Processing for Science

"@Home" projects band together and proliferate
By Charles Q. Choi

TEMPERATURE MODELING of the earth by the computing project Climateprediction.net depends on data that are divvied up in chunks and crunched by home users. Fans of the spacetime continuum can now uncover gravitational ripples at their desks thanks to the February launch of Einstein@Home. The project is one of the latest of at least 60 "@home" projects now on the Internet, in which personal-computer users can donate spare processor power to help solve scientific problems. And no need to choose one mission over another: @home software can now multitask, and enough microchip muscle exists to handle many more distributed-computing projects.
Save for computationally intense tasks such as rendering graphics, typical modern PCs that perform at least one billion floating-point operations per second (that is, most home computers built since about 2000) almost never employ their full power. Distributed computing takes advantage of this spare capacity, dividing large tasks into tinier ones and sending them over the Internet for usually idle computers to work on. The result is unparalleled processing muscle: IBM's BlueGene/L, now the most powerful supercomputer, cranks out about 70 trillion flops; meanwhile SETI@home conservatively runs off roughly 500,000 PCs at more than 100 trillion flops, says SETI@home director David P. Anderson.

Since the first public distributed-computing project--the Great Internet Mersenne Prime Search--was launched in 1996 to look for large prime numbers, virtual supercomputing projects have emerged for the serious (testing potential drugs with FightAIDS@home) to the sublime (the Monkey Shakespeare Simulator). Anderson expects hundreds of @home projects to emerge in the next few years and the number of participating CPUs to reach 30 million from the roughly 1.3 million of today.
A key development in the surge is the formation of distributed-computing platforms that can host multiple projects. Among the biggest is the Berkeley Open Infrastructure for Network Computing (BOINC), which hosts SETI@home and Einstein@Home as well as the formerly independent Climateprediction.net, which joined in August. In coming months BOINC partners will include FightAIDS@home, PlanetQuest and Orbit@home. Other umbrella distributed-computing software platforms include Grid.org, which is running two projects to find compounds against cancer and predict three-dimensional protein structures from amino acid sequences, and Find-a-Drug.org, which currently has nine projects looking for drugs against various ailments, such as malaria and Creutzfeldt-Jakob disease, the human relative of mad cow disease.
Such @home hosts are also time-savers for scientists. BOINC, for instance, offers open-source infrastructure code so researchers do not have to write their own. It can take several person-years to develop the software, because it must perform unobtrusively on different operating systems in up to a million computers while protecting against erroneous results and malicious attacks. "We want to make it easy for scientists to get access to millions of computers' worth of processing power," says Anderson, who also directs BOINC.
Anderson estimates that, for a typical computer, the practical upper limit for the number of @home projects is roughly 12. At that point, its processing power is parceled so thin that projects consider it useless. A service that rotates a PC automatically between projects is possible in the future, he adds. Still, umbrella platforms might interfere with one another if operating simultaneously on the same computer. But with the roughly 200 million privately owned computers in the world, notes Ed Hubbard, president of United Devices in Austin, Tex., which runs Grid.org, "there's plenty of room for everybody."

New Dinosaur Documents Shift from Meat to Veggie Diet

A treasure trove of fossils uncovered in Utah is helping paleontologists understand why some meat-eating dinosaurs evolved into vegetarians. The bones represent a new species belonging to a group known as the therizinosaurs, plant-eating cousins of Jurassic Park's Velociraptor.
Scientists unearthed some 1,700 bones, which date to 125 million years ago, from the base of the Cedar Mountain rock formation in Utah. According to James Kirkland of the Utah Geological Survey, hundreds to thousands of individual dinosaurs could have perished at the two-acre dig site. The researchers recovered bones representing about 90 percent of the skeleton of the new species, Falcarius utahensis, which walked on two legs and stood over four feet tall. Although no feathers turned up, the team posits that the beast was covered in shaggy protofeathers because direct evidence for feathers has been discovered on fossils of its close relatives in China.

Indeed, most of the fossils of other known therizinosaurs have come from China and Mongolia, with just one 90-million-year-old specimen hailing from New Mexico. "Falcarius utahensis shows the beginning of features we associate with plant-eating dinosaurs, including a reduction in size of meat-cutting teeth to leaf-shredding teeth, the expansion of the gut to a size needed to ferment plants, and the early stages of changing the legs so they could carry a bulky body instead of running fast after prey," Kirkland explains. This discovery thus places the most primitive therizinosaurs in North America. Study co-author Scott Sampson of the University of Utah notes that the rise of plant-munching therizinosaurs in Utah "may have been directly linked to the spread of flowering plants about 125 million years ago." --Sarah Graham

RELATED LINKS:
Dinosaurs and Other Monsters

Mouse Research Bolsters Controversial Theory of Aging

Aging is a process we humans tend to fight every step of the way. The results of a mouse study underscore the potential of antioxidants as a weapon in that battle: animals genetically modified to produce more antioxidant enzymes lived longer than control animals did. They also exhibited fewer age-related health problems overall.
The free radical theory of aging posits that substances with unpaired electrons attack the body's molecules and cause the functional decline of organs over time. Thus, antioxidants, which neutralize free radicals, should slow this deterioration. But animal models of aging designed to test the hypothesis have so far shown contradictory results.

In the new work, Peter S. Rabinovitch of the University of Washington and his colleagues engineered mice to produce higher-than-normal amounts of the enzyme catalase. Within cells, catalase removes hydrogen peroxide, a waste product of metabolism that could otherwise lead to damaging oxygen free radicals. In a paper published online this week by Science, the team reports that animals with higher levels of catalase in their mitochondria--the cell's energy-producing organelles--lived 20 percent longer on average than control animals did. What is more, mice in this so-called MCAT group had healthier heart tissue than normal mice and showed fewer mutations in their mitochondrial DNA. "This study is very supportive of the free-radical theory of aging," Rabinovitch says. "It shows the significance of free radicals, and of reactive oxygen species in particular, in the aging process."
Animals that overexpressed catalase in other parts of the cell, such as the nucleus, also exhibited longer life spans than their normal counterparts did, but the gains were modest. As such, the scientists note, the results reinforce the importance of mitochondria as a supplier of free radicals. The researchers have no plans to modify humans to increase protein expression, but they point out that future drug development could focus on protecting the body from free radicals. --Sarah Graham

RELATED LINKS:
The Science of Staying Young
The Truth about Human Aging
The Serious Search for an Antiaging Pill

Nanoparticles Pass Muster as Vectors for Gene Therapy

Image: COURTESY OF THE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES

Gene therapy, in which a viral vector is used to modify defective genes or replace missing ones, has shown significant potential as a way of treating disease in animal models. But its use in humans has been hampered by safety concerns, including some fatalities in clinical trials. Researchers have thus been looking into the possibility of using nonviral vectors, which should carry fewer inherent risks, to deliver therapeutic genes. In a paper published online this week by the Proceedings of the National Academy of Sciences, scientists report that silicon nanoparticles can perform this task successfully in mice.
Paras N. Prasad of the State University of New York (SUNY) at Buffalo and his colleagues manufactured nanoparticles using organically modified silicon. The surface of these particles can be tailored to target specific cells. The team used the tiny units to transport a fluorescent marker gene to dopamine neurons in the brains of mice. After injecting the nanoparticles, the researchers observed brain cells fluorescing using a new imaging technique that works on live animals. According to the report, the study is the first in which a nonviral vector has shown efficacy comparable to that of a viral delivery system in an animal model. What is more, a month later none of the animals had experienced adverse effects from the procedure.

The researchers also investigated the possibility of manipulating the behavior of specific brain cells, instead of solely tagging their presence. In so doing, they discovered that the nanoparticles can be used to reactivate adult stem cells by altering a nuclear growth factor receptor. The team will next test the approach on larger animals. "In the future," says study co-author Earl J. Bergey, also at SUNY Buffalo, "this technology may make it possible to repair neurological damage caused by disease, trauma or stroke." --Sarah Graham

Why Cats Don't Cotton to Sweets Explained

The lure of sweets is the downfall of many a dieter. Cats, however, are indifferent to sugar, a trait that is rare in the mammal kingdom. Now scientists have figured out why. Felines apparently carry a defect in a gene that encodes part of the mammalian sweet taste receptor.
A lack of interest in sweets has been observed not only in house cats, but also in wild ones such as lions, tigers and jaguars. "One possible explanation for this behavior is that felines are unable to detect sweet-tasting compounds like sugars and high intensity sweeteners because their sweet taste receptor is defective," remarks Xia Li of the Monell Chemical Senses Center in Philadelphia. Li led a team of researchers to investigate the genetics of taste in cats. They determined that the animals lack 247 base pairs in a gene called Tas1r2, which encodes T1R2, one of two protein subunits that make up the sweet receptor in most mammals. "This type of gene is known as a pseudogene and is somewhat like a molecular fossil," Li says. "It presumably once coded a functional protein, but no longer does so."

The other half of the sweet receptor, known as T1R3, is normal in cats. "What we still don't know is, which came first: carnivorous behavior or the loss of the T1R2 protein," notes senior author Joseph G. Brand of Monell. "With regard to the gene, is this a case of 'use it or lose it'"? The scientists describe the work in the July issue of the journal PLoS Genetics. --Sarah Graham

New Planet Discovered in the Solar System?

John Roach
for National Geographic News

August 1, 2005
A chunk of rock and ice that may be a planet has been discovered in the farthest reaches of the solar system, astronomers announced Friday. The object, currently called 2003 UB313, orbits the sun and is larger than Pluto, traditionally considered the ninth planet in the solar system.

The news came hot on the heels of the announcement of the discovery of a separate planet-like object at the edge of the solar system (see "New Pluto-Size Object Discovered in Solar System")—and amid fears that a rogue astronomer may been attempting to announce the UB313 discovery as his or her own.


The discovery of UB313 is likely to reignite the debate over the definition of "planet"—and over how many objects in the solar system are deserving of the name.

The sequence of events surrounding the UB313 announcement may also change how such objects are announced in the future, according to Brian Marsden, director of the International Astronomical Union's Minor Planet Center in Cambridge, Massachusetts.

UB313 is being called a scattered disk object or an extreme member of the Kuiper belt. The belt is a ring of icy debris that floats on the fringes of the solar system beyond Neptune.

The object is currently about 97 times farther from the sun than Earth is, or about three times farther from the sun than Pluto. Its orbit is more eccentric than Pluto's, taking it from 38 to 97 times the sun-Earth distance over a 560-year period.

UB313 is the farthest known object in the solar system—even further than Sedna, a planetoid discovered nearly two years ago (see "New Planetoid Found in Solar System—Most Distant Yet"). The newfound object is also among the five brightest Kuiper belt objects, as seen from Earth.

The sheer size of the object means that it can only be classified as a planet, according to Mike Brown, an astronomer at the California Institute of Technology in Pasadena, who announced the object's discovery.

Brown made the discovery with Chad Trujillo of the Gemini Observatory on the Mauna Kea volcano in Hawaii, and David Rabinowitz of Yale University in New Haven, Connecticut.

The team had originally planned to report the discovery of UB313 in October after more detailed observations. But they decided on an early announcement after it became clear that savvy Web users could—if they were so inclined—track down UB313 observation data online and use it to claim the discovery as their own, Marsden said.

Planet Debate

Brown and his colleagues are uncertain of the exact size of the object, but its brightness and distance from the sun tell them that it is at least slightly larger than Pluto. At one-fifth the mass of our moon, Pluto is the smallest of the nine planets.

"We are 100 percent confident that this is the first object bigger than Pluto ever found in the outer solar system," Brown said in a media statement.

Marsden, of the Minor Planet Center, said there "isn't much doubt" that 2003 UB313 is bigger than Pluto. However, he rejects the idea that the newly discovered object deserves planet status.


"If anything, it suggests we really seriously should go back to eight [planets in the solar system]—the traditional 19th-century ones," Marsden said.

Pluto was discovered in 1930. At the time, astronomers believed Pluto's mass was equal to Earth's. Since then refinements in measurement techniques have revealed the planet's relatively diminutive size.

Marsden said he proposed in 1999 to include Pluto in the catalog of what is now almost a hundred thousand sequentially numbered small bodies. The move would have effectively stripped Pluto of its status as a planet, at least in some astronomical circles.

The proposal was dropped, however, after objections from a minority of astronomers who wanted to preserve Pluto's historical significance.

Now that an object bigger than Pluto has been discovered, Marsden said, this is an ideal time to rectify matters.

If 2003 UB313 is to be called a planet, then a couple of dozen other Kuiper belt objects should be too, as well as the asteroid Ceres and perhaps a dozen other objects in the asteroid belt, Marsden added.

Discovery and Announcement

Brown, Trujillo, and Rabinowitz first observed 2003 UB313 on October 21, 2003, using the Samuel Oschin Telescope at Caltech's Palomar Observatory in San Diego County, California.

At the time, the object was so far away that its motion went undetected. It wasn't until January of this year that the object's orbital path was uncovered.

Since then the team has been studying UB313 with other telescopes. They planned to announce the discovery in October with more detailed information on its size and composition.

The team was also planning to announce the discovery of another large Kuiper belt object, 2005 FY9, in October.

The announcement of both objects was suddenly moved up to July 29 after an unexpected announcement from another group of astronomers, Marsden said. On July 28 a team led by Jose-Luis Ortiz at the Instituto de Astrofísica de Andalucía in Granada, Spain, had announced to the Minor Planet Center the discovery of 2003 EL61, another planet-like object at the edge of the solar system.

Brown's team also had independently observed EL61 and had posted on a Web site an abstract of a paper on the object on July 19. They plan to present their EL61 paper at an astronomy conference this September in Cambridge, England.

The U.S. astronomers, though, had not reported their EL61 discovery to the Minor Planet Center, which is the official governing body for the recognition of such discoveries.

The Minor Planet Center's Marsden said the timing of the Spanish team's discovery "struck me as a little odd," given that Brown's paper on EL61 had been posted online just ten days earlier. In e-mail discussions with Brown about the issue, the Caltech astronomer told Marsden about the two other objects and asked for advice.

"While he didn't care if the other object might [be] scooped, he did care about the big one [2003 UB313]," Marsden said.

Before Marsden replied to Brown, he learned from a colleague that someone had already calculated the orbits of 2003 UB313 and 2005 FY9. This other party had based his or her calculations on Brown's observation data from a Chilean telescope, which is readily available on the Web.

Marsden shared the information with Brown and urged him to make the announcement July 29.

"We had to assume that the [stranger's use of Brown's data] was malicious and that the person was going to use the information to attempt to claim he had discovered the objects himself. Thus we had to announce late on a Friday afternoon with no preparation," Brown wrote in an e-mail interview.

Marsden does not suspect that Ortiz's team is responsible for the suspected foul play. He also noted that Internet insecurity has made it tougher for scientists to check and double-check their findings before going public.

"It's a little startling to realize that the records of telescope pointings are available on the Internet. There's so much stuff out there that it's hard to keep something you found secret while you really study it and then prepare a proper publication about it," Marsden said.

Photo in the News: Panda Baby Boom Arrives on Pink Paws

July 12, 2005—Forget sharks: The summer of the panda is upon us, and it's padding in on 20 pink paws. Last week alone five giant panda cubs were born in captivity: one at Washington, D.C.'s National Zoo and two pairs of twins (one of which is pictured above) at China's Wolong panda reserve.
A newborn giant panda is about as big as a stick of butter and lacks the familiar black-and-white markings for its first month or so of life. Successful births in captivity are extremely rare—and extremely prized by conservationists, given the species's dwindling numbers. About 1,600 giant pandas remain in the wild, plus about 160 living in zoos and breeding centers, according to the National Zoo.

Adding a circle-of-life pallor to the otherwise rosy news, China this week announced that the world's oldest known giant panda, a female named Mei Mei, had died at a zoo in the city of Guilin at age 36—or about 108 in human years.

—Ted Chamberlain

Giant Catfish May Be World's Largest Freshwater Fish

Photograph by Suthep Kritsanavarin

Fishers in northern Thailand netted this huge catfish in the Mekong River on May 1. Nearly nine feet long (2.7 meters) and as big as a grizzly bear, the behemoth tipped the scales at 646 pounds (293 kilograms). Experts say the fish, which belongs to the species known as the Mekong giant catfish, may be the largest freshwater fish ever recorded.

Thai fishers struggled for more than an hour to haul in the record-breaking Mekong giant catfish. Officials from Thailand's Inland Fishery Deparment then used a performance-enhancing drug to stimulate the pituitary gland of the female fish in order to prepare it for a breeding program (above). Despite efforts to keep the bear-size catfish alive, it died and was later eaten by villagers.

The species is listed as critically endangered by the World Conservation Union (IUCN) and faces a high risk of extinction in the wild. The rare specimen, captured in the Mekong River in Chiang Khong district, is the largest since Thailand began keeping records in 1981.

Thai fisheries officials had hoped to release this adult female Mekong giant catfish after they stripped it of eggs (above) for a captive-breeding program. But the whopping fish, which was as big a grizzly bear, didn't survive.

Listed a critically endangered by the World Conservation Union (IUCN), the Mekong giant catfish is one of the world's largest freshwater fishes. Other contenders include the Chinese paddlefish and the dog-eating catfish—another Mekong River giant.

Editor's Note: It was initially reported incorrectly that the giant catfish caught in Thailand was male.

After a record-breaking Mekong giant catfish died, residents of Hat Khrai, a Thai village on the Mekong River, butchered the fish for its meat.

"Mekong people believe it's a sacred fish, because it persists on plant matter and 'meditates'"—in the deep, stony pools of the Mekong River—"somewhat like a Buddhist monk, said Zeb Hogan, a fisheries biologist who studies the largest freshwater fish in the world. A WWF conservation fellow and National Geographic Society Emerging Explorer, Hogan has received funding from the National Geographic Society Conservation Trust.

Mekong giant catfish attract high prices in Thailand, because eating the fish is supposed to bring good luck. Likewise, the Chinese believe that catfish meat boosts intelligence and prolongs life.

Mars Life May Be Contaminated by Spacecraft, Experts Warn

Hillary Mayell
for National Geographic News

July 26, 2005
Is there life on Mars? If there is, NASA might be contaminating it with microbes from Earth.

The concern prompted the Washington, D.C.-based National Research Council (NRC) to issue an advisory yesterday urging the U.S. space agency to adopt more stringent spacecraft-sterilization techniques.


Microbes (microscopic organisms that humans live with every day) can survive in much more extreme environments than previously believed—places of superheated temperatures, radiation, freezing cold, high salt concentrations, or extreme dryness.

"The science we've been operating on, gathered during the Viking 1 and 2 missions in the 1970s, is completely outdated," said University of California planetary scientist David Paige. Paige is also a member of the private, nonprofit NRC.

NASA's Viking landers were the first spacecraft to land on Mars and conduct scientific research. Viking 1 and Viking 2 landed on July 20 and September 3, 1976, respectively.

"The planetary protection policies that we have are rooted in the era of Viking. … ," Paige said. "Since then we've found that microbes are a lot more rugged than we originally thought," he added. "In addition, Mars might be more hospitable to life than we originally thought." For example, scientists have found evidence that there could be liquid water—which is necessary for life on Earth—at many places on the Mars. (See a photo of a "frozen sea" on Mars.)

Scaled-Back Sterilization

The early spacecraft that landed on Mars were thoroughly sterilized. But as money for the space program got tight, the expensive cleansing process was cut back.

Now that more is known about both Mars and microbes, the NRC is advising NASA to develop and implement new methods and rules to detect and eliminate microorganisms on robotic spacecraft. The techniques currently used to clean spacecraft only detect heat-resistant and spore-forming bacteria. The scientists are concerned that NASA's screening-and-cleaning process does not detect all the microbes that might be present on the spacecraft.

The advisory, which is based on a NASA-funded report by the NRC, recommends that all future landers be 100 percent sterilized. The NRC also suggests that NASA undertake a research program to find and test improved techniques within the next three years.

RNA to the Rescue

Novel inheritance patterns violate Mendel's laws
By JR Minkel

MUTATION of fused petals (left) disappeared in descendants, which appeared normal (right). The central dogma of modern biology holds that genetic information is inherited in the form of DNA, copied into RNA and expressed as protein; pride of place goes to DNA. But the spectacular discovery that a species of plant can summon up genes its parents have lost highlights biologists' increasing recognition of RNA as a more versatile and important molecule in its own right.
RNA already has a special place among biological molecules. It can store genetic information, as DNA does, but it can also adopt complex three-dimensional shapes and catalyze chemical reactions on itself, as proteins do. "RNA is DNA on steroids," says Robert Reenan, a geneticist at the University of Connecticut. "It can do just about anything." Life probably began as an "RNA world," in which concatenations of RNA molecules pulled double duty as genetic template and reproductive machinery.

The mustard plant Arabidopsis thaliana may be revealing another way in which life exploits RNA's capacity for genetic storage. Susan J. Lolle and Robert E. Pruitt of Purdue University study Arabidopsis whose petals are fused. Such plants have two mutant copies of a gene called hothead, which differ from the normal gene by a single base pair. Strangely, in a few percent of the offspring of Lolle and Pruitt's mutants, one copy of hothead spontaneously reverted to the normal version, repairing its point mutation. Even one such event is statistically unlikely outside of rapidly reproducing bacterial colonies. The investigators systematically ruled out mundane explanations, such as cross-pollination of a mutant plant by a normal one, an extremely high mutation rate or the presence of another, hidden copy of hothead.
Hothead mutants contained changes in other parts of their DNA, too, all of which matched the sequences of the plants' grandparents or great-grandparents but not their parents. This match suggested that a backup copy of the ancestral plants' genome was somehow being passed down, the researchers reported in the March 24 Nature. If true, such leapfrogging would circumvent the normal rules of genetics established by Gregor Mendel in 1865. Because the investigators could find no DNA to play the role, they have proposed that the backup template is double-stranded RNA (which ordinarily has just a single strand). "Double-stranded RNA is hot because that's what's needed for RNA interference," a common way of deactivating genes, says Richard Jorgensen, a plant scientist at the University of Arizona, "but there's no reason it couldn't be a DNA molecule either, and there's no reason it has to be double-stranded."
RNA would be a convenient mechanism, however, because researchers have uncovered several ways in which it modifies the expression or structure of DNA, and it might explain the mysterious production of RNA molecules that do not result in proteins. Several species, including Arabidopsis, rice, mice and humans, copy a surprising amount of RNA from the "wrong" DNA strand--that is, the strand opposite the one that specifies a protein. "Maybe this is where some of that template is coming from," says Joseph Ecker, a plant biologist at the Salk Institute for Biological Studies in La Jolla, Calif. Plants have many enzymes capable of duplicating RNA, Ecker notes, as well as a system for transporting the chemical between cells.
The Purdue group speculates that a separate genetic archive may serve as a hedge against hard times, such as an extended drought, by allowing a plant to access genes that helped its ancestors persist. In this sense, it would bear some resemblance to another strange property of RNA, called recoding.
A next step is determining how widespread the effects are. Unexplained cases of spontaneous reversions also appear in human genetic diseases, although the natural frequency of such events is unclear. Pruitt, for one, would be surprised if the mechanism were exclusive to plants: "It's hard to believe something that general wouldn't persist in other organisms."
JR Minkel is a frequent contributor.

His Brain, Her Brain

It turns out that male and female brains differ quite a bit in architecture and activity. Research into these variations could lead to sex-specific treatments for disorders such as depression and schizophrenia

By Larry Cahill

Image: SLIM FILMS On a gray day in mid-January, Lawrence Summers, the president of Harvard University, suggested that innate differences in the build of the male and female brain might be one factor underlying the relative scarcity of women in science. His remarks reignited a debate that has been smoldering for a century, ever since some scientists sizing up the brains of both sexes began using their main finding--that female brains tend to be smaller--to bolster the view that women are intellectually inferior to men. To date, no one has uncovered any evidence that anatomical disparities might render women incapable of achieving academic distinction in math, physics or engineering. And the brains of men and women have been shown to be quite clearly similar in many ways. Nevertheless, over the past decade investigators have documented an astonishing array of structural, chemical and functional variations in the brains of males and females.

These inequities are not just interesting idiosyncrasies that might explain why more men than women enjoy the Three Stooges. They raise the possibility that we might need to develop sex-specific treatments for a host of conditions, including depression, addiction, schizophrenia and post-traumatic stress disorder (PTSD). Furthermore, the differences imply that researchers exploring the structure and function of the brain must take into account the sex of their subjects when analyzing their data--and include both women and men in future studies or risk obtaining misleading results. Sculpting the Brain Not so long ago neuroscientists believed that sex differences in the brain were limited mainly to those regions responsible for mating behavior. In a 1966 Scientific American article entitled "Sex Differences in the Brain," Seymour Levine of Stanford University described how sex hormones help to direct divergent reproductive behaviors in rats--with males engaging in mounting and females arching their backs and raising their rumps to attract suitors. Levine mentioned only one brain region in his review: the hypothalamus, a small structure at the base of the brain that is involved in regulating hormone production and controlling basic behaviors such as eating, drinking and sex. A generation of neuroscientists came to maturity believing that "sex differences in the brain" referred primarily to mating behaviors, sex hormones and the hypothalamus.

MORE ON THIS ARTICLE OVERVIEW · Brains SIDEBARS · A Gray Matter · Sizable Brain Variation · Wired Preferences? · The Stressed Hippocampus · The Amygdala and Emotional Memory Several intriguing behavioral studies add to the evidence that some sex differences in the brain arise before a baby draws its first breath. That view, however, has now been knocked aside by a surge of findings that highlight the influence of sex on many areas of cognition and behavior, including memory, emotion, vision, hearing, the processing of faces and the brain's response to stress hormones. This progress has been accelerated in the past five to 10 years by the growing use of sophisticated noninvasive imaging techniques such as positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI), which can peer into the brains of living subjects. These imaging experiments reveal that anatomical variations occur in an assortment of regions throughout the brain. Jill M. Goldstein of Harvard Medical School and her colleagues, for example, used MRI to measure the sizes of many cortical and subcortical areas. Among other things, these investigators found that parts of the frontal cortex, the seat of many higher cognitive functions, are bulkier in women than in men, as are parts of the limbic cortex, which is involved in emotional responses. In men, on the other hand, parts of the parietal cortex, which is involved in space perception, are bigger than in women, as is the amygdala, an almond-shaped structure that responds to emotionally arousing information--to anything that gets the heart pumping and the adrenaline flowing. These size differences, as well as others mentioned throughout the article, are relative: they refer to the overall volume of the structure relative to the overall volume of the brain.

Differences in the size of brain structures are generally thought to reflect their relative importance to the animal. For example, primates rely more on vision than olfaction; for rats, the opposite is true. As a result, primate brains maintain proportionately larger regions devoted to vision, and rats devote more space to olfaction. So the existence of widespread anatomical disparities between men and women suggests that sex does influence the way the brain works. Other investigations are finding anatomical sex differences at the cellular level. For example, Sandra Witelson and her colleagues at McMaster University discovered that women possess a greater density of neurons in parts of the temporal lobe cortex associated with language processing and comprehension. On counting the neurons in postmortem samples, the researchers found that of the six layers present in the cortex, two show more neurons per unit volume in females than in males. Similar findings were subsequently reported for the frontal lobe. With such information in hand, neuroscientists can now explore whether sex differences in neuron number correlate with differences in cognitive abilities--examining, for example, whether the boost in density in the female auditory cortex relates to women's enhanced performance on tests of verbal fluency.

Such anatomical diversity may be caused in large part by the activity of the sex hormones that bathe the fetal brain. These steroids help to direct the organization and wiring of the brain during development and influence the structure and neuronal density of various regions. Interestingly, the brain areas that Goldstein found to differ between men and women are ones that in animals contain the highest number of sex hormone receptors during development. This correlation between brain region size in adults and sex steroid action in utero suggests that at least some sex differences in cognitive function do not result from cultural influences or the hormonal changes associated with puberty--they are there from birth. Inborn Inclinations Several intriguing behavioral studies add to the evidence that some sex differences in the brain arise before a baby draws its first breath. Through the years, many researchers have demonstrated that when selecting toys, young boys and girls part ways. Boys tend to gravitate toward balls or toy cars, whereas girls more typically reach for a doll. But no one could really say whether those preferences are dictated by culture or by innate brain biology.

Image: MIRKO DIKSIC Montreal Neurological Institute, McGill University, FROM PNAS, vol. 94, PAGES 5308-5313, ©1997 NATIONAL ACADEMY OF SCIENCES USA PET SCANS, such as those above made by Mirko Diksic and his colleagues at McGill University, reveal that the brains of males produce serotonin at a faster rate than those of females. Serotonin influences mood, so the finding may help make sense of the observation that more women than men suffer depression. To address this question, Melissa Hines of City University London and Gerianne M. Alexander of Texas A&M University turned to monkeys, one of our closest animal cousins. The researchers presented a group of vervet monkeys with a selection of toys, including rag dolls, trucks and some gender-neutral items such as picture books. They found that male monkeys spent more time playing with the "masculine" toys than their female counterparts did, and female monkeys spent more time interacting with the playthings typically preferred by girls. Both sexes spent equal time monkeying with the picture books and other gender-neutral toys. Because vervet monkeys are unlikely to be swayed by the social pressures of human culture, the results imply that toy preferences in children result at least in part from innate biological differences. This divergence, and indeed all the anatomical sex differences in the brain, presumably arose as a result of selective pressures during evolution. In the case of the toy study, males--both human and primate--prefer toys that can be propelled through space and that promote rough-and-tumble play. These qualities, it seems reasonable to speculate, might relate to the behaviors useful for hunting and for securing a mate. Similarly, one might also hypothesize that females, on the other hand, select toys that allow them to hone the skills they will one day need to nurture their young. Simon Baron-Cohen and his associates at the University of Cambridge took a different but equally creative approach to addressing the influence of nature versus nurture regarding sex differences. Many researchers have described disparities in how "people-centered" male and female infants are. For example, Baron-Cohen and his student Svetlana Lutchmaya found that one-year-old girls spend more time looking at their mothers than boys of the same age do. And when these babies are presented with a choice of films to watch, the girls look longer at a film of a face, whereas boys lean toward a film featuring cars.

Of course, these preferences might be attributable to differences in the way adults handle or play with boys and girls. To eliminate this possibility, Baron-Cohen and his students went a step further. They took their video camera to a maternity ward to examine the preferences of babies that were only one day old. The infants saw either the friendly face of a live female student or a mobile that matched the color, size and shape of the student's face and included a scrambled mix of her facial features. To avoid any bias, the experimenters were unaware of each baby's sex during testing. When they watched the tapes, they found that the girls spent more time looking at the student, whereas the boys spent more time looking at the mechanical object. This difference in social interest was evident on day one of life--implying again that we come out of the womb with some cognitive sex differences built in. Under Stress In many cases, sex differences in the brain's chemistry and construction influence how males and females respond to the environment or react to, and remember, stressful events. Take, for example, the amygdala. Goldstein and others have reported that the amygdala is larger in men than in women. And in rats, the neurons in this region make more numerous interconnections in males than in females. These anatomical variations would be expected to produce differences in the way that males and females react to stress.

To assess whether male and female amygdalae in fact respond differently to stress, Katharina Braun and her co-workers at Otto von Guericke University in Magdeburg, Germany, briefly removed a litter of Degu pups from their mother. For these social South American rodents, which live in large colonies like prairie dogs do, even temporary separation can be quite upsetting. The researchers then measured the concentration of serotonin receptors in various brain regions. Serotonin is a neurotransmitter, or signal-carrying molecule, that is key for mediating emotional behavior. (Prozac, for example, acts by increasing serotonin function.) The workers allowed the pups to hear their mother's call during the period of separation and found that this auditory input increased the serotonin receptor concentration in the males' amygdala, yet decreased the concentration of these same receptors in females. Although it is difficult to extrapolate from this study to human behavior, the results hint that if something similar occurs in children, separation anxiety might differentially affect the emotional well-being of male and female infants. Experiments such as these are necessary if we are to understand why, for instance, anxiety disorders are far more prevalent in girls than in boys.

Another brain region now known to diverge in the sexes anatomically and in its response to stress is the hippocampus, a structure crucial for memory storage and for spatial mapping of the physical environment. Imaging consistently demonstrates that the hippocampus is larger in women than in men. These anatomical differences might well relate somehow to differences in the way males and females navigate. Many studies suggest that men are more likely to navigate by estimating distance in space and orientation ("dead reckoning"), whereas women are more likely to navigate by monitoring landmarks. Interestingly, a similar sex difference exists in rats. Male rats are more likely to navigate mazes using directional and positional information, whereas female rats are more likely to navigate the same mazes using available landmarks. (Investigators have yet to demonstrate, however, that male rats are less likely to ask for directions.) Even the neurons in the hippocampus behave differently in males and females, at least in how they react to learning experiences. For example, Janice M. Juraska and her associates at the University of Illinois have shown that placing rats in an "enriched environment"--cages filled with toys and with fellow rodents to promote social interactions--produced dissimilar effects on the structure of hippocampal neurons in male and female rats. In females, the experience enhanced the "bushiness" of the branches in the cells' dendritic trees--the many-armed structures that receive signals from other nerve cells. This change presumably reflects an increase in neuronal connections, which in turn is thought to be involved with the laying down of memories. In males, however, the complex environment either had no effect on the dendritic trees or pruned them slightly.

But male rats sometimes learn better in the face of stress. Tracey J. Shors of Rutgers University and her collaborators have found that a brief exposure to a series of one-second tail shocks enhanced performance of a learned task and increased the density of dendritic connections to other neurons in male rats yet impaired performance and decreased connection density in female rats. Findings such as these have interesting social implications. The more we discover about how brain mechanisms of learning differ between the sexes, the more we may need to consider how optimal learning environments potentially differ for boys and girls. Although the hippocampus of the female rat can show a decrement in response to acute stress, it appears to be more resilient than its male counterpart in the face of chronic stress. Cheryl D. Conrad and her co-workers at Arizona State University restrained rats in a mesh cage for six hours--a situation that the rodents find disturbing. The researchers then assessed how vulnerable their hippocampal neurons were to killing by a neurotoxin--a standard measure of the effect of stress on these cells. They noted that chronic restraint rendered the males' hippocampal cells more susceptible to the toxin but had no effect on the females' vulnerability. These findings, and others like them, suggest that in terms of brain damage, females may be better equipped to tolerate chronic stress than males are. Still unclear is what protects female hippocampal cells from the damaging effects of chronic stress, but sex hormones very likely play a role.

The Big Picture Extending the work on how the brain handles and remembers stressful events, my colleagues and I have found contrasts in the way men and women lay down memories of emotionally arousing incidents--a process known from animal research to involve activation of the amygdala. In one of our first experiments with human subjects, we showed volunteers a series of graphically violent films while we measured their brain activity using PET. A few weeks later we gave them a quiz to see what they remembered. We discovered that the number of disturbing films they could recall correlated with how active their amygdala had been during the viewing. Subsequent work from our laboratory and others confirmed this general finding. But then I noticed something strange. The amygdala activation in some studies involved only the right hemisphere, and in others it involved only the left hemisphere. It was then I realized that the experiments in which the right amygdala lit up involved only men; those in which the left amygdala was fired up involved women. Since then, three subsequent studies--two from our group and one from John Gabrieli and Turhan Canli and their collaborators at Stanford--have confirmed this difference in how the brains of men and women handle emotional memories.

The realization that male and female brains were processing the same emotionally arousing material into memory differently led us to wonder what this disparity might mean. To address this question, we turned to a century-old theory stating that the right hemisphere is biased toward processing the central aspects of a situation, whereas the left hemisphere tends to process the finer details. If that conception is true, we reasoned, a drug that dampens the activity of the amygdala should impair a man's ability to recall the gist of an emotional story (by hampering the right amygdala) but should hinder a woman's ability to come up with the precise details (by hampering the left amygdala). Propranolol is such a drug. This so-called beta blocker quiets the activity of adrenaline and its cousin noradrenaline and, in so doing, dampens the activation of the amygdala and weakens recall of emotionally arousing memories. We gave this drug to men and women before they viewed a short slide show about a young boy caught in a terrible accident while walking with his mother. One week later we tested their memory. The results showed that propranolol made it harder for men to remember the more holistic aspects, or gist, of the story--that the boy had been run over by a car, for example. In women, propranolol did the converse, impairing their memory for peripheral details--that the boy had been carrying a soccer ball.

In more recent investigations, we found that we can detect a hemispheric difference between the sexes in response to emotional material almost immediately. Volunteers shown emotionally unpleasant photographs react within 300 milliseconds--a response that shows up as a spike on a recording of the brain's electrical activity. With Antonella Gasbarri and others at the University of L'Aquila in Italy, we have found that in men, this quick spike, termed a P300 response, is more exaggerated when recorded over the right hemisphere; in women, it is larger when recorded over the left. Hence, sex-related hemispheric disparities in how the brain processes emotional images begin within 300 milliseconds--long before people have had much, if any, chance to consciously interpret what they have seen. These discoveries might have ramifications for the treatment of PTSD. Previous research by Gustav Schelling and his associates at Ludwig Maximilian University in Germany had established that drugs such as propranolol diminish memory for traumatic situations when administered as part of the usual therapies in an intensive care unit. Prompted by our findings, they found that, at least in such units, beta blockers reduce memory for traumatic events in women but not in men. Even in intensive care, then, physicians may need to consider the sex of their patients when meting out their medications.

Sex and Mental Disorders ptsd is not the only psychological disturbance that appears to play out differently in women and men. A PET study by Mirko Diksic and his colleagues at McGill University showed that serotonin production was a remarkable 52 percent higher on average in men than in women, which might help clarify why women are more prone to depression--a disorder commonly treated with drugs that boost the concentration of serotonin. A similar situation might prevail in addiction. In this case, the neurotransmitter in question is dopamine--a chemical involved in the feelings of pleasure associated with drugs of abuse. Studying rats, Jill B. Becker and her fellow investigators at the University of Michigan at Ann Arbor discovered that in females, estrogen boosted the release of dopamine in brain regions important for regulating drug-seeking behavior. Furthermore, the hormone had long-lasting effects, making the female rats more likely to pursue cocaine weeks after last receiving the drug. Such differences in susceptibility--particularly to stimulants such as cocaine and amphetamine--could explain why women might be more vulnerable to the effects of these drugs and why they tend to progress more rapidly from initial use to dependence than men do.

Certain brain abnormalities underlying schizophrenia appear to differ in men and women as well. Ruben Gur, Raquel Gur and their colleagues at the University of Pennsylvania have spent years investigating sex-related differences in brain anatomy and function. In one project, they measured the size of the orbitofrontal cortex, a region involved in regulating emotions, and compared it with the size of the amygdala, implicated more in producing emotional reactions. The investigators found that women possess a significantly larger orbitofrontal-to-amygdala ratio (OAR) than men do. One can speculate from these findings that women might on average prove more capable of controlling their emotional reactions. In additional experiments, the researchers discovered that this balance appears to be altered in schizophrenia, though not identically for men and women. Women with schizophrenia have a decreased OAR relative to their healthy peers, as might be expected. But men, oddly, have an increased OAR relative to healthy men. These findings remain puzzling, but, at the least, they imply that schizophrenia is a somewhat different disease in men and women and that treatment of the disorder might need to be tailored to the sex of the patient. Sex Matters in a comprehensive 2001 report on sex differences in human health, the prestigious National Academy of Sciences asserted that "sex matters. Sex, that is, being male or female, is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research."

Neuroscientists are still far from putting all the pieces together--identifying all the sex-related variations in the brain and pinpointing their influences on cognition and propensity for brain-related disorders. Nevertheless, the research conducted to date certainly demonstrates that differences extend far beyond the hypothalamus a nd mating behavior. Researchers and clinicians are not always clear on the best way to go forward in deciphering the full influences of sex on the brain, behavior and responses to medications. But growing numbers now agree that going back to assuming we can evaluate one sex and learn equally about both is no longer an option.

LARRY CAHILL received his Ph.D. in neuroscience in 1990 from the University of California, Irvine. After spending two years in Germany using imaging techniques to explore learning and memory in gerbils, he returned to U.C. Irvine, where he is now an associate professor in the department of neurobiology and behavior and a Fellow of the Center for the Neurobiology of Learning and Memory.

MORE TO EXPLORE:

Sex Differences in the Brain. Doreen Kimura in Scientific American, Vol. 267, No. 3, pages 118–125; September 1992.

Sex on the Brain: The Biological Differences between Men and Women. Deborah Blum. Viking Press, 1997.

Male, Female: The Evolution of Human Sex Differences. David Geary. American Psychological Association, 1998.

Exploring the Biological Contributions to Human Health: Does Sex Matter? Edited by Theresa M. Wizemann and Mary-Lou Pardue. National Academy Press, 2001.

Brain Gender. Melissa Hines. Oxford University Press, 2004.