Science Roundup There are links throughout Science Roundup to articles on *Science Online* (http://www.scienceonline.org/). All AAAS members now have access to the full text of these articles. If you have not yet activated your *Science Online* subscription, you may do so at http://www.sciencemag.org/sub/activate/basic/ First, a very quick word from our sponsor: Invitrogen provides Life Science Researchers worldwide with essential tools designed to save time, save effort, and produce more reliable results. A few of the innovative technologies now available are discussed below. For more information, please visit http://www.invitrogen.com/ SCIENCE ROUNDUP Contents of this edition: Building Strong Bodies, in Many Ways Pheromone Power Not Just Rods and Cones Kinesin: Inching Along Cancer Therapy Roadblock Medical Progress Beyond the Leg Band Becoming Human High-Pressure Microbes Satellite Views of Tropical Climate Shifts In Brief . . . A Galen Portrait Building Strong Bodies, in Many Ways http://www.sciencemag.org/content/vol295/issue5557/#specialintro "What a piece of work," as Hamlet marveled, "is a man" -- at least until the intricate machinery of the human body confronts organ failure, lost limbs, blindness, and a wide variety of other insults wrought by accident and time. But, as was amply displayed in a blockbuster special issue of *Science* on 8 Feb 2002, the art of designing new, off-the-shelf replacement parts for damaged bodies has progressed well beyond the realm of prosthetic legs, dentures, and glass eyes: bioengineers, materials scientists, cell biologists, and physicians are pooling their talents to create functional replacement parts of great complexity that could soon become common in the clinic. In nine Viewpoint articles in the issue, biomedical researchers reviewed: -- the state of the art in the development of self-contained artificial hearts and artificial blood substitutes; -- new interest in portable "bioartificial livers" that can support liver function while the patient awaits a transplant (or until the patient's own liver heals itself); -- the challenges and opportunities implicit in engineering artificial bone, skin, and other tissues; -- efforts to develop biomedical materials that, rather than being inert, can stimulate cell-signaling or gene-expression responses that actually help the body heal itself; -- the prospects of restoring mobility through robotic limbs, vision through retinal prostheses, and hearing through cochlear implants; -- and the cellular, molecular, and bioengineering strategies being brought to bear on repairing injured spinal cords. Complementing these reviews were news articles on issues such as xenotransplantation, tendon repair, and that greatest and most emotionally fraught of all biomedical challenges, the quest to extend the human life-span itself. Pheromone Power For a range of animals, specialized signaling chemicals called pheromones hold the key to determining sexual identity. But how do the scent-based cues purveyed by these substances work on a molecular level? Work published on 22 Feb 2002 by Stowers et al. ( http://www.sciencemag.org/cgi/content/short/295/5559/1493 ) revealed that, in mice, an animal's interpretation of the pheromone signal (and the consequent constellation of sex-specific behaviors controlled by those chemicals) hinges on the action of a single gene. That gene, *TRP2*, encodes a protein expressed exclusively in the mouse's vomeronasal organ (VNO), a collection of 400 neurons that's known from previous work to play a key role in pheromone detection. The researchers created a mouse lacking the *TRP2* gene, and from that mouse bred strains containing two, one, or no copies of the gene. They then introduced to male mice from each strain "intruder" mice emanating a strong pheromone signal -- females in estrus, or castrated (and, thus, nonaggressive) males whose hindquarters had been swabbed with pheromone- laced urine from normal males. Mice with even one copy of *TRP2* displayed normal behavior, mating with the intruder females and fighting with the intruder males. But the mice lacking *TRP2* showed no aggression toward intruder males and, in fact, attempted to mate with intruders of both genders -- a result suggesting that, in the absence of the pheromone cue, the behavioral "default setting" is to make love, not war. As M. Beckman noted in a related news article ( http://www.sciencemag.org/cgi/content/short/295/5556/782a ), the notion that the biologically vital function of sex recognition is governed by a single gene was surprising. And the fact that pheromone cues in mice are processed by the VNO, a system vestigial in humans, hints that we have largely abandoned pheromones in our own mating behavior. Not Just Rods and Cones In recent years, scientists have unearthed a wealth of information regarding the internal "clock" that marks out a mammal's daily circadian rhythms -- and have even tied regulation of the internal clock to a specific area of the brain, the suprachiasmatic nucleus (SCN). But precisely which light-sensitive cells signal the SCN to reset the clock with daylight's return has remained a puzzle: even animals lacking the retina's well-known visual photoreceptors, rods and cones, still have light-responsive circadian clocks. On 8 Feb 2002, two landmark papers in *Science* put that enigma to rest, identifying a new class of light-sensing retinal cells tied directly into the SCN and nailing down the photopigment that actually does the work. Berson et al. ( http://www.sciencemag.org/cgi/content/short/295/5557/1070 ) extracted from rats a subset of retinal ganglion cells (RGCs) previously shown to be connected to the SCN, and recorded the cells' response to light. RGCs, the cells that transmit rod- and cone-harvested impulses to the brain's visual centers via the optic nerve, are not generally light-sensitive themselves -- but Berson et al. found that the tiny subset of RGCs wired to the brain's circadian master control did indeed fire when exposed to light. Meanwhile, Hattar et al. ( http://www.sciencemag.org/cgi/content/short/295/5557/1065 ) established that the photosensitive subset of RGCs expressed the photopigment melanopsin, a finding that closed the loop on earlier work that had suggested melanopsin as a prime candidate for the circadian photopigment. The work of the two research groups, and of other scientists who helped solve the RGC puzzle, is reviewed in an accompanying News Focus by M. Barinaga ( http://www.sciencemag.org/cgi/content/short/295/5557/955 ). Kinesin: Inching Along The intricate transport system within cells, by which membrane- bound vesicles are ferried along microtubules to their intracellular destinations, hinges partly on the two-headed motor enzyme kinesin, which does much of the heavy lifting. For some time, the prevailing view of kinesin's mechanism has held that this protein "steps" evenly and symmetrically down the microtubule, 8 nanometers at a time, its two heads alternately swinging one in front of the other, like a child's hands negotiating monkey bars. But Hua et al. ( http://www.sciencemag.org/cgi/content/short/295/5556/844 ), in the 1 Feb 2002 *Science*, threw down the gauntlet to that orthodox view with a novel set of experiments. The group pinned the distal end of individual kinesin molecules (ordinarily attached to the vesicle or other organelle being transported in the cell) to a glass plate. They then allowed the other end of the kinesin molecule, with microtubule still attached, to swing freely, and chemically switched on the molecular motor at a controlled rate. Because the hand-over-hand model requires that the two heads swap places, the model predicts that the free-swinging microtubule would rotate 180 degrees for each kinesin step. The Hua et al. group, however, saw *no* net rotation of the microtubule -- an observation that led them to suggest that kinesin crawls down the microtubule much like an inchworm, with one head always leading and one always trailing. A news article by J. Couzin ( http://www.sciencemag.org/cgi/content/short/295/5556/780 ) reviewed the work, and the controversy it has generated in the motor-protein community. Cancer Therapy Roadblock One of the most promising research pathways in cancer therapy over the past few years has been in the design of agents that block angiogenesis (the rapid proliferation of new blood vessels that accompanies a tumor's growth), and that thereby can shrink tumors by choking off their oxygen supply. But research published by Yu et al. in the 22 Feb 2002 *Science* ( http://www.sciencemag.org/cgi/content/short/295/5559/1526 ) suggests that the road to effective antiangiogenic therapy could have its pitfalls. The group studied two colon cancer cell lines -- one with functional copies of the *p53* tumor suppressor gene (*p53*+/+ cells), and one with that gene inactivated (*p53*-/- cells), as it is in roughly half of human cancers. After transplanting the two cell lines into two groups of lab mice, Yu et al. found that, whereas the *p53*+/+ tumors shrank significantly when exposed to a cocktail of antiangiogenic drugs, the *p53*-/- cells survived the treatment far better, showing only modest shrinkage. Although the antiangiogenic drugs were still effective in shutting down blood vessel growth, cells lacking *p53* apparently have developed a diabolical defense: they survive better than other cells in low-oxygen, or hypoxic, conditions. (Indeed, Yu et al. found that using antiangiogenic drugs on natural tumor cell populations, which include both *p53*+/+ and *p53*-/- cells, may actually select for growth of the more resistant *p53*-/- variety). As is noted in an accompanying news article by J. Marx ( http://www.sciencemag.org/cgi/content/short/295/5559/1444a ), the result doesn't necessarily dim the promise of antiangiogenic therapies; even the hardiest tumor still needs *some* oxygen to survive. But the work does suggest that, to be effective on natural tumors, antiangiogenic drugs may need to be used in combination with other treatments. Medical Progress Here are a few other stories of biomedical importance that appeared in *Science* during February: --Auluck et al. ( http://www.sciencemag.org/cgi/content/short/295/5556/865 ; 1 Feb 2002), in a study using fruit flies as a model, demonstrated the possible utility of boosting the level of molecular "chaperones" -- heat shock proteins that help misfolded proteins to refold -- in preventing or treating Parkinson's disease (PD). In an accompanying Perspective ( http://www.sciencemag.org/cgi/content/short/295/5556/809 ), S. L. Helfand described how work with this fly model could map to studies of the human disease. --Rezaie et al. ( http://www.sciencemag.org/cgi/content/short/295/5557/1077 ; 8 Feb 2002) isolated the gene responsible for the inherited form of primary open-angle glaucoma (POAG) -- the most common form of adult-onset glaucoma, afflicting 33 million persons worldwide. As noted in a Perspective by J. S. Friedman and M. A. Walter ( http://www.sciencemag.org/cgi/content/short/295/5557/983 ), the work could help with early detection of this devastating disease and may even point toward new treatments. --Wengelnik et al. ( http://www.sciencemag.org/cgi/content/abstract/295/5558/1311 ; 15 Feb 2002) identified a new class of potentially potent agents against malaria, which kills more than a million persons a year. As J. Marx explained in a related news article ( http://www.sciencemag.org/cgi/content/short/295/5558/1207b ), the new compound, called G25, fights the malaria parasite by blocking its ability to wrap itself and its offspring in a protective lipid membrane while holed up in its host's red blood cells. Result: In tests on rodents and primates infected with *Plasmodium falciparum*, the fiercest strain of malaria, low doses of G25 led to rapid and complete cure of the disease. Beyond the Leg Band Keeping tabs on migratory bird populations, which can sweep the length and breadth of continents on their long journeys, is something of a logistical nightmare for ecologists. Traditionally, they have relied on the awkward proposition of marking individual animals and -- they hope -- finding the marked animals later. Two studies published in *Science* during February offered novel approaches to the age-old problem of monitoring flocks: --Rubenstein et al. ( http://www.sciencemag.org/cgi/content/short/295/5557/1062 ; 8 Feb 2002), studying the winter migration patterns of North American blue-throated warblers, borrowed a page from stable isotope geochemistry: They used hydrogen-2 (deuterium) and carbon-13 -- the abundance of which varies predictably by latitude and is recorded in metabolically inert tissues such as feathers -- as "tracers" for bird migrations. The researchers found that the isotopic abundances in feathers of birds wintering in the western Caribbean islands differed significantly from those of birds wintering in the eastern Caribbean islands -- and, because blue- throated warblers (like many migrating birds) grow new feathers before migrating, the data established that these two distinct subpopulations of warblers started out their migrations at different points. Hobson ( http://www.sciencemag.org/cgi/content/short/295/5557/981 ), in a Perspective, wrote that the work could prefigure "an explosion in the use of stable isotopes to examine a myriad of unanswered ecological questions about animal migrations." --Weimerskirch et al. ( http://www.sciencemag.org/cgi/content/full/295/5558/1259 ; 15 Feb 2002), in a paper in *Science*'s Brevia section, opted for a different, no less novel solution to the bird-tracking problem: they fashioned miniature, self-contained loggers that could be tracked by the spaceborne Global Positioning System (GPS) -- capable of recording position to within a few meters -- and attached the loggers to wandering albatrosses. The result was a glimpse, in unprecedented detail, of the birds' flight patterns and foraging behavior. Becoming Human Sites such as the caves at Lascaux, Altamira, and Grotte Chauvet offer eloquent testimony of creativity and cognition among our ancient forebears. But did the appearance of such "modern" human behavior flash forth in a revolutionary burst, fueled by sudden genetic change around 50,000 years ago? Or was the development of modern behavior a more protracted affair, stretched out over tens of thousands of years? A special News Focus in the 15 Feb 2002 issue, "Becoming Human," explored both recent controversies surrounding the development of the earliest hominids ( http://www.sciencemag.org/cgi/content/short/295/5558/1214 ) and the combination of fossil, cultural, and genetic evidence that is fueling debate over just when modern *Homo sapiens* appeared -- and how the species came to be endowed with its cultural abilities ( http://www.sciencemag.org/cgi/content/summary/295/5558/1219 ). In the same issue, Henshilwood et al. ( http://www.sciencemag.org/cgi/content/short/295/5558/1278 ) reported a startling find from a cave on South Africa's southern coast: two pieces of red ochre, containing a series of geometrical scratches and designs, that date from some 77,000 years before the present -- and that the researchers interpreted as the earliest known art. The age of the engravings, Henshilwood et al. noted, predates the oldest Upper Paleolithic manifestations of culture in Eurasia by some 35,000 years. Although the interpretation is controversial, the South African find represents potentially powerful evidence against a "big bang" of modern human behavior -- and for a more gradual emergence of culture. High-Pressure Microbes The past two decades have seen the discovery and description of a remarkable menagerie of microbial "extremophiles" -- organisms that survive and thrive in bubbling sulfur pools, boiling hydrothermal vents, and hypersaline lakes. Now Sharma et al. ( http://www.sciencemag.org/cgi/content/short/295/5559/1514 ), in research published in the 22 Feb 2002 issue of *Science*, have established that two comparatively "ordinary" microbes can stand up to pressures rivaling those 50 kilometers inside the Earth's crust. The group adapted diamond-anvil cells, commonly used in high-pressure mineralogical and petrological experiments, to serve as an observatory for studying the reaction of *Shewanella oneidensis* and the near-ubiquitous *E. coli* to pressures in excess of 1000 megapascals (10,000 times atmospheric pressure). Using molecular spectroscopy to monitor the rate of formate oxidation (a fundamental metabolic process for these microbes), Sharma et al. found that metabolism, though slowed, clearly continued at these high pressures for both of these microorganisms. What's more, the bacteria, though morphologically changed by their visit to the gigapascal world, remained viable once pressure was reduced to standard atmospheric. The conclusion, according to the researchers: "Pressure may not be a significant impediment to life" -- a potentially important finding for calculating the odds of life in extreme environments such as the deep oceans of Ganymede, the polar caps of Mars, and subduction zones on Earth. Satellite Views of Tropical Climate Shifts Two reports in the 1 Feb 2002 issue of *Science* highlighted, in the words of D. L. Hartmann ( http://www.sciencemag.org/cgi/content/short/295/5556/811 ) in an accompanying Perspective, "just how little we know" about the forces driving climate variations on the time scale of decades. Chen et al. ( http://www.sciencemag.org/cgi/content/short/295/5556/838 ), examining data on the flux of thermal radiation from Earth's surface over the past decade and a half, tied the general increase in outgoing thermal radiation to a strengthening of large-scale tropical atmospheric circulation systems -- but also noted that the period covered by the data was too short to determine whether that strengthening was due to natural variability or anthropogenic forcing. In the same issue, Wielicki et al. ( http://www.sciencemag.org/cgi/content/short/295/5556/841 ) compiled two decades of tropical radiative-flux data from satellite measurements, and concluded that the atmospheric energy budget of the tropics "is much more dynamic and variable than previously thought." The group's work revealed rapid changes in longwave radiation flux, on the order of as much as 8 watts per square meter, associated with phenomena such as El Nino and the eruption of Mt. Pinatubo. That's an important result for climate modelers, because radiative flux variations of as little as one watt per square meter can influence the output of climate simulations. In Brief . . . Each week, *Science*'s Brevia section presents short research reports of broad general interest to the journal's readers. Among the work featured in Brevia this month: --Cibelli et al. ( http://www.sciencemag.org/cgi/content/full/295/5556/819 ; 1 Feb 2002) reported that they had developed embryonic stem cells from primate parthenotes -- embyros grown from unfertilized eggs incapable (at least in mammals) of growing into fetuses -- and that they had coaxed those cells into differentiating into a variety of tissues, including neurons and spontaneously beating cells resembling those of the heart. A news article by C. Holden ( http://www.sciencemag.org/cgi/content/short/295/5556/779a ) discussed the work and its ethical implications. --Dubrova et al. ( http://www.sciencemag.org/cgi/content/full/295/5557/1037 ; 8 Feb 2002) provided unambiguous evidence that families living downwind of the former Soviet Union's Semipalatinsk nuclear test facility in Khazakstan have experienced germline mutations at nearly double the rate of those in uncontaminated areas. Background on the study and its possible ramifications appeared in a news article by R. Stone ( http://www.sciencemag.org/cgi/content/short/295/5557/946a ). --Whitchurch et al. ( http://www.sciencemag.org/cgi/content/full/295/5559/1487 ; 22 Feb 2002) found that extracellular DNA plays a crucial role as "glue" in the establishment of bacterial biofilms -- communities of cells enclosed in a polymerlike matrix that are strongly resistant to antibiotics, and that are associated with chronic infections wreaked by bacteria such as *Pseudomonas aeruginosa*. The group also found that deoxyribonuclease I (DNase I), an enzyme that slices up DNA, prevented biofilms from growing, and suggested that DNase I treatment might be useful in preventing bacterial biofilms in a variety of disease contexts. A Galen Portrait http://www.sciencemag.org/cgi/content/short/295/5556/800 February's "Portraits of Science" essay focused on Galen, the ancient physician of the city of Pergamum in western Turkey. In the essay, author V. Nutton noted that although many of the conclusions presented in Galen's voluminous writings (which "constitute about 10% of all that remains of Greek literature before A.D. 300") turned out to be spectacularly wrong in the light of modern medicine, the methods he pioneered -- which combined logic, practical experience, and a devotion to experimentation -- were largely sound. Galen, Nutton observed, "claimed to have performed a dissection every day for most of his working life" to enhance his understanding of anatomy. And the Renaissance thinkers such as Harvey and Vesalius, who ultimately overthrew Galen's physiological and anatomical dogma, nonetheless used Galen's own methodology in doing so. "The spirit of Galen," concluded Nutton, "can thus be said to have triumphed over his conclusions." ©2001 ANBio - Associação Nacional de Biossegurança. All rights reserved.