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Science  29 May 1998:
Vol. 280, Issue 5368, pp. 1285

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    Solving the Brain's Energy Crisis

    1. Ann Gibbons


    Humans have voracious brains. A newborn's brain consumes 60% of the energy the baby takes in. And that's just the beginning. That lump of gray matter doubles in size in the first year of life, and by adulthood, human brains weigh roughly a kilogram more than the brains of similar-sized mammals. Many researchers think energy intake limits brain size in many mammals. Yet the human brain and body as a whole don't use any more energy than smaller brained mammals of similar body size, so something must be making up for the brain's outsized appetite. As Leslie C. Aiello, a paleoanthropologist at University College London, puts it: “Where does the energy come from to fuel the large brain?” And if there is an energetic constraint on how big a brain can get, how did our ancestors overcome that limit?

    Last month at the annual meeting of the American Association of Physical Anthropologists (AAPA), anthropologists debated two solutions to the brain's energy crisis: One, called the expensive tissue hypothesis, is that big brains in adults are fueled by the energy saved in humans' relatively small gastrointestinal (G.I.) tracts, which we can afford because of our high-quality diet. The other idea, the maternal investment hypothesis, proposes that most of the extra energy comes early in life—from mom, through the placenta during pregnancy and through breast milk between birth and age 4, when the human brain reaches 85% of its adult size.

    At the moment, as researchers test and amplify each theory, it's unclear if either one is right; it may be that both play a role at different times in development. Either way, a growing number of anthropologists and neuroscientists are analyzing the potential constraints on brain evolution, testing their ideas with data from genetics, neuroscience, and comparative physiology. “The notion of understanding brain change in terms of the constraints on the body is an interesting and novel way of coming at this problem,” says Cornell University neuroscientist Barbara Finlay.

    Most evolutionary theories focus on the environmental or social factors that might have favored big brains, but this approach analyzes another variable: the underlying physical constraints that had to be overcome to build an oversized brain. By putting the two together, researchers hope to come up with more realistic evolutionary scenarios of how changes in our ancestors' behavior or ecology, such as hunting and living in large groups, helped them evolve bigger brains. Says paleoanthropologist Dean Falk of the State University of New York, Albany: “I'm really all for this approach. We have to attend to the energetics or we're not going to get selection for a bigger brain going on at all.”

    Researchers have long known that an animal's body size is a critical influence on brain size, as shown at the turn of the century by renowned Dutch paleontologist Eugene Dubois. Brains consume large quantities of energy in making neurotransmitters and firing axons, and bigger bodies have bigger hearts and lungs to supply more energy and oxygen to the brain. That's why elephants and baleen whales can have brains four to six times larger than those of humans. But humans are different. Our brains have tripled in size since Lucy and her fellow australopithecines, with brains roughly the size of a chimpanzee, began to walk upright on the African savanna 3 million years ago. But our bodies aren't even twice as big. “Humans, in fact, have the largest brain size relative to body size among placental mammals,” says University of Zurich primatologist Robert D. Martin.

    Nor do humans conform to another pattern that Martin noticed in the early 1980s when he was pondering the question of human brain size. Research on basal metabolic rates, or how much energy an animal consumes while resting, showed that in mammals, the size of the newborn's brain tends to correlate with the mother's metabolic rate. Martin and others reasoned that supporting a bigger brain requires a higher energy consumption. Yet humans' basal metabolic rate is no higher than that of large sheep, which have brains five times smaller. Humans are apparently getting enough energy to feed their brains without increasing their overall energy intake, so it must be coming from some other source.

    That source is the gut, according to the expensive tissue hypothesis, first proposed in 1995 by Aiello and physiologist Peter Wheeler of Liverpool John Moores University and revised last month by Aiello at the AAPA. The pair reviewed studies of humans and found that most of the basal metabolic rate—more than 70%—goes to fuel the brain, heart, kidney, liver, and G.I. tract. To find out if the demands of any of these organs were reduced to fuel the human brain, they compared the mass of each organ in adult humans with that expected for a primate of similar body size. Only the G.I. tract was smaller than expected—and it was about 60% of the size expected for a similar-sized primate. “The increase in mass and energy consumption of the human brain appears to be balanced by an almost identical reduction in the size of the gastrointestinal tract,” concludes Aiello.

    Aiello speculates that we could reduce our gut size to free up energy for a larger brain because of a dietary change that was taking place as brain size expanded. Our ancestors were shifting from a heavily vegetarian diet, which requires a massive gut to digest plants and nuts, to a more easily digestible, nutritious diet that included meat and requires less gut tissue.

    Other researchers are now testing Aiello's idea. Harvard University primatologist Richard Wrangham and his students compared pigs—animals “rumored to be quite smart,” says Wrangham—with mammals such as cattle, sheep, goats, and deer. Pigs have small stomachs compared with these mammals, but their brains are no larger, showing that the gut-brain trade-off didn't apply to them. Other studies have shown that the theory doesn't hold for birds or bats. In fact, it may apply only to some primates. But Aiello and Wrangham aren't bothered by this. “Other animals, such as birds, have different energetic challenges,” says Aiello. Birds, for example, put their energy into large hearts for flight and have small guts and brains. “I'm not worried about it,” agrees Wrangham. “I think Aiello and Wheeler have got the right answer.”

    But Martin thinks another source of energy may be more important in building and fueling big brains: energy donated by the mother. He thinks the obvious place to look for extra energy in humans is during the “crunch time” for brain development—from gestation until age 4, when the brain reaches 85% of its full adult size. That trail led straight to the mother, who “provides most of the energy in gestation, then in lactation, which is 3 to 4 years in hunter-gatherers,” says Martin.

    Indeed, work by other researchers makes it clear that during gestation at least, the human system has evolved to allow maximum energy transfer between mother and offspring. The human placenta is particularly greedy, sucking nutrients from the mother's bloodstream more aggressively than in other primates, according to recent work by Harvard University evolutionary biologist David Haig. He notes that in humans the placenta invades the uterine lining more deeply than in other primates. This energy drain continues in lactation. Human gestation is over well before brain growth is complete, in contrast to other animals. Lactation takes up the slack, says Martin. In effect, human gestation continues in the first year of life. “We achieve our big brains in continuing our fetal pattern of growth in the first year of life, and human milk must be pumping in energy,” says Martin. Thus humans can afford such big brains because their mothers make such an enormous investment in them, nursing them until brain growth is almost complete.

    The only way human mothers can donate so much energy to brain growth in their infants is by taking in extra energy themselves. Paleoanthropologist Alan Walker of Pennsylvania State University, University Park, has an as-yet-unpublished proposal about how human ancestors met this need. Like Aiello, he thinks the switch to a diet high in protein and fat 2 million years ago, with the advent of hunting, was crucial. In his scenario, however, the new diet's role in brain evolution allowed a fetus to pull this much energy from the mother without killing her.

    Social changes may have played a role, too. As our species evolved, mothers could increasingly count on family members to feed them and to help care for their young, so they could invest more in pregnancies and infants, says Cambridge University behavioral neuroscientist Eric Keverne. “Mothers were getting access to more and more energy, through tool use, cooking, eating meat,” says Martin. “It's progressive.” So in a positive feedback loop, a higher energy intake allowed larger brains—which in turn led to even more energy intake.

    So where do humans muster the energy to fuel their brainpower—mom or cheap guts? Aiello suggests both may be true. Humans may tap mom's energy resources during the period of peak brain growth in gestation and early childhood. Once weaned, small guts in later childhood and adulthood would free up energy to help sustain the expensive brain.

    Despite the enthusiasm for this approach, other researchers have offered a basic challenge to the assumption behind both ideas. Although huge quantities of energy go into a working brain, energy may not be the key limiting factor in brain size, says Oxford University evolutionary biologist Paul Harvey: “There's no reason to suspect that the reason other mammals don't have big brains is that they are energetically limited.”

    He challenges the data that led to the assumption of an energy limit on brain growth: the link between metabolism and brain size. He and Oxford colleague Mark Pagel showed in 1988 in the journal Evolution that animals with high basal metabolic rates for their body size, such as shrews, do not produce large-brained young. “I don't see this as an energetics problem,” says Harvey, whose work with Pagel suggests that the way to grow larger brains is to have long gestation times, late weaning, and fewer offspring per litter.

    Others aren't ready to give up on the correlation. Martin, responding in a talk at the AAPA, says that if one incorporates length of gestation and lactation and animals' degree of independence at birth, the link between metabolism and brain size holds up.

    Despite the critics, the energetic approach is making its mark, as researchers accept the possibility of energetic constraints on evolution. This “is making us do experiments to measure how much energy the mother is putting into her offspring,” says Francisco Aboitiz, a neuroscientist at the University of Chile in Santiago; he is comparing brain growth in different species of rats to see how different parts of the brain have evolved in response to varying ecological conditions. In the end, both hypotheses may be pieces in a complex puzzle—important physiological constraints that had to be overcome before selection could sculpt a larger brain. “I'm sure there's no single answer,” says Aiello: “These things all work together. It all depends on your ecology.” And perhaps on the size of your gut or the amount of your mother's energy.


    In Mice, Mom's Genes Favor Brains Over Brawn

    1. Ann Gibbons

    University of Zurich primatologist Robert D. Martin remembers the shock he got when behavioral neuroscientist Eric B. Keverne invited him to take a look inside the refrigerator in his lab at the University of Cambridge. He saw bodies of chimeric mice—some with big brains and small bodies, others with small brains and big bodies.

    What surprised Martin was that the big-brained mice were bred to express more copies of genes inherited from their mothers, while those with the big bodies expressed more paternal genes. That result parallels Martin's notion that in humans, mothers invest extra energy in their young to promote larger brains (see main text).

    Keverne's genetic studies in mice suggest a possible mechanism through which mothers might promote such an expansion of the brain. He studies a process called genomic imprinting, in which regulatory genes silence one copy of a gene—either the one from the father or the one from the mother—so that offspring get just a single dose of the gene. The mice in his freezer, research published 2 years ago in the Proceedings of the Royal Society, London, suggest that “the selection pressures for a big brain are coming through the matriline,” says Keverne.

    Brains vs. brawn.

    Mice bred to overexpress maternal genes have big brains (left), while those expressing more paternal genes have big bodies (right).


    It may seem odd that mothers and fathers select for different features in their offspring, but evolutionary biologists say that males and females often have different strategies for propagating their genes—mating strategies being the prime example. In the mice, the maternal genes were expressed in the neocortex and portions of the “executive brain” important for reasoning, while the paternal genes were expressed in the brainstem, which controls more instinctive and hormonally driven behavior such as sex. Martin argues that although it costs more to invest in brainy young, for mothers this “is the best long-term investment. … Mothers are pushing for the highest quality [offspring] they can afford.”

    But when it comes to fathers, the researchers are left speculating; no one knows why fathers would favor big bodies over big brains. One possibility, Martin suggests, is that fathers' genes may survive best when there are many offspring. Thus fathers' genes may be selected to promote less expensive offspring with small brains—which allows mothers to have more offspring.

    Primates, with their complex social structures, have a proportionally large executive brain, and this trend is most pronounced in humans. Thus Keverne speculates that genomic imprinting may have been a factor in human brain evolution, too. Studies of human genetic diseases do show that maternal and paternal genes make different contributions to brain development—but the nature of each contribution has yet to be parsed.


    Taiwan, U.S. Team Up to Chase Shadows

    1. Peter Weiss
    1. Peter Weiss is a science writer in Washington, D.C.

    When a star in a telescope's view winks out, a passing cloud or bird is usually to blame. But astronomers think that sometimes, the shadow could be cast by a distant ball of ice and dust in a vast, uncharted comet reservoir beyond Neptune known as the Kuiper Belt. A U.S.-Taiwanese collaboration has set out to chase these shadows. It is building a robotic, three-telescope array to look for stellar blackouts from a mountain range in central Taiwan, beginning in 2000.

    By counting and measuring these blackouts, the Taiwanese American Occultation Survey, or TAOS—a million-dollar joint effort of NASA, the Lawrence Livermore National Laboratory in California, Taiwan's Academia Sinica and National Central University, and others—aims to estimate the number of objects in the Kuiper Belt and determine their size distribution. The results could force astronomers to “rethink the comets,” says astronomer David Jewitt of the University of Hawaii, Honolulu, co-discoverer of the first Kuiper Belt object in 1992.

    Jewitt explains that comets, stored in the Kuiper Belt and the more distant Oort Cloud, “are thought to be fragments from the solar nebula that didn't change.” The new size census could show how pristine they are, he says. “If they have been repeatedly smashed, it's likely they have changed,” says Jewitt, who is enthusiastic about the new survey, although he is not a participant.

    Objects from the Kuiper Belt can be seen when they plunge into the inner solar system as comets. All but the largest objects in the belt itself—those with diameters exceeding 100 kilometers—are invisible to ground-based telescopes, however. So Livermore astronomer Charles Alcock and his U.S. and Taiwanese colleagues conceived of the star-shadow strategy for counting the billion or so icy bodies there. Alcock explains that the technique should detect objects with diameters as small as 1 to 2 kilometers at the distance of the Kuiper Belt. If the object lies much farther away, starlight bleeding around it should wash out the shadow. If the shadow is due to a much closer object, a large telescope should be able to spot the culprit directly.

    The comet hunters plan to monitor star fields that lie along the ecliptic, the plane of the solar system, and contain many bright, pinpoint stars. Three wide-angle, half-meter telescopes, linked electronically, will be dedicated to the task. Two will stand 10 meters apart—far enough that electronic noise and other sources of error are unlikely to affect both simultaneously. A third, “outrigger” scope will observe the same region of the sky from 7 to 10 kilometers away.

    When a star blinks out, other checks will kick in before the shadow will be tallied as a denizen of the Kuiper Belt. If many adjacent stars were also blotted out, for example, that would suggest that the culprit was a bird or plane. If the stellar eclipse registers at slightly different times at the outrigger and at the other telescopes—proportional to Earth's 30-kilometer-per-second velocity around the sun—observers at large telescopes will be asked within 2 hours of the sighting whether they can see the interloper. If they can, the odds are it's something too nearby to be in the belt. If not, the TAOS collaborators will estimate its size from how long the occultation lasts.

    Because the swarms of objects in the Kuiper Belt are scattered through such a large volume of space, the telltale alignments should be rare. So the survey plans to take snapshots as rapidly as five times per second for some 3000 stars at a time, collecting an unprecedented billion starlight measurements nightly from all three telescopes. Even so, the researchers expect to identify just a handful of comet occultations—from three to 1000—in the 100 billion measurements to be taken per year.

    To deal with the flood of data, the comet census will draw on data-crunching technology pioneered in another star survey directed by Alcock, called the MACHO project. MACHO also monitors vast swarms of stars, but it is searching for the temporary brightening or “microlensing” of a star that results when a distant, massive object—a planet or a burned-out star—passes across the line of sight, and its gravity focuses the light of the background star.

    NASA is providing $350,000 to the Kuiper Belt project over 3 years, with an additional $220,000 this year coming from Livermore's internal coffers. Taiwan is footing an equal or larger share of the cost, team members say, and will pay for two of the three telescopes, which are now on order.

    Locating the observatory in Taiwan makes sense because the ecliptic is high in the sky there. But Taiwanese participants also hope that the facility will help their country nurture its own world-class scientific establishment. “There is a widely held view in Taiwan that science and technology is the future of the country's well-being,” says Kwok Yung “Fred” Lo, an Academia Sinica astrophysicist on the TAOS project. “TAOS is special because it is the first scientifically significant astronomy project to be located in Taiwan.”


    Transmuting Light Into X-rays

    1. David Kestenbaum

    Despite all the recent advances in laser technology, one dream device remains elusive: No one has yet figured out how to make a tabletop instrument that can pump out a beam of high-intensity, coherent x-rays. Such a device would give researchers Superman-like eyes to peer into living cells or catch the swift dances of molecules during a chemical reaction. Now researchers have the beginnings of such a tool. A report on page 1412 describes a trick for boosting visible laser light efficiently into the soft x-ray range.

    In principle, making a laserlike beam of x-rays, whose waves march in lockstep with each other, is straightforward: Start with a visible light laser, then use a series of crystals to double the frequency of the light, boosting its energy until it reaches the x-ray range. The technique works well for reaching ultraviolet frequencies, but unfortunately, standard frequency-doubling crystals are opaque to x-ray light. So scientists have had to look elsewhere for the energy kick, and most have focused on replacing the crystal with a gas that can more easily transmit x-rays.

    When a laser plows into gas, it ionizes most of the atoms, creating a storm of free electrons. But occasionally, says Henry Kapteyn, a physicist at the University of Michigan, Ann Arbor, the laser can pull an electron far out of its orbit and then “slam it back down onto the same atom.” When that happens, the atom shoots out a photon that can pack several hundred times the energy of an individual photon in the original laser beam. The process, harmonic conversion, can generate photons in the x-ray range.

    But harmonic conversion is horribly inefficient, in part because the gas tends to slow down the laser light much more than it does x-rays. So if the laser blasts through a long volume of gas (which would be necessary to produce a significant quantity of x-rays), the x-rays generated at the front are out of step with those made further back. “[The x-rays] tend to cancel each other out,” says physicist Margaret Murnane, also at Michigan.

    Murnane, Kapteyn, and their colleagues found a way around this problem by equalizing the speed of the laser light and the x-rays in the gas. First they put the gas, argon in this case, in a precisely machined glass tube that acts as a “waveguide.” The waveguide corrals and speeds up the laser light as it zigzags through but doesn't disturb the higher frequency x-rays. Then the team adjusted the pressure of the gas, which fine-tunes the velocity of the two beams, until they marched along at the same pace.

    At a “magic pressure of 30 torr,” says physicist Andy Rundquist, x-rays shot out of the 3-centimeter-long tube with a surprising intensity when the team blasted the gas with light from a titanium-doped sapphire laser. “At 2:00 in the morning, I was yelling and screaming in the lab,” he recalls. Roughly one in 100,000 photons made the jump to x-rays, at least 100 times the proportion seen before, he says. The device, which emits x-ray pulses lasting just 20 femtoseconds, is “the first practical, coherent soft x-ray source,” says Kapteyn.

    That has some researchers itching to build one of their own. “This will be a wonderful new tool,” says Ken Kulander, a physicist at Lawrence Livermore National Laboratory in California, who hopes to use it to excite molecules and watch how they fall apart. “You could even think of using [such] lasers to manipulate [or control] chemistry.” Visible-light lasers can drive reactions, he says, “but this opens up a whole new set of states that you can probe.”

    The technique is “very clever,” agrees Janos Kirz, a physicist at the State University of New York, Stony Brook. But he points out that it's not yet capable of making the higher energy x-rays needed for imaging cells. “What everyone wants,” he says, is x-rays of wavelengths between 2.3 and 4.3 nanometers, a region called the “water window.” In this range, x-rays can slip undisturbed through water and scatter off very small objects, allowing scientists to make detailed images of tiny structures in live cells, which are mostly water.

    Several other groups are beginning to see similar gains with waveguides and think a high-intensity x-ray beam in the water window may be in sight. “We could do it in a few years,” says Eric Clement, a physicist at the University of Bordeaux in France. Christian Spielmann, a physicist at the University of California, San Diego, is more cautions. It will take a very high intensity laser to make enough x-rays in the water window to be of use, he points out. And such high intensities may, in turn, ionize so many atoms that it spoils the harmonic effect, he says: “This is a first step, but there are many more steps to go.”


    New Clues to Alcoholism Risk

    1. Constance Holden

    The going's been mighty slow, but the ardor for nailing down genes related to alcoholism continues undimmed. At a press conference held last week in Washington, D.C., researchers in the multicenter Collaborative Study on the Genetics of Alcoholism (COGA), now into its 10th year, reported what they called some “significant milestones.” Those included debunking one candidate for an “alcoholism gene,” coming up with some new hot spots in the human genome where such genes might be located, and firming up a link between alcoholism and a certain type of genetically influenced brain wave.

    Looking ever more dubious, according to the COGA people, is the controversial hypothesis that a gene encoding a particular variant of a receptor for the neurotransmitter dopamine increases a person's risk of alcoholism and other addictions. Biologist Howard Edenberg of Indiana University School of Medicine in Indianapolis reported that “we found absolutely no evidence” for such a link. In 105 families of alcoholics, the suspect gene was not transmitted any more often to alcoholics than to nonalcoholics.

    Psychiatrist Ernest Noble of the University of Texas Health Science Center in San Antonio, a leading proponent of the dopamine-receptor gene hypothesis, says he is undeterred by the findings. Family-based linkage studies—as opposed to association studies done in the general population—lack sufficient “power” to detect the effect, he says; and besides, the COGA researchers are looking only at alcoholism when the effect may not rise to significance unless other compulsive disorders are also taken into account.

    COGA researchers have, however, found hints of other genes that might increase the risk of alcoholism. Psychiatrist Theodore Reich of Washington University School of Medicine in St. Louis described a linkage study in which researchers scanned 291 markers (segments of DNA that vary from one person to another) in pairs of siblings—987 people in all—from 105 families. By identifying markers shared by alcoholic siblings, the researchers found “highly suggestive” evidence that chromosomes 1 and 7 carry alcoholism susceptibility genes, “modest” evidence for such genes on chromosome 2, and “suggestive” evidence for chromosome 4, said Reich.

    A similar study by Jeffrey Long and David Goldman of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) on an entirely different population—a community of alcoholism-prone Southwest American Indians—confirmed that chromosome 4 may contain alcoholism susceptibility genes. The study also produced what Long called “strong suggestive evidence” of involvement by chromosome 11.

    The DNA stretches implicated are already known to carry genes that could influence behavior, including pleasure seeking and compulsive overindulgence. The chromosome 2 region, for example, carries one gene related to the control of endogenous opioids and another that controls production of leptin, a peptide involved in appetite and obesity. The chromosome 11 area includes many genes that direct the production and metabolism of various brain chemicals.

    Psychiatrist Henri Begleiter of the College of Medicine at the State University of New York Health Science Center at Brooklyn, COGA's principal investigator, noted that “it's a very long road from genes to behavior.” But he reported progress in identifying what may be one point along that road: a genetically influenced brain wave, called the P3 wave. Visual or auditory stimuli evoke this oscillation in the brain's electrical activity, which is associated with recognition and attention, and Begleiter found deficits in the wave in alcoholics and in many close relatives of alcoholics. He also said that recent, soon-to-be-published research with adolescents by psychologist William Iacono of the University of Minnesota, Minneapolis, has shown that P3 deficits go not only with alcoholism and drug addiction but also with antisocial behavior and learning disorders. Begleiter says, “We have evidence that [P3 deficit] is a good index of central nervous system disinhibition,” which characterizes all those conditions.

    NIAAA director Enoch Gordis emphasized that we are far from the day when alcoholism genes could be useful as predictors for individual risk. The gene search is infinitely more difficult than that in a single-gene disease, he said: Alcoholism genes are multiple, they interact in unknown ways, and they have incomplete penetrance, which means you can have the genes but not be an alcoholic. As Gordis puts it, “these genes are for risk, not for destiny.”


    Temperature Rise Could Squeeze Salmon

    1. Nigel Williams

    Modest rises in sea surface temperatures, in line with predictions of global warming over the next half-century, could make salmon disappear from much of the North Pacific Ocean. That possibility is suggested by a new review of a 40-year database that examines how fluctuating water temperatures affect the distribution of this commercially important fish. “This is a major study of enormous importance highlighting the need to study fish throughout their natural environments,” says fisheries biologist John Everett, head of research at the U.S. National Marine Fisheries Service in Silver Spring, Maryland.

    The study of sockeye salmon (Oncorhynchus nerka) appears in the April edition of the Canadian Journal of Fisheries and Aquatic Science. In it, David Welch of Canada's Department of Fisheries and Oceans in British Columbia and Japanese colleagues at the National Research Institute of Far Seas Fisheries in Shimizu in central Honshu mine data from major salmon surveys and sea-temperature measurements taken by the Japanese, Canadian, and U.S. governments going back to the mid-1950s. These data are equivalent to “29.1 years of continuous ship survey time,” says Welch.

    Although laboratory experiments have shown that sockeye salmon are capable of surviving in waters warmer than 20 degrees Celsius, the study found that from November to March, the fish are only found in regions where the surface temperature is below 7 degrees Celsius. The maximum temperature rises to 15 degrees by August before dropping back to 7 degrees by November, the team finds. Such “sharp thermal limits,” says Welch, are evident in all months (except October, for which data are lacking) and in all regions where sampling extended into sufficiently warm ocean regions. “Lethal limits for Pacific salmon are generally well above 20 degrees Celsius, so the remarkably low thermal limits observed result in sockeye salmon being excluded from vast areas of the North Pacific that are otherwise potentially habitable,” says Welch.

    These findings have led the authors to speculate that water temperatures interact with another factor—the need to minimize basic metabolic rates when food supplies are low—in shaping where the fish live. Laboratory studies have found that basal metabolic rates for cold-blooded animals rise exponentially with temperature. In other words, the fish may be avoiding warmer water because food supplies are insufficient to maintain such high metabolic rates.

    The new studies also suggest a potentially devastating impact on salmon populations from predicted patterns of global warming caused by increasing concentrations of atmospheric CO2. “A rise of 1 to 2 degrees Celsius in sea surface temperature in the Northern Pacific by the middle of the next century is a real possibility,” says climate modeler Simon Tett at the Hadley Centre for Climate Change in Bracknell, U.K. Such a change could shrink the range of the salmon dramatically, largely restricting it to the Bering Sea. “Although much attention has been paid to the possibility that some stocks of salmon near the southern end of their range may be adversely affected by climate warming in fresh water, events happening in the marine phase could be even more disruptive,” says Welch. In addition, he says, a northern shift in their ocean habitat would force the salmon to travel farther to reach their breeding rivers, resulting in smaller fish with fewer eggs.

    The next step is to see whether other cold-blooded organisms display a similarly clear response to temperature variations. “So few studies have been done,” says Everett. “We need urgently to know more about the effect of environmental temperatures on aquatic ecosytems.”


    Growing Joints Use Their Noggins

    1. Steven Dickman
    1. Steven Dickman is a writer in Cambridge, Massachusetts.

    Some arthritis sufferers might wish their joints would just go away, but new research presented on page 1455 of this issue shows that jointlessness is not a happy alternative. Molecular embryologists Richard Harland and Lisa Brunet at the University of California, Berkeley, and Jill and Andrew McMahon at Harvard University, have found that mice lacking noggin, a gene first discovered as important in brain and nerve development, have no joints at all. Instead, they have stubby, continuous limbs—along with a fatal array of other developmental defects.

    noggin is “a new link in the chain of creation of limbs” and the rest of the skeleton, says cell biologist Bjorn Olsen of Harvard Medical and Dental Schools. Harland's finding is a step toward a more detailed understanding of embryonic development, adds molecular biologist Sejin Lee of Johns Hopkins University, and offers potential medical benefits in diseases where there is too much bone or even too little.

    The new finding is just the latest role for noggin, which William Smith, then in Harland's lab, and Harland identified in 1992 after setting out to find the “neural inducer,” a molecule that orders cells to become brain and nervous system tissue in early embryos. The gene earned its name when they found that frog embryos injected with its messenger RNA grew exceptionally large heads. The noggin protein also mimics the activity of a powerful piece of tissue in the developing frog known as “Spemann's organizer,” which can make back-of-the-body (dorsal) tissue out of front-side (ventral) tissue. Finally, 2 years ago, Harland's team showed that in binding assays and cell culture, noggin inhibits powerful proteins that stimulate bone growth, the so-called bone morphogenetic proteins (BMPs).


    Mice missing the noggin gene have paws lacking joints.


    With noggin playing all these developmental roles, Harland half expected that when the team turned off the gene in their mice, the resulting animals would be no more than “a ball of mush.” Indeed, the knockout mice did not survive until birth. But they developed enough to offer a new insight into noggin's function.

    The mouse showed a variety of intriguing skeletal abnormalities. “Every single bone is affected,” says Harland, with the most obvious defects, such as shorter bones, in the vertebrae, ribs, and limbs. And in keeping with the gene's role in the brain, “there are very clearly characterized neural defects,” including occasionally a brain and spinal cord not enclosed by bone. But the bones in the heads and upper bodies of the mice are much less affected by the knockout than bones farther toward the animals' tails. And dorsoventral patterning doesn't seem to be much affected. This implies that noggin has counterparts that can perform its functions near the head and in dorsoventral patterning, says Harland.

    Most strikingly, the mice appear to lack all joints. Instead, their limbs are nearly continuous segments of bone, flanked by excess cartilage. That makes sense, says Harland, because during normal development, cartilage is laid out like a pencil sketch in the shape of the bones-to-be. Bone gradually fills in this cartilaginous sketch except in predetermined locations such as at the ends of the putative bones. In those spaces, the cartilage then disappears, leaving room for joints like knees and knuckles. In the knockout mice, the cartilage does not do this disappearing act. Without noggin, the thinking goes, bone-forming proteins go out of control, recruiting additional cells from neighboring areas into the prebone cartilage.

    But here too noggin apparently does not act alone, according to work by Harland's and other labs. Instead, it apparently sends signals to a BMP family member called GDF-5, which has been shown to be important in joint formation, and also interacts with another limb-building protein, Sonic hedgehog. Therefore, says Olsen, noggin “is not a master molecule” that regulates everything else. Because BMPs are regulated by the powerful family of patterning genes known as hox, he proposes that noggin is a link in the pathway, somewhere downstream of hox genes and upstream of BMPs, that governs the patterning of limbs.

    Uncovering the molecular basis of this pathway has clinical implications, because many diseases, from osteoarthritis to osteoporosis, involve either too much bone or too little. Biotech companies are already avidly testing BMPs as potential drugs; two are in clinical trials now for healing bone breaks. But these molecules are, if anything, too powerful, says Lee. “The challenge,” he says, “is to limit bone growth to what is clinically desirable.”

    Limiting bone growth is where noggin might come in. Regeneron Pharmaceuticals of Tarrytown, New York, is studying whether noggin and other BMP inhibitors can put the brakes on the excess bone growth that arises in about 10% of hip replacement patients as well as in some patients with osteosarcomas and prostate cancer metastases, says biochemist Neil Stahl of Regeneron.

    Systemic use of noggin could have unwanted side effects, because the BMPs it inhibits are found everywhere from skin to gut to bone, warns Rik Derynck, a cell and developmental biologist at the University of California, San Francisco. But eventually, drug companies might use their noggins to provide novel treatments for overgrown bone.


    New Method Churns Out TB Mutants

    1. Carol Potera
    1. Carol Potera is a free-lance writer in Great Falls, Montana.

    By and large, bacteria are much easier to study in the laboratory than more complex, multicellular organisms. But every rule has its exceptions, and for microbiologists one of the cruelest has been Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The microbe's recalcitrance in the lab has hindered researchers in their efforts to design better drugs for combating TB, which is the world's leading killer among infectious diseases, claiming more than 3 million lives worldwide every year. Now, that impasse may be at an end.

    In order to ferret out new drug targets, researchers want to identify the genes that pathogens need to survive and infect the host—a task usually accomplished by creating wholesale mutations in the microbial genome and then screening for mutants defective in those abilities. Until a few months ago, this was very hard to do with M. tuberculosis, partly because the vehicles typically used to create the mutations—small bits of DNA called transposons that insert randomly into the genome and inactivate any gene they happen to interrupt—do not readily penetrate the microbe's tough, waxy coat.

    Last fall, however, a team of scientists led by microbiologist William Jacobs and immunologist Barry Bloom of the Albert Einstein College of Medicine in New York City, reported creating a new kind of vehicle—a cross between a bacterial virus and a circle of DNA called a plasmid—that's much more efficient at producing mutations in M. tuberculosis. By now, Bloom, Jacobs, and their colleagues have generated thousands of M. tuberculosis mutants, some of which have affected the pathogen's survival and virulence. And they are just getting started.

    “With these techniques, researchers should be able to make mutations in virtually every gene of Mycobacterium tuberculosis,” says Ann Ginsberg, program officer for tuberculosis at the National Institute of Allergy and Infectious Diseases. “Once you have mutants, you can understand gene functions. It allows you to answer a lot of questions about the pathogenesis of the disease.” Along with pointing to targets for new drugs, the mutants might also lead to new ways to protect against TB: vaccines based on the avirulent strains Bloom and his colleagues are generating.

    The Einstein team has been on the trail of better ways of producing M. tuberculosis mutants for more than a decade. Early on, Jacobs reasoned that the barrier posed by the microbe's waxy coat might be circumvented by taking advantage of viruses that naturally infect mycobacteria. With few such viruses available commercially, Jacobs turned to a handy source—his own backyard in the Bronx.

    Bacterial viruses, or phages as they are called, are common soil dwellers, and so Jacobs screened soil from his yard looking for any that infect M. tuberculosis efficiently. He won the “prokaryotic Lotto,” he says, in 1987 when he found a mutant bacteriophage that infects M. tuberculosis at a frequency seven orders of magnitude higher than its parent.

    It's difficult to package transposons into a phage, so Jacobs combined the phage DNA with a plasmid from another bacterium, Escherichia coli—a creation he christened a “phasmid.” Besides accommodating transposons, the plasmid DNA tricks E. coli into copying the entire recombinant molecule, churning it out in large quantities. The researchers then introduce the phasmid DNA into M. smegmatis, a mycobacterium that doesn't have its pathogenic cousin's waxy coat, so its cell wall can be breached with a jolt of electricity. There the phasmid replicates, forming phage particles that will infect M. tuberculosis.

    In an added twist, the researchers mutated the phage itself so that it replicates only at 30 degrees Celsius. As a result, it doesn't kill infected cells kept at higher temperatures but merely transfers in the phasmid DNA, along with its transposon, which can then jump into the mycobacterial DNA, causing mutations. This procedure has proved very efficient at making M. tuberculosis mutants; the researchers have so far collected 10,000. “We keep making them, and hopefully we will statistically accumulate enough to cover all the genes,” says Bloom.

    But the mutants are already providing insights into the biochemical machinery that mycobacteria need to cause disease. For example, the Albert Einstein researchers traced loss of virulence in one mycobacterial mutant to a transposon interrupting the gene encoding a sigma factor, a protein that helps turn on other genes. Another mutant lost its virulence because it could no longer synthesize the amino acid leucine. “The various mutants tell us what typical Mycobacteria need to survive and grow,” says Jacobs. That should make M. tuberculosis much less of a mystery to researchers looking to develop better TB drugs and vaccines.


    Young Ages for Australian Rock Art

    1. Ann Gibbons

    Two years ago, archaeologists caused an international stir with their dates for a remote rock shelter called Jinmium in the Northern Territory of Australia. The dates of 116,000 to 176,000 years ago made the shelter by far the earliest trace of humans in Australia, and its circular carvings the oldest known rock art in the world. But archaeologists questioned the dates, partly because they were obtained with a method that has yielded spectacularly early dates at other sites (Science, 10 October 1997, p. 220). Now the results are in from a painstaking effort to redate Jinmium, and the doubters have been vindicated.

    In this week's issue of Nature, a team headed by geochronologist Richard Roberts of La Trobe University in Melbourne, Australia, reports that Jinmium's age is a completely unremarkable 10,000 years. The new dates “nail the coffin shut” on the claim that humans have been in Australia two to three times longer than previously thought, says geochronologist Jack Rink of McMaster University in Hamilton, Canada.

    The early dates for Jinmium came from a team led by archaeologist Richard Fullagar of the Australian Museum, who is also a co-author on the new paper. For the early dates, he used a method called thermoluminescence dating (TL), which relies on a clock driven by natural radiation in common minerals like quartz. As long as the mineral remains in the dark, the radiation bumps electrons from their normal positions in the minerals' crystal lattice into defects, or “traps,” at a regular rate. But exposure to sunlight or heat empties the electrons from the traps and sets the clock to zero. The traps refill over time, and scientists can read the clock by emptying them in the lab, either by heating the sample (TL) or by tickling it with light (optically stimulated luminescence, or OSL). The material glows as the electrons drop back into the lattice; the more intense the glow, the more time has passed since the sediments last saw daylight.

    But those dates can be contaminated. In the paper in Nature, Roberts's team notes that pebbles of older rock—crumbly sandstone from the boulder wall and the bedrock below—were jumbled into the sediments being dated. When Roberts used OSL to tease dates from individual mineral grains, he was able to distinguish old grains of bedrock from the grains of sediment that would reveal the true age of the shelter. His conclusion: The base of the deposit at Jinmium is no more than 10,000 years old, and some of the quartz grains were laid down more recently. That means humans were at the site “no more than 10,000 years ago,” says Roberts.

    These ages agree with radiocarbon dates from the upper layers of the deposit. Besides removing a puzzle in Australian prehistory, says Rink, the new dates should restore confidence in luminescence dating, which is a powerful tool when applied correctly.


    Regulation of Body Weight

    1. Paula A. Kiberstis,
    2. Jean Marx

    Body weight is a lot like the weather: Everybody talks about it, but no one seems able to do much about it. But in the past few years, researchers have learned a great deal about the physiological mechanisms that help people keep their energy intake and expenditures in balance—as well as how that balance may be upset. In this special issue, Science examines the recent progress in our understanding of what causes obesity and the outlook for new strategies aimed at prevention and treatment.

    In the opening Article, J. O. Hill and J. C. Peters focus on prevention, arguing that we will not “cure” obesity until we cure the environmental factors that promote overeating and discourage physical activity. But genetic factors also play a role, and A. G. Comuzzie and D. B. Allison discuss progress in the difficult task of tracking down the genes that predispose to obesity. S. C. Woods and colleagues review the molecular signals that together ensure that food intake is in synch with the body's immediate and long-term energy needs. Identification of those molecular signals, as well as new obesity genes, is now pointing the way to new therapeutic strategies for losing weight, which are discussed by L. A. Campfield and colleagues. Still, as B. T. Walsh and M. J. Devlin remind us in their overview of the eating disorders anorexia nervosa and bulimia nervosa, defects in body weight regulation can manifest themselves in a variety of ways, some far more devastating than the addition of a few extra pounds.

    In the News component of the special issue, two stories focus on who's getting fat and what the consequences might be—a topic that is still being debated, as some researchers contend that not all overweight people need to lose weight. And finally, the third News story deals with the identification of new proteins that might help regulate a person's metabolism and thus his or her tendency to gain weight.

    Answers to the hidden neuropeptides

    1. leptin: mouse's tail; 2. GHRH (growth hormone releasing hormone): vine on fence; 3. orexin: Mrs. Spratt's skirt; 4. TRH (thyrotropin releasing hormone): Mrs. Spratt's bustle; 5. CCK (cholecystokinin): Mrs. Spratt's napkin; 6. MSH (melanocyte stimulating hormone): Mrs. Spratt's hair; 7. CRF (corticotropin releasing factor): the feather on Mrs. Spratt's hat; 8. GLP-1 (glucagon-like peptide-1): spilling from the teacup; 9. AGRP (agouti-related protein): cloud; 10. MCH (melanin concentrating hormone): thatch of cottage; 11. neuropeptide Y: smoke from chimney; 12. galanin: Jack Spratt's lapel; 13. agouti: trunk of pear tree.


    Obesity: How Big a Problem?

    1. Ingrid Wickelgren


    Today, practically everyone is concerned about his or her weight—and seemingly with good reason, as it's clear that people have been getting fatter (see p. 1367). By the most stringent definition, more than half of U.S. women and men age 20 and older are now considered overweight and nearly one-quarter are clinically obese. What's more, many studies have linked being overweight to increased risk for heart disease, diabetes, and cancer, leading the World Health Organization and officials such as the former U.S. Surgeon General C. Everett Koop to declare an epidemic of obesity in the United States and around the globe.

    They claim that heavy people are not only harming themselves, but are also emptying everyone's pockets. In the United States, the Institute of Medicine says, fat people are costing citizens more than $70 billion annually in both direct health care costs and indirect ones such as lost productivity. “We can't become complacent about this epidemic of obesity, which seems to be worsening over time,” says JoAnn Manson, an endocrinologist at Brigham and Women's Hospital in Boston.

    But recently many obesity experts have come to believe that these alarms are overstated, and that many people, particularly those who are only moderately overweight and otherwise healthy, shouldn't worry about shedding their excess pounds. They point out that many of these studies don't account for confounding factors associated with obesity, such as a sedentary lifestyle. Thus, the evidence may not, in fact, warn against body fat per se but rather against lack of physical activity.

    Too much population growth?

    Including the so-called “preobese” (BMIs between 25.0 and 29.9), more than half the U.S. population above 20 years of age is overweight, and nearly a quarter is clinically obese (dark shading).


    These experts add that even if being overweight is risky, there is scant proof that weight loss leads to a longer life in healthy overweight people. Given that few people can lose weight and keep it off, they question the wisdom of this approach. “Americans spend about $40 billion per year on weight-loss treatments, mostly in the form of diets and dietary foods, and this approach is clearly not working,” says Steven Blair, research director of The Cooper Institute for Aerobics Research in Dallas.

    This revisionism has stirred plenty of controversy. Nutrition researcher John Foreyt of Baylor College of Medicine in Houston, for one, notes that “obesity is the driver” for health risks including high lipid levels, high blood pressure, and high blood sugar. But other doctors and scientists are advocating a more individual approach to weight loss: examining each person's risks, which depend not only on weight, but also on age, distribution of body fat, family history of disease, and current health problems such as high blood pressure. “It's very tricky how you decide whether an individual should be subjected to the rigors of weight reduction,” says endocrinologist Rudolph Leibel at Columbia University College of Physicians and Surgeons in New York City.

    Weighing the risk

    The modern medical case against obesity began to build in 1959, with the publication of the Metropolitan Life Insurance Company tables. Based on studies of hundreds of thousands of policy holders, the tables said that the risk of premature death increases steadily as weight increases above the so-called “desirable weight,” corresponding to about 126 pounds (57 kg) for a 5′4” (1.63 m) woman and 154 pounds (70 kg) for a 5′10” (1.78 m) man—remarkably lean standards that about 80% of American men and women now exceed.

    Several studies since then have supported that view, including two reported in 1983. One of these, from Helen Hubert and her colleagues at the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland, and Framingham, Massachusetts, included 5209 men and women between 30 and 60 years old from the Framingham area who were initially weighed and examined in 1949. The researchers found that the degree by which these people exceeded their desirable weight predicted—independent of age, smoking, and other variables—their incidence of coronary disease and consequent deaths 26 years later.

    In the same year, epidemiologist Robert Garrison and his NHLBI colleagues published data on the 2000-plus men in the Framingham Heart Study cohort showing that men who were just 20% above their desirable weight had significantly elevated mortality from all causes. “Slight overweight carries a risk for a lot of people,” says Garrison, now at the University of Tennessee Health Sciences Center in Memphis, an idea, he adds, that “remains correct” today.

    Garrison's view got a big boost in 1995, when Manson and her colleagues published two sets of results from the prospective Nurses' Health Study, a cohort of more than 115,000 young and middle-aged female nurses who had been followed for 14 to 16 years. The two reports related rates of death and cardiovascular disease to body mass index (BMI), defined as an individual's weight in kilograms divided by the square of his or her height in meters.

    The researchers found the lowest mortality rate in women with BMIs of less than 19. Compared to these very skinny women—today the BMI of the average U.S. woman is about 26—the risk of death increased by 20% for BMIs from 19 to 24.9, 60% for BMIs of 27 to 28.9, and by more than 100% for BMIs of 29 and higher. Heart disease risk showed a similar trend. “Average weight is associated with a substantial increase in risk of heart disease,” Manson concludes.

    The most recent study showing that skinny is safe appeared in the 1 January issue of The New England Journal of Medicine. June Stevens at the University of North Carolina, Chapel Hill, and her colleagues followed a cohort of more than 62,000 men and 262,000 women from the American Cancer Society's Cancer Prevention Study I for 12 years, and they found that the lowest death risk from any cause and from cardiovascular disease for women and men up to age 74 was associated with BMIs between 19 and 21.9.

    The link between excess weight and an increased risk of death apparently does not hold for the elderly, however. Stevens and her colleagues found no increase in the death rate as BMIs increased, even to very high levels, for subjects 75 years old and up. And in the April American Journal of Public Health, statistician Paula Diehr of the University of Washington, Seattle, and her colleagues found no effect of increased body weight on the 5-year mortality of more than 4000 nonsmoking men and women who were 65 to 100 years old. “The link between BMI and mortality is weaker for older adults than for younger ones,” Diehr says.

    Moreover, not all studies show that being slightly overweight carries an increased risk of mortality in younger persons. Several indicate that the risk is very low over a wide distribution of weights and that the low point in that is closer to a BMI of 24 than 19. In the 15 April American Journal of Epidemiology, for example, statistician Ramon Durazo-Arvizu, epidemiologist Richard Cooper, and their colleagues from Loyola University Medical Center in Maywood, Illinois, reported 12-year follow-up data on 13,242 men and women who participated in the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study.

    They found that mortality was lowest at a BMI of 27.1 for black men, 28.8 for black women, 24.8 for white men, and 24.3 for white women—all very near the average BMIs for those groups. What's more, the authors determined that for BMIs spanning nine units around the safest value, mortality was no more than 20% higher. This range includes 70% of the population. “Others suggest that a BMI of less than 19 is optimal, and that's questionable,” Durazo-Arvizu says.

    Cooper and Durazo-Arvizu believe the strength of their study rests on the fact that the results apply to the entire NHANES cohort, in contrast to those of other studies in which subgroups of smokers and people who were ill had been eliminated because those factors are thought to decrease weight while boosting the risk of death. Still, when the Loyola team weeded out smokers, they found that their results were very similar to those for the entire group.

    Who should lose

    One reason for these conflicting results, say experts, may be that measures of fatness alone leave out other factors that can affect just how much risk excess weight confers. These include the location of the additional fat, because many experts think that abdominal fat is more hazardous than lower body fat (see sidebar), and also an individual's fitness. Indeed, recent evidence indicates that being unfit confers an even greater risk of death than being overweight does.

    In a study of 21,856 men of varying body sizes presented last May at the annual meeting of the American College of Sports Medicine in Denver, statistician Chong Lee at the University of Alabama, Birmingham, the Cooper Institute's Blair, and their colleagues found that unfit, lean men with BMIs of 25 or less had twice the risk of mortality from all causes than fit overweight men with BMIs of 27.8 or greater.

    Where do you stand?

    The chart shows how BMIs (numbers in squares) vary with weight and height. Some think that BMIs of 26 to 27 carry moderate health risks, with risks increasing further as BMIs rise.


    Because fatter people tend to have lower activity levels, their sedentary lifestyles may thus at least partly account for their increased risk of disease and death. “I am concerned that these studies [on obesity risk] may have been overemphasized, primarily because the great majority do not take physical activity or cardiorespiratory fitness into account,” says Blair. Still, there's little doubt that serious overweight, as indicated by a BMI over 30, increases the risk of death—by anywhere from 50% to 150% depending on the study. But that raises another puzzle: So far epidemiologists have been unable to gather abundant evidence that losing weight extends life-span.

    Researchers have had good reason to expect that it should. Back in the mid-1970s, nutritional biochemist George L. Blackburn and his colleagues at the New England Deaconess Hospital (now the Beth Israel Deaconess Medical Center) in Boston showed that loss of just 10% of body weight in about 200 people who were 50% to 100% overweight produced significant drops in their blood pressure, blood levels of heart-damaging lipids called triglycerides, and blood-sugar levels. Weight losses also increased levels of high density lipoproteins (HDLs), which are supposed to protect against cardiovascular disease by helping rid the body of cholesterol.

    Since then, thousands of studies have confirmed and refined these results. One of the best comes from a team led by Lars Sjöström at the University of Göteborg in Sweden, who studied the effect of weight changes on cardiovascular risk factors in 842 severely obese patients, some of whom underwent surgery to reduce their weight. As the researchers reported in the November issue of Obesity Research, blood pressure and levels of triglycerides, HDL cholesterol, and insulin began improving at weight drops of 10% of body weight.

    But although losing weight clearly improves metabolic risk factors in overweight people in the short run, it is unclear whether this effect will last. “Even if you maintain weight loss, we don't know whether cardiovascular risk factors will stay down after 5 to 10 years,” Sjöström says. “That must be proven.”

    What's more, it has been hard to establish the benefits of losing weight on life expectancy. In fact, a number of prospective epidemiological studies have shown that weight loss actually increases mortality. These studies had an inherent problem, however. They failed to separate intentional weight loss from unintentional drops in weight, which are often caused by illness. As a result, the death rate among weight losers may have been artificially high because many of them were sick. “If you don't adequately control for underlying illness, what's good about weight loss may end up looking bad,” says David Williamson, an epidemiologist with the Centers for Disease Control and Prevention in Atlanta.

    So in 1995, Williamson, along with Elsie Pamuk of the National Center for Health Statistics in Hyattsville, Maryland, and their colleagues reanalyzed data from 43,457 overweight middle-aged white women who had been asked about their history of intentional weight loss back in 1959 to ‘60 as part of the Cancer Prevention Study I and whose death rate was assessed 12 years later.

    Williamson's team found that overweight women who intentionally lost weight and also had obesity-related health problems had a 20% mortality reduction. This was mostly due to a 40% to 50% decline in obesity-related cancers, such as those of the breast, uterus, and cervix, as well as a 30% to 40% decrease in diabetes-associated mortality. In as yet unpublished results, Williamson and his colleagues have seen similar mortality reductions, mostly due to drops in diabetes-linked deaths, for intentional weight loss in overweight men with obesity-related health problems.

    But in both studies, the overweight men and women with no preexisting illnesses who had intentionally lost weight showed no consistent reduction in mortality. “There is not good evidence that intentional weight loss in obese people without obvious comorbidities is beneficial,” Williamson says. He speculates that some people may be resistant to the health effects of obesity.

    Other health experts emphasize that recommending weight loss is often futile, in any case. As a result, given the considerable effort, and in many cases, expense, required to lose weight, some physicians conclude that it simply may not be worth it. “Until we have better data about the risks of being overweight and the benefits and risks of trying to lose weight, we should remember that the cure for obesity may be worse than the condition,” write Jerome Kassirer and Marcia Angell, editors of The New England Journal of Medicine, in a 1 January editorial.

    Instead, these critics of obligatory weight loss favor emphasizing a healthier lifestyle, including exercise and an improved diet. Last year, researchers reported that participants in the Dietary Approaches to Stop Hypertension Trial could lower their blood pressure within 2 weeks by consuming more fruits and vegetables and less saturated fat—without losing weight. Says Blair: “I think we should emphasize behavior, eating a healthful diet, and regular physical activity, and not focus so much on the scale.”

    But others, such as Baylor's Foreyt, disagree. Given the epidemiological evidence linking obesity and disease, he says, weight loss itself is likely to be beneficial. He says that people with a BMI of 27 should “certainly” slim down, as should thinner people who have other risk factors like high blood pressure.

    Adds Alison Field of Brigham and Women's Hospital in a 16 April letter to the editor in The New England Journal: “Even a modest degree of excess weight is associated with an increased risk of hypertension and diabetes, … and clinicians would be remiss if they didn't discuss weight loss and weight maintenance with their overweight patients.”

    People on both sides of the debate can agree about one thing, however. An ounce of prevention is worth more than a pound of cure. Adults in their 20s and 30s, in particular, often gain a lot of weight and would be well advised not to do so. “Preventive measures are better than beating on obese people, who really can't do anything about it,” Kassirer says. Brigham's Manson concurs: “My recommendation is to avoid exceeding a BMI of 25 by avoiding substantial weight gain during adulthood.”

    Perhaps, in the future, new medications may help those who need them to battle their weight (see p. 1383). But until then, as exercise physiologist Glenn Gaesser of the University of Virginia, Charlottesville, writes in another letter to The New England Journal, we might be wise “to heed one of Hippocrates' more insightful, if less well-known, aphorisms: ‘Do not allow the body to attain extreme thinness, for that, too, is treacherous, but bring it only to a condition that will naturally continue unchanged, whatever that may be.’”

    Additional Reading


    Do 'Apples' Fare Worse Than 'Pears'?

    1. Ingrid Wickelgren

    While some experts debate how risky it is to be overweight and just who should slim down (see main text), others insist that it's not just how much fat you have but where you carry it that affects your risk of disease. In their view, fat inside the abdomen, as opposed to flab on the thighs and buttocks, is the main culprit. “There's growing enthusiasm” for the idea that abdominal fat increases the risk of such serious conditions as diabetes and cardiovascular disease, says lipid researcher Ronald Krauss of Lawrence Berkeley National Laboratory in California.

    The problem, these researchers say, is that abdominal fat cells quickly break down stored lipids and dump the resulting fatty acids into the bloodstream. That could in turn cause a dangerous rise in blood levels of the sugar glucose and triglyceride fats. But others argue that abdominal fat is secondary to the true problem, which leads to both disease and bulging bellies: excessive production of hormones that surge into the blood during stress.

    Although a French physician named Jean Vague linked abdominal fat to disease in 1947, few obesity researchers took the idea seriously until 1982 when endocrinologist Ahmed Kissebah's group at the Medical College of Wisconsin in Milwaukee showed that women with abdominal obesity are less efficient at breaking down glucose—a defect that can augur type II diabetes—than are lean controls or heavy women with mostly lower-body fat. The researchers also found a clue as to why: Abdominal fat cells are much larger, and much more adept at breaking down lipids into fatty acids, than fat cells on the leg and buttocks. The Milwaukee group reasoned that the flood of fatty acids might interfere with glucose metabolism.

    Outline of danger.

    People with mostly upper body fat (apples) may face more health risks than pear-shaped people.

    Since then, many researchers have confirmed and extended these results. They've shown that when free fatty acids from the blood bombard muscle cells, the cells have trouble taking up glucose. That raises blood-glucose levels and, thus, the risk for type II diabetes. In addition, fatty acids from belly fat have direct access—by way of the portal vein—to the liver, where they suppress the normal breakdown of insulin, the hormone that enables cells to absorb glucose. As a result, blood-insulin levels rise, making muscle, fat, and liver cells less sensitive to the hormone—a condition that could further augment blood-glucose levels.

    The fatty acid overload also seems to coax the liver to churn out more triglyceride fats and dump them into the blood, where they can, in large amounts, promote atherosclerosis and increase the risk of heart attack. What's more, lots of free fatty acids might even raise blood pressure—perhaps by increasing the sensitivity of arteries to hormones like epinephrine that make them contract.

    But fatty acids, or even fat, might not be the primary culprit at all, says obesity researcher Per Björntorp of the University of Göteborg in Sweden. He proposes that the real cause of the ills that have been linked to abdominal obesity—as well as the belly fat itself—is stress hormones like cortisol.

    Björntorp came to that conclusion after his team found, in studies of thousands of people, that individuals whose cortisol levels spike during the day because of chronic stress have significantly more abdominal fat than people whose daily cortisol rises and falls in the natural cycle. The researchers also think they know why: Abdominal fat cells are densely peppered with the receptors through which cortisol exerts its effects and that can, when stimulated, promote fat absorption.

    What's more, because cortisol independently causes insulin resistance and can spur the production of heart-damaging lipids, the hormone alone could account for many of the ill effects attributed to excess abdominal fat. “I think fat in the belly is an index of the basic hormonal disturbance,” Björntorp says. “The fat itself may or may not be a disease-generating factor.”

    Kissebah suggests another factor that might help explain the link between abdominal fat and disease. He notes that belly fat may be an indicator for genes that influence both where fat is deposited and disease risk. But he adds that however the abdominal cells get fat, the fatty acids they release might compound the problems created by stress or genes. “I think all three things are working together,” Kissebah says.


    As Obesity Rates Rise, Experts Struggle to Explain Why

    1. Gary Taubes

    In the United States of the 1990s, signs of health consciousness are everywhere—except at people's waistlines. Low-fat foods, health clubs, and athletic gear have become multibillion-dollar industries, with Nike and Gatorade seemingly only slightly less ubiquitous than Microsoft. Statistics suggest that this health awareness is paying off. Since the early 1960s, blood pressure and blood cholesterol levels have been dropping, while rates of coronary heart disease mortality have declined by more than half. Given these trends, you might expect to see a trim, well-toned population, but you don't.

    Since 1980, weights in the United States have been inflating at an alarming rate—and the rest of the world seems to be following suit (see sidebar). Currently, 22.5% of the U.S. population is considered to be clinically obese—compared to only 14.5% in 1980—and the end to the increase does not appear to be in sight. What's more, this “obesity epidemic,” as many public health experts call it, affects all demographic groups, including children.

    Much less clear is what's behind the increase, especially the big leap that seems to have occurred in the 1980s. Although many researchers blame increased food availability and declining physical activity (see p. 1371), “we don't have a terrific answer,” says Bill Dietz, who directs the division of nutrition and physical activity at the Centers for Disease Control and Prevention (CDC). “We have not clearly identified the major changes in eating behavior or activity sufficient to account for the recent rapid increase in obesity.”

    Going up.

    With the possible exception of preobesity (BMIs from 25.0 to 29.9), the prevalence of all classes of obesity seems to have ticked upward during the 1980s.


    The epidemic shows up mainly in data from the National Health and Nutrition Examination Surveys (NHANES), carried out by the National Center for Health Statistics (NCHS). So far there have been four data “cycles,” covering the years 1960 to 1962 (known as the National Health Examination Survey or NHES), 1971 to 1974 (NHANES I), 1976 to 1980 (NHANES II), and the latest, conducted from 1988 to 1994 (NHANES III). The surveys include both interviews in the home and physical examinations and are considered to be a realistic portrait of the state of American health. “Through a very complex sampling process, they are felt to be representative of the U.S. population—across all ages, income strata, and ethnic groups,” says Bill Harlan, head of the Office of Disease Prevention at the National Institutes of Health (NIH).

    The NHES survey, completed in 1962, found that 12.8% of the population was obese, with obesity defined as having a body mass index (BMI) greater than 30. [The BMI is calculated by dividing a person's weight in kilograms by their height in meters squared. By this measure, a 5'10” (1.78 m) individual would be considered overweight at 175 pounds (80 kg) and obese at 210 pounds (95 kg).] The prevalence of obesity increased only modestly in the next 2 decades, going to 14.1% in the NHANES of 1971 to 1974 and 14.5% in the NHANES II of 1976 to 1980. But then the epidemic apparently set in.

    By NHANES III, completed in 1994, the prevalence of obesity had increased by more than half, to 22.5% of the population. By the end of the survey, some 55% of the total population was officially considered overweight. “That is the big jump that has everyone concerned and surprised,” says NCHS epidemiologist Katherine Flegal. Adding to the concern, the prevalence of obesity was slightly higher in the second 3 years of NHANES III than in the first, an indication that the epidemic might still be spreading.

    Perhaps even more disturbing is the finding that obesity seems to be on the rise in all segments of the population. “There is a suggestion that the increases are a little greater in middle-aged men than in other groups,” says Flegal. “But beyond that … the increase is similar for men and women, for nonsmokers and smokers, and for all educational levels.”

    Even children haven't escaped. For children and adolescents, the BMI indicating overweight varies with age, so the adult definitions of overweight and obesity do not apply. Instead, the NHANES researchers identify children as overweight if they are over the age-specific 85th percentile of weight from the earliest survey and obese if they are above the 95th percentile. Using these definitions, the trends in children are only slightly different than in adults.

    For instance, in boys ages 6 through 11, the percentage of those considered overweight showed a steady increase from 15.2% to 22.3% between 1963 and 1991. The percentage of overweight young girls stayed relatively constant through the first three surveys and then jumped from 15.8% to 22.7% between NHANES II and the first half of NHANES III. The same trends appear in adolescents ages 12 through 17. The most dispiriting numbers from NHANES are in African-American children and adolescents, although the sample size was small: The percentage of boys defined as obese jumped from 2.0% to 13.4%, while obesity rates in girls went from 5.3% to 16.2%.

    Those are the data. The reasons behind them are less clear. According to work by Flegal and her colleagues, perhaps 20% of the increase in overweight adults may be due to smoking cessation. “Men typically gain 8 to 9 pounds [3.5-4 kg], and women 11 to 13 pounds [5-6 kg], when they quit,” says clinical psychologist Tom Wadden of the University of Pennsylvania.

    Researchers generally attribute the rest of the increase to simple caloric imbalance. Somehow in the 1980s, the thinking goes, the effects of modernization—of computers, remote controls, and one or more cars in every garage—combined with an unprecedented abundance of cheap, energy-dense food to produce a population that eats more while becoming ever less physically active. “Food is probably cheaper and more available than it's ever been in history,” says Xavier Pi-Sunyer, a Columbia University obesity researcher who recently chaired an NIH obesity task force. “At the same time, the workforce has gone to all kinds of labor-saving devices that mean most people at work are sedentary. They're also commuting longer, spending more hours sitting in a train or a car; they're passive observers at entertainment.”

    The catch is that none of this can be backed up by data. Both dietary intake and physical activity are very hard to measure on a population-wide scale. The dietary data that are available, says Flegal, show an average increase of a few hundred calories per day between NHANES II and NHANES III. Although that might account for the increased prevalence of obesity, “it's very hard to say whether the increase we're seeing is real or due to methodological improvements,” Flegal says.

    As for physical inactivity, the CDC's Behavioral Risk Factor Surveillance System suggests it is not increasing and may even be decreasing. “If you squint your eyes,” says CDC epidemiologist David Williamson, “it looks pretty flat over time.”

    That raises another possibility, although it too has little evidence to support it: that Americans aren't getting fatter, they're just getting heavier, maybe because they're exercising. If Americans are exercising more, as the Nike phenomenon suggests, then they could be putting on lean body mass, which weighs more than fat. This could also help explain the decreases in blood pressure, blood cholesterol, and coronary heart disease mortality. But few obesity experts buy the idea. Dietz points out, for example, that everybody is getting heavier, including young boys and girls, and you just wouldn't expect that pattern if exercise was the explanation.

    The bottom line, says Flegal, is that the increase is probably due to too much food and too little activity, but that still has to be backed up by good data. “It's probably just what we think it is. … Everybody assumes it must be true, but the data don't quite fit.”


    Weight Increases Worldwide?

    1. Gary Taubes

    By now, it's well established that obesity in the United States is reaching epidemic proportions (see main text). For the rest of the world, the data are spotty at best. But because hints of the same trend show up around the globe, the World Health Organization (WHO) and the International Obesity Task Force (IOTF) have declared an obesity epidemic on a global scale. As the IOTF puts it, obesity, which increases the risk of developing such potentially fatal conditions as diabetes and heart disease, “poses one of the greatest threats to human health and well-being as the 21st century approaches.”

    The best evidence for an increase outside the United States comes from the United Kingdom, where data from the National Health Survey suggest that obesity rates jumped from 6% to 15% in men and from 8% to 16.5% in women between 1980 and 1994. For the rest of the world, the data from national health surveys and studies of small population samples look like this:

    n In the Americas outside the United States, only Brazil and Canada have collected trend data. In Brazil, between 1976 and 1989, obesity prevalence increased from 3.1% to 5.9% in men and from 8.2% to 13.3% in women. In Canada, between 1978 and 1992, obesity prevalence went from 6.8% to 12.0% in men and 9.6% to 14.0% in women.

    n In Europe, studies from Finland, the Netherlands, and Sweden suggest that the prevalence of obesity is increasing slightly in men and not at all in women. In contrast, an unpublished study in the former East Germany suggests that between 1985 and 1992, rates of obesity increased from 13.7% to 20.5% in men and 22.2% to 26.8% in women.

    n In the Western Pacific region, the prevalence of obesity in Australia increased from 9.3% to 11.5% in men and from 8.0% to 13.2% in women between 1980 and 1989. In China and Japan, studies suggest that obesity may be increasing slightly in men but not in women. And then there are what nutritionist Tim Gill, scientific secretary for the IOTF, calls “horror stories,” such as Western Samoa, where between 1978 and 1991 urban obesity rates went from 38.8% to 58.4% in men and from 59.1% to 76.8% in women.

    n In Southeast Asia, the only meaningful data come from two small studies in Thailand, suggesting that between 1985 and 1991 obesity prevalence increased from 2.2% to 3.0% in men and from 3.0% to 3.8% in women.

    n In Africa, the only trend data come from Mauritius, where one study suggests that obesity prevalence increased from 3.2% to 5.3% in men and 10.4% to 15.2% in women between 1987 and 1992.

    Because of the poor quality of the data, says Gill, “you always have to reinforce the fact that we are on thin ice here making statements about levels of obesity.” Still, he says, the consistency of the increases around the world is what makes the situation worrisome. As a result, the IOTF and WHO are working under the assumption that what is happening in the United States will eventually spread to the rest of the world as well. “Many things occur in modernization, and they occur in different times in different countries,” he says. “The States happens to be at the fore of a number of changes that may in fact be conducive to obesity.”


    Uncoupling Proteins Provide New Clue to Obesity's Causes

    1. Trisha Gura
    1. Trisha Gura is a science writer in Cleveland.

    Just about everybody who has struggled to shed and keep off pounds has envied those lucky few who apparently can eat whatever they want and never change their dress size. Metabolism—the way we break down food and use it for energy—may make at least part of the difference. Some people simply have lower metabolic rates, and thus a greater tendency to gain weight, than others. Now, researchers may be getting a handle on what accounts for those differences.

    Just over a year ago, they identified what appear to be the first human “uncoupling proteins” (UCPs). Originally discovered decades ago in the special brown fat cells that animals such as bears burn up while hibernating, UCPs are so called because they dissociate the reactions that break down food from those that produce the body's chemical energy. In effect, they punch holes in the energy-production pipeline, raising the body's resting metabolic rate.

    Because the lost chemical energy is dissipated as heat, UCPs help hibernators and other cold-adapted animals maintain their core body temperatures in frigid weather. But people don't have brown fat, except in small amounts when they are newborns, and researchers did not think that the proteins had much effect on human metabolism. The new work now challenges that assumption, because its shows that other human tissues, including ordinary fat and muscle, make proteins very similar to the animal UCPs.

    There's no proof yet that these human UCP relatives uncouple metabolism and energy production. But researchers are scrambling to pin down their role, because if human UCPs do have the predicted function, their discovery could help provide a better understanding of obesity as well as improved treatments for the condition. “The field is burgeoning,” says Mary Ellen Harper, a metabolic physiologist at the University of Ottawa in Canada. She and others suggest that variations in UCP production or activity may be what cause some people to have lower or higher metabolic rates—and thus greater or lesser tendencies to get fat—than others.


    When activated by cold, uncoupling proteins (UCPs) let hydrogen ions pass through the inner mitochondrial membrane, thereby abolishing the hydrogen ion gradient needed to drive ATP synthesis. Nucleotide binding prevents the UCP from doing that.


    But even if that's not the case, UCPs might be good targets for obesity therapy, especially as they appear to act mainly in fat and muscle, whereas many other weight-regulatory molecules seem to work mainly in the brain (see p. 1378). By hiking up UCP activity, “you could boost your metabolic rate and you wouldn't act on the central nervous system,” with the potential that has for causing side effects, says physiologist Eric Ravussin at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Phoenix. “It's like jogging without jogging.”

    The first uncoupling protein (UCP1) was discovered independently in the mid-1970s by biochemist David Nicholls at the University of Dundee in the U.K. and Daniel Ricquier at the National Center for Scientific Research (CNRS) in Paris. At the time, researchers already knew that hibernating animals, and also cold-adapted rodents, use special fat cells, the brown adipocytes, to produce body heat. To try to find out more about how these cells work, Ricquier kept lab rats in either cold or warm temperatures and then looked for differences in the proteins made by the brown fat cells. Sure enough, he found that the fat cells of the chilly rats churn out a 32-kilodalton protein that is not made by the cozier animals.

    At about the same time, Nicholls and his team identified the mitochondria, the tiny kidney-shaped organelles that serve as the cells' powerhouses, as the source of heat released by brown fat. The mitochondria use the energy contained in dietary sugars, fats, and other nutrients to drive the synthesis of the high-energy compound adenosine triphosphate (ATP). This process depends on an electrochemical gradient set up across the inner of the two mitochondrial membranes when protons (positively charged hydrogen ions) are pumped out of the interior chamber of the mitochondrion.

    By injecting a radioactive compound into fat cells and then measuring its concentration on either side of the mitochondrial membrane, Nicholls and his colleagues showed that the inner membrane of brown fat mitochondria is very permeable to protons. Ultimately, the researchers traced this leak to a protein in the mitochondrial membrane that came to be known as UCP1.

    By creating the leak, UCP1 reduces the number of ATPs that can be made from a given amount of food, thereby raising the body's metabolic rate and generating heat. Normally, though, the protein is kept in an inactive state by nucleotides that bind to the protein. Then, when the animal needs extra heat, it activates neurons that release the neurotransmitter norepinephrine at the surfaces of the brown fat cells, and the hormone then sets in motion a chain of events that releases the inhibition.

    For many years, uncoupling proteins didn't appear to play an important role in body metabolism in people. Humans have a UCP1 gene, but it's active only in their brown fat, which disappears shortly after birth. Still, measurements of the amount of oxygen that human and other animal cells consume when they metabolize food show that anywhere from 25% to 35% of that oxygen is being used to compensate for mitochondrial proton leaks. “There is a significant proportion of uncoupling going on all the time,” says Harper, who performed such oxygen-consumption studies in the laboratory of Martin Brand at the University of Cambridge. What causes that uncoupling has been unclear, but the novel UCP family members may provide an explanation.

    Craig Warden, a geneticist at the University of California, Davis, working with Ricquier in Paris and Sheila Collins's team at Duke University, came on the first of these early last year. While combing through genetic databases, the researchers identified sequences strongly resembling those in UCP1. After cloning the corresponding gene, they showed that the protein, UCP2, is expressed in tissues ranging from the brain to muscle and fat cells.

    Warden says he was inspired to look for UCP1 relatives because he had heard Louis Tartaglia of the biotech firm Millennium Pharmaceuticals in Cambridge, Massachusetts, talking about his team's discovery of such a protein at a meeting. The Millennium team held up on publishing their results, however, until the company filed for patents, which it has since received on the UCP2 gene and its potential use in diagnosing an individual's risk of becoming obese.

    A third human UCP made its debut on the heels of UCP2's discovery. A trio of research groups—one headed by Jean-Paul Giacobino at the University of Geneva in Switzerland, another by Brad Lowell at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, and a third by Mark Reitman at the NIDDK labs in Bethesda, Maryland—independently cloned the gene for this protein, UCP3, which seems to be active mostly in muscle cells.

    No one knows for sure whether UCP2 and −3 behave like UCP1, although circumstantial evidence suggests they do. For example, the family members look startlingly alike. Both the UCP2 and −3 genes are about 56% identical to the UCP1 gene. “That is pretty high homology,” Lowell says, and suggests that the genes' products have similar functions.

    Further evidence that the new proteins uncouple oxidation and ATP synthesis comes from experiments in which the researchers engineered either yeast or muscle cells from mice to express extra copies of UCP2 and UCP3. Compared to mitochondria of normal cells, those from the UCP-loaded cells show a lower membrane potential—a sign that the proton gradient is leaking. “It's a strong indication that UCP2 and UCP3 uncouple, at least in yeast and other transfected cells,” says Giacobino.

    Mitochondria from UCP2-altered yeast cells also tend to use more oxygen, another sign of uncoupling. Researchers are now conducting similar experiments to measure oxygen consumption by mitochondria from the mouse cells.

    While researchers wait for proof that UCP2 and −3 are bona fide uncouplers, they are also pursuing hints that variations in these genes could affect body weight. In one study of 640 French Canadians, for example, Claude Bouchard at Laval University in Quebec, working with Ricquier and Warden, showed that certain DNA sequences that flank the UCP2 gene are found primarily in people with low metabolic rates. The researchers also have evidence that those markers may be linked to body mass and percentage of fat in obese individuals within the group.

    Similarly, NIDDK's Ravussin, Warden, and their colleagues found that certain changes in the UCP2 gene seem to be associated with a sluggish resting metabolic rate in a group of 76 Pima Indians and more weakly associated with obesity in a group of 1000 Pimas. Only old people showed the linkage with obesity, however. “If this variant really does something to metabolic rate, we think it may take time to show up in body weight,” Ravussin suggests.

    Now his team is looking at some promising variations (polymorphisms) located in the regions that help to regulate the activity of the UCP3 gene. These, too, seem to be linked with obesity or slow metabolism, although Ravussin emphasizes that these findings are preliminary.

    On a more cautious note, however, not all studies have supported a connection between the human UCPs and obesity. For example, Danish investigators at the Steno Diabetes Center and Hegedorn Research Institute in Copenhagen couldn't find anything unusual about the UCP2 variants carried by 35 obese or diabetic patients. In a study of 60 patients, they also failed to find any link between those conditions and UCP3 polymorphisms.

    Muddying the picture still further are studies of how UCP and gene expression change when animals and people are temporarily starved. If the proteins are, in fact, calorie burners, their activity would be expected to drop when food is scarce. Instead, the studies seem to show that total fasting actually increases the activity of their UCP2 and −3 genes. “You would think that starvation would be the worst time your body would decide to increase energy expenditures,” says Lowell.

    Olivier Boss, working with Giacobino and Patrick Muzzin at Geneva, has results that may resolve this paradox, however. They show that although going without food altogether sparks UCP2—and more dramatically, UCP3—gene activity in various tissues of rats, restricting the animals' food by more than 60% of normal amounts actually decreases the expression of UCP1 in brown fat and UCP3 in muscles. The difference, Boss and others say, could hinge on how the body responds to a reduction in food as opposed to total cessation.

    The body has to maintain its core temperature, and when totally deprived of food, it may do this by turning up its UCPs, even at the cost of burning its fat stores. In less dire circumstances this may not be necessary, however, and the body may turn down UCP activity to save energy.

    One dietary study does fit the calorie-burner hypothesis: Collins, at Duke, found that a high-fat diet can turn up the activity of the UCP2 gene and protect mice against obesity. She, along with Duke's Richard Surwit and their colleagues, stumbled onto the finding when they started feeding high-fat diets to their murine subjects. Two strains, called A/J and black kalas, managed to stay svelte on such diets, but the third, known as C57-black, immediately fattened up.

    When Collins compared the UCP2 genes in the strains, she found a possible explanation: differences in genes' regulatory regions. What's more, the sequence differences apparently affect gene expression. “Kala behaves like [the equally slim] A/J in that it up-regulates UCP2 messenger RNA very quickly in response to a high-fat diet,” says Collins. In contrast, the C57 mice did not display a comparable increase.

    To get more definitive proof that UCP2 and −3 are involved in regulating basal metabolic rates, and thus weight gain or loss, researchers like Lowell and many others are working to engineer mice in which the genes encoding the proteins are either knocked out or overactive. If these manipulations have the postulated effects, then the race will be on to find drugs that can combat obesity by turning up the activity of the proteins. “If one were to identify small molecules that one would take through the oral route, then we might be able to stimulate the uncoupling proteins enough to reduce body weight,” says Tartaglia at Millennium.

    Still, obesity research is full of dashed hopes. Biochemist Ricquier remembers how in the 1960s physicians treated obese individuals with nonspecific uncoupling drugs. They did help burn fat by hiking resting metabolic rates. But in some cases ATP formation plunged to zero—with fatal results.

    Given those failures, he says, the key now is to figure out how the uncoupling proteins work and then nudge them to work just a little harder. “If we could develop compounds that very slightly increase the level of uncoupling—by 1% or 2%,” Ricquier suggests, “then we would simply increase fat oxidation and thermogenesis.” And that could boost the resting metabolic rates of millions of people and whittle away their days of perpetual dieting.