Notebook

Contents Pivotal pump Leptin limbo Clue to obesity Biotech Web site Helping hand Mapping malaria Notebook Pictured above are pigmented bacterial colonies of Deinococcus radiodurans, the most radiation-resistant organism currently known. DEINO-MITE CLEANUP In 1956, investigators discovered a potentially invaluable cleanup tool in an unlikely place. A hardy bacterium called Deinococcus radiodurans unexpectedly thrived in samples of canned meat thought to be sterilized by gamma radiation. The bacterium soon earned the distinction of being the most radiation-resistant organism known on the planet. Hoping that the D. radiodurans' genome might reveal the secrets to this rare attribute, the U.S. Department of Energy chose the bacterium to be among a group of organisms that they'd pay The Institute for Genomic Research (TIGR) in Rockville, Md., to sequence--research TIGR recently had published (O. White et al., "Genome sequence of the radioresistant bacterium Deinococcus radiodurans R1," Science, 286:1571-7, Nov. 19, 1999). D. radiodurans might be part of the solution to a nasty cleanup problem: Thousands of DOE-monitored waste sites around the country contain high levels of radioactivity, toxic chemicals, and heavy metals. Investigators guess that the bacterium's genome--composed of two circular chromosomes of 2.6 million and 400,000 base pairs, and two smaller circular molecules, a megaplasmid of 177,000 base pairs and a plasmid of 45,000 base pairs--withstands radiation due to its phenomenal rate of DNA repair. It recovers from doses of radiation that induce as many as 200 complete double-stranded breaks in the chromosome. "There don't seem to be any new systems," explains TIGR president Claire Fraser. "There seem to be more systems ... and more redundant systems than you see in any other organism." The functions of only 50 percent of the bacterium's genes have been discovered, so many radiation-resistance genes likely have yet to be identified. But, says Fraser, "It's very clear that it's not just the presence of a handful of genes that confers radiation resistance. It's likely due to multiple features, multiple pathways, multiple strategies that work together that all contribute." This complex interaction of factors will, according to Fraser, make the bioengineering of D. radiodurans' resistance secrets into other organisms difficult. More promising is supplementing the bacterium's radiation resistance with additional metabolic pathways from other organisms that are capable of toxic chemical and heavy metal cleanup.--Eugene Russo ATTACHMENT AND ADHERENCE The murky question of why some diabetic patients do not adhere well to their medications and glucose monitoring looks clearer now, thanks to a new study. It shows that a particular style of emotional and relational behavior called "dismissing attachment" can have a significant, adverse effect on a patient's treatment adherence. Moreover, adherence worsens in such patients who rate communication with their doctors as poor. Dismissing attachment, characterized by compulsive self-sufficiency and difficulty obtaining support from others, is one of four general styles of relational behavior described by attachment theory, which was developed in the 1950s and 1960s. The new work, by University of Washington acting assistant professor of psychiatry and behavioral sciences Paul S. Ciechanowski and colleagues, involves 367 diabetic subjects. It analyzes their hemoglobin (HbA1c) levels, a biological indicator of glucose control, in light of various other factors, including attachment styles and quality of the patient-provider relationship. Those patients with dismissing attachment who rated communication with their providers as poor had the worst glucose control, representing a statistically significant risk of disease complications. The results were announced at the 46th annual meeting of the Academy of Psychosomatic Medicine, Nov. 18-21 in New Orleans. Attendee Gregory L. Fricchione, director of medical psychiatry services at Brigham and Women's Hospital in Boston, remarked, "This is perhaps the most powerful mammalian [behavioral] strategy, that of attachment." He added that the new findings could lead to a paradigm shift in bedside manner. Ciechanowski has submitted a paper for publication.--Steve Bunk UBIQUITOUS TAG When sperm meets egg, all but 100 or so of its mitochondria are left behind. The lucky few to enter are diluted by the 100,000 mitochondria already there, then vanish by the time the fertilized egg has become a four- or eight-celled ball. A team from Oregon Health Sciences University in Beaverton, the International Center for Cancer Research and Developmental Biology in Santiago, Chile, and the department of zoology at the University of Coimbra in Portugal reveals how male mitochondria are tagged, targeted, and escorted to the lysosomes for dismantling (P. Sutovsky et al., "Ubiquitin tag for sperm mitochondria," Nature, 402:371, Nov. 25, 1999). The ringleader is ubiquitin, a protein that labels cellular structures for destruction. Gerald Schatten, endowed professor of cell-developmental biology at Oregon Health Sciences, compares it to aluminum-can recycling. "You tag the cans, and later the garbage truck comes and recycles the material for reuse." The researchers labeled ubiquitin red using antibodies, and sperm mitochondria green/yellow with a vital dye, and then watched the male mitochondria vanish in rhesus monkey and cow eggs. But when they fertilized cow eggs with sperm from an Asian wild gaur, a different species, the male mitochondria persisted, suggesting species specificity to the egg's attack. Mitochondria are labeled in the male. "The recycling tag does not appear to affect the function of the sperm mitochondria until after they enter the egg. At that time they encounter the egg's destruction machinery--and the 'death sentence' written during spermatogenesis is then executed during development," explains Schatten. The long-awaited demonstration of selective male mitochondria destruction has several implications. Use of mitochondrial DNA sequences as a "molecular clock" in evolution research may have to be rethought, or at least recalibrated, if male mitochondria sneak in when sperm and egg are genetically dissimilar. This escape may also explain the notorious poor condition of newborn cloned mammals, which may be due to heteroplasmy, the phenomenon of two mitochondrial populations fighting for control in a cell. Consequences for humans may be imminent. Infertility clinics around the world, led by the Institute for Reproductive Medicine at St. Barnabas Hospital in West Orange, N.J., are trying to reverse the biological clocks of women by performing "organelle therapy" or "cytoplasmic donation." Women over 40, who ostensibly have eggs with aged cytoplasm, are treated by microinjection of their eggs with cytoplasm from eggs donated by younger women. Some pregnancies and births have occurred, and the group reported in Toronto in September at the American Society for Reproductive Medicine meeting that this results in heteroplasmy. That is, the tissues have mitochondria from ... the older woman's egg and also from the younger egg cytoplasm," says Schatten. Stay tuned.--Ricki Lewis NONINVASIVE DETECTION Alzheimer's plaques--only five to 200 micrometers in size--are too small to be detected in a live patient by magnetic resonance imaging. Definite diagnosis comes only after an autopsy of the deceased patient. Helene Benveniste, associate professor of anesthesiology, and colleagues from Duke University Medical School are working toward a procedure to view neuritic plaques in Alzheimer's animal models by magnetic resonance microscopy (MRM) (H. Benveniste et al., "Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy," Proceedings of the National Academy of Sciences, 69:14079-84, Nov. 23, 1999). MRM uses a higher magnetic field, stronger magnetic-field gradients, and smaller radio frequency coils than magnetic resonance imaging. Two magnetic resonance contrast parameters, T2* and diffusion, called pulse sequences, can manipulate the magnetic field to achieve high-resolution images. The group found that T2* was sensitive for detection of plaques while studying tissue samples from the hippocampi of three nondemented individuals and five Alzheimer's patients. The plaques appeared as black, spherical objects. The researchers later stained the same tissue samples to view the plaques in the traditional manner. The group is now working on the challenges of in vivo imaging. "You have to work around the background noise caused by breathing and a beating heart to get the high resolution we saw in vitro, down to 40 microns," explains Benveniste. Though use in humans is many years away, this technology could provide an invaluable tool in studying the early progression of neuritic plaques and Alzheimer's disease in animal models.--Nadia S. Halim NEW NIDDK DIRECTOR Allen M. Spiegel has been appointed director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), effective Nov. 15. Spiegel's signal transduction research has helped define the genetic basis of several endocrine diseases. His research established that inherited disease can be caused by defects in G proteins, which serve as a chemical bridge between hormone receptors and effectors. He has also helped clone the tumor suppressor gene responsible for multiple endocrine neoplasia type 1 (MEN 1).--Paul Smaglik THE PAINS OF MEMORY Pain may be one way evolution has enabled organisms to learn about their surroundings. Even unicellular organisms explore their environment by gravitating toward nutrients and away from noxious stimuli. By remembering such associations, living things stand to improve their chances for survival. Perhaps it's not that surprising, then, that memory and pain seem to share certain mechanisms. "It's obviously biologically useful not only to detect the noxious stimulus but to remember that a stimulus is potentially dangerous," explains Clifford J. Woolf, a professor of anesthesia research at Massachusetts General Hospital in Charlestown, Mass. "We think this was one of the first drives for the development of a nervous system and of the capacity to store information." Woolf's group recently discovered that a mechanism called extracellular signal-related protein kinase (ERK), a protein already thought to have a role in learning and memory, also plays a part in our "remembering" painful stimuli (R. Ji et al., "Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity," Nature Neuroscience, 2:1114-9, Dec. 1, 1999). After an injury, tissue damage for example, the initial pain sensation often gives way to a period of persistent pain or hypersensitivity to pain, a soreness or tenderness. ERK is part of a signal transduction pathway that produces prolonged changes in the cell that outlast the initiating stimulus. It may also be involved in the synaptic changes thought to underlie memory formation in the hippocampus. "When we experience pain hypersensitivity, it may be triggered by something in the periphery," Woolf explains. "But the actual expression of the change in pain experience is due to changes within neurons within the nervous system." Woolf notes that there have always been known similarities between mechanisms, but that they're stronger than originally suspected. "What was surprising for us was that the switch-on of this intracellular cascade occurs very quickly, within a very short period, and then persists for some time," he comments. "And [it] seems to have a very robust and specific role in producing pain mechanisms." Woolf's group also showed that they could reduce pain hypersensitivity by blocking the ERK signal transduction cascade--suggesting that novel analgesics might somehow target that pathway. The required specificity, however, will be tough to achieve. His group now hopes to find the genes switched on by these signal transduction pain pathways in order to understand how gene machinery can be altered as part of the pain phenomenon. Doing so may give them insight into why chronic pain persists after the pain-inducing stimulus is long gone.--Eugene Russo

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