect a cure. Intelligence agencies are stepping up their efforts to better judge the threat of smallpox attacks. The Clinton administration believes that clandestine supplies probably exist in Iraq and North Korea and could cause the disease to emerge suddenly. In 1992 a Soviet official named Kanatjan Kalibekov, now known as Ken Alibek, defected to the United States, claimed that Moscow had made smallpox weapons, and suggested that the virus might have been sold or hidden here. His book, Biohazard (Random House, 1999), describes the biological weapons. "Where other governments saw a medical victory, the Kremlin perceived a military opportunity," Alibek concludes. --Ilene Schneider

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July 1999

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