Fossil Teeth From Ethiopia Support Early, African Origin for Apes
- Ann Gibbons
Fossils of a new species of large-bodied ape are giving a rare glimpse of the origins of the African apes. This week in Nature, a team of Ethiopian and Japanese researchers reports the discovery of nine teeth that resemble those of modern gorillas—but that belonged to an ape that lived about 10 million years ago in the Afar Rift of Ethiopia. The team suggests that the newly discovered ape, called Chororapithecus abyssinicus, might have been a primitive gorilla or a close relative. If so, it pushes back the origin of gorillas from about 8 million years ago to more than 10.5 million years ago, says paleoanthropologist Gen Suwa of The University Museum of the University of Tokyo.
Gorilla or not, several experts agree that an ape of this antiquity in Africa strikes a blow at a hypothesis that the common ancestor of African apes arose in Eurasia and migrated to Africa. “These are very important fossils,” says Alan Walker, a paleoanthropologist at Pennsylvania State University in State College. “They show that apes have always been in Africa—that they didn't come from Europe and Asia.”
Paleoanthropologists have known for decades that apes (Hominoidea) arose in Africa, where researchers have found diverse apes from 22 million to 12 million years ago. But despite many searches, almost no ape fossils have been found in Africa between 12 million and 7 million years ago, with the notable exception of a 9.5-million-year-old upper jaw from Kenya. Some researchers inferred that apes went extinct in Africa while other apes flourishing in Eurasia gave rise to the ancestors of modern African apes.
When the researchers discovered the first canine of Chororapithecus on the last day of their field season in February 2006, they realized it came from within the fossil gap. “I knew it was some kind of big ape,” says paleoanthropologist Berhane Asfaw of the Rift Valley Research Service in Addis Ababa.
Returning to the site last March, they found eight molars. The teeth, from at least three individuals, were “indistinguishable” in size and proportions from those of gorillas. Micro-computed tomography scans showed more similarities. The team proposed the animal as an early member of the gorilla clade.
The detailed analysis of the teeth is “one of the best I've seen,” says paleoanthropologist Jay Kelley of the University of Illinois, Chicago. Still, he and others say the teeth may have belonged to apes that had independently adapted to a gorillalike diet. Suwa acknowledges in Nature that the dental evidence for a close relationship with gorillas is “inconclusive” but adds that no other living or fossil apes this big have molars as specialized for shredding fibrous vegetation.
If Chororapithecus is indeed an early form of gorilla, it would falsify the Eurasian-origins hypothesis, says Walker. It would also push back the origin of gorillas to between 10.5 million and 12 million years ago. That is at least 2 million years earlier than most large nuclear DNA studies predict, says Sudhir Kumar, an evolutionary geneticist at Arizona State University in Tempe. Such a shift would also force researchers to recalibrate when the human and chimp lineages split to between 7 million and 10 million years ago (up from 5 million to 7 million), and when orangutans split from other apes to between 15 million and 23 million years ago (up from 14 million).
But a key author of the Eurasian-origins hypothesis, paleoanthropologist David Begun of the University of Toronto in Canada, says it is too soon to “dismiss the Eurasian evidence,” including traits linking Miocene apes in Europe to later African apes—and also too soon to recalibrate the ape family tree.
Regardless of whether Chororapithecus is a true protogorilla, it finally provides some hard data with which to test evolutionary models. “It's nice indeed to have at least something hominoid from this time and place,” says Harvard University paleoanthropologist David Pilbeam.
- POSTDOCTORAL TRAINING
NSF, NIH Emphasize the Importance of Mentoring
- Yudhijit Bhattacharjee
Like apprentices in other fields, U.S. postdocs work for peanuts and are discouraged from pursuing their own ideas in return for the chance to learn the profession. But supervisors must also hold up their end of the bargain by being good mentors. That's what two key science agencies have reminded investigators this month in policy directives that emphasize their role in helping postdocs grow into independent researchers.
The message is tucked into the newly enacted America COMPETES Act (Science, 10 August, p. 736). It requires researchers to include a mentoring plan in every grant application to the National Science Foundation (NSF). It's also contained in a statement issued by the National Institutes of Health (NIH) clarifying that its grantees may use some of their time to mentor postdocs and students. Both make it clear to universities that “postdocs are not just to be treated like workers,” says Alyson Reed, executive director of the National Postdoctoral Association (NPA) in Washington, D.C.
Under the COMPETES Act provision, NSF grant applicants must document proposed mentoring activities, which could include “career counseling, training in preparing grant applications, guidance on ways to improve teaching skills, and training in research ethics.” Although many applicants already do this, says James Lightbourne, an adviser in the NSF director's office, making it a requirement should encourage principal investigators (PIs) to take mentoring more seriously. The provision codifies and expands a pilot effort started last year by NSF's geosciences directorate (Science, 11 August 2006, p. 748).
The NIH statement (grants1.nih.gov/training/q&a.htm#mentor) says that grantees can count time spent training students and postdocs as grant-related activities provided the training is related to the research being funded. That would enable postdocs to attend workshops and seminars relevant to their project, says Walter Schaffer, senior scientific adviser for extramural research at NIH. But Schaffer says it would not allow PIs to dispatch their postdocs to teach graduate students.
The policy is a small step forward, says Keith Micoli, an NPA board member and a researcher at the University of Alabama, Birmingham. But more steps are needed. “If postdocs can't do work on a project that's not funded by the grant,” he asks, “how can they be expected to conduct preliminary experiments to apply for their own grants?”
China, Vietnam Grapple With 'Rapidly Evolving' Pig Virus
- Dennis Normile
A pig disease ravaging China now appears to have spilled into Vietnam. Scientists fear that a deadlier strain of a longtime foe, porcine reproductive and respiratory syndrome (PRRS), or blue-ear disease, may be on the loose.
“We're fairly confident that there has been an outbreak of PRRS here,” says Andrew Speedy, who represents the U.N. Food and Agriculture Organization (FAO) in Vietnam. An FAO mission that completed a weeklong visit to Vietnam on 20 August also uncovered many secondary infections that increase the disease's death toll, Speedy says. The team concluded that PRRS can likely be controlled through vaccination and antibiotic treatment of secondary infections.
PRRS was first identified in the United States in the mid-1980s; the causative arterivirus was isolated in 1991. The virus does not infect humans. In pigs, it attacks macrophages, which ingest and remove invading bacteria. With a crippled immune response, pigs are susceptible to secondary infections. Adults usually recover and develop immunity, but the virus and secondary infections can kill piglets, whose ears often turn blue from the secondary infections.
“The evolution of the virus is really quite startling. It is probably one of the most rapidly evolving viruses that I know of,” says Trevor Drew, head of virology at the Veterinary Laboratories Agency in Weybridge, U.K. He explains that, typically, a virus circulating in a new host initially causes severe disease and becomes less pathogenic over time. With PRRS there is evidence that the opposite has occurred: A nonpathogenic strain was circulating among pigs in North America before it evolved and started causing disease.
An even nastier strain seems to be on the rampage in China, killing sows as well as piglets. This strain first appeared in the summer of 2006. China has reported losing 400,000 pigs to the disease through death or culling in 2006 and another 243,000 this year, although some contend that official numbers vastly understate the losses.
In an analysis of viral samples from pigs in China published online in PLoS ONE on 13 June, a group led by George Gao, a microbiologist who heads the Institute of Microbiology in Beijing, described a genetic variation that may be responsible for the virus's increased deadliness. Drew, who finds that claim plausible, says that the possibility of a new and deadlier strain “is very worrisome.”
Media outlets, including an article last week in The New York Times, reported allegations that China has refused to share virus samples and cooperate with international organizations. Drew says that's not so, pointing to Gao's paper and to China's reporting on the outbreak to the Paris-based World Organisation for Animal Health. Guo Fusheng of FAO's Beijing office says that the organization has not yet asked China's Ministry of Agriculture for samples or to allow an outside team to investigate, although it expects to make a formal request shortly.
Vietnam didn't wait to be asked. The disease was first reported there in March. Last month, the government asked FAO for assistance after the outbreaks increased in June and July. Samples have been sent to U.S. labs for analysis.
- RIVER MONITORING
New York Research Institute Hopes to Go With the Flow
- Erik Stokstad
An ambitious plan to monitor the entire Hudson River in real time is one step closer to reality, thanks to a new collaboration with IBM announced last week. The ultimate goal is a system that could track the movement of PCB-contaminated sediment, for example, or warn a commercial power plant to shut its intake valve temporarily because of an approaching school of fish. “It will be the first real-time, distributed river network in the world,” says John Cronin, director of the nonprofit Beacon Institute for Rivers and Estuaries in New York.
The River and Estuary Observatory Network (REON) is part of a new wave of observing networks, like the even more ambitious Integrated Ocean Observing System, a federally funded program to expand and link regional coastal networks (Science, 3 August, p. 591). Meanwhile, another group of scientists is hoping to interest the National Science Foundation in funding a network of eight to 10 research stations around the country that would study threats to water supplies.
Since 2003, the Beacon Institute has been coordinating a prototype, called Riverscope. Researchers from Lamont-Doherty Earth Observatory and Rensselaer Polytechnic Institute have measured temperature, salinity, and other variables in a few spots along the Hudson River. Although REON is still early in the design phase, heavyweights have already signed on. The state of New York has committed $50 million, most of which will support a new research building. Groundbreaking is expected in 2009 at Denning's Point near Beacon, New York, but scientists hope to begin deploying new sensors this spring.
On 16 August, the Beacon Institute announced a major partnership: IBM will pick up the tab for a new computer system designed to analyze streams of data in real time—a contribution worth perhaps tens of millions of dollars. “It is very, very exciting,” says ecologist Margaret Palmer of the University of Maryland Center for Environmental Science in Cambridge, Maryland.
The river network will be IBM's first public application of its System S, a new type of computer system called stream computing that can handle many types of data—such as video and sound—simultaneously. With processors distributed near the sensors, the system can filter and classify the data in real time and autonomously decide whether to take more detailed or frequent readings at a particular site, for example, during flooding. “The system will learn,” says IBM's Harry Kolar, who says that IBM is getting a chance to test its technology.
A second phase, at least 10 years away, would include permanent sensors and perhaps even robotic submersibles that can beam back data. This full system will require another $150 million of fundraising, Cronin estimates. Philip Bodgen, who directs the Gulf of Maine Ocean Observing System, says he thinks the institute has a good chance of finding the money needed for ongoing maintenance and operations because the Hudson River is less challenging logistically than the ocean and the project is more visible to potential donors.
Once running, REON could be used for everything from studying the impact of fertilizers to monitoring the quality of drinking water. “It will be a net savings to the state to get ahead of their environmental problems,” predicts Thomas Harmon, an environmental engineer at the University of California, Merced.
Out-of-Body Experiences Enter the Laboratory
- Greg Miller
Out-of-body experiences are associated more with tabloid newspapers, New Age Web sites, and large doses of hallucinogenic drugs than serious scientific discussion. Yet they're often reported by reputable people who suffer from migraine headaches, epilepsy, and other neurological conditions. Intrigued by such accounts, some researchers are trying to figure out how the brain creates an aspect of human consciousness so fundamental that we take it for granted: the perception that the “self” conforms to the borders of the physical body.
Now, two teams of cognitive neuroscientists independently report on pages 1048 and 1096 methods for inducing elements of an out-of-body experience in healthy volunteers. Both groups used head-mounted video displays to give people a different perspective on their own bodies. Each team also drew upon the sense of touch to enhance the illusion. Although details of the experience differed, the people in both experiments reported feelings of dissociation from their bodies. The researchers say their findings will pave the way to new brain-imaging studies of body perception and could have practical applications, such as helping virtual-reality programmers design environments that make users feel as if they are really there.
“It's striking because when you hear about out-of-body experiences, it sounds so deeply weird,” says Chris Frith, a cognitive neuroscientist at University College London who did not participate in the new research. “These studies show you can actually manipulate it experimentally.” The illusions add to evidence that the brain's representation of the physical body is malleable and can be modified by information from the senses, Frith says.
For one of the studies, a team led by Bigna Lenggenhager and Olaf Blanke, both of the Swiss Federal Institute of Technology in Lausanne, asked people to stand in front of a camera while wearing video-display goggles. In one experiment, subjects saw the camera's view of their own back, computer-enhanced to create a three-dimensional “virtual own body.” When the subjects' backs were stroked with a highlighter pen at the same time they saw their virtual back being stroked, they reported that the sensation seemed to be caused by the highlighter on their virtual back, making them feel as if the virtual body was in fact their own body.
Moreover, when the researchers turned off the video display, guided the subjects back a few steps, and then asked them to blindly return to their former position, subjects overshot the spot where they'd actually been standing and walked to a point closer to the apparent location of their virtual body.
Adopting a similar strategy to attempt to induce out-of-body experiences, Henrik Ehrsson of the Karolinska Institute in Stockholm, Sweden, asked men and women to sit in a chair and don a video headset connected to two cameras that provided a stereoscopic view of their backs. As a subject viewed his or her own back from behind, Ehrsson used two plastic rods to simultaneously stroke the subject's chest and a location behind the subject's back. Although people felt the rubbing on their chest, in the headset they could only see Ehrsson's arm moving behind their back, reinforcing the sense that they were sitting at a location behind their actual body. The experience often elicited surprised giggles, says Ehrsson, who has tried it out himself. “You really feel that you are sitting in a different place in the room and you're looking at this thing in front of you that looks like yourself and you know it's yourself but it doesn't feel like yourself,” he says. “It's almost like you're looking at a dummy.” Nearly all subjects reported similar impressions on a questionnaire.
Ehrsson also repeated the illusion with electrodes attached to each person's fingers to measure skin conductance, a physiological measure of emotional arousal. Then he swung a hammer in front of the cameras so that it appeared to hit the region where people perceived themselves to be. The hammer posed no physical danger, but changes in skin conductance indicated that subjects registered a threat (they also reported feeling anxious). By showing that people respond emotionally as if they were located at a position behind their physical body, the findings provide additional evidence that the subjects buy into the illusion, Ehrsson says.
Both experiments show that visual perspective and coordination between the senses of vision and touch are important for the sensation of being within the body, says Peter Brugger, a neuroscientist at University Hospital Zürich in Switzerland. Yet neither study replicated the full-blown out-of-body experiences in which people report “an enormously compelling sensation of separation from the body,” he notes. Even so, Brugger says, these illusions may be as close as it is possible to get in the lab.
Previous research has pointed to several brain regions, including the intersection of the temporal and parietal lobes, that may be involved in producing out-of-body experiences in neurological patients, Blanke says. The new illusions can be used to examine which of these brain regions contribute to which aspects of these strange experiences, and that in turn, says Blanke, could lead to a better understanding of how the brain generates a concept of self.
Epidemiologist Sees Flaws in Papers on Genes and Gender
- Jennifer Couzin
An epidemiologist who for years has critiqued the veracity of published papers has now tackled a hot area in genomics, sex-based genetic differences. He argues that most reported findings are poorly documented and that about a sixth may actually be wrong.
As researchers move beyond uncovering new disease genes and into the realm of gene-environment interactions, John Ioannidis, a clinical and molecular epidemiologist at the University of Ioannina School of Medicine in Greece, decided to follow them. He wondered especially about genetic associations with diseases that seem to vary by gender—for example, a particular gene variant that confers increased risk in women but not in men, an effect that may be modulated by hormones. Hundreds of such associations have been reported. But when Ioannidis and two colleagues analyzed data from 77 papers covering everything from multiple sclerosis to lung cancer to anger, they found that19 had at least one claim they judged to be “spurious,” or apparently incorrect. Only four papers contained neither spurious nor insufficiently documented claims, says Ioannidis.
He and his colleagues searched online for papers whose titles touted gender variation in gene effects, then examined each claim (a total of 432 sex-difference claims in the 77 papers). To determine whether claims were spurious, they considered the groups being compared—for example, older men and older women, which would be appropriate, or older men and younger women, which would not. They looked for evidence in the paper that claims reached statistical significance. Those without were judged not sufficiently documented. The analysis was published in the 22/29 August issue of the Journal of the American Medical Association.
Of the gene-gender findings, says Ioannidis, “there is a problem with just accepting them and believing that they're true.” Proper documentation was found in only 55 claims, or 13% of the total.
The Ioannidis paper reinforces concerns about the quality of published genetics results, says Neil Risch, a genetic epidemiologist at the University of California, San Francisco. Still, he defends some findings in the field, such as a greater risk for women with an Alzheimer's gene and a greater risk for males who carry a gene variant linked to rheumatoid arthritis. The Ioannidis analysis did not pick up these papers in its literature search because it netted only those with “polymorphism” and either “sex” or “gender” in the title.
Some scientists whose papers Ioannidis has critiqued agree that it's difficult to know whether a finding will hold until it's been replicated. “Admittedly, the strength of an observation such as ours lies not only with the experimental design, but with the ability of other investigators to reproduce the observation,” wrote Judith Miller, a kidney disease specialist at the University of Toronto, Canada, in an e-mail. David Christiani, an epidemiologist at Harvard School of Public Health in Boston, agreed in an e-mail that his 2004 study in Chest on acute respiratory distress syndrome had limited statistical power but added that this was noted in the paper.
Ioannidis, however, thinks that researchers need to do a much better job of stating the limits of their findings. “The papers should have been published,” he says, noting that “nothing is perfect.” But “better transparency” is sorely needed.
“People make claims from their data that just are not there,” agrees Kathleen Merikangas of the National Institute of Mental Health in Bethesda, Maryland. Contributing to the problem, she says, is that many studies that fail to replicate a genetic finding are never published because they're “not new and exciting, or the scientists themselves don't find that it's going to advance their career.”
- INFECTIOUS DISEASE
Racing to Defuse a Bacterial Time Bomb
- Richard Stone
Once ignored as an obscure disease, melioidosis and the frighteningly versatile bacterium that causes it are drawing attention as a bioterror threat
UBON RATCHATHANI, THAILAND— A Thai man with lank black hair and grizzled stubble lolls on a cot parked in a hallway outside a crowded ward. The 61-year-old farmer answers tersely as a senior physician, Wipada Chaowagul, quizzes him. When the man was admitted on 9 May with sepsis and an abscess in his chest wall, Wipada fingered an old nemesis: melioidosis. But although nearly nine out of 10 melioidosis patients in Thailand with septic shock die, somehow the farmer beat the odds. After spending 2 months in Sappasithiprasong Hospital here in northeastern Thailand, the taciturn man with watery eyes is almost well enough to go home.
Wipada can't explain how the farmer, who suffers from kidney disease, managed to fend off a bacterium, Burkholderia pseudomallei, that in its fiercest incarnation kills most of its victims. Indeed, there is no shortage of scientific puzzles surrounding melioidosis. Over the 2 decades that Wipada has studied the once-obscure malady, more and more experts have become intrigued by the ability of B. pseudomallei to alter its form and survive in environments as disparate as soil, distilled water, and the human body.
“There's something incredibly interesting and important going on with pseudomallei, and nobody knows what that is,” says Colin Manoil, a geneticist at the University of Washington, Seattle.
Melioidosis is largely confined to Southeast Asia and northern Australia and, fortunately for the rest of the world, researchers don't anticipate the shape-shifting bug breaking out of its ecological cage anytime soon. But its characteristics make it an insidious threat as a bioweapon. The bacteria can hide in the body for decades. Once the time bomb detonates, a constellation of symptoms allows melioidosis to masquerade as other ailments. Although many patients are rushed to the hospital with acute disease, others have symptoms more akin to tuberculosis or cancer, says Sharon Peacock of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok. Misdiagnosis can prove fatal: B. pseudomallei is impervious to all but a few antibiotics.
“It's not as scary as anthrax or smallpox,” says Peacock, who has spent 20 years on the trail of melioidosis. “But it still has a significant terror factor. Once soil is contaminated, B. pseudomallei is very hard to get rid of.”
Scientists know they are up against a worthy foe. “Viruses are very smart. Bacteria are normally not so smart. pseudomallei acts like a virus” in its deviousness, says Surasakdi Wongratanacheewin, director of the Melioidosis Research Center at Thailand's Khon Kaen University. Hoping to strengthen their defenses, researchers launched a drug trial this month at Sappasithiprasong. And a pilot experiment is under way in Ubon Ratchathani to take the battle to B. pseudomallei's home turf: Thailand's ubiquitous rice paddies.
The Great Mimicker
Melioidosis was first described from opium addicts in Burma in 1911, and in 1947, two cases involving POWs held in Siam were reported in the British Medical Journal. It wasn't until the Vietnam War, however, when U.S. soldiers came home with the disease, that melioidosis attracted significant attention in the West. The first Thai case was reported in 1955. “No one had ever seen this before,” says tropical medicine specialist Sompone Punyagupta, former president of Vichaiyut Hospital in Bangkok. In the 1960s, scientists isolated B. pseudomallei from soil throughout Thailand and determined that about a third of Thai soldiers sampled had antibodies to it. But with no further confirmed cases among the Thai population, Sompone says, researchers “concluded that it was not a clinically important disease.”
That assessment changed in 1973, when Sompone took over a tropical medicine unit at Ramathibodi Hospital in Bangkok and realized that untold numbers of melioidosis cases were being overlooked or misdiagnosed as TB or other ailments. He dubbed the disease “the Great Mimicker.” The bacterium eluded detection in part because it grows slowly in culture. Back then, dishes were typically discarded after 3 days, says Sompone, because other pathogens of interest form colonies within hours of inoculation. After giving B. pseudomallei colonies more time to form, he says, “we began to see more and more cases.”
Since then, scientists have sketched a picture of a malady most perplexing. It's unknown whether B. pseudomallei lives freely in soil, in association with rhizomes that stud roots, or in a host like an amoeba. “It infects humans by accident,” says Peacock. In northeast Thailand, nearly everyone has been exposed by age 4, although about 30% of the population shows no antibody response, Peacock says. Researchers suspect that B. pseudomallei enters the body through cuts or abrasions, or through the lungs. In Ubon Ratchathani province, the incidence fell 3 years ago when boots were handed out to curb leptospirosis, a waterborne disease, says Direk Limmathurotsakul, who runs MORU's Lab Melioid at Sappasithiprasong Hospital. But the farmers didn't like wearing boots, and case numbers shot back up (see graph). “The incidence looks quite bad this year,” says Surasakdi.
Once the bacterium enters its human host, illness can set in within hours. “Many patients deteriorate very fast,” says geneticist Sirirurg Songsivilai, assistant president of Thailand's National Science and Technology Development Agency. In other people, the bacterium lays low for years. Two years ago, researchers reported the curious case of an 82-year-old U.S. veteran held as a Japanese POW in Indochina during World War II. In 2004, he developed an infected ulcer on his right hand. Lab tests confirmed melioidosis—a whopping 62 years after his presumed exposure to B. pseudomallei (Journal of Clinical Microbiology, February 2005, p. 970). Although no one knows for sure where the microbe lurks in asymptomatic people, likely hideouts include the lymph nodes, reticular epithelial cells, the spleen, and bone marrow. “We don't understand how the body tolerates it so long,” says Peacock. Antibodies don't seem to confer protection.
In more than half the known cases, a chronic illness such as diabetes or kidney disease is the spark that ignites a latent infection or allows infection from a fresh exposure. In Thailand, about 75% of cases occur during the rainy summer, when farmers slog barefoot in paddies, planting rice. Person-to-person transmission is rare, and relapses are common. “Patients need to be followed up for the rest of their lives,” says Sirirurg.
Although melioidosis cases pop up sporadically around the world (see map), only northern Australia rivals Thailand in prevalence. The subtropical climate is similar to Thailand's, and in both places the typical patient is someone exposed regularly to soil. But Australian patients, who are treated in intensive-care wards, are much more likely to survive than Thai patients, who are usually treated in ordinary wards.
An emerging threat
MORU microbiologist Vanaporn “Lek” Wuthiekanun knows better than most experts what melioidosis means to victims and to clinicians. “My heart sinks when I open an incubator and see a pseudomallei culture. I wonder if the patient is still alive,” says Lek, who, with MORU colleagues, has developed immunofluorescence microscopy as an additional tool for rapid diagnosis. The more B. pseudomallei colonies that sprout from a single sample, the grimmer the prognosis.
At MORU's main lab at Mahidol University in Bangkok, Lek is running a simple experiment with chilling implications. In 1993, she put some B. pseudomallei cells in double-distilled water to see how long the bacterium can survive in sterile conditions without sustenance. Fourteen years later, to the astonishment of Lek and her colleagues, the bacteria are still alive.
Scientists are striving to unravel the genetic machinery that underlies B. pseudomallei's exceptional hardiness and virulence. Its penchant for morphing—a phenomenon called phenotype switching—appears to be central to its versatility. “There is unbelievable variability in how it presents itself. It's like a population of several different organisms,” says Manoil. MORU researchers have identified seven morphotypes, each with a distinct gene-expression pattern. Type 1 is most often cultivated from people and soil. “If you cause it to switch to another morphotype by starving it, for example, a whole battery of things switches on or off,” Peacock says.
Three years ago, Matthew Holden, a pathogen genome analyst at the Wellcome Trust Sanger Institute in Hinxton, U.K., and 47 colleagues published B. pseudomallei's genome (Proceedings of the National Academy of Sciences, 28 September 2004, p. 14240). It weighs in at a hefty 7.25 million base pairs on two chromosomes (most bacteria have one), and its chromosomes are dotted with “genomic islands” harboring genes acquired from other organisms. “Much of the genome is devoted to functions that equip it to survive and thrive in the environment,” says Holden. That includes “a well-stocked arsenal of virulence factors,” he says.
Like salmonella and shigella, the bacterium appears to use a molecular syringe to invade host cells. Other elements of its repertory remain shadowy. “The virulence mechanisms of this bug are virgin territory,” says Manoil, who is working with Sirirurg at Siriraj Hospital in Bangkok to probe the relation between B. pseudomallei's morphotypes and virulence. Genetic differences between strains will shed light on variations in virulence and on the bacterium's enigmatic origins, predicts Bart Currie, head of the melioidosis research program at the Menzies School of Health Research in Darwin, Australia. Also intriguing are the mutational hot spots, called short sequence repeats, that are found in two-thirds of its genes. “When I first heard about this, I was stunned,” says Manoil. The bottom line, Holden says, is that B. pseudomallei is “adept at adapting.”
A gnawing fear is that terrorists may exploit this resourceful bug. Unsettlingly, one of the few biowarfare agents ever deployed is a cousin of B. pseudomallei's, B. mallei, which causes glanders, a disease that primarily affects horses but can also cause an illness in people that's similar to melioidosis. The bacterium, unleashed on Allied forces in World War I, evolved from B. pseudomallei.
Melioidosis is more sinister than glanders. “It's different from most other potential bioweapons in that melioidosis is actually an important human disease,” Manoil says. There is no vaccine. And because it takes months on antibiotics to eradicate the bacterium from the body, treating many patients in an emergency “would be extremely expensive, difficult to manage, and pose an enormous burden,” says Herbert Schweizer, a microbiologist at Colorado State University in Fort Collins who will speak at a biothreat symposium at the 5th World Melioidosis Congress in November in Khon Kaen.
Preparedness against melioidosis is sorely lacking in countries where the disease is not endemic, Schweizer says. But its ability to taint food or water has led the U.S. Department of Homeland Security and two other agencies to designate “determining the growth and survival characteristics” of B. pseudomallei in foods as a research priority.
At ground zero
Every Tuesday in Ubon Ratchathani, Wipada, vice director of Sappasithiprasong Hospital, runs a melioidosis clinic for survivors. Relapses can occur years after an initial bout. Suwan Baoyai, a 36-year-old diabetic, came in last December with a fever and abscesses in her spleen and right armpit. “I feel strong enough to work in the rice field now,” she says. After 7 months of antibiotics, however, the mass in her armpit has not disappeared.
A short walk away, a technician at MORU's Lab Melioid is busy inoculating agar plates under a safety hood. The lab has documented more than 3000 cases since 1986, with northeast Thailand having the highest incidence in the world. Thanks to its location at the disease's epicenter, the laboratory also has been at the forefront of drug testing. In a clinical trial in the late 1980s, researchers found that the antibiotic ceftazidime nearly halved the death rate, bringing overall mortality down from 90% to 50%. (In Thailand, the death rate of septic shock patients remains stubbornly around 90%.)
Earlier this month, Lab Melioid launched a trial pitting ceftazidime against the antibiotic of choice for treating septic melioidosis in Australia, meropenem. Scientists expect to enroll more than 500 patients over 3 years. Another team is testing whether granulocyte colony-stimulating factor, a cytokine that boosts neutrophil counts, can help save patients with sepsis.
One counterintuitive treatment strategy might be to block a Toll-like receptor (TLR), an immune system protein, that recognizes B. pseudomallei but appears to interfere with other components of the immune response. A team led by Joost Wiersinga of the Academic Medical Center in Amsterdam, the Netherlands, infected two strains of knockout mice: one deprived of TLR-2, which detects Gram-positive bacteria, the other lacking TLR-4, which detects Gramnegative bacteria. Although B. pseudomallei is Gram-negative, it has a sugar on its cell wall that interacts with TLR-2. The TLR-4 knockouts were as likely as normal mice to succumb to melioidosis, whereas TLR-2 knockouts, surprisingly, had a big survival advantage, the researchers reported last month in PLoS Medicine. “We've been puzzling over the mechanism,” Wiersinga says. The next step, he says, is to test whether compounds that muzzle TLR-2 reduce the severity of melioidosis in mice.
A vaccine, meanwhile, is a distant dream. “This is going to be a tricky one,” Peacock says. Because the presence of antibodies does not appear to be protective, she says, a vaccine must also stimulate the cellular immune response. A few groups are scouring B. pseudomallei's virulence factors for vaccine candidates. But “there's still a long way to go,” Surasakdi cautions.
A different strategy is to unleash competing microbes that knock down B. pseudomallei soil concentrations to levels that cause few or no infections. (A high density is correlated with a high infection rate.) At MORU, Lek added Effective Microorganisms—a commercially available biofertilizer loaded with beneficial bacteria—to soil that had been sterilized and seeded with B. pseudomallei. The biofertilizer suppressed B. pseudomallei.
Now Lek is trying this out on a rice field on the outskirts of Ubon Ratchathani. A 10-yearold boy, under the watchful eyes of his proud father, is using a motorized plow to prepare a paddy for transplantation while his younger brother, also barefoot, stands idly in the middle of the paddy. The boys are up to their ankles in mud that is almost certainly teeming with B. pseudomallei.
Earlier this summer, Lek added Effective Microorganisms to a nearby paddy and left another paddy untouched. Over the coming months, she will compare how B. pseudomallei fares in the two plots. “It's too early to say anything,” Lek says. But for millions of people at risk of falling prey to the Great Mimicker, even a long shot is one worth taking.
Curation in Crisis
- Michael Bawaya*
As the ranks of excavated artifacts grow, museums are running out of space—and money—to care for them all
In the storage area at the McClung Museum at the University of Tennessee, Knoxville, row upon row of boxes are stuffed with brown paper bags, which are in turn filled with hundreds of thousands of artifacts ranging from 10,000 to 200 years old. The artifacts, including stone tools, pottery, and arrowheads, were excavated during the 1960s and 1970s when the Tennessee Valley Authority (TVA) dammed the Tennessee River and its tributaries, flooding archaeological sites along the banks.
Researchers visit the collections about 10 times a year, but museum curator Lynne Sullivan, like many of her counterparts elsewhere, faces a tough job caring for them. Some of the bags have split, spilling their contents into the boxes. And the artifacts' provenance information—where they came from, which is vital to their research value—is written on the bags. TVA is required by law to care for the artifacts, which belong to the federal government, but the strapped agency doesn't have the money. So the University of Tennessee has stepped up to provide space and staffing, but it can't afford to rehabilitate the collections.
The result: a curatorial crisis. “We don't even know at some level what's going on in those bags,” Sullivan says, adding that some of the metal artifacts—axes, knives, gun parts, and hoes—are rusting.
Sullivan isn't alone in her plight. Many collections in other repositories are in “much worse shape,” she says. Indeed, says Dean Snow, president of the Society for American Archaeology, “the curation problem is at crisis proportions.” The effects are being felt not only by researchers using museum collections but also by archaeologists in the field, who worry about where to store the artifacts they recover—and whether they should recover any at all. “I think it's the end of the days of endless archaeology,” says archaeologist Teresita Majewski of Statistical Research Inc., a cultural resource management firm in Tucson, Arizona.
The curatorial problem has been brewing for decades. In 2000, a report on the U.S. Army Corps of Engineers' collections—millions of artifacts occupying nearly 50,000 cubic feet of space that could fill a dozen tractor-trailers—concluded that in about 75% of cases, artifacts had been stored in improper conditions and were quietly disintegrating; about 10% needed immediate attention. “If not properly cared for soon,” the report concluded, “many [artifacts] will lose their educational and research value.” As archaeologist and former curator Julia King of St. Mary's College of Maryland in St. Mary's City explains, good curation is essential because it is not the objects alone but “the relationships between the artifacts that are the critical contribution of archaeology.” Curating the corps' collection, which includes projectile points and stone tools from some of the New World's earliest inhabitants, would cost an estimated $20 million, officials estimate.
In December 2005, Heritage Preservation, a nonprofit organization in Washington, D.C., made the first comprehensive survey of U.S. collections held in the public trust. They found that roughly 20% of archaeological collections need better care and that more than 40% of bulk cataloged archaeological collections have an unknown status, meaning that they hadn't recently been inspected by archaeological staff.
Lack of space is a critical problem. Federal and state laws often require archaeological surveys before construction work, so collections swell wherever development is rapid. A repository at the University of California, Los Angeles' Fowler Museum is almost full, says curator Wendy Giddens Teeter. In Arizona, the fastest growing state in the country, archaeologists are doing more than twice as much work as they did several years ago, says Majewski. The governor recently appointed a commission to study the curation problem, and the resulting report predicted that Arizona's principal repositories will be full in 5 to 10 years; the state's main repository, Arizona State Museum in Tucson, is now storing some items offsite.
As a result, archaeologists are thinking harder about what they collect. “For decades and decades, people were collecting everything and keeping it all,” says S. Terry Childs, an archaeologist with the National Park Service in Washington, D.C. Now, archaeologists try to choose a representative sample of artifacts, she says. “They are thinking about 'What do I keep?'” Those decisions must be made in the field, and they aren't always easy, says King. She mentions a dig in Maryland in which one of her colleagues, working pro bono, left the artifacts in the ground instead of cleaning and analyzing them. He identified them—and the house he was trying to date—as 20th century; later, more detailed excavation showed that it was 19th century.
One extreme solution is the use of no-collection surveys, says Childs, in which researchers simply record artifacts' location on the surface and leave them there. “This is just horrible,” she says, adding that anecdotal reports suggest such surveys are on the rise. Omitting actual artifacts risks the discipline's integrity, agrees Christopher Pulliam of the Army Corps of Engineers. “Archaeology professes to be a science,” he says. “If one can't replicate research results or reanalyze the materials from a site, then [archaeology] can't proclaim to be a science.”
Another solution is to remove redundant items or those with little research value, called deaccessioning. For example, until a few years ago, the San Diego Archaeological Center in California housed 30 boxes of 30-year-old, decomposing soil samples owned by the Department of Defense. Given their minimal research value, center director Cindy Stankowski kept representative samples of various soil types and threw away the rest.
But artifacts uninteresting to some are valuable to others. Back in the 1990s, King co-directed the excavation of the 17th century home of Charles Calvert, governor of Maryland, and found many brick fragments. Bricks were considered expendable and most were discarded, but King says some revealed the earliest evidence of a decorative technique used in the Chesapeake Bay region.
The federal government is drafting new rules to guide deaccessioning some of their hundreds of millions of artifacts; the Department of the Interior alone is responsible for 90 million artifacts. The government tried to implement deaccessioning regulations in 1991 but backed off after ferocious opposition from archaeologists, who said that even artifacts of no research value now might yield important information when examined with future technologies. But Childs, who chairs the working group drafting the guidelines, says the current effort is likely to be more successful. The guidelines are expected to be made available for public comment in the next 6 months or so.
Despite the gloomy outlook, many archaeologists see signs of progress, as institutions such as the National Endowment for the Humanities and Save America's Treasures, both in Washington, D.C., recognize the value of certain archaeological collections and pay to restore them. But there's much to do. “The problem with collections is that they're not considered sexy,” says Childs. She and others note that many more Ph.D.s are awarded for field-based than collections-based research, and that few universities offer classes in collections management. She and her collections-minded colleagues hope to change that. The future of archaeology,” says Childs, “is in excavating the collections.”
Who Ranks the University Rankers?
- Martin Enserink
Everyone would like to score well in an academic beauty contest. But is it really possible to assess an institution's worth?
Who gets to take credit for Albert Einstein's Nobel Prize? The question seems absurd, but it's important for the reputations of two Berlin universities. The reason: Even Nobels bagged 90 years ago are counted in the “Shanghai ranking,” an influential list of the world's 500 best universities. Both Free University (FU), founded in West Berlin in 1948, and Humboldt University (HU), on the other side of the former Wall, claim to be the heirs of the University of Berlin, the erstwhile home of Albert Einstein and many other Nobelists.
The resulting tug of war has had bizarre results. When the team at Shanghai Jiao Tong University produced its first ranking in 2003, it assigned the prewar Nobels to FU, helping it earn a respectable 95th place. Swayed by protests from the other side of town, the team assigned them to HU in 2004, propelling it to 95th rank and dropping FU by more than 100 places. After FU in turn cried foul—and many e-mails between Germany and China later—the team simply took both universities out of the race. Both are still missing in the 2007 edition, published 3 weeks ago.
The controversy is just one among many in the booming business of university rankings. Invented by the magazine U.S. News & World Report in 1983 as a way to boost sales, these academic beauty contests—called “league tables” in the U.K.—now exist at the national level in a dozen countries; there are a handful of European and global lists as well. Almost all have come under fire from universities, scientists, and, in some cases, fellow rankers.
This year, for instance, presidents of more than 60 liberal arts colleges refused to participate in a key component of the U.S. News & World Report rankings, published last week. The rankings, they wrote, “imply a false precision and authority” and “say nothing or very little about whether students are actually learning at particular colleges or universities.” Last year, 26 Canadian universities revolted against a similar exercise by Maclean's magazine.
The critics take aim not only at the rankings' methodology but also at their undue influence. For instance, some U.K. employers use them in hiring decisions, says Ellen Hazelkorn of the Dublin Institute of Technology, adding that funding organizations, philanthropists, and governments are paying increasing attention as well. France's poor showing in the Shanghai rankings—it had only two universities in the first top 100—helped trigger a national debate about higher education that resulted in a new law, passed last month, giving universities more freedom.
So how do you measure academic excellence? Most rankings start by collecting data about each university that are believed to be indicators of quality. After giving each a different, predetermined “weight,” the indicators are added up to a total score that determines a university's rank. But there are vast differences in the number and the nature of the indicators, as well as the way the data are obtained.
National university rankings cater primarily to aspiring students about to choose where to study, which is why they focus on education. In the U.S. News & World Report ranking of “national universities,” for instance (there are separate lists for many other types of institutions and programs), student retention rates count for 20%, the average amount spent on each student for 10%, and alumni donations, believed to reflect student satisfaction, for 5% (see graph). The University Guide published by the Guardian newspaper in the U.K. has a formula with some of the same indicators, but also a 17% weight on graduates' job prospects.
Most international rankings, meanwhile, put a heavy emphasis on research output. That's in part because they are aimed more at policymakers but also because education systems and cultural contexts are so vastly different from country to country that solid and meaningful data are hard to come by. Average spending per student, for instance, doesn't tell you much if you compare China with Germany. Nonetheless, the Times Higher Education Supplement (THES) tries to capture education with a few very simple indicators that it believes to be universally valid: the staff/student ratio and the percentages of students and staff from overseas, regarded as a measure of a school's international cachet.
Ranking education poses another problem: Many rankings rely on universities themselves to provide key data, “which is always a deal with the devil,” says Alex Usher of the Educational Policy Institute Canada in Toronto, who studies rankings. There are documented cases of universities cheating in the U.S. News rankings, for instance, and although U.S. News crosschecks the data with other sources, there are always ways to manipulate them. For example, colleges are known to encourage applications just so they can reject more students, thus boosting their score on the “student selectivity” indicator.
Even more controversial are peer-review surveys, in which academic experts judge institutions. THES, for instance, assigns a whopping 40% to the opinions of more than 3700 academics from around the globe, whereas the judgment of recruiters at international companies is worth another 10%. But when researchers from the Centre for Science and Technology Studies (CWTS) at Leiden University in the Netherlands compared the reviewers' judgments with their own analysis—based on counting citations, an accepted measure of scientific impact—they found no correlation whatsoever. “The result is sufficient to seriously doubt the value of the THES ranking study,” CWTS Director Anthony van Raan wrote in a 2005 paper.
The discrepancy might explain why—to the delight of Australian academics and newspapers—six universities from Australia ended up in the THES top 50 in 2004, wrote Van Raan, who suspected “strong geographical biases” in the review. Martin Ince, a contributing editor who manages the THES ranking, says that the survey has gotten better since 2004 and has a good geographical balance. He believes Australia's strong showing may have been the result of aggressive marketing of its universities in Asia. But he concedes that reputation surveys may favor “big and old universities.”
Peer review is also a major bone of contention in the U.S. News ranking. “We get a list of several hundred institutions, and we're simply asked to rank them on a scale of 1 to 5. That's preposterous,” says Patricia McGuire, president of Trinity University in Washington, D.C., and one of those who boycotted the reputation survey this year. The ranking can't value what her school excels at, she says: providing a degree to mostly minority women from low-income backgrounds.
U.S. News editor Brian Kelly dismisses the boycott's significance. The ranking has always had its detractors, he says, but more than half of university officials still fill out the questionnaire. And the magazine could always find other people to review schools.
The Shanghai ranking avoids all of these problems by eschewing university-provided data and expert reviews. Instead, it uses only publicly available data, such as the number of publications in Nature and Science, the number of Nobel Prizes and Fields Medals won by alumni and staff, and the number of highly cited researchers. The result is a list based almost exclusively on research. Nian Cai Liu, who heads the Institute of Higher Education at Shanghai Jiao Tong University, started the ranking 5 years ago because he wanted to know how Chinese universities were placed in the global pecking order. When colleagues started asking for the data, Liu put them on a no-frills Web site, which now gets thousands of visits a day.
But as the Berlin quarrel shows, the ranking has its own problems. For example, Shanghai credits the institution where the Nobelist worked at the time of the award. And that can make a difference. Andrew Fire's 2006 Nobel in physiology or medicine helped his current institution, Stanford University in Palo Alto, California, move up from third to second place, even though Fire did his groundbreaking work on RNA interference while at the Carnegie Institution in Baltimore, Maryland.
Universities that focus on social sciences or humanities also tend to suffer under the Shanghai system. Recognizing that scientists in those disciplines gravitate to different journals, Liu doesn't count Nature and Science papers and redistributes that 20% share across other indicators. Still, the effect is noticeable: In 2006, the well-respected London School of Economics and Political Science ended up in the 201-300 tier (this far down the list, Liu no longer gives individual ranks), whereas the THES awarded the school 17th place.
Well aware of their influence, and the criticisms, the rankers themselves acknowledge that their charts aren't the last word. U.S. News & World Report, for instance, advises students to take many factors into account when choosing a college. A pop-up window on Liu's Web site warns that “there are still many methodological and technical problems” and urges “cautions” when using the results.
In response to the critics, some rankers are also continuously tinkering with their formulas. But that opens them up to another criticism, namely, that a university can appear to become significantly better or worse in a single year. Many have accused U.S. News of changing its method precisely to shake up the tables and thus boost sales, a charge the magazine rejects.
In part to boost their credibility, the rankers have founded the International Rankings Expert Group (IREG), which in 2006 came up with a set of ranking guidelines. Called the Berlin Principles, they stress factors such as the importance of transparency, picking relevant indicators, and using verified data. Usher, an IREG member, concedes that the principles are quite general in nature because they are the “biggest common denominators” among groups of rankers with very different views. Many rankings aren't fully compliant with the rules yet, says CWTS researcher Henk Moed.View this table:
U = one university in the top 100
* includes Hong Kong (3 universities)
Who's right? Although both agreed that the U.S. led the list and the U.K. came second, the 2006 Shanghai and THES rankings differed markedly on where Earth's 100 best universities were located.
SOURCE: SHANGHAI JIAO TONG UNIVERSITY, THES
Some believe the way forward lies with more sophisticated ways of presenting the data. The group in Leiden, for instance, produces rankings of European universities based purely on publication and citation data and presents them as not one but four tables. Each uses a different variable; the yellow ranking, for instance, looks at the total number of papers produced, whereas the green ranking (billed as the “crown indicator”) is based on papers' impact, adjusted so that it doesn't reward bigger institutions or those working in fields in which scientists cite each other more often. The results aren't as simple as a single list, Moed concedes, but they do provide a more complete picture.
Others are going further. The Centre for Higher Education Development (CHE) in Gütersloh assesses German university departments without trying to aggregate them, and the departments are simply slotted into top, middle, and lower tiers. It also allows the user to sort universities based on their own favorite indicators. Obviously, a ranking such as this one makes for less compelling newspaper or magazine copy-like a Miss Universe contest without a winner. But a spokesperson for Die Zeit, the German newspaper that publishes the CHE rankings, says its annual university guide is a bestseller anyway, and the interactive design lures many readers to its Web site.
With all the complaints, it's easy to forget that rankings have benefits as well, says Moed. Competition spurs universities to actually perform better, he says, and the rankings provide students and policymakers with answers—even if they're imperfect—to legitimate questions about quality. Other rankers point out that universities tout the results if they do well, and they don't like being excluded. Perhaps that's why the presidents of the competing Berlin universities announced shortly after the 2007 Shanghai ranking appeared that they would sit down again to discuss the legacy of Einstein and his illustrious colleagues. A compromise might propel both back onto the list in 2008.
Einstein might have appreciated the irony. A sign in his office at Princeton reportedly read: “Not everything that counts can be counted, and not everything that can be counted counts.”
- MOLECULAR BIOLOGY
Cancer's Perpetual Source?
- Jean Marx
The discovery of tumor cells that behave like stem cells suggests why cancer may be so hard to eradicate—and how new therapies might be targeted
Beginning about 15 years ago, John Dick's team at the University of Toronto in Canada provided a new clue as to what makes cancer such a formidable foe. They found that only a tiny population of leukemia cells could transmit the cancer from one experimental animal to another. More remarkably, the cells had a property previously seen only in stem cells: the ability to produce an exact copy of themselves each time they divide, thereby maintaining the ability to reproduce in perpetuity. These so-called cancer stem cells, Dick suggested, might be what makes the disease so hard to eradicate with radiation or chemotherapy.
Since then, such cells have been found in many other cancers, including those of the breast, brain, colon, and head and neck. “Cancer stem cells are being identified in virtually every cancer,” says Max Wicha of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Not everyone is convinced that the stemlike cells found in cancers play such a key role in tumor growth and maintenance. But if that idea is correct, “the ramifications could be huge,” says Craig Jordan of the University of Rochester School of Medicine and Dentistry in New York state. In that event, therapies that target cancer stem cells may prove more effective than current cancer treatments. Indeed, radiation and many chemotherapeutic drugs wipe out dividing cells, but stem cells may be quiescent most of the time and so may survive these treatments. “You can reduce tumor bulk 90%, and in no time at all, the tumor will take over again,” says Levy Kopelovich of the National Cancer Institute in Bethesda, Maryland, which held a workshop in mid-May on stem cells as targets for cancer prevention.
Cancer researchers are beginning to understand what makes cancer stem cells dangerous. Among other things, they foster the formation of new blood vessels needed to feed tumor growth. Recent work is also uncovering the cellular signaling pathways that control cancer stem cell proliferation, raising hopes of new treatments that selectively kill these cancer seeds. Indeed, some existing cancer drugs and others that may soon be tested in people appear to target the cells, new studies indicate. “By gaining a sophisticated understanding of how normal and cancer stem cells differ, we'll be able to design a new class of drugs that is less toxic,” predicts Sean Morrison of the University of Michigan Medical School in Ann Arbor.
For the first decade after Dick's discovery, the clinical importance of cancer stem cells seemed limited, because leukemias are much rarer than solid cancers. But interest in the cells began to take off in 2003. That year, a team led by Michael Clarke, then at the University of Michigan Medical School, spotted cancer stem cells in breast cancers, and Peter Dirks of the Hospital for Sick Children in Toronto and his colleagues identified them in a variety of brain cancers (Science, 5 September 2003, p. 1308).
In the past several months, that early trickle of results has turned into a flood. In the 4 January issue of Nature, for example, two independent teams, one led by Dick and the other by Ruggero De Maria of the Istituto Superiore di Sanità in Rome, reported the discovery of cancer stem cells in colon cancer, and others have reported finding them in cancers of the prostate, lung, pancreas, head and neck, and the deadly skin cancer melanoma. “Cancer stem cell research has gone from an interesting sidelight to mainstream in a very short time,” Jordan says.
What's more, cancer stem cells display an array of traits that aid in their proposed role of driving and maintaining cancer growth. For example, Jeremy Rich's team at Duke University in Durham, North Carolina, looked at their ability to resist radiation.
In one key set of experiments, these researchers transplanted cells obtained from human glioblastomas, which are highly malignant brain tumors, into mice and then subjected the animals to radiation doses similar to those used to treat human patients. Other than surgery, Rich says, “radiation therapy is the most effective [treatment] for brain tumors, but it is rarely curative.”
The transplantation results, which appeared in the 7 December 2006 issue of Nature, suggest an explanation. In irradiated tumors, the proportion of cancer stem cells went up from about 2% to about 8%, as indicated by the number bearing the protein CD133, a marker for brain cancer stem cells. This shows that those cells survived the radiation whereas other tumor cells succumbed.
The stem cells overcame the radiation, further analysis suggested, because they repair the DNA damage it induces more effectively than nonstem cancer cells do. “I thought that was a great paper,” says Clarke, who's now at Stanford University in Palo Alto, California. “It provided experimental evidence for what we've all been predicting.”
A second way that cancer stem cells may pose a threat is by stimulating angiogenesis, the formation of new blood vessels that support tumor growth. For example, the Duke team recently found that glioma stem cells in culture produce much more of the angiogenesis-promoting protein VEGF than do other glioma cells.
The VEGF discovery suggests that one current drug may be a prototype of therapies that target cancer stem cells. Bevacizumab (Avastin) is an antibody designed to block VEGF action that is already used for cancer therapy. And when the Duke team transplanted human glioma stem cells into mice and treated the animals with the antibody, “the tumors from cancer stem cells shrank dramatically,” Rich says. “It looks like bevacizumab is a kind of anticancer-stem cell therapy.”
And cancer stem cells may have yet another dangerous property: the ability to drive metastasis, the spread of tumors in the body. The presence of tumor cells in the bone marrow of breast cancer patients is a bad prognostic sign, indicating that such patients have a high risk of cancer spread. Last fall, Marija Balic, Richard Cote, and their colleagues at the University of Southern California in Los Angeles reported that roughly 70% of the tumor cells in bone marrow carry the surface markers of breast cancer stem cells. Although it hasn't been proven that those cells seed metastatic tumors, such a possibility is in line with the idea that cancer stem cells are the tumor-initiating cells. Other research has shown that genes involved in cell migration and tissue invasion are highly active in breast cancer stem cells.
Searching for vulnerability
In their search for ways to disrupt cancer stem cell activities, researchers are focusing heavily on the signaling pathways needed for their maintenance and development. And several intriguing connections between genes already linked to cancer development have emerged.
At this year's annual meeting of the American Association for Cancer Research in April, Hasan Korkaya, a member of Wicha's group at Michigan, reported that reducing expression of PTEN, a known tumor suppressor gene, in cultured human breast cancer cells increased cancer stem cell populations by as much as fivefold. Boosting expression of the HER2 oncogene at the same time doubled that increase. In addition, such cells migrate more in culture, an indication that they may seed metastases. This might help explain why women whose breast cancers have both loss of PTEN and extra HER2 copies usually have a poor prognosis.
Other work also points to PTEN loss as a trigger for cancer stem cells. Early last year, Owen Witte's team at the David Geffen School of Medicine in Los Angeles found that when PTEN is deleted in the prostate cells of mice, the number of cells bearing a stem cell marker called Sca-1 increases, and small premalignant growths form in the prostate. And Linheng Li's team at the Stowers Institute for Medical Research in Kansas City, Missouri, has found that deleting PTEN in cells lining the intestines leads to the production of stem cells that form polyps that can develop into full-blown cancers. Finally, Morrison's team has found in mice that PTEN deficiency promotes the formation of leukemia stem cells while depleting normal hematopoietic stem cells.
This suggests, he notes, that it may be possible to selectively strike cancer stem cells. Indeed, Morrison and his colleagues have evidence that the drug rapamycin, which can help make up for PTEN loss, can prevent leukemia development in their mouse model while at the same time restoring normal hematopoietic stem cell function. This is “exciting,” Morrison says, “because it offers the possibility of developing therapies that kill cancer stem cells but are less toxic in normal tissue.” Rapamycin is already used clinically as an immunosuppressant and is being studied in cancer therapy, and the group hopes to begin a clinical trial to test it in patients with acute myeloid leukemia (AML).
Researchers seeking to target cancer stem cells are also looking at several more pathways previously implicated in stem cell maintenance. Among these are the Wnt pathway, which is implicated in intestinal and other cancers, and also the Polycomb and sonic hedgehog pathways.
Some surprising aspects of cancer stem cells may also provide unexpected new targets for therapies. In a recent screen of 1267 compounds in a library of pharmacologically active agents, Dirks and his colleagues identified 160 agents that decreased the proliferation of brain cancer stem cells in lab cultures. Many of these drugs affected unexpected neuronal functions, such as neurotransmission, which were supposed to be properties of mature neurons rather than unspecialized stem cells. The mechanisms that control cancer stem cell growth “may be more diverse than what we see right now,” Dirks says.
Even a folk remedy is showing some promise against cancer stem cells. Rochester's Jordan, working with Dianna Howard's team at the University of Kentucky Medical Center in Lexington, has evidence from both cells in culture and a mouse model that the drug parthenolide—the active ingredient in a herbal remedy called feverfew—specifically kills AML stem cells.
In addition to simply screening for compounds that kill cancer stem cells, Dick and his colleagues are going after leukemia stem cells with an antibody that binds to a protein called CD44 that is highly expressed on the surface of AML cells. When the researchers transplanted human AML stem cells into mice and then administered the antibody, the treatment apparently abolished the tumor stem cells driving the leukemia. Closer examination showed that the antibody prevents AML stem cells from migrating to the spleen and bone marrow, where they would otherwise reside. “The [leukemia] stem cells still need to interact with their niche, and if you interfere with their trafficking, they can't maintain themselves,” Dick says.
Even if cancer stem cells can't be killed or their spread blocked, they might be restrained in another way: by inducing them to lose their “stemness” and differentiate into nonrenewing cells. Last December, Angelo Vescovi of the University of Milan-Bicocca in Italy and colleagues reported in Nature that bone morphogenetic proteins inhibit the tumorigenic properties of human glioblastoma stem cells in this fashion. “It's an interesting paper,” says Dirks. “It opens up the field to considering differentiation” as a therapeutic goal.
Despite the outpouring of results in the past few years, fundamental questions remain about cancer stem cells. One big issue concerns the nature of the original cell that gives rise to them. “That's a harder question than people appreciate,” Jordan says. “It doesn't have to start with a normal stem cell.” In work done a few years ago, Irving Weissman's team at Stanford University examined the genetic mutations in human AML cells and concluded that the original cancer-causing mutations can strike more developmentally advanced, although still immature, progenitor cells.
About a year ago, Scott Armstrong and colleagues at Children's Hospital Boston provided further support for that idea. Many leukemia cells feature gene translocations in which two genes, previously separate from one another, become joined and produce so-called fusion proteins. Human AML cells, for example, make a fusion protein called MLLAF9. When the Children's Hospital workers genetically engineered granulocyte-macrophage progenitor cells to produce MLL-AF9 and transplanted the cells into mice, they gave rise to a leukemia similar to AML. Subsequent isolation of leukemia stem cells from the mice showed that they resembled the original granulocyte-macrophage progenitors but had activated genes needed for self-renewal.
Indeed, work published by the Clarke team in the 12 June issue of the Proceedings of the National Academy of Sciences suggests that stem cells of a given type of cancer may arise from different cells. For these experiments, the researchers looked at colon cancer stem cells obtained from four different patients. There were “subtle differences” in cancer stem cell characteristics from patient to patient, says Clarke. “This suggests that the cell of origin varies from patient to patient.”
Despite the huge growth in the cancer stem cell field, skeptics remain. One potential problem is that virtually all the work has involved transplanting human cancer cells into immunodeficient mice. This has raised concerns that the experiments do not accurately reflect what happens during cancer development in humans. Indeed, Andreas Strasser and his colleagues at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, have recently challenged the idea that only rare cancer stem cells can initiate tumor formation.
Instead of using human leukemia cells, these researchers worked with mice genetically engineered to develop leukemia. When they injected leukemic cells from these animals into genetically compatible healthy mice, all the recipients developed leukemia, even those injected with as few as 10 cells, Strasser's team reported in the 20 July issue of Science (p. 337). That could not have happened if only a tiny minority of tumor cells had the ability to initiate tumor formation, as the stem cell hypothesis holds, Strasser says. He suggests that the mouse doesn't provide the right environment for the growth of human cancer cells, so that only a few manage to survive and multiply, thus creating a false impression that tumor-initiating cells are rare. “Those data have been massively overinterpreted,” Strasser maintains.
Dick disagrees. He notes that the cancer stem cell hypothesis rests on the prospective isolation of distinct populations of tumor-initiating and noninitiating cells rather than just on the rarity of cancer stem cells. Dick points out that his team has re-created human leukemias in mice by injecting the animals with normal human blood-forming cells that had been engineered to carry a fusion gene known to make cells leukemic (Science, 27 April, p. 600).
These animals, which are more comparable to Strasser's genetically engineered mice, developed leukemias similar to those seen in humans, and the frequency of tumorinitiating cells was relatively high—one to two in 100—rather than the one in a million seen in the early experiments. Other researchers have reported similar results. Dick suggests that different cancers will vary in cancer stem cell frequency, depending on the particular oncogenic pathways operating in the cells.
Although others share Strasser's skepticism about cancer stem cells and many uncertainties remain, there is one sure bet. Given the possible importance of cancer stem cells as therapeutic targets, the field will continue to grow. And at least one skeptic has already been convinced. Duke University's Rich says that he came into the research hoping to disprove the importance of cancer stem cells. Now, he says, “we are very early in studying cancer stem cells, but understanding them may impact the way we diagnose and treat patients in the near future.”
Murder in Mesopotamia?
- Andrew Lawler
Recent finds in Syria provide persuasive evidence that northern Mesopotamia rivaled the south in the race to build cities—and that it attracted enemies
Braving a trench filled with rat poison, archaeologists in Syria have found the remains of dozens of youths killed in a fierce confrontation nearly 6000 years ago—as well as evidence that the celebrating victors feasted heartily on beef in the aftermath. The researchers expect to find many more victims next year when excavations resume on a site that offers a rare window into violent conflict at a critical period of prehistory.
The surprising discovery is at the ancient site named Tell Brak, which scholars now believe was one of the world's earliest cities (Science, 9 June 2006, p. 1458). The 40-meter-high mound, located within sight of the Iraqi border in northeastern Syria, has been continuously excavated for more than 30 years but is only now revealing its surprising size and sophistication at this early age. Two papers published this week in Antiquity and Science lay out the case for a sprawling urban center in the 5th and 4th millennia B.C.E. rivaling contemporary settlements in southern Mesopotamia, long considered the undisputed birthplace of humanity's first cities.
A third paper—slated to be published this fall in the journal Iraq—will detail the mass burials at Tell Majnuna, half a kilometer north of the main tell at Brak. Local workers expanding a grain-storage facility last year were using bulldozers to cut into Majnuna—which means “crazy” in Arabic—and dig trenches, which they filled with rat poison to protect the grain. University of Edinburgh, U.K., archaeologist Philip Karsgaard investigated and spotted several layers of bone; this spring, Brak field director Augusta McMahon won permission from the landowner to excavate the site.
The first mass burial pit, on the western edge of the mound, has so far revealed the bones of at least 34 young to middle-aged adults, but only a small portion has been excavated. “There could be hundreds and potentially thousands,” says McMahon, an archaeologist at the University of Cambridge, U.K. At least two skulls show signs of injuries that may have been the cause of death. The absence of feet and hand bones and the fact that many of the skulls apparently rolled off when the bodies were tossed into the pit hints that they were left to decompose before burial. On top of the skeletons was a mass of pottery, mostly vessels for serving and eating, and cow bones—evidence of a large feast.
A second mass burial pit is a dozen meters away, on the slope of the small mound, and appears to be from the same time. At least 28 individuals—also mostly youthful—were found in this burial, which includes clusters of long bones that may have been carried there by the armload. As in the first pit, there is a mass of pottery and cow bones, and fingers, hands, and feet are mostly absent.
A third area on the other side of the mound revealed a thick layer of ash more than 1 meter deep. It has yielded 13 skeletons of adults ranging in age from 20 to 45 and two children. Unlike the ones in the mass burials, these bodies appear to have been laid to rest carefully. The ages again hint at a violent death, but the pottery may come from a slightly later era; radiocarbon analysis results are not yet available, and McMahon says that all three areas have been only partly excavated.
McMahon says the site contains clear evidence of a violent confrontation. But she doesn't know whether the victors were defending or attacking Brak, or whether the feast commemorated victory or defeat. “We need at least another season to understand what happened,” says Joan Oates, a Cambridge University archaeologist and Brak project director who began working on the site in the 1970s with her husband, David, who died in 2004.
From the pottery, Oates estimates that the Majnuna incident took place around 3800 B.C.E. She says Brak appears to have survived the confrontation and to have been destroyed 2 centuries later. After that event, influence from southern Mesopotamia begins to appear, and by 3400 B.C.E., southern pottery dominates the archaeological record.
Something similar took place at the nearby site of Hamoukar. Archaeologists from Syria and the University of Chicago in Illinois recently found evidence of a fierce battle at Hamoukar during the same period as the destruction of Brak, including hundreds of sling bullets, although archaeologists disagree whether they were actual weapons or had another use. In the past season, the Hamoukar excavators found a half-dozen burials from the period with a mix of genders and ages, although no obvious signs of violence are present. They also found a sling bullet lodged in a plastered wall, additional evidence that the bullets were weapons, says University of Chicago dig co-director Clemens Reichel. After the battle, residents appear to have lived as temporary squatters amid the ruins; not long after, as at Brak, southern pottery appears. Both Oates and Reichel say this transition marks the demise of an independent northern Mesopotamian urban culture.
There are few examples of mass burials in the prehistoric Near East. The most dramatic is a pit found in 1997 at Domuztepe in central Turkey, containing the remains of nearly 40 people along with cattle, sheep, and goat bones, dating to 5700 to 5600 B.C.E. The victims, both male and female, range from infants to the elderly; numerous skulls show signs of fractures, and some skulls were chopped off. The human bones also show signs of burning, says dig co-director Elizabeth Carter of the University of California, Los Angeles, and cannibalism has not been ruled out.
A late-3rd millennium B.C.E. site called Titris Höyük in south central Turkey includes 19 skulls of mostly young men, with evidence of blunt-force trauma, but these are carefully arranged in an oval basin, says archaeologist Guillermo Algaze of the University of California, San Diego. Third millennium B.C.E. Mesopotamian texts describe similar scenes; the famous Stele of Vultures, for example, boasts of a Sumerian king heaping up corpses of enemies and depicts vultures carrying off their severed heads. The theme of victors celebrating a feast after a battle also is found in inscriptions of the era, adds archaeologist Glenn Schwartz of Johns Hopkins University in Baltimore, Maryland.
Brak was a thriving trade center and settlement both before and after the Majnuna incident. Working at the main mound in a deep cut, Oates and her colleagues recently unearthed evidence that the locals imported raw materials from hundreds of kilometers away and transformed them into manufactured goods in the 2 centuries or so before the mass burials. Researchers believe such a city might well have drawn the unwelcome eye of raiders or invaders.
Although lacking the drama of a battle or massacre, Oates's discovery offers an important glimpse into the era just before writing and large-scale urbanization transformed the ancient Middle East. The excavators uncovered several connected rooms dating to about 3900 B.C.E. and containing large piles of obsidian—a valuable volcanic glass used for cutting tools and obtained from distant Anatolia—along with imported jasper, marble, serpentine, and diorite stones used for beads. Also present was a large chunk of raw bitumen—the gooey substance that comes from eastern Mesopotamia—as well as mother-of-pearl inlay from local mollusks. Spindle whorls used for weaving wool littered the site, and a cache of 50 clay balls—either weapons or blanks for stamping ownership seals—lay in a corner of one room, its perishable container long decayed. “This is not household industry but a much larger institution,” says Oates. “And evidence for industrial-based manufacture using imported raw material doesn't exist anywhere else” at or before this period, she adds.
The most unusual find was a chalice with a white marble base and black obsidian bowl held together at its seam with bitumen. The upper rim once contained another material, possibly gold, which was removed in antiquity. “We've not seen anything like this before,” says Reichel. Found amid other coarser pottery, the drinking vessel, along with a stamp seal showing a lion being caught in a net—a classic Near Eastern symbol of royalty—suggests a well-stratified society in late 5th millennium Brak, adds Oates.
An earlier building in the trench, which dates to about 4000 B.C.E., included large numbers of grinding stones, big ovens, basalt pounders, carefully crafted stone and bone tools, flint and obsidian blades, mother-of-pearl inlay, and clay spindle whorls. A street paved with pottery shards runs along the western side of the complex and to the city's northern gate. Part of the building and its street entrance remain buried under the high tell. The finds show an extraordinary continuity in manufacturing in a single area over a long period of time, Oates adds.
Brak's activity was not confined to the main tell. A close examination of the surrounding area reveals settlement in the period of 4200 to 3900 B.C.E. extending over an astonishing 55 hectares, an order of magnitude larger than other settlements of the time. During the first half of the 4th millennium B.C.E., Brak had more than doubled in size and its population density also increased. Only one city in southern Mesopotamia—Uruk—was likely larger in this era. And unlike Uruk, which was densely populated primarily in the center, early Brak appears to have featured various clusters of neighborhoods separated by open space. This more dispersed pattern, says Harvard University archaeologist Jason Ur in his report this week in Science (p. 1188), could show the existence of a less hierarchical social system than among the southerners.
The triple series of finds at the Brak dig, which is sponsored by the British School of Archaeology in Iraq, the British Academy, and Cambridge University's McDonald Institute for Archaeological Research, has drawn the rapt attention of other scholars. “It's absolutely unique and fantastic,” says Algaze. “It is now clear that northern Mesopotamia is not the backwater people used to believe,” adds Schwartz. With war in Iraq preventing exploration of the alluvial soil of the south, researchers are content to keep looking north for data on how the first urban centers coalesced.