News this Week

Science  24 Oct 2003:
Vol. 302, Issue 5645, pp. 312
1. AGRIBIOTECHNOLOGY

Mixed Message Could Prove Costly for GM Crops

2. Gretchen Vogel

Backers of genetically modified (GM) crops were rooting for a knockout. Industry was anxiously awaiting the results of a 3-year experiment on the effects of three modified plants—beets, maize, and oilseed rape—on hundreds of plant and insect species across Great Britain. Supporters hoped that the engineered crops would be a boon to farmers without inflicting more punishment on the environment than do conventional crops. But when the results of the largest-ever GM field trials were unveiled last week, they hardly served to bolster prospects for the technology: Cultivation of beets and oilseed rape clearly had deleterious effects on wildlife and native plants. Only GM maize proved more environmentally friendly than its non-GM counterpart.

The findings could turn out to be a knockout blow, but not the sort that GM enthusiasts were hoping for. U.K. government officials, once discretely bullish on agbiotech, studiously avoided lining up on the wrong side of public opinion, which squarely opposes the commercial planting of GM crops. “I cannot see any European government ignoring these results and their effect on wildlife,” Elliot Morley, the environment minister, told The Guardian newspaper last week. At best, the GM row will be much harder to hoe in Europe. “This is going to create more controversy rather than less,” says David Andow, an entomologist at the University of Minnesota, Twin Cities.

Whatever the political ramifications, scientists are praising the field trials as a premier example of environmental impact assessment. “This is a landmark effort,” says ecologist Allison Snow of Ohio State University, Columbus. It “is the most comprehensive study of its kind ever,” says Guy Poppy, an ecologist at the University of Southampton, U.K. “We've never had such a wonderful data set.”

To help decide whether to recommend that the European Union approve these GM crops for commercial planting, the U.K. government commissioned a series of studies. Two were released earlier this year; a scientific review found little risk to human health (Science, 25 July, p. 447), and an economic analysis indicated that GM crops could ultimately benefit consumers and farmers. A third study, in the works since 1999, investigated how wildlife might be affected by crops modified to resist herbicides.

Nineteen researchers from six agricultural research stations across England, Scotland, and Wales designed a trial comparing three GM crops—the ones closest to approval for commercial planting in the U.K.—with conventional counterparts at more than 200 field sites across Britain. These varieties were modified to resist “broad spectrum” herbicides; that makes farming easier, because herbicides can be sprayed directly on the crops and kill only weeds. Normally, farmers must douse the soil with herbicides before weeds sprout, then spray again with different herbicides that target particular weeds.

But killing weeds inflicts collateral damage on the environment. Wildlife depends on weeds: Some native insects feed on them, butterflies sip their nectar, and birds eat the seeds. Populations of the skylark, corn bunting, and other common birds of the British countryside have declined over the past 30 years. Their woes are blamed in part on ever more intensive agricultural practices that suppress weeds on croplands.

3. MIDDLE EAST

Islamic Science Is Casualty of War on Terrorism

1. Richard Stone

SEIYUN, YEMEN—A convoy of four-wheel-drive vehicles, escorted by heavily armed troops, tears through the palm-studded Hadramout Valley. This oasis is best known in the West as the birthplace of Osama bin Laden's father, and with Al Qaeda fugitives on the run, local authorities take no chances with visitors. Yet the delegation that pulled into the fortress-like governor's complex here earlier this month was unusual: a contingent of scientists from Europe, the United States, and elsewhere who came to brainstorm how to boost the prospects for science throughout the Islamic world.

That's a formidable task. Two years after the 11 September terror attacks raised Western awareness of the plight of Muslim scientists (Science, 26 October 2001, p. 766), little has emerged to improve their lot. Islamic governments are mostly deaf to the pleas of scientists. “The present situation in the Islamic world is appalling,” says Pakistan's science and technology minister, Atta-Ur-Rahman. According to the Arab Human Development Report 2003, released earlier this week by the United Nations, Arab countries on average spend 0.2% of their national output on research, much of which goes to salaries.

Moreover, many collaborations with the West torn asunder by the terror attacks have been slow to mend; others may never be mended. U.S. visa restrictions since 9/11 have crimped scientific exchange and training. Arab student numbers in the United States, for example, have fallen about 30% over the past few years, according to the U.N. Meanwhile, calls for a Western-led “Marshall Plan” for Islamic science have come to nought. If anything, “things have gotten worse,” says Abdulkarim Al-Eryani, a Yale-trained microbiologist and political adviser to Yemen President Ali Abdullah Saleh.

The region's scientific leaders are not counting on heaps of assistance from the West in the near future. Atta and others are redoubling their efforts to get their own governments to stump for research. Last week in Kuala Lumpur, he persuaded representatives of the 57 nations of the Organization of the Islamic Conference to set aside “major national funds” for research programs, including cross-border ones, coordinated by OIC's science committee. But the delegates would not agree to Atta's request to commit to a humble figure for the fund: 0.1% of gross domestic product.

Coaxing Islamic governments to embrace science is the stiffest challenge. In countries such as Yemen with minor petroleum reserves and widespread poverty, investment in science is a low priority. “Science in Yemen today has no role in the economy because we lack a critical mass of scientists,” says Moustafa Bahran, Saleh's science adviser, who organized the conference held here from 11 to 13 October. It needn't cost an arm and a leg to get involved in cutting-edge science, however. Yemen and other countries “should look at bioinformatics,” says Nasser Zawia, a Yemen-born neurotoxicologist at the University of Rhode Island, Kingston. “All you need is a computer and a brain to catch up.”

A far grander approach, some at the conference argued, would be to launch an Islamic version of the U.S. National Science Foundation's Experimental Program to Stimulate Competitive Research (EPSCoR), which has helped build research capacity in the poorer U.S. states. The philosophy of the program, which requires states to match funds, is to “recognize excellence and invest some money into it, or if excellence doesn't exist, you put it there,” says Montana State University's Gary Strobel, a former point person for EPSCoR in Montana. Strobel collaborates with researchers in Yemen studying species on Socotra Island off the south coast.

Until a sustained effort to dramatically raise the scientific game in Islamic countries materializes, the world is unlikely to be a safer place, many argue. “To fight religious extremism, you need to train more scientists,” says Zawia. “Right now we're pushing them in the wrong direction.”

4. PLANETARY SCIENCE

Failed CONTOUR Comet Mission Melted Itself Down

1. Richard A. Kerr

A NASA investigation board has concluded that a recent mission to explore a comet was probably done in by exhaust from its own propulsion system. Mission engineers skimped on trouble-shooting exercises that might have spotted the problem ahead of time, it says, and outside reviewers failed to look closely enough. The mission's tight budget, observers say, may have doomed it.

The Comet Nucleus Tour (CONTOUR) spacecraft, launched in July 2002, was scheduled to make a 4-year tour of two comets. On 15 August, after 6 weeks in Earth orbit, its own solid-propellant rocket motor ignited to send the craft into a solar orbit that would have brought it alongside comet Encke next month. The maneuver was not monitored from Earth, but the next day three separate objects were spotted near CONTOUR's expected trajectory, and attempts to contact CONTOUR were unsuccessful.

In a report submitted last week, the NASA board concluded that mission engineers had most likely misgauged the heating of the back end of the spacecraft by exhaust gases from the internally mounted rocket. “So stuff melted,” says the board's chair, NASA chief engineer Theron Bradley. The commercial rocket motor's successful track record may have lulled mission engineers into a false sense of safety, the report notes. “They were dealing with some other, known problems,” says Bradley, “and weren't inclined to chase after things they didn't think would be a problem.”

CONTOUR was the sixth mission in NASA's Discovery program, begun in 1994 as a way to stretch NASA's space science dollars (Science, 15 November 2002, p. 1320). Johns Hopkins University's Applied Physics Laboratory (APL) in Laurel, Maryland, managed the mission for principal investigator Joseph Veverka of Cornell University. The panel faults the review process used by NASA and APL to make sure that everything was going smoothly. Both organizations need to improve their technical reviews, which “are often high-level and based on viewgraph presentations,” notes the report.

That's all well and good, says John Appleby, APL's supervisor for civilian space programs. But added oversight might well have exceeded CONTOUR's $158 million budget, he says. “Maybe you spend more money and get more analyses,” says Appleby. “If we'd had the benefit of more analyses, the motor would have been placed further outside the [spacecraft] body.” The tendency to skimp on space mission engineering “is not unique to CONTOUR,” says Noel Hinners of the University of Colorado, Boulder, who has held high-level positions in both NASA and the aerospace industry. Similar problems contributed to the Columbia space shuttle tragedy and the loss of the twin Mars 1998 missions, he says. The trick, says Hinners, is to “recognize [early on] what everything is going to cost” and budget accordingly. 5. ASTRONOMY Asteroid Returns 66 Years After a Close Brush With Earth 1. Govert Schilling* 1. Govert Schilling is an astronomy writer in Utrecht, the Netherlands. A potential killer asteroid, lost since it visited our neighborhood 66 years ago, has finally been sighted again. Astronomers are relieved to announce that the kilometer-wide rock known as Hermes will not get uncomfortably close to Earth within the next century. What's more, a close look suggests that the asteroid might actually be twins. “Hermes is a dangerous object,” says Timothy Spahr of the International Astronomical Union's Minor Planet Center (MPC) in Cambridge, Massachusetts. The asteroid was discovered by German astronomer Karl Reinmuth in 1937, when it zipped within 800,000 kilometers of Earth but vanished before astronomers could nail down its orbit. “Every once in a while someone said: ‘Hey, where's Hermes?’ It was kind of nerve-racking,” says Spahr. “We're happy to have it back.” On 15 October Hermes turned up as a faint speck of light in photos made by the Lowell Observatory Near-Earth Object Search program in Flagstaff, Arizona. Brian Skiff noticed the object and sent the images to MPC, where Spahr tracked down other recent observations of the asteroid and concluded that it almost certainly had to be Hermes. Final confirmation came when the new orbit was firmly linked to the scant observations of 1937. On 21 October, astronomers at the 300-meter Arecibo radio telescope in Puerto Rico announced that Hermes might really be two lumps of rock, each 300 to 450 meters wide, locked in tight mutual orbits. The asteroid's return comes as no surprise to Lutz Schmadel and Joachim Schubart of the Astronomisches Rechen-Institut in Heidelberg, Germany. Two years ago they predicted that Hermes would approach Earth in October 2003, on the basis of previously unstudied photographic plates from 1937. “Unfortunately, the American astronomers apparently were not aware of our prediction,” says Schmadel. “So the recovery is truly accidental.” Hermes will make its closest approach to Earth on 4 November, at a safe distance of 7 million kilometers. In the next 100 years or so, it won't get any closer than about 3 million kilometers. Although the asteroid's eccentric, chaotic orbit makes it hard to predict what will happen in the distant future, astronmers say the new observations ensure it won't get lost again. And it will now finally receive a proper number, like more than 60,000 other asteroids whose orbits have been determined. Says Schmadel: “This exceptional asteroid deserves an exceptional number, like 66,666 or 70,000.” 6. BIOMEDICAL FUNDING In Step With Advocates, NIH Backs Targeted Research Centers 1. Jocelyn Kaiser Patient advocacy groups routinely celebrate the creation of a new center or passage of a bill that sets aside money for research on a specific disease. But last week two lobbies were recognized in an unusual seven-round salute. The National Institutes of Health (NIH), jumping ahead of a proposed congressional mandate, announced that it is funding four new centers to study environmental causes of breast cancer. And in a separate decision, NIH responded to a 2001 congressional directive by selecting three universities as homes for research centers on muscular dystrophy. The breast cancer centers, funded at a total of$5 million a year for 7 years, will look at how factors such as diet and exposure to chemicals affect breast development. The grants mark the latest victory for the National Breast Cancer Coalition (NBCC), a lobbying group headed by Philadelphia attorney Fran Visco. Eleven years ago, after a failed effort to boost breast cancer research at the National Cancer Institute (NCI), NBCC helped persuade Congress to designate a new Department of Defense breast cancer research program, which is funded at $150 million in 2004. Visco says that her group now has a firm foothold at NIH, too. NBCC began meeting with experts to discuss the centers idea 5 years ago, arguing that too little is known about the environmental triggers for breast cancer. The group focused on the National Institute of Environmental Health Sciences (NIEHS) as a host, rather than NCI, Visco says, because it has “a more open mind and a more flexible structure” that would allow advocates to participate. Representative Nita Lowey (D-NY) introduced a bill supporting the effort; the proposal and a Senate version are now pending in committees. Gwen Collman, an NIEHS scientific program administrator, says that her institute had been planning the centers “before we knew about the legislation,” which “just confirmed” the agency's intentions. Besides, the questions to be studied are “not new,” she says. Rather than wait for Congress to act, NIEHS and NCI solicited proposals and named the winners last week. The four centers* will conduct collaborative animal studies of whether chemicals such as dioxin, the plastics ingredient bisphenol A, and genestein, a plant estrogen, influence the development of mammary tissue. They will also follow cohorts of prepubescent girls to look for possible triggers of early puberty, which is a known risk factor for breast cancer. “It's been a wonderful opportunity to pull together people who would never have thought of working on this problem in this coherent a way,” says principal investigator Sue Heffelfinger, a cancer biologist at the University of Cincinnati. The other group that scored last week is the Muscular Dystrophy Association (MDA), which was cited by name in an NIH press release as a probable co-sponsor of research. Several NIH institutes are funding three new centers for up to$1 million a year each for 5 years. They will look for cellular and molecular clues to muscular diseases and study gene and stem cell therapies. MDA, which lobbied for a 2001 law requiring NIH to create the centers, plans to give them supplements of up to $500,000 per year for 3 years. Creating the centers “is a significant step forward,” says Sharon Hesterlee, director of research development for MDA in Tucson, Arizona. After such triumphs, disease activists are not likely to rest on their laurels. NBCC, for one, plans to treat this week's announcement as a small down payment for the new centers. Five million dollars a year may be a nice beginning, but it “isn't anywhere near enough,” Visco says. She is aiming for$30 million per year, the amount in the Lowey bill. Meanwhile, the Institute of Medicine is putting finishing touches on a review ordered by Congress that will examine whether the growing number of disease-specific centers created through advocacy is a good idea.

• *University of Cincinnati, Ohio; Fox Chase Cancer Center, Philadelphia; University of California, San Francisco; Michigan State University, East Lansing.

• †University of Pittsburgh; University of Washington, Seattle; University of Rochester, New York.

7. PALEONTOLOGY

Hulking Dinosaurs Were Buoyant But Unseaworthy

ST. PAUL, MINNESOTA—Sauropod dinosaurs—the stout, four-footed, long-necked variety—have enjoyed an on-again, off-again relationship with water. Early dino artists showed them submerged in lakes, eating soft aquatic plants. When scientists realized that the water pressure would have collapsed the animals' lungs, they moved sauropods onto dry land. Ever since, the big beasts have sturdily marched across the floodplains, taking dips only when absolutely necessary.

The landlubbers got their feet wet again here last week. At the annual meeting of the Society of Vertebrate Paleontology, paleontologists took a fresh look at how these gargantuan creatures would have fared if they did take the plunge. A computer model indicates that sauropods would have ridden high in the water and would likely have been very unstable. Another experiment also suggests that water would have shifted their balance even at shallow depths. The studies “give us a little window on some possible behaviors that we didn't think about before because we were so against sauropods in the water,” says paleontologist Kristi Curry Rogers of the Science Museum of Minnesota in St. Paul.

One reason scientists plunked sauropods into lakes in the first place was to explain strange trackways that bore only the marks of the animals' front feet. With its butt bobbing, the story went, a sauropod pulled itself along with its forelimbs. Decades later, Martin Lockley of the University of Colorado (UC), Denver, and colleagues argued that the dinosaurs had kept all fours squarely on land but that the narrower forefeet had simply sunk deeper into the sediment, causing the resulting “manus” tracks to stand up better to erosion. “Everyone was very pleased, because we didn't have to float our sauropods,” says trackway specialist Joanna Wright of UC Denver.

But paleontologist Jeff Wilson of the University of Michigan (UM), Ann Arbor, wasn't so sure. Most sauropods, he noted, had their centers of mass closer to their back feet. So Wilson and Dan Fisher of UM measured the stress exerted by the limbs of plastic models of various sauropods. When they added water, all four limbs stayed on the bottom of the tank, but the front limbs began to bear a greater share of the load—exerting up to 20 times more stress for a Brachiosaurus in hip-deep water (2 to 3 meters). That could explain the manus-only trackways, they say.

Don Henderson of the University of Calgary, Canada, went one better. Using a computer model that took into account the distribution of muscles, bone, and air spaces inside the dinosaurs' bodies, he dunked virtual sauropods into virtual lakes. The lungs and relatively porous bones in Henderson's 3D reconstructions made the animals float like “colossal corks,” he says—so high that a Brachiosaurus in shoulder-deep (4.7-meter) water couldn't have touched bottom with its hind limbs, just as early interpretations of the trackways assumed. Other types of sauropods, such as Diplodocus and Apatosaurus, floated with their front limbs higher than their hind limbs; they could not have made the manus-only tracks, Henderson says.

Once all fours were off the bottom, sauropods were in for trouble, Henderson's model indicates. Although the long neck and tail would have kept them relatively poised from front to back, the animals would have been prone to capsizing. “It's on a knife edge,” Henderson says. “The slightest wave would tip it sideways.” To Henderson, that suggests sauropods would have had trouble swimming. Others think they probably could have managed, albeit awkwardly. No one, however, is planning to march sauropods back into the water for good.

8. GENETICS

The Grand Canyon's Cattalo

1. Anne Minard*
1. Anne Minard is a science writer in Flagstaff, Arizona.

FLAGSTAFF, ARIZONA—A new genetic analysis may be bad news for a bison herd of dubious pedigree that's been making trouble in the Grand Canyon. Early indications are that the animals are chock-full of cow DNA.

The herd, owned by the state of Arizona, has been straying from its normal range and venturing into Grand Canyon National Park, creating mud and dust wallows and trampling native vegetation. Park scientists would like to get rid of the beasts. They pushed for tests to determine whether the herd showed hybridization with cattle, noting that the park's job is to protect native species—and cows are anything but native (Science, 21 March, p. 1835).

Preliminary results show that more than 90% of the animals sampled have cow genes. James Derr, a molecular geneticist at Texas A&M University in College Station, tested the first 13 samples and plans to analyze more of the 150-member herd in early November. So far, the results line up with other studies by Derr. He has documented pure bison genetics in the vast majority of herds on federal lands. But most private and state herds, including Arizona's, originated with entrepreneurs such as Charles “Buffalo” Jones, whose “cattalo” experiments sought to cross bison and cows. Those herds almost always harbor cow genes.

Genetics may not be enough to condemn the Arizona herd, however. “It's one thing to have the science,” says Jeffrey Cross, the park's chief of natural resources, but “it's another thing when that science leads to a management decision.” Arizona wants the bison to stay, with or without cow genes: An annual buffalo hunt brings in more than $40,000 a year. 9. SCIENTIFIC PUBLISHING Opening the Books on Open Access 1. David Malakoff* 1. With reporting by Edna Francisco. This month the Public Library of Science unveiled a free electronic, open-access journal based on author fees. Will this financial model work? When Parisian scholar Denys de Sallo founded Journal des Sçavans, the world's first scientific journal, he charged 5 sous for the inaugural issue in 1665. Après de Sallo, le déluge: Science publishers now churn out more than a million papers a year in about 20,000 journals, with annual subscription prices as high as$20,000.

Leaping hurdles

The new journal appears to be off to a solid start. Its 13 October inaugural issue included nine research papers, including one headline-grabber on a monkey whose brain had been wired to move a robotic arm. Curious readers created gridlock on the PLoS Web site last week.

Each monthly issue is expected to contain about 10 research papers and an array of less technical offerings. PLoS is also distributing about 30,000 free print copies of the first three issues. (Annual print subscriptions will cost $160.) The next issue is already “shaping up nicely,” says PLoS Executive Director Vivian Siegel, a former editor of Cell. But keeping up the pace will be a challenge, she says. So far, many of the submissions have been recruited from like-minded allies. PLoS “faces not just one hurdle but a whole race of hurdles” in expanding that pool, Varmus acknowledges. “We're unknown, online, and contentious —plus we're asking them to pay.” Resistance, says Siegel, is particularly strong among young academics, who worry that publishing in PLoS will do less for their chances of securing tenure and research grants than would publishing in more established journals. Indeed, interviews with a half-dozen randomly selected young scientists at major U.S. research institutions suggest that PLoS is not an easy sell. Despite the publicity blitz, most of the academics were only vaguely familiar with the concept. Nace Golding, a first-year faculty member at the University of Texas, Austin, voiced a typical view when he said he'd be “pretty skeptical” about submitting a paper that might win a slot in an established marquee journal. “I've seen lots of new journals crash and burn,” says the 36-year-old electrophysiologist, who has had papers in prestige journals such as Nature and Neuron. And PLoS's$1500 fee “would be a major disincentive, especially since I can publish elsewhere for free.” Still, the concept of open access appeals to him, and not just for philosophical reasons: Free online papers are likely to reach more readers, he figures, and therefore attract more citations.

The price of rejection

Along with goodwill in the community, the open-access movement needs a business model that can work. Just 2 years ago, PLoS organizers estimated that they could put out a first-rate journal for just $300 per published paper. “We were a little naïve,” Eisen says now. Even PLoS's current price tag of$1500 per paper has many publishing executives wondering if the operation—which has hired six professional editors and five other staff members and promised to waive fees for scientists who can't pay—can survive after its grant from the Moore Foundation expires.

The problem for PLoS is that prestige comes at a price. Selectivity means high rejection rates, with editors spending a lot of time processing material that is ultimately rejected, and even more effort recruiting and polishing papers that are published. Science, Nature, and Cell, for instance, reject the vast majority of submissions; Science rejected more than 90% of the 11,000 manuscripts submitted last year. “We spend more rejecting papers than we do accepting them,” says executive publisher and AAAS head Alan Leshner. Fees would have to be $10,000 per paper or more to cover the roughly$10 million a year it currently costs to produce Science's news and editorial content, not including production, he estimates.

Nature publisher Jayne Marks agrees with Leshner that it would cost “far in excess of PLoS's per-paper fee” to publish her for-profit journal. Cell, also a for-profit, didn't respond to a request for comment, but several other marquee biomedical publishers said that $1500 per paper is below their operating costs. “We could not do what we do at that price,” says Chris Lynch, an executive at The New England Journal of Medicine. Open-access advocates, however, take issue with such comparisons. PLoS Biology doesn't plan to match the labor-intensive news sections and nonresearch content in such journals, and it won't need to satisfy commercial profit margins that can top 40%. And, unlike many nonprofit societies, PLoS won't need to subsidize other, nonjournal activities. Backers argue that their real accounting cousins are the journals that sit just below Science and Nature in the scholarly pecking order. For them, says consultant Waltham, “$1500 per paper is not completely out of court.” It's also roughly equivalent to what authors of a single article currently pay for page charges, reprints, or color graphics in some elite journals. Indeed, several nonprofits that have decided to experiment with the author-pays model, such as the U.K.-based Company of Biologists, have set introductory charges at just $500 to$800 per paper, although some warn that those prices are far below actual costs.

Open access's biggest current player, meanwhile, has bet that it can profitably produce rank-and-file biomedical journals online for $500 per paper. Since its start in 2001, the U.K.-based commercial publisher BioMed Central has started about 100 titles and attracted nearly 8000 manuscripts, rejecting about half. Using a highly automated manuscript management system, “we've demonstrated that open access works and is affordable,” says publisher Jan Velterop. Velterop projects that the company will become profitable within several years if submissions grow at current rates. PLoS hopes to break even within 5 years by following BioMed Central's lead, says Varmus, who serves on the U.K. publisher's board. The key to its strategy is to launch a fleet of journals, starting next year with a second flagship title, PLoS Medicine. By 2008, the publisher could have up to 15 broad disciplinary journals covering major biomedical fields and up to 50 less labor-intensive specialty titles, Varmus says. Some could be journals published in cooperation with established societies, and author fees could vary by title, he adds. PLoS may also copy BioMed Central's effort to sell “memberships” to universities, government agencies, and companies at fees commensurate with their size; researchers working at member institutions could then publish in any of the allied journals for free. But PLoS won't rely just on publishing fees to stay afloat, Varmus says. The publisher may also sell advertising or online sponsorships and seek grants to develop specialized software tools or educational services built around the journals. It's still seeking donations for start-up publishing costs, too, he says. Finding the money Although such added revenue will help, the success of PLoS's plan still hinges on authors' ability to pay. Government research grants currently include relatively small sums for publishing, and some funders bar grantees from paying page charges or related costs. To solve that problem, Varmus and others want funders to consider publishing fees as the final, relatively cheap step of a research project. They've made some headway with that argument. Earlier this year, the Chevy Chase, Maryland-based Howard Hughes Medical Institute, the largest biomedical research charity in the United States, said it would give each of its 350 investigators up to$3000 a year to publish in open-access journals. And the Wellcome Trust, the U.K.'s largest research charity, recently took a similar step, urging grantees to use discretionary funds in their grants for open-access charges. So far, NIH and other U.S. government funding agencies haven't taken a stand, although both allow researchers to pay publishing charges out of their grants.

Some doubt that the author-pays model will fly outside the relatively flush biomedical sciences, however. “I just don't think that the PLoS business model is easily applicable to the rest of science,” says Richard O'Grady, executive director of the American Institute of Biological Sciences (AIBS), which represents 60 nonbiomedical life science societies. “Some ecologists are lucky if their whole grant is that big.”

Along with many other society executives, O'Grady is running the numbers to see if AIBS can afford to turn its monthly journal, BioScience, into an open-access publication. “Our costs would be about $1000 per page,” he says, meaning$7000 for a typical article. The author-pays model “doesn't seem to be a good fit for our kind of journal,” he says.

Physicists probably have the most experience with the concept of open access, having pioneered the online preprint archive that allows researchers to post papers long before they appear in journals. The field also has several successful open-access publications. But many of the biggest titles still charge for subscriptions, and that's unlikely to change soon, predicts Martin Blume of the American Physical Society (APS), one of the discipline's biggest publishers. He estimates that per-paper fees for APS's Physical Review Letters journals would have to be in the $1500 range if the journals went open access, a sum that could spark an author rebellion. A major chemistry publisher is also standing pat for now. “We have a model that is working perfectly well; our authors aren't demanding we adopt some other,” says Robert Bovenschulte, head of publications for the American Chemical Society in Washington, D.C. Rough transition PLoS backers acknowledge that their approach may not suit all disciplines. But they believe that, like it or not, scientific societies must begin to wean themselves from their dependency on print-based revenues. Libraries and online readers have already begun to cancel print subscriptions, they note, eroding circulation for many journals. And that trend is expected to worsen. “We bash the open-access people for not having a sustainable model,” notes one society executive, “but it's not clear ours is going to last, either.” Some publishers, including AAAS, have introduced “site licenses”: subscriptions that provide full access to online journals for anybody at a subscribing institution. These have broadened access to papers and helped shore up society revenues. But they have also put more pressure on print circulations and library budgets. What an Author Pays for Online Open Access$1500 per paper

PLoS Biology

$500* Nucleic Acids Research FREE Journal of Insect Science$560

New Journal of Physics

$500 Journal of Biology$800*

Development

What an Author Could Pay if These Journals Went Open Access *

∼$10,000 per paper Science “far in excess of”$1500

Nature

∼$7000 BioScience http://www.aibs.org/ “more than double”$1500

New England Journal of Medicine

One big problem for societies interested in making the switch to open access is finding new sources of revenue. A slew of studies have concluded that converting a typical journal can cut costs by about 30% by eliminating printing and distribution expenses. That leaves publishers scrambling to cover the remainder with author charges and other sources. Journals that earn significant advertising income face an even rougher road, because online advertising hasn't proved nearly as lucrative as print. The worst-case scenario, say executives, is that current revenue sources will dry up before a journal has established new ones.

A few publishers are experimenting with approaches that they hope can get them through the bottleneck. One idea is a surcharge—roughly equivalent to what it would cost to order reprints—for authors who want instant open access for their papers. Another tactic sets initial author fees artificially low and then raises them as subscription revenue tails off.

Two months ago, the British Medical Journal (BMJ) also said it was scrapping its decade-old policy of allowing free access to its Web site. Dwindling print subscriptions and advertising troubles prompted the move, wrote editors Richard Smith and Tony Delamothe. BMJ's print circulation dropped 9% last year, they reported, compared with just 4% for 25 sister journals that keep their content behind electronic walls. If BMJ remained free online, they noted, “we will have nothing to replace the revenue lost from cancelled paper subscriptions.” It plans to charge up to $30 for online access. Open-access skeptics argue that the reversals highlight the movement's shaky financial assumptions. But advocates see them as growing pains and are quick to note that all is not lost. JHEP's early archive, from 1997 to 2001, is still freely accessible. And BMJ isn't planning to block everything. Its research papers, for instance, are expected to remain freely available. Still, both sides agree that the changes suggest that open-access publishers are still in a very steep part of the learning curve. 12. SCIENTIFIC PUBLISHING House Bill Triggers Internecine Battle 1. David Malakoff The debate over open-access science publishing is often abrasive. But the jousting got especially rough earlier this year after a political thrust by the Public Library of Science (PLoS). The contretemps started in late June, when Representative Martin Sabo (D-MN) introduced a bill to prevent private publishers from monopolizing information by barring copyright protection for “any work” derived from research “substantially funded” by the government (Science, 4 July, p. 29). PLoS's Michael Eisen endorsed the bill (H.R. 2613) at a Washington, D.C., press conference, saying it was needed to fix a “scandalous” system that forced taxpayers to “pay twice”: once for the research, and again to see the results. Eisen also talked about cancer patients not being able to freely access the results of studies that might improve their prospects. That idea was picked up by the general media. But it also triggered an immediate backlash from many scientists and their societies, who saw it as an attack on the tried-and-true means of communicating new research findings. “It was absurd; they left the impression that people are dying because of mean old publishers,” says Lisa Dittrich, managing editor of Academic Medicine, published by the Association of American Medical Colleges in Washington, D.C. Margaret Reich, publications director for the American Physiological Society, took aim at the double-payment claim in the August issue of The Physiologist. “Some of my tax dollars also go to … farm subsidies, and I don't see anyone handing me free loaves of Wonder Bread,” she wrote. And Michael Held, executive director of the Rockefeller University Press, wrote in the Journal of Cell Biology that the Sabo bill is “a thinly veiled attempt by Harold Varmus and … PLoS to eventually force all publishers into” open access. The response from PLoS and its allies included some needling of Held, whose journals charge subscriptions, for posting his editorial freely online. “Thank you for making so abundantly clear what the benefit and power is of open access,” jibed Jan Velterop of BioMed Central, the U.K.-based open-access publisher. “Not so much by what you say, but definitely by what you do.” Recently, however, PLoS has backed away from actively promoting the Sabo bill (which isn't expected to pass). It has also moved to make peace with some societies, realizing that it may need to work closely with them on future joint ventures. Says Varmus: “We generated some hostility that I would just as soon not have.” 13. MODERN HUMAN ORIGINS MEETING Tracing the Road Down Under 1. Leigh Dayton* 1. Leigh Dayton writes from Sydney, Australia. SYDNEY, AUSTRALIA—Fifty human-origins researchers gathered here at the University of New South Wales from 29 to 30 September. The genetic, archaeological, and environmental data they presented sketches a new picture of the colonization of Australia by both humans and canines. For millions of years, Australia was chiefly a marsupial playground, home to killer kangaroos, giant wombats, and tigerlike carnivores —but not to people. Humans and their commensals finally arrived sometime in the last 100,000 years or so, but researchers have argued heatedly over exactly when. Most experts plump for about 40,000 years ago, whereas a splinter group argues for an early arrival at least 60,000 years ago, probably from several parts of Asia. At the meeting, researchers presented new genetic and paleoecological evidence that has the warring parties edging a bit closer to agreement. This emerging view sees early Australians arriving on the continent perhaps as much as 60,000 years ago and reaching widespread occupation 15,000 years later. Like immigrants today, settlers may have come via two routes, one along the coast of Arabia, India, and south Asia and another down from China and central Asia. “This work sounds exciting,” says Chris Stringer, head of the human origins group at the Natural History Museum in London. “Such an age [for colonization] would not surprise me.” The sharp disagreement about when humans arrived in Australia stems from the wide range of dates yielded by different techniques, sometimes for the same bit of bone. For example, the age of Australia's oldest known human remains, a skeleton known as “Mungo Man,” has been set by various techniques at between 40,000 and 68,000 years, with the most recent work pointing to 42,000 years. Dating expert Ed Rhodes of Australian National University in Canberra plotted all the dates from fossils and artifacts associated with early Australians and concludes that, based on the very limited existing data, the “best fit” is that people first arrived 45,000 to 48,000 years ago. “It may be earlier, but there's not enough data” to be certain, he said in Sydney. The paleoecological data, however, fit a scenario of even earlier arrival, with widespread occupation by 45,000 years ago, according to paleoecologist Peter Kershaw of Monash University in Melbourne. He analyzed data from seven deep land and marine cores from in and around Australia, which offer a continuous, 300,000-year record of pollen and charcoal. Charcoal peaks are associated with fires, and Kershaw spotted two, at 45,000 and 130,000 years ago. He attributes the 45,000-year peak to widespread human activity. “The earlier peak is most easily explained by climate change, but an early arrival is possible,” he says. Genetic evidence presented in Sydney also tends to support an early arrival, as well as providing clues to the routes taken. Molecular anthropologist Sheila van Holst Pellekaan, of the University of New South Wales and Sydney University, and Oxford University population geneticist Rosalind Harding compared mitochondrial DNA (mtDNA) from 188 Aboriginal people from remote parts of Australia to 61 mtDNA samples from people around the world. According to van Holst Pellekaan, preliminary analysis reveals three “very ancient” sets of mutations, called haplogroups, that are distinctive to Australia. Some variations within one haplogroup are shared by people living along a geographic line from southern India and southeast Asia, thus suggesting a migration route. Likewise, some variations within the other haplogroups are shared predominantly with people along a line originating in China and Indonesia. The findings imply a two-pronged entry, although that needs confirmation, says van Holst Pellekaan. As for timing, “Sheila wouldn't put a date on it, but I will,” says Harding. She argues that the steadily ticking “molecular clock” traditionally used by geneticists is unrealistic and produces ages that are too young. Instead, Harding uses random mutation rates, which she claims more accurately reflect the natural world. Assuming two different rates, Harding concludes that the ancient haplogroups arose either 60,000 or 90,000 years ago, suggesting an arrival in Australia well before 40,000 years ago. Other researchers also turned up some evidence for a route through India. Geneticist Rodney Scott of the University of Newcastle and John Hunter Hospital in New South Wales and his colleagues compared differences in genes coding for cytokines—cells that regulate an inflammatory response to infection—in 118 Aborigines from Australia's Northern Territory, 262 Britons and European Australians, and 32 Bangladeshi. They found that the genotypes rare in Aborigines were common in Britons and European Australians, and vice versa, with the Bangladeshi results in the middle. “The results suggest a gene flow across the Indian subcontinent towards Australia,” concludes Scott, although he adds that the work is preliminary and must be confirmed. Molecular anthropologist John Mitchell of La Trobe University in Melbourne, who has tracked human migration through the Y chromosome, says the findings presented in Sydney make sense in terms of both timing and route. “This is definitely what the Y chromosome data show,” says Mitchell, referring to work he published in 1999 in Human Biology. Despite the lingering disparity over dates, he says, “overall, a pattern is clearly emerging.” 14. MODERN HUMAN ORIGINS MEETING On the Trail of the First Dingo 1. Leigh Dayton* 1. Leigh Dayton writes from Sydney, Australia. SYDNEY, AUSTRALIA—Fifty human-origins researchers gathered here at the University of New South Wales from 29 to 30 September. The genetic, archaeological, and environmental data they presented sketches a new picture of the colonization of Australia by both humans and canines. Australia's national dog, the dingo, is famous for its wolflike howls and wild ways. But new genetic work suggests that all of today's feral hounds are descendants of an ordinary domestic pooch from the islands of Southeast Asia. And although dingoes have spread across the continent, their ancestors arrived Down Under in a single introduction roughly 5000 years ago, says molecular biologist and geneticist Alan Wilton of the University of New South Wales in Sydney. “The founding event was small,” says Wilton, who presented the work. “It may have been one pair or a group of closely related dogs. It may even have been a single pregnant dog.” The new study is “very convincing and thorough,” says evolutionary biologist Robert Wayne of the University of California, Los Angeles, an expert on the domestication of the dog. “It really suggests there was a single founding event.” Until now, dingo DNA had not been studied for clues to the dog's origins, and their fossil record is sparse. The earliest documented fossils are a mere 3500 years old, and dingoes never reached the island of Tasmania, which was separated from the mainland by sea level rise 12,000 years ago. Thus experts had concluded that the dog arrived between 3500 and 12,000 years ago, most likely about 5000 years ago—long after dogs were trotting after their humans in most of the rest of the world. Wilton and his colleagues, including Peter Savolainen of the Royal Institute of Technology in Stockholm and others in Sweden and New Zealand, compared a 582-base-pair stretch of noncoding mitochondrial DNA (mtDNA) in 211 dingoes from across Australia, 676 dogs from around the world, 38 Eurasian wolves, and 19 pre-European dog fossils from Polynesia. They discovered that “all dingoes have a very similar type of DNA,” says Wilton. “Any variation is only a single mutation away from the main type.” That profound homogeneity shows that the founding population must have been just a few dogs, he says. Assuming a steady mutation rate, the team estimates that all the dingo mutations did indeed arise in the past 5000 years. Combining these results with previous work, Wilton can sketch dingo history. Last year, in a study on the origin of domestic dogs, Savolainen and colleagues showed that dogs were first domesticated from wolves in East Asia about 15,000 years ago (Science, 22 November 2002, p. 1610). In the new study, Wilton found the dingo “main type” in some dogs in East and Southeast Asia, Siberia, Japan, and the Indonesian archipelago. “Have you ever seen a New Guinea Singing Dog? It's a dingo with stumpy legs,” jokes Wilton. Thus he suggests that the ancestor of the dingo and its cousins appeared in China 10,000 to 15,000 years ago and was brought south by people, with Indonesia as the last port of call. “Australia was the end of a long chain of migration,” he says. Still, he notes that some dingoes must have been taken back to Indonesia in the early days, because some Indonesian dogs have lice and parasites that evolved in kangaroos. Unfortunately for romantics, the team found that wolves—the original wild dogs—do not carry the dingo main type. That scotches the notion that the dingo too had wild roots. Instead, the wild behavior seen today developed because the original domestic mutts went feral soon after they were brought to Australia, says Wilton. Dingo lovers may be relieved to know that despite their domestic beginnings, dingoes are still special: They're a unique remnant of an early, undifferentiated dog. “Dogs were just dogs then,” says Wilton. “Breeds are a fairly new thing.” But the dingo's unique gene pool may be vanishing, thanks to inbreeding with modern dogs. Already 80% of dingoes along the Australian east coast are hybrids, and no programs are in place to isolate “pure” dingoes in the wild, says Wilton. “It gets worse all the time,” he claims. “They may be extinct in 50 years.” 15. MOLECULAR ELECTRONICS Next-Generation Technology Hits an Early Midlife Crisis 1. Robert F. Service Researchers had hoped that a new revolution in ultraminiaturized electronic gadgetry lay almost within reach. But now some are saying the future must wait Two years ago, the nascent field of molecular electronics was riding high. A handful of research groups had wired molecules to serve as diodes, transistors, and other devices at the heart of computer chips. Some had even linked them together to form rudimentary circuits, earning accolades as Science's 2001 Breakthrough of the Year (Science, 21 December 2001, p. 2442). The future was so bright, proponents predicted that molecular electronics-based computer chips vastly superior to current versions would hit store shelves in 2005. Now, critics say the field is undergoing a much-needed reality check. This summer, two of its most prominent research groups revealed that some of their devices don't work as previously thought and may not even qualify as molecular electronics. And skeptics are questioning whether labs will muster commercial products within the next decade, if at all. “There are a number of parts of the field that really weren't critically tested before being publicized and published. So people are having to backpedal,” says Paul Weiss, a chemist at Pennsylvania State University, University Park. Adds chemist Jim Tour of Rice University in Houston, Texas, who has been one of the field's most vocal proponents: “I'm surprised it took this long to have some things confronted.” At the top of that list, Tour and others say, are questions of exactly what is going on at the heart of some devices advertised as molecular electronics. Some of the doubts center on work by researchers at Hewlett-Packard and the University of California, Los Angeles (UCLA). In 1999, Stan Williams, who directs quantum science research at HP Labs in Palo Alto, California, teamed up with UCLA chemists Fraser Stoddart and Jim Heath—now at the California Institute of Technology (Caltech) in Pasadena—to create transistors that used the movements of molecules called rotaxanes to turn electric currents on and off in the devices. But because the molecules were pinned between pairs of electrodes, outsiders said it was difficult to be sure what was going on. Critics suggested that the voltages used to switch the molecules might also be wreaking havoc with the metal electrodes above and below them. They proposed that when the voltage was turned on, the resulting electric field could cause metal atoms to form tiny filaments across the molecular gap between the electrodes, changing the conductivity of the material. Concerned that this might be the case, Heath split with his former HP partners and ordered his own research group to replace one of the metal electrodes with a semiconductor—a move that in theory should have prevented the metal filaments from growing. Now it appears that those concerns were well founded. At a grantees meeting sponsored by the Defense Advanced Research Projects Agency (DARPA) in late July, Williams reported that new experiments by Mark Bockrath, another Caltech colleague, revealed that the creation and dissolution of the metal filaments between the electrodes was probably responsible for the changes in conductivity and the switching behavior. Williams maintains that the devices still qualify as molecular electronics, because the rotaxanes are acting as a one-molecule-thick insulator, an essential part of the device. But others balk at the characterization, as the molecular layer isn't directly responsible for the electronic switching. No matter what the mechanism is or what it's called, Williams contends that commercial prospects for HP's systems are bright, and they may even offer advantages over similar molecule-based electronics. One selling point he cites is the devices' on-off ratio, a number that describes the increase in current that occurs when the voltage is turned on. Computer chipmakers typically strive for ratios of at least 50:1 to ensure that signals pierce the inevitable background noise. Heath's rotaxane-based switches manage 8:1. But the HP devices, Williams says, have an on-off ratio of 10,000:1 or more. The discovery that metal filaments are likely responsible for the switching “hasn't stopped us from building working devices,” Williams says. The HP team has reported making a 64-bit memory storage device, and Williams says that it will soon report devices of much higher complexity. Still, others say that the new insight into what's going on inside HP's devices raises at least as many questions as it answers. For example, how stable could devices that depend on metal atoms moving back and forth be in the long run? “It may not be bad, but it throws a curve ball,” says David Bocian, a molecular electronics expert at UC Riverside. New questions are arising about some of Tour's early results as well. At the July DARPA meeting, Weiss reported that tests on some of Tour's molecules revealed that a key electronic signature, originally thought to play a role in their operation, may have been an artifact. In 1999, Tour teamed up with physicist Mark Reed of Yale University and others and reported that devices containing short polymers called phenylene ethynylene molecules showed an electronic effect known as negative differential resistance, or NDR (Science, 19 November 1999, p. 1550). When most molecules are subjected to stronger and stronger electric voltages, they become more conductive. But when Reed and Tour placed their molecules between a pair of electrodes, they saw the reverse: The conductivity decreased as the voltage rose. That property, the researchers suggested, could be exploited to serve as an electronic switch. Still, questions persisted here, too. Because the molecules in Reed and Tour's experiments were also pinned between two metal electrodes, there was no way to check whether the NDR signature was really coming from the phenylene ethynylene molecules. To find out, Weiss suggested replacing the top electrode with an electrically conductive scanning electron microscope tip that would pass electrons to individual molecules, record their electronic behavior, and capture images of the molecules, all at the same time. When Weiss ran the experiments, the NDR signatures proved to be intermittent and inconsistent and were therefore probably an experimental artifact, Weiss says. Both Weiss and Tour caution that the new results don't prove that a similar artifact caused the previous NDR readings. “They are different experimental systems,” Tour says. But what the new work does show, Weiss says, is that electrically active molecules in molecular electronics experiments can behave in wildly different ways depending on whether they are surrounded by electrodes or by other materials. The implication for all molecular electronic devices: Ensuring that large networks of molecular electronic circuits all perform in an identical manner will be much harder than some of the field's boosters have implied. Weiss's results weren't all bad news. His team did find that the phenylene ethynylene molecules could switch using a mechanism not involving NDR. The group's current hypothesis, Weiss says, is that subjecting the molecules to an electric field shifts them between two stable configurations, one of which carries current between electrodes more efficiently than the other. But it remains unclear here too how durable devices made with shifting molecules are likely to be. Other concerns continue to dog the molecular electronics field as well. At a debate over the future of molecular electronics held last month at UCLA,* Edwin Chandross, a chemist recently retired from Lucent Technologies' Bell Labs, said that for molecular electronics devices to make it to market, researchers will have to solve a host of real-world problems. One of them, he suggested, was the likelihood that when researchers deposit hot metal atoms to form the electrodes in their materials, the atoms react with rotaxanes and other organic electronic materials, altering them in unforeseen ways. Heath—Chandross's sparring partner in the debate—countered that numerous tests in his lab have shown that the rotaxanes survive the metal deposition process unscathed, and they continue to work as switches. But even though that may be the case, Chandross pointed out that the Caltech group's devices lose their ability to switch after only a few dozen cycles. “To say ‘never’ is foolish, but within a decade I think we won't see large-scale memory or computing chips,” Chandross says. Heath acknowledges that high-end computer applications, such as memory and logic, won't come soon. But he stresses that it's far too early to give up on the field. “It is much easier to tear down something than build something up,” Heath says. Chemists, he adds, have just begun to explore ways to increase the stability and durability of electronically active molecules. But perhaps more important, Heath adds, molecule-based systems can handle tasks silicon-based electronics simply can't touch. Several groups, for example, have created molecular electronic-based devices capable of acting as sensors and are working to wire them to larger-scale electronics. And Heath says that his group is making steady progress on developing molecule-based electronic sensors that can detect particular chemical signals inside cells. So even if molecular electronics doesn't dethrone silicon from the top of the computing world, it may still work its way into the marketplace by carrying out tasks silicon just can't master. • *One-Day NanoSystems Symposium and First Cram Debate, UCLA, 22 September 2003. 16. BIODIVERSITY New Chinese Center Marks a Coming of Age for Field 1. Dennis Normile The International Center for Studies of Evolution and Biodiversity will allow Chinese scientists to move beyond cataloging flora and fauna TOKYO—Shi Suhua, a botanist at Sun Yat-sen University in southern China, hit an intellectual wall as she was exploring a new area: mangrove evolution. She felt that she was over her head in population genetics and needed help. Then she learned about a workshop on the topic, taught by University of Chicago evolutionary geneticist Chung-I Wu, at the Kunming Institute of Zoology, more than 1000 kilometers away in Yunnan Province. The short course she attended in the summer of 2002 “opened a window on another world,” she says. Peer interactions of the kind that stimulated Shi's work may soon be available to hundreds more Chinese researchers, as Wu and colleagues from China, Germany, and the United States are getting ready to inaugurate a new interdisciplinary facility. The International Center for Studies of Evolution and Biodiversity (ICSEB), to be housed at the Kunming Institute, hopes to train the next generation of Chinese evolutionary biologists and ecologists and forge ties with scientists throughout the world. It will draw support from the Chinese Academy of Sciences (CAS), Germany's Max Planck Society, and the University of Chicago. The new center, to be launched next week with a ceremony in Kunming followed by a symposium in Beijing, represents a scientific coming of age for Chinese studies of biodiversity. Chinese scientists have done an outstanding job of collecting specimens and cataloging the country's extensive flora and fauna, says biologist Uli Schwarz, director of the new Shanghai Institute for Advanced Studies (SAIS). But the time is ripe, he says, to synthesize the data and address larger interdisciplinary topics, such as interactions among species and changes in an ecological community over time. “The center will bring together what are now rather isolated efforts, provide an infrastructure for synthesis of data, and be a bridge between China and the outside,” says Wu, its founding director. The drive to integrate findings has also prompted Fudan University in Shanghai to set up a department of ecology and evolutionary biology. Li Jin, dean of biological sciences at Fudan and a professor of genetics at the University of Cincinnati, Ohio, says that the new department will be the first of its kind in China and will cooperate closely with the Kunming center. ICSEB's location in China's rugged southwest is no accident; the organizers placed it in Kunming to take advantage of the region's “astounding biodiversity,” says Schwarz, who retired last year from the Max Planck Institute for Developmental Biology in Tübingen, Germany. SAIS, which is partly funded by the Max Planck Society, has been supporting collaborations between the Kunming Institute and a number of top Max Planck scientists, including Svante Pääbo, an evolutionary geneticist and director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, and Thomas Mitchell-Olds, a plant geneticist at the Max Planck Institute for Chemical Ecology in Jena. The new center is modeled roughly on the National Center for Ecological Analysis and Synthesis at the University of California, Santa Barbara—but without some of its resources, such as heavy-duty computing facilities. Starting with a shoestring budget of about$100,000, Wu hopes to persuade CAS to underwrite a $1 million budget for the center's second year of operation. Wu says he hopes the center can offer its first round of workshops in the spring. But researchers like Shi are already benefiting. She and her group are applying what she's learned about population genetics to an analysis of genetic diversity among mangrove populations, and they hope to collaborate with Wu on a study of plant speciation. This is precisely the type of teamwork, according to Wu, that the new center is designed to foster. 17. Preventing Toxicity With a Gene Test 1. Eliot Marshall To test or not to test? That is the question clinicians are asking about screening for genes that affect how the body metabolizes drugs For more than 30 years, doctors have been using a powerful cell-killing compound to cure leukemia in children. This wonder drug—6-mercaptopurine (6MP), synthesized by the late Gertrude Elion and George Hitchings—has saved thousands of lives. But it has a dark side. Researchers discovered more than 20 years ago that it is extremely toxic in patients with an inherited metabolic flaw. The drug can accumulate rapidly, wiping out essential bone marrow and leading to infections. About 8 years ago, teams led by William Evans of St. Jude Children's Research Hospital in Memphis, Tennessee, and Richard Weinshilboum of the Mayo Clinic in Rochester, Minnesota, pinpointed flaws in an enzyme-producing gene called TPMT on chromosome 6. A DNA test became available in the 1990s. It tells patients whether they are in one of three risk categories: standard, with a copy of the normal TPMT gene from each parent; slightly elevated, with a deficient gene from one parent; or extremely high, with two deficient genes. People in the last category, roughly 1 in 300 Caucasians, should not receive standard 6MP therapy, physicians say. It could kill them. Only one fatality has been reported in the medical literature: In 1993 a heart-transplant patient in Germany received a drug in the same class (a thiopurine) to suppress immunity and died of sepsis. Afterward, a blood test revealed a metabolic deficiency. But many young leukemia patients have suffered well-documented, life-threatening bouts of 6MP toxicity. This makes a strong case for genetic testing before prescribing 6MP, argue cancer researchers such as Evans and Howard McLeod of Washington University in St. Louis, Missouri. The tests might be used not just for cancer therapy but also for the drug's unapproved or “off-label” treatment of inflammatory diseases. But the medical community remains skeptical. Like other promised benefits of genomic medicine, this one has run into complaints about its cost ($100 to $300 per test), technical issues about how to recalibrate drug doses, and doubts about physicians' ability to understand test results. Such real-world headaches seem to keep pushing the human genome sequence's payoff just beyond reach. Indeed, several influential physicians recently declared that testing for TPMT risks should not be mandated. Doing so, they say, could endanger patients by causing delays in therapy. Several pediatric cancer specialists have also said they don't want the government even encouraging prospective TPMT testing. Therapy should be guided by experience and well-established blood cell counts, they say, not a gene test. For now, the U.S. Food and Drug Administration (FDA) seems unlikely to recommend one. The resistance has surprised champions of genomic medicine. A leader in pharmacogenetic studies, Russ Altman of Stanford University, acknowledges that genotyping for drug risks has been a hard sell. In all, says FDA pharmacogenetic expert Larry Lesko, about 20 drug labels now mention reactions that may be influenced by genetic differences, but none recommends a gene test or related dose guidelines. Adds Altman: “Everyone thought TPMT would be the big one to do first. I must admit there is not a single case of a genetic variation where the standard of care is to test first. … We have not yet broken through.” Still, the TPMT case suggests that genomic medicine is gaining momentum, albeit slowly. Genotyping to prevent adverse drug reactions may indeed be one of the first applications to win broad acceptance, but the pace will depend a lot on how physicians respond. Patients who face risks of toxicity may be among the first to recognize the benefits, and they may bring along the doctors. No advice, thanks The question of whether to add an advisory on gene testing to the 6MP package label is now before FDA. The agency's new administrator, Mark McClellan, has said that one of his top five priorities is to raise the profile of genomics in FDA decisions. Partly because of McClellan's interest, says Lesko, the agency is taking a look at 6MP. It's the second drug to undergo an explicit genetic risk review but only the first to be evaluated as possibly requiring a gene test before use. The other one was a new drug, atomoxetine, approved by FDA in January for treatment of attention deficit hyperactivity disorder. The manufacturer, Eli Lilly of Indianapolis, Indiana, agreed to include information in the package informing doctors that patients who have a toxic reaction or fail to benefit may have a gene-driven metabolic irregularity. It also mentioned that a test is available to help analyze such irregularities—with no suggestion that the test be done in advance. Because the toxic effects of 6MP are greater than those of atomoxetine, FDA asked an outside panel to consider whether the label for 6MP should go further and recommend gene testing in advance to prevent toxicity. At a critical review on 15 July, pediatricians on the FDA's Oncologic Drugs Advisory Committee (ODAC) were not enthusiastic. The panel agreed that the 6MP label should be modified to include more information about inherited TPMT deficiency—but no recommendation for gene testing. The most disturbing potential risks discussed at the ODAC session concerned children with acute lymphocytic leukemia (ALL) who developed new cancers after being treated with 6MP and cranial irradiation. In a 1999 study, Mary Relling, a pharmacist-researcher at St. Jude, reported that half the children (three of six) who developed these fatal tumors over an 8-year period had at least one abnormal gene. To lower the risk of secondary tumors, cranial irradiation is not combined with 6MP therapy today. But Relling thinks that TPMT deficiencies may have contributed to earlier tragedies, and she's confident that testing would reduce the risk of toxicity in routine therapy. Naomi Winick, an oncologist at the University of Texas Southwestern Medical Center in Dallas, representing the 238 institutions in the Children's Oncology Group (COG) that treat 80% of pediatric patients in North America, isn't persuaded. She says TPMT testing would not have prevented the tumors, and she doesn't think the cases are relevant to the debate. She told the FDA panel that the data are too sketchy to justify routine TPMT screening. “I'm not against genetic testing,” she explained in a telephone interview. “I just don't think it's necessary for this test to be mandated before giving [6MP].” She objects to the added cost and complexity. More than 2000 children are treated for ALL in North America each year, she points out; if one patient in 300 is at risk for a genetically determined 6MP overdose, “most hospitals would never see one.” She fears that the tests would spread alarm and compromise therapy. “This drug has been used for 30 years,” Winick notes; cancer therapists manage its toxicity every day by watching blood counts that enable them to cut the 6MP dose before the consequences are irreversible. A greater risk, Winick told ODAC, is that doctors might become overly cautious, delaying 6MP therapy or reducing doses too much after discovering that a patient has a single TPMT-deficient gene. Although about 10% of Caucasians have at least one risky gene, no validated studies have been published indicating how much the 6MP dose should be reduced for them, she and others point out. “Leukemia is a fatal illness,” Winick reminds: “I worry about [6MP] underdosing.” Pro-testers Physicians care deeply about their patients and are “understandably conservative” about adopting new technologies, says Mayo's Weinshilboum, who also briefed the ODAC panel. And they're wary of gene testing. But he says: “I would prefer to see a recommendation for testing prior to drug therapy.” Both the Mayo Clinic and St. Jude now routinely genotype ALL patients for TPMT genes before giving 6MP. But most do not. Even Evans of St. Jude says he understands that cost is a barrier, but he thinks that, “ideally, everyone would be tested before these drugs are prescribed.” Some champions of testing—like Evans—acknowledge that they have a financial stake in it, which also raises questions about their objectivity. St. Jude and Mayo, for example, have an interest in key TPMT gene patents and have earned income from them. But money isn't the issue, argues Nancy Keene, a patient advocate, member of the pediatric subcommittee of ODAC, and mother of a survivor of childhood ALL. Given the huge medical bills a cancer patient incurs, Keene says,$100 to $300 for one lifetime TPMT test doesn't seem extravagant: “I'm mystified by the resistance to a simple blood test that might save children's lives.” Evans, likewise, fails to understand why tests are seen as perilous. Just the opposite, he says. Most cancer patients take several toxic drugs at once; a common response to seeing a patient's blood count drop with toxicity is to cut back slightly on all chemotherapy, he says. Doing so with homozygous TPMT-deficient patients, however, would mean skimping on the drugs they can tolerate while overloading them with the one (6MP) they cannot. Evans says the 6MP dose needs to be cut 90%—not given a typical “tweak” of 25%—while other doses can remain high. The gene test “allows you to zero in on the drug that's causing the problem.” Other testing advocates such as McLeod and Relling concede that research is needed on the 10% of patients who have a single deficient TPMT gene, but they still think the argument for testing is strong. These patients are most likely to cause confusion and receive unnecessarily low 6MP doses, Winick fears. Not enough is known about how they metabolize 6MP to make firm dose recommendations. But Relling points out that they tolerate far larger doses than homozygotes do and therefore can be managed as normal patients are—by monitoring blood cell counts. Relling missed the ODAC meeting but was so disappointed with it that she wrote a sharp letter to FDA on 7 August. “The alternative” to testing TPMT genes, she wrote, “is to continue to use our arbitrary and unscientific approaches to dosage adjustments.” She suggested simple answers to the fears expressed by the oncologists. The hypothetical concern that some doctors “might make a mistake” in interpreting data, she concluded, “is not an adequate justification for withholding information from all clinicians.” Concerns about 6MP have prompted Winick to ask COG to rewrite the protocols for treatment of ALL. Winick says the new guidelines will include detailed information on genetic risks, gene testing, and dosing of TPMT-deficient patients. No deadline has been set for finalizing them. Having observed COG's methods, however, patient advocate Keene thinks it may take years. Off label FDA's review focused exclusively on cancer, ignoring the biggest arena of thiopurine use: for inflammatory diseases. FDA did so because cancer therapy is the sole officially approved use of thiopurines. In reality, physicians prescribe 6MP and its cousin azathioprine, which is converted to 6MP in the body, far more widely to treat “off-label” conditions. FDA is unlikely to address this issue, says one biotech executive, unless someone files an application for a drug covering these uses. And that won't happen, he adds, because the drug is now generic and cannot earn the big profits required to support a new FDA filing. According to Prometheus Laboratories of San Diego, California, maker of a generic azathioprine called Imuran, most of its product goes to patients with ulcerative colitis, Crohn's disease, rheumatoid arthritis, and related diseases. Company spokesperson Beth Kriegel reports that data from IMS Health, a market research firm in Fairfield, Connecticut, indicate that as of June, 10 times more 6MP has been used by gastroenterology patients than cancer patients. Prometheus recently acquired an exclusive license to market the TPMT test, and gastroenterologists are its major clients. Still, it's not standard procedure to test before prescribing. Some clinicians say that 6MP and related compounds may not be as dangerous in these applications as in cancer therapy because dose levels are set lower, at least at the start. But Winick suggests that there is a stronger argument for testing these patients: Unlike children with leukemia who get very frequent tests that could spot a declining blood cell count, indicating toxicity, she says, “I'm not sure that [off-label users] have a blood count done every week.” Although the prescribed drug doses are likely to be lower, the period of use can be long. One prominent gastroenterologist, Stephen Hanauer of the University of Chicago, says blood tests are done frequently enough to avoid serious toxicity. Hanauer last month won a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to run a 15-center, 2-year trial of azathioprine to treat inflammatory diseases. “We rely on functional assays” that measure blood cell counts, he says, and they work just fine. If the count drops, the patient is taken off thiopurines. Nevertheless, many other physicians are looking at genotypes. Kriegel says the volume of tests performed by Prometheus, which sells the drug and the test, is rising; roughly 20,000 have been done to date. Although drug regulators and oncologists remain wary of screening for TPMT genes, there clearly are patients out there who are ready to embrace the technology. If Kriegel is right, their numbers are growing. 18. First Check My Genome, Doctor 1. Eliot Marshall The dangerous reactions some people have to the cancer drug 6MP may offer the most dramatic case for gene testing (see main text), but many other vulnerabilities may soon be checkable with a simple DNA test. The biggest player in this DNA diagnostics market is Roche Molecular Diagnostics in Pleasanton, California. It is seeking U.S. and European regulatory clearance for a battery of gene tests to be included on a single device, the “AmpliChip CYP450,” a microarray developed with the genomics company Affymetrix of Santa Clara, California. The chip will test for variations in two genes: CYP2D6 and CYP2C19. They affect how people process about 25% of drugs on the market, says Walter H. Koch, the company's senior director of pharmacogenomics. Initially, Roche plans to market it primarily for patients using antipsychotic and antidepressant drugs, the efficacy of which varies greatly depending on CYP2D6 genes. Some people with CYP2D6 variations also get no pain relief from codeine or related drugs. The company will translate the results for physicians into metabolic function categories, from poor to ultrarapid. In January 2003, Seryx of New York City launched a genotyping service called Signature Genetics that also zeroes in on similar “cytochrome p450” enzyme genes as well as NAT2, a gene that affects the efficacy of anti-HIV medications. The service is marketed to physicians, who receive a 50-page footnoted analysis with the results to share with the patient. CEO Fred Mannausau says the company charges about$2000 for the initial test and a subscription of \$350 a year for scientific updates. Mannausau said that “fewer than 1000” clients have signed up so far.

A handful of other companies are promising that they will soon have validated genotype assays ready to offer the medical community. Genaissance Pharmaceuticals of New Haven, Connecticut, for example, is planning a test for risky genes that can lead to the heart arrhythmia known as “long QT syndrome.” But the number of commercial companies has declined sharply since the 1990s, from over a dozen to just a handful, says Michael Murphy, CEO of Gentris Inc., a North Carolina pharmacogenomics firm that processes genotypes for clinical trials. Koch confirms that “you don't see much pharmacogenetic testing going on in the clinic right now.”

One of the main brakes on progress, says Christopher Austin, a former Merck executive now at the National Human Genome Research Institute in Bethesda, Maryland, is that “physicians are not generally familiar with the idea” that common gene variations can have a dramatic impact on how well drugs work. Says Richard Weinshilboum of the Mayo Clinic in Rochester, Minnesota: “We need to educate physicians broadly about the vocabulary and concepts that underlie genomic medicine.”

There may be no cultural revolution in the next few years, Weinshilboum acknowledges. But students now in medical school are getting the message. He predicts that when they begin to practice, they will be ready for the new genomic technology—and it will be ready for them.

19. The Twists and Turns in BRCA's Path

1. Jennifer Couzin

Nine years after the much-anticipated discovery of two breast cancer genes, genomic medicine for the disease remains elusive, but surprising insights abound

A mislabeled cell sample and a whim sent Alan D'Andrea down an unfamiliar path.

“We weren't intending to work on breast cancer,” recalls the pediatric oncologist, who's based at Dana-Farber Cancer Institute in Boston. His life's interest is Fanconi anemia, a devastating genetic disorder that leaves young children prone to multiple cancers. But in 2002 a geneticist in his lab, examining what she thought was an unknown specimen, saw a familiar chromosomal pattern and diagnosed the tumor as coming from a Fanconi child. The sample, it turned out, had been mislabeled; it belonged to a woman with BRCA1, a gene discovered in 1994 that puts young women at high risk of hereditary breast and ovarian cancer.

So what was it doing here, being confused with Fanconi's? Of all the cancers Fanconi patients develop, breast and ovarian are rarely among them. But the BRCA1 tumor cells so closely resembled Fanconi cancer cells, with their trademark pattern of starlike, broken chromosomes, that D'Andrea couldn't shake the mix-up from his mind.

At the time, six of the eight Fanconi anemia genes had been cloned, and researchers were struggling to find the rest. On the barest of hunches, D'Andrea gathered cells from children diagnosed with Fanconi's who had none of the cloned Fanconi genes. He sent them to the hospital's diagnostics lab with instructions to sequence for BRCA1 and BRCA2, another closely related breast cancer gene identified in 1995.

This time, the diagnostics team was bewildered. A technician called D'Andrea and complained that some of these cells clearly weren't from a Fanconi child. They were from someone with mutations in BRCA2.

“Of course,” he says, “it wasn't a mistake at all.” This Fanconi gene was the BRCA2 gene, and these children had mutations in copies they'd inherited from both parents. (Women with BRCA2 have mutations in only one copy.) A single dose of mutated BRCA2 conferred one condition; a double dose, it now appeared, conferred another.

This electrifying discovery is just one of the latest twists in the BRCA genes' strange odyssey. When the genes were discovered almost a decade ago, scientists were elated, predicting that the genes would illuminate not only this rare form of inherited cancer but common breast cancers as well. But that hope soon faded.

Recently, however, disappointment has given way to renewed excitement. Instead of solving the enigma of breast cancer, as many anticipated, the BRCA genes have begun weaving together a rich but also puzzling tapestry of defects that drive diverse cancers—prostate and pancreatic and, as D'Andrea found, the spectrum associated with Fanconi anemia. Meanwhile, it is undisputed that the mutated BRCA genes target the ovaries and, especially, the breasts; but why they do remains mysterious. The BRCA experience suggests that the path from gene discovery to genomic medicine will be longer and more circuitous than many envisioned at the outset (see sidebar).

Early hopes dashed

Some of the first evidence for a gene tied to hereditary breast cancer was released at a 1990 meeting, when geneticist Mary-Claire King, then at the University of California, Berkeley, told a hushed audience how her genetic sleuthing had paid off. By working with families riddled with breast and ovarian cancer—in many cases, across several generations, with several siblings in each—King and her colleagues had traced a suspect gene to a swath of chromosome 17. Her announcement ignited a race to isolate the gene itself.

Four years later, scientists at Myriad Genetics in Salt Lake City, Utah, nailed the gene, which they called BRCA1. (The company now holds patents on the diagnostic test to detect gene carriers.) Fifteen months later a second gene, BRCA2, was isolated by an international team led by Richard Wooster and Michael Stratton of the Institute of Cancer Research in Sutton, U.K. Having a single copy of either mutated gene appeared to confer at least an 80% chance of developing breast cancer; the risk of ovarian cancer was somewhat lower but still well above the lifetime norm, hovering between 20% and 65%.

Just 5% of breast cancer cases are linked to the BRCA genes. But other cancer genes identified previously, such as that for the childhood eye cancer retinoblastoma, had shed light on cases of the same cancer in patients who didn't inherit the mutated gene. Geneticists hoped that BRCA would do the same for the 95% of breast cancer patients who are not BRCA carriers. “We thought BRCA would unravel the mystery of carcinogenesis in the breast,” says Larry Norton, head of the solid tumor division at Memorial Sloan-Kettering Cancer Center in New York City.

Immediately, researchers began testing breast and ovarian tumors from women with no family history of disease. They reasoned that, even though these women hadn't inherited either of the defective genes from a parent, the genes could have mutated before or during cancer's development. If so, they would be visible in cancerous cells.

To their dismay, says Norton, such sporadic cancers didn't contain mutated copies of either BRCA gene, leading researchers to reluctantly conclude that BRCA1 and BRCA2 could shed no light on common breast and ovarian cancers. Since then, however, researchers have learned that both BRCA genes interact with other genes and proteins—a crowd collectively known as the BRCA pathway. Although the BRCA genes themselves appear unconnected to common, nonhereditary cancers, emerging evidence suggests that defects in other parts of the BRCA pathway might be critical not only in driving breast cancer but other cancers as well.

Following the BRCA path

Researchers have spent the better part of a decade trying to decipher the BRCA genes' function. Both genes, they now know, help mediate damage to a cell's DNA, but explaining precisely how has been daunting. (A pair of papers on pages 636 and 639 seek to more precisely pin down BRCA1 functions by analyzing discrete sections of the gene.)

Hints that BRCA affects DNA damage, which in turn spurs hereditary cancers, emerged in the late 1990s. David Livingston and Ralph Scully of Harvard Medical School in Boston reported in Cell that when a cell divides, the healthy BRCA1 protein interacts with another protein called RAD51. This protein helps direct chromosome recombination, the swapping of pieces that takes place during an early stage of cell division. The implication was that BRCA1 also participates in this process.

An ocean away, cancer biologist Ashok Venkitaraman and others in his lab at the University of Cambridge were puzzling over a mouse model of BRCA2. A physician, Venkitaraman had been studying chromosome abnormalities in leukemias and lymphomas. When evidence began building that the BRCA genes triggered similar abnormalities, he shifted to this new terrain.

Over the course of a frenetic week in the summer of 1997, Venkitaraman's group found that mouse cells with BRCA2 don't divide properly, and chromosomes in the offspring cells wound up with structural defects. (It was these same defects in Fanconi's that sparked D'Andrea's confusion years later.) Furthermore, Venkitaraman's group found, the damaged cells could acquire a second defect, which prevented them from self-destructing the way they should.

Despite such insights, the function of both BRCA genes—and how they differ— remains frustratingly fuzzy. One of the most enduring puzzles is why breast tissue is so susceptible to mutated BRCA1 or BRCA2—which, in women who inherit one of the genes, is found in every cell in their body. Although the genes have been tentatively linked to an increased risk of other cancers, including pancreatic cancer and breast and prostate cancer in men, there's no question that associated tumors occur disproportionately in women's breasts and, to a lesser extent, in their ovaries. Scientists studying other inherited cancer genes, such as those linked to retinoblastoma or the childhood kidney cancer Wilms tumor, have also struggled with this question.

In BRCA's case, one potential culprit is the hormone estrogen. Cancer biologist Chuxia Deng of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, studies mice that are born without a BRCA gene. Treating those mice with estrogen, he found, overstimulates genes and proteins in a hormone-activating pathway. Deng is now testing whether those effects spur tumor formation.

Scientists also wonder whether a find announced last fall could help explain why female BRCA carriers, and not males, disproportionately develop BRCA-driven cancers. Harvard's Livingston and his colleagues reported that when cells contain a mutated BRCA1 gene, the X chromosome structure—and expression of at least one of its genes—goes awry.

Females have two X chromosomes; during embryonic development, one of the chromosomes is randomly silenced in somatic, or nonsex, cells. This prevents women from receiving a double dose of X chromosome genes in somatic cells. But cells with mutated BRCA1, Livingston and his colleagues reported in Cell, couldn't fully shut down their second X chromosome. This may explain why women, as opposed to men, so often develop cancer when they inherit a malfunctioning BRCA1 gene, he says.

As they continue dissecting BRCA gene functions, scientists are returning to the questions that preoccupied them in the mid-1990s, when the genes were first discovered. They're trying to link features of sporadic breast cancers with the BRCA pathway, that swath of proteins with which one or both genes interact. Soon after linking BRCA2 to Fanconi anemia, for example, D'Andrea gathered a small number of breast and ovarian tumor samples from women who didn't have mutations in either BRCA gene. In about 20% of the samples, he and his colleagues found, another gene in the pathway was abnormally silent. “We don't really know much about whether other components of the pathway are dysfunctional” in many nonhereditary breast cancers, says Alan Ashworth, director of the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London, although he and others are looking.

Weaving a web

Using BRCA as a clue to unlock cancer's mysteries is proving fruitful far beyond breast and ovarian cancer. “BRCA proteins are unveiling a functional network,” says Venkitaraman. “And the proteins that are in that network are implicated in a wide range of cancers.”

One of those proteins is behind a genetic disorder called ataxia-telangiectasia (AT). Like Fanconi's, AT predisposes children to multiple cancers; scientists have also long debated whether one mutated AT gene ups the chance of breast cancer. In 1999, geneticist Stephen Elledge, now at Harvard Medical School in Boston, and his colleagues at Baylor College of Medicine in Houston, Texas, reported an intriguing connection between AT and BRCA1. It was already known that like BRCA1, the normal AT gene helps correct DNA damage. But Elledge's team uncovered a deeper biochemical link: When DNA damage occurs in normal cells, the healthy AT protein zooms into action and modifies the BRCA1 protein to enhance its performance. Only when healthy AT protein is present can BRCA1 do a superior job.

Like so many other BRCA discoveries, it's still not clear how this one fits into the bigger picture. But it's another sturdy link in the chain uniting cancer-causing proteins that had long been studied separately.

20. Choices--and Uncertainties--for Women With BRCA Mutations

1. Jennifer Couzin

The thrill of identifying the BRCA genes came with a big dose of uncertainty where patients were concerned. “When the gene was first discovered, most geneticists were jumping up and down,” recalls Daniel Haber, director of the cancer center at Massachusetts General Hospital in Boston. “But it wasn't clear what we were going to offer patients.”

A decade later, choices abound. But scientific understanding of the BRCA genes (see main text) still lags behind the yearning among carriers for lifesaving medical advice. The relatively small number of women who carry deleterious mutations in a BRCA gene—which produces a truncated BRCA protein—makes designing studies tough, say frustrated researchers. So although the gap has narrowed, clinicians and patients operate with sometimes scanty information.

Clinicians still can't provide firm estimates of the hazard conferred by these mutations. Lifetime risk varies from about 40% to 80% for breast cancer, and 15% to 65% for ovarian cancer. That compares with a 10% breast cancer risk and a 1% or 2% ovarian cancer risk in the general population.

“The great question in front of us is, Why are there differences in risk in BRCA carriers?” says Kenneth Offit, chief of clinical genetics at Memorial Sloan-Kettering Cancer Center in New York City. Environmental factors or undiscovered genes are likely the culprits.

One study reported on page 643 suggests that gene-gene interactions may be key. Mary-Claire King of the University of Washington, Seattle, and her colleagues, including Offit, identified 104 women who carried BRCA gene mutations. By comparing age, family history, cancer status, and other factors, the team determined that these women had an overall lifetime breast cancer risk of 82%. Although the individual risk varied, most environmental factors, such as the number of pregnancies, had only a modest effect.

In practical terms, even if a BRCA mutation points to a 50%, lower-end chance of breast cancer, this is hardly reassuring, especially because BRCA breast cancers tend to be aggressive. Early on, doctors recommended surgery for mutation carriers to remove ovaries and breasts. The approach was largely untested, but many patients embraced it. Work by Steven Narod of Sunnybrook and Women's College Health Sciences Centre in Toronto, Canada, found that at his hospital and another in Utah, about 65% of healthy carriers agree to oophorectomy and 25% to mastectomy.

Today, it's clear that surgery dramatically cuts risk, says Lawrence Brody of the National Human Genome Research Institute in Bethesda, Maryland. Oophorectomy appears to slash ovarian cancer risk by 85% to 95% and breast cancer risk by 50%. (Lowered estrogen levels are thought to explain the latter.) One large study in review at the Journal of Clinical Oncology by epidemiologist Timothy Rebbeck of the University of Pennsylvania in Philadelphia found that mastectomy cut breast cancer risk by at least 90%. But questions persist about risks following surgery, such as the chance of developing cancer in residual tissue, says Mark H. Greene, chief of the clinical genetics branch at the National Cancer Institute in Bethesda. “I'm a little bit more skeptical” that these questions have been answered, he says. Greene and his colleagues are recruiting women with BRCA mutations or a family history of ovarian cancer for a 7-year study. Among those choosing oophorectomy, the researchers will study the potential complications of early menopause. Meanwhile, some centers are studying whether magnetic resonance imaging, which is more sensitive than mammography, can detect very early cancers in BRCA carriers.

Drug therapies for healthy BRCA carriers pose a vexing challenge. For certain types of breast cancer, so-called estrogen-driven tumors, the hormone blocker tamoxifen can both prevent and treat the disease. (These cancers are identified not by genetics but by tests of the tumor cells for estrogen receptors.) Because BRCA1 tumors are nearly always negative for estrogen receptors, and tamoxifen has side effects, standard practice largely rejects its use in healthy carriers.

But the question remains open. One reason is a puzzling but undisputed paradox about BRCA1 breast cancers. Ovary removal, which prevents many BRCA breast cancers, forces a plunge in estrogen levels. If blunting hormones can stop cancer, then the drop suggests that hormones are helping drive it in the first place, even if tumors are negative for estrogen receptors.

“I believe that the overwhelming majority of BRCA tumors respond to hormonal manipulation” as prevention therapy, says Barbara Weber, director of the breast cancer program at the University of Pennsylvania and one of the first to counsel BRCA carriers. She hypothesizes that BRCA1 tumors switch from estrogen-positive to-negative in their earliest stages, explaining why they test negative by the time they're detected. Toronto's Narod agrees. He reported in a retrospective study in 2000 that tamoxifen inhibited cancer recurrence among 75% of 384 women with BRCA tumors in one breast.

But some say the evidence is too scanty to make recommendations, especially given the drug's drawbacks, such as an increased risk of uterine cancer. The only other study found that tamoxifen didn't prevent BRCA breast cancer—but it included only eight women. “I'm very skeptical that there's data that anybody could in good faith [share with] a patient,” says Lewis Chodosh, an endocrinologist at the University of Pennsylvania.

Right now, cancer patients who carry BRCA mutations don't receive treatment that targets the genetic defect. But many hope to change that. Platinum therapies such as cisplatin, used to treat various other cancers, kill cells with defects in chromosome recombination—such as those induced by a mutated BRCA gene, notes Alan Ashworth, director of the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London. He's crafting a protocol for a platinum drug study of BRCA carriers with metastatic breast cancer. To recruit BRCA patients, Ashworth plans media events to promote the trial.

Narod argues that the rarity of BRCA mutation carriers may always force judgments without comprehensive science. The ideal tamoxifen study with thousands of women, he notes, is a pipe dream. “It's very easy to say we don't have the information, so we can't provide the treatment,” he says. “But we may never have it.”

21. Race and Medicine

1. Constance Holden

Genetic studies of population differences, although controversial, promise clues to disease as well as new drug targets, scientists believe

Mention race and medicine in a group of scientists, and you are likely to provoke a range of heated opinions on whether it is useful, or even ethical, to consider how people of different ancestry respond to disease and treatments. No one disputes that some diseases strike disproportionately in some racial or ethnic groups—thalassemia in people whose ancestors came from the Mediterranean area, sickle cell anemia in people of African origins, for example. Less clear-cut than these single gene disorders—but the subject of increasing research—is the medical significance of a host of more subtle gene variants that appear in differing frequencies in various populations and that seem to influence a multitude of conditions.

So far, few candidate genes have been spotted, and the evidence is largely circumstantial. Some scientists dismiss the data as too preliminary, or the differences as insignificant. They worry that emphasizing biological differences in how people of different racial and ethnic groups respond to disease and treatments could unfairly stigmatize some patients and lead to inferior health care. Yet many scientists see exploration of differences among ancestral groups as a way to learn more about complex diseases and ultimately improve treatment for some groups of patients.

Already, drug companies are hunting for genetic reasons behind commonly observed medical differences between groups. Scientists are doing retrospective genetic analyses of data from drug trials. And 18 months ago a company called NitroMed launched a trial of a heart drug directed at compensating for what is believed to be a nitric oxide (NO) deficiency in many African Americans.

Everyone's ultimate dream is to have evidence on individual genotypes to guide medicine, a development that would make racial identity biologically irrelevant. But that is decades away. Meanwhile, some scientists maintain that race can serve as a useful, if crude, indicator in sorting out why people experience diseases—and their treatments—differently and in finding new targets for drugs.

The argument

The chief argument against the notion that biological race can be medically meaningful is that there are far more genetic differences among individuals than there are between different ancestral groups. Neil Risch of Stanford University says that comparison is misleading, however. He and others argue that if 30% of one population can't metabolize a certain drug, compared with 10% of another population, the between-group variability is low because most people in both groups lack this metabolism polymorphism. Nonetheless, this variation is significant when it comes to estimating the probability of response to treatment, he says. Geneticist David Goldstein of University College in London agrees: “If you say on average the difference between West Africans and Europeans is slight, that does not rule out a great many variants that influence how people respond to drugs.”

Joel Buxbaum, who studies the molecular basis of disease at Scripps Research Institute in La Jolla, California, is persuaded as well. “A call to ignore [race] in diagnosis and treatment is a call to ignore biology,” he says. “Research in the last 35 years has uncovered significant differences among racial and ethnic groups in their rate of drug metabolism, in clinical responses to drugs, and in drug side effects.”

The most definitive evidence is on different levels of certain drug-metabolizing enzymes found in whites, blacks, and Asians. Some of these differences are quite dramatic; for example, Genaissance Pharmaceuticals in New Haven, Connecticut, has found a mutation of a major metabolism-controlling enzyme that occurs in 30% to 40% of Asians and less than 5% of members of other groups. Such findings help explain what many doctors have long observed—that many people of East Asian ancestry need smaller than average doses of a variety of heart, pain, and psychotropic drugs.

Less well documented—and more controversial—is emerging evidence on different patterns of cardiovascular disease among various populations. Researchers are looking for biological roots not only of the well-known differences between blacks and whites, but also of another, much less publicized pattern of heart disease that disproportionately affects Asian Indians. Although neither of these groups seems more disease-prone in its ancestral environment, modern diets and lifestyles—particularly increased consumption of salt and fat, smoking, and inactivity—hit them hard. Even when investigators try to control for environmental factors that could explain group differences, says cardiologist Clyde Yancy of the University of Texas Southwestern Medical Center in Dallas, “you can still see excess expression of disease.” Yancy and others see this as strong evidence for something genetic at work. But teasing it apart from other risk factors is proving daunting.

African-American risks

Blacks don't have more heart attacks than whites, but in the United States they die sooner from cardiovascular problems—both heart failure and strokes, says Yancy. They also have 10 times the rate of kidney failure, three times the incidence of cardiac hypertrophy, and more than twice the rate of diabetes, a destroyer of blood vessels. High blood pressure, which afflicts almost one-third of the U.S. black population, is the engine that, in large part, drives these related conditions. It leads to excess stress on organs, which respond with hypertrophy, or abnormal cell growth. Intertwined with the problem is a shortage of nitric oxide and, in many cases, excess salt sensitivity that in turn leads to fluid retention. Heart failure in blacks often occurs from damage to the left ventricle, which is responsible for sending freshly oxygenated blood through the body. Indeed, according to Yancy, in blacks, heart failure “may be a different disease with less favorable outcomes” than in whites.

Scientists are looking for genes that would explain these patterns, in particular for genes related to hypertension. Because NO, the chemical responsible for keeping blood vessels fit and toned, is important in the action of ACE (angiotensin-converting enzyme) inhibitors, genes for NO synthase, the enzyme most important for vascular NO production, are prime candidates. Dennis McNamara of the University of Pittsburgh Medical Center says the prevalence of certain versions of these genes is “much different in blacks and whites.” The variant that ACE inhibitors work best with is found in 60% of whites but only 30% of blacks, he says.

Also blood pressure-related is the gene for transforming growth factor-β (TGF-β). A group led by Phyllis August at Weill Medical College of Cornell University in New York City reported in 2000 that TGF-β1 is overexpressed in black patients with end-stage renal disease or severe hypertension—and more so than in white patients with the same diseases. This looks like a promising genetic candidate for hypertension, the authors say, because TGF-β1 regulates substances that act both as vasoconstrictors and as growth factors for vascular cells.

In addition to genes involved in high blood pressure, researchers have found a significant difference between blacks and whites in genes that manipulate the response of the sympathetic nervous system to hormones like adrenaline. Stephen Liggett and colleagues at the University of Cincinnati reported last fall that possessing a combination of two particular versions of alpha and beta adrenergic receptors raised heart failure risk for blacks 10-fold. The high-risk version of the alpha receptor occurs almost exclusively in people of African origin and is present in about 40% of U.S. blacks, says Liggett. The researchers believe that depressed receptor function leads to excess release of norepinephrine, which is bad for the heart. The study is relevant for the use of beta-blockers, which inhibit the effects of adrenaline on beta receptors and which may be less effective in black heart patients. Liggett's team reported in the September issue of Nature Medicine that the high-risk beta receptor, which is also more common in blacks, raises the risk of heart failure in both mice and people and forebodes a poor response to beta-blockers.

Drug trials

Clinical trials have not been particularly helpful in illuminating such differences, says McNamara, because usually at least 80% of participants are white, and the pooling of data often obscures any racial differences.

That is why many researchers are particularly excited about the first clinical trial of a heart failure treatment that exclusively targets African Americans. It was launched in March 2001 by NitroMed, a company in Bedford, Massachusetts, to test a drug that may be uniquely beneficial to heart patients with NO deficiencies. The first-of-its-kind trial, called A-HeFT (for African-American Heart Failure Trial), is testing a drug called BiDil that was originally developed in the 1980s. BiDil combines vasodilators with an NO source and antioxidant properties to help potentiate treatment by ACE inhibitors. All patients in the trial will get standard medication; half will also get BiDil. Scientists believe that the trial, which has been endorsed by an array of groups, including the Association of Black Cardiologists Inc., should produce some definitive data on the role of so-called NO subsensitivity in heart disease. McNamara, who calls the trial “very unique and very important,” says he and colleagues will do a genetic substudy, looking at a number of candidate markers for correlations with treatment response.

Researchers are also combing through data from earlier big heart trials. To get a fix on the nature of the suspected racial difference in response to beta-blockers, Buxbaum and colleagues are looking at data from BEST (the Beta-Blocker Evaluation of Survival Trial), which tested a nonselective beta-blocker called Bucindilol. In 2700 people with congestive heart failure, black patients as well as sicker ones generally failed to benefit from the drug. So the scientists are genotyping the 600 black patients to see if they can spot a genetic marker that will serve as a better indicator than race for whether the drug is likely to work. The results will be put in a DNA bank available for other investigators.

Although these studies are important, says Yancy, there is still no substitute for getting data from really big populations, not only to find vulnerability genes but to sort out what's “normal”—that is, genetic patterns (in any race or ancestral group) that do not predispose to heart disease. He has high hopes for another initiative, called UNITE-HF, led by the University of North Carolina with support from the drug company AstraZeneca, a U.K.-based company with U.S. headquarters in Wilmington, Delaware. UNITE-HF is collecting blood samples from the country's “stroke and heart attack belt” in the southern and southeastern United States. So far investigators have samples from some 800 ambulatory heart patients, both black and white, which they will analyze for the prevalence of suspect genes.

Indian hearts

The other population with a big heart disease problem is South Asian Indians. “Until 50 years ago it was hardly ever heard that Indians had high heart attack risk,” says cardiologist Prakash Deedwania of the University of California, San Francisco, Fresno, School of Medicine. But as more Indians are becoming westernized, many now have heart attacks as early as their mid-30s, and, he says, “the risk is enormously high all over the world.” A major risk factor is diabetes, which, according to figures collected by F. P. Cappuccio of St. George's Hospital Medical School in London, is roughly four times as prevalent among Indians (in urban India and abroad) as in Londoners. Indians also tend to have high levels of triglycerides and low levels of HDL, the “good” cholesterol. One evolutionary explanation is the “thrifty gene hypothesis”: Over the millennia people in India endured cyclical famines; those who fared best were those who could conserve energy in abdominal fat. Now, for those exposed to plenty, this ability has turned into a disadvantage.

Some preliminary evidence for a genetic connection is emerging. Michael Miller, director of the Center for Preventive Cardiology at the University of Maryland Medical Center, says his group has found a high prevalence of an alteration in the apolipoprotein C3 gene, which regulates triglyceride metabolism, in Indians living in the United States. The researchers found this polymorphism by taking blood samples from 99 attendees at an Indian festival in Northern Virginia, as they describe in the January 2001 American Journal of Cardiology. This alteration is also associated with low HDL levels, says Miller, and possibly also insulin resistance. The group is now looking to see if people in India show the same pattern.

Investigators in New Delhi have already reported from a genetic analysis of 139 healthy males in Northern India that almost one-third carried a related variation in the apolipoprotein gene, a rare mutation in Caucasians. Furthermore, it was twice as frequent among those with elevated triglycerides—a risk factor for coronary artery disease.

More clues on how genetic variation could translate into different responses to medication should come from a new 6-week clinical trial, sponsored by AstraZeneca. It will compare Crestor (rosuvastatin), a new cholesterol-lowering drug that won government approval in August, with an older one (atorvastatin) in South Asian Americans. Deedwania says it will be the largest prospective trial ever done on Indians, with some 800 subjects from 150 centers around the country. Miller says Crestor may be better for Indians because it does a little better job at raising HDL.

Many Indian doctors believe that the Indian vulnerability to heart disease is striking enough to justify more preventive vigilance. Cardiologist Enas Enas, director of the Coronary Artery Disease in Indians Foundation in Lisle, Illinois, has stated that the goals of treatment for high blood pressure and obesity should be at least 10% lower, and cholesterol 20% lower, for Asian Indians than the goals recommended for Caucasians.

Era of transition

Increasing awareness of possible genetic contributions to ethnic differences is reflected in a recommendation issued last January by the U.S. Food and Drug Administration (FDA). Calling for more scrutiny of subpopulations, FDA wants drug testers to use racial divisions specified by the Census Bureau “to ensure consistency in evaluating potential differences in drug response.”

Drugmakers are already on the lookout for genetic subgroups that could divulge new targets for therapeutic drugs. “I think we all believe there's a lot of potential there,” says Gary Palmer, a Pfizer vice president in New York. Pfizer is particularly interested in hypertension-related genes in blacks and diabetes-related genes that could account for the high rates of the disease in both Asian Indians and Native Americans. AstraZeneca is also looking for population differences in drug response in its clinical trials. Spokesperson Gary Bruell says that if the company found that a drug has a “profound effect” on a particular group, it would label and promote it accordingly. “If a population doesn't benefit, that could end up on the label too,” he adds.

Companies will probably be getting more help from outfits like Genaissance, set up 6 years ago to develop and market genetic data. “Our company was founded on the principle that human genetic variation is critical to drug response,” says Claiborne Stephens, vice president for genetics. The obvious way to make a first cut at that variation, he notes, is to look at how evolution parceled out different versions of various genes according to the environments in which early human populations evolved.

One of its projects is a detailed data repository of more than 7000 genes from 93 whites, blacks, and Asians, including information on the origins of their parents and grandparents, which companies can use as a reference in clinical trials. This is enough to give “a reasonable idea of what the gene frequencies are” in those groups, says Stephens (see chart).

Although everyone agrees that data are still preliminary, there's been enough talk to get people concerned over how these findings could affect medical care. For example, Richard Cooper, a cardiologist at Loyola University Medical Center in Chicago, worries that any new information on race differences will lead to inferior care for nonwhites. He says that so far, the best data on biological race differences are only “mixed,” and even where differences do exist they are never great enough to justify any race-based generalizations in the absence of genetic tests. He says there's no evidence that risk factors don't operate the same way for all groups. BiDil developer Jay Cohn of the University of Minnesota, Twin Cities, agrees that the best treatment is the same for any race. But he wouldn't have a problem with, say, prescribing a drug that will boost NO in a black heart patient. If a doctor knows that a trait is “more common in one population than another,” that could be enough to “consider modifying one's treatment strategy,” he says.

Although scientists hope that the advent of genomic medicine will obviate the need to grapple with race issues, Goldstein warns that the day of individually tailored treatments may be far away. Even after relevant genes are identified, it will be a chore to sort out what all the alleles do, he says. And so far, only a handful of such genes have been identified. “Pharmacogenetic studies are in their absolute infancy,” he says. So “the big question is the interim strategy: how to use ancestry now.”