News this Week

Science  28 Jun 2002:
Vol. 296, Issue 5577, pp. 2310
  1. INTELLECTUAL PROPERTY

    Arrest of Ex-Harvard Postdocs Raises Questions of Ownership

    1. Andrew Lawler

    BOSTON—Two former Harvard University researchers face up to 25 years in prison and a $750,000 fine for allegedly conspiring to steal Harvard-owned trade secrets and for shipping university property across state lines. The defendants—a Chinese citizen named Jiang Yu Zhu and his Japanese-born wife, Kayoko Kimbara—were arrested last week and are in jail in California pending extradition to Massachusetts. But some researchers have expressed sympathy for the defendants and worry that the government is overreacting.

    The case, laid out in a stark FBI complaint filed on 17 June, marks the latest attempt by U.S. law enforcement agencies to crack down on intellectual property theft in university labs (Science, 18 May 2001, p. 1274). The complaint describes late-night experiments carried out without the knowledge of the couple's boss, Harvard Medical School cell biologist Frank McKeon, as well as shipments of material with great potential commercial value to a Japanese company and a Texas lab where Zhu later worked. Neither McKeon nor Harvard will comment on the particulars of the case.

    But the FBI's complaint shows a lack of understanding of how science works, say some scientists. Postdocs frequently work late hours, they note, and many researchers take materials with them when they move to new jobs and seek help from companies. In addition, Harvard recommended Zhu for his next job, and university officials admit that they didn't conduct a formal investigation of events in the lab.

    Zhu graduated from the prestigious Beijing University and received his doctoral degree in biochemistry from Temple University in Philadelphia before going to work for McKeon in 1997. Kimbara received her doctoral degree from Tokyo University in 1998 and started working in McKeon's lab late that year with funding from the Japan Society for the Promotion of Science. According to the 12-page complaint, the researchers screened genes and proteins in search of new agents to help prevent organ transplant rejections. By early 1999, Kimbara had identified two promising genes, a find the FBI says “had significant commercial potential.” Both had signed a document assigning Harvard all rights to any invention or discovery made at the university, according to the complaint.

    Something missing?

    The FBI has accused Jiang Yu Zhu and Kayoko Kimbara of stealing material from Frank McKeon's lab at Harvard Medical School.

    CREDIT: JASON DECROW/AP

    At that point, the complaint notes, the two began working late and refused to have “meaningful discussions” with McKeon. In October 1999, Harvard filed a provisional patent on the two genes, listing Zhu and Kimbara as inventors in the initial application. McKeon later learned, although the complaint does not say when, that the research fellows were not sharing data about several additional promising genes they had discovered. But McKeon and colleagues apparently thought enough of Zhu's work to recommend him for a position at the University of Texas, San Antonio. “That hiring was based on recommendations by people at Harvard”—including McKeon, says David Sharp, deputy director of the biotechnology institute there.

    After getting the job offer in December 1999, the complaint alleges, Zhu e-mailed an unnamed biochemical company in Japan saying that he hoped to commercialize his research and that he believed the Harvard patent would fail. Zhu sent the gene products to Japan, without McKeon's permission, so that the company could make antibodies against them. The complaint says that Zhu had also arranged secretly to ship more than 30 boxes of biologicals, books, and documents to Texas from Harvard in late December 1999. Harvard lab personnel later found that “many of the items left in the [Harvard] lab by Zhu and Kimbara had been mislabeled or otherwise corrupted,” the complaint states. Allegations of serious scientific misconduct typically trigger a formal investigation, but there was none in this case, says a Harvard spokesperson. One researcher familiar with Harvard's procedures says, “That probably means they found no grounds for a formal investigation.”

    In June 2000, Harvard recovered a “significant percentage” of the materials—worth about $300,000 according to the complaint—and the researchers left Texas that summer and moved to California after their annual contracts were not renewed. But it wasn't until last week that the FBI, citing the risk of flight, arrested and jailed the researchers.

    Zhu has spent the past 18 months as a postdoc at the University of California, San Diego, in Jean Wang's lab. She says that his work has been “excellent” and that he voluntarily disclosed the problems with Harvard before he was hired. “I offered Zhu a position because I believe in a second chance, especially for young people,” says Wang, adding that she thought the matter had been settled. Kimbara is now a postdoc at the Scripps Research Institute in La Jolla, California.

    Wang describes McKeon as “brilliant but superparanoid” about sharing his work with other labs. Other scientists familiar with McKeon's lab concur with that assessment and speculate that Zhu and Kimbara might simply have been afraid to ask McKeon for permission to send materials to others. And many scientists say young researchers are not always aware of the intricate laws governing commercial applications of their work. “Intellectual property in the United States is a bit of the Wild West,” says David Zapol, who co-chairs a Web site set up to help Hiroaki Serizawa, a researcher accused last year of helping a colleague steal lab secrets. To Zapol, the new case smacks of racial profiling of Asians.

    Next week the government will seek to extradite the defendants to Massachusetts, the first step in preparing for a trial. The prospect of a courtroom battle disturbs Wang, who says, “I don't think we want the federal government to sniff around in our business.” In the meantime, the case might prompt postdocs and their mentors to reexamine who owns their work.

  2. PALEONTOLOGY

    China Regains Fossils Seized in California

    1. Yimin Ding,
    2. Erik Stokstad*
    1. Ding Yimin writes for China Features in Beijing.

    BEIJING—Fourteen tons of Chinese fossils are back in their native country after a failed attempt to smuggle them into the United States. The shipment, which includes a 225-million-year-old ichthyosaur and a large number of exquisite crinoids—a kind of echinoderm called a sea lily—dating from the same period, arrived here earlier this month after being seized a year ago in San Diego, California. Chinese officials described the incident for the first time on 11 June.

    The reshipment, which Chinese officials say is the largest of its kind, is part of the country's ongoing campaign to protect its cultural and scientific relics against looters. “They are very precious fossils,” says Li Jianjun, executive deputy curator of the Beijing Natural History Museum, where the fossils are now housed. “To our joy, we have found that 90% of the fossils” have not been tampered with.

    Back home.

    The U.S. government has returned to China these crinoids and 14 tons of other smuggled fossils.

    CREDIT: CHINA FEATURES

    Almost all of the 110 pieces of fossils, which arrived in 93 boxes, are believed to have originated in Guizhou Province in southern China. They date from the early part of the late Triassic period, 227 million to 220 million years ago, when reefs in the region were drowned by anoxic, 500-meter-deep water—ideal conditions for preservation. “As crinoids go, they're pretty stunning,” says paleontologist Chris Maples of Indiana University, Bloomington. Crinoids are relatively rare in Triassic rocks, and the meter-tall specimens of the enigmatic Traumatocrinus are important for evolutionary studies because the group survived the Permian mass extinction some 20 million years earlier, notes Dan Lehrmann, a geologist at the University of Wisconsin, Oshkosh. In addition to the 4- to 5-meter-long ichthyosaur and the crinoids, the cache includes 10 specimens of a marine reptile called Keichousaurus and some fish fossils.

    Science was not able to piece together the circumstances that led U.S. officials to act. Officials from China's State Administration of Cultural Heritage say that the fossils were seized in June 2001 by the U.S. Customs Service as they arrived in San Diego and that customs officials contacted Chinese diplomats in New York to arrange for the return of the material. An agency spokesperson declined to provide any information about the case, however, saying that “it is the long-standing policy of the U.S. Customs Service to not discuss matters that may relate to investigation.”

    The fossils will be stored in a just-completed warehouse and exhibited once they are curated, says the museum's Li, who adds that the fossils will also be made available to outside collaborators for comparative studies. In the meantime, Chinese paleontologists welcome the windfall. “I am happy to see them back,” says Wang Xiaofeng of the Yichang Institute of Geology and Mineral Resources in Hubei Province. Wang's team has studied fossils of crinoids, Keichousaurus, and other marine creatures at a site in the Guanli area of Guizhou.

  3. COUNTERTERRORISM

    Academies Weigh In on Homeland Defense

    1. David Malakoff

    Get better organized, get more outside help, and get going—immediately. That's what the U.S. government must do to develop and deploy the technologies needed to fight terrorism, says a blue-ribbon scientific panel this week in a report likely to influence the shape of the Department of Homeland Security, proposed earlier this month by the White House (Science, 14 June, p. 1944). In particular, the panel says, the government needs a new institute to help it chart and coordinate counterterrorism research.

    That idea and other recommendations are getting guarded reviews in Congress. But the chair of the House Science Committee, before which the report was unveiled this week, welcomes the report. “This report helps ensure that R&D stays high on the homeland defense agenda,” says Representative Sherry Boehlert (R-NY). Some biomedical researchers, meanwhile, are criticizing the White House's blueprint for the department, saying that it could complicate antibioterrorism efforts.

    The report* is the first public product of a crash effort by the U.S. scientific community to respond to the 11 September terrorist attacks. On its own initiative—and using its own money—the U.S. National Academies of Sciences and Engineering and the Institute of Medicine asked more than 150 researchers to assess the nation's vulnerability to terrorist attack and to identify the technologies, research, and policy changes needed to boost defenses. A 24-member panel, led by former National Cancer Institute head Richard Klausner and science policy specialist Lewis Branscomb of Harvard University, distilled their advice into a 382-page report covering everything from safeguarding nuclear weapons and water supplies to improving air-filtration systems and chemical sensors.

    Terror talk.

    Lewis Branscomb (left) and Richard Klausner see science playing a major defense role.

    CREDIT: RICK KOZAK

    There are seven ways the government can use existing technologies to enhance security, the panel concludes. They include deploying better systems for tracking and protecting nuclear and other materials—such as chlorine gas—that could be used as weapons, boosting the production of bioterror treatments, and improving communications among emergency personnel. A number of these efforts are already under way, the panel noted.

    A list of areas in which research is “urgently” needed includes the development of a more resilient electric-power grid, better computerized tools for intelligence analysts and emergency officials, and new methods and standards for safeguarding and decontaminating buildings. The government also should fund more social science studies on how people respond to emergencies, says the report, and recruit “credible” spokespersons to keep the public informed.

    Current efforts to coordinate counterterrorism research, the report found, are “not appropriately organized.” One improvement would be a high-level research czar at the new department. Another would be the creation of a Homeland Security Institute, an independent nonprofit group that could hire specialists and carry out studies quickly. “The government needs greater access to expertise,” says Klausner.

    The first response to the report is likely to come from Congress, which is also getting advice from other scientists. The American Society for Microbiology, for instance, last week criticized the Administration's plan to give the proposed department authority over bioterrorism-related research and regulatory programs currently run by the National Institutes of Health and the Centers for Disease Control and Prevention. The extra layer of bureaucracy, the group says, would “create unpredictability … [and] divert monies from research.” Both the White House and Congress have promised to complete work on the department before the end of the year.

    • *Making the Nation Safer: The Role of Science and Technology in Countering Terrorism (National Academy Press, 2002).

  4. EXOPLANETS

    Winking Star Unveils Planetary Birthplace

    1. Richard A. Kerr

    Astronomers want to know how we came to be, how a life-friendly chunk of rock came to form about our star. Lingering clues from our solar system are proving subtle and hard to read (Science, 31 August 2001, p. 1581). And disks of dust and gas spinning around other stars where planets might be forming today are still little more than fuzzy, unchanging patches of light in even the most powerful telescopes. But a group of astronomers has stumbled on a newborn star whose protoplanetary disk has fortuitously set up a monitor of its own innermost workings. By simply measuring the star's brightness, researchers are seeing how a protoplanetary disk works. It's the closest, most detailed look at the cauldron of planet formation anyone is ever likely to have.

    As astronomers know from observing nascent stars, a star forms in the midst of a ball of dust and gas, the remainder of which can collapse into a spinning disk resembling the rings of Saturn. Planets could agglomerate in such disks, but the disks seen so far have been nearly featureless and unchanging on human time scales, with any protoplanets invisibly small. But in 1997, astronomy students led by astronomer William Herbst of Wesleyan University in Middletown, Connecticut, noticed one new star—just 3 million years old versus the sun's 4500 million years—that faded dramatically every few weeks to 4% of its normal brightness.

    Planetary pinwheel.

    Wave crests (red) churned by a growing body may block starlight.

    CREDIT: GEOFFREY BRYDEN/JPL/NASA

    Something, it seemed, was periodically blocking the light of star KH 15D in the constellation Monoceros. After a recent international observing campaign organized by Herbst and graduate student Catrina Hamilton of Wesleyan, “now we're sure we can predict what it's going to do,” Herbst said last week at the “Scientific Frontiers in Research on Extrasolar Planets” meeting in Washington, D.C. Every 48.3 days, the star's light dims steadily over 2.4 days, stays dim for about 18 days, and then brightens back to normal during another 2.4 days. Alternate dimmings progress slightly differently, suggesting that whatever obscures the star, there are two of them circling it every 96.72 days at an orbital distance of 0.3 times the Earth-sun distance, or closer than Mercury orbits the sun.

    Herbst and colleagues “are really scratching our heads over this,” but it appears that the inner region of this protoplanetary disk, where rocky, Earth-like planets might be forming, is behaving much as Saturn's rings do. Rather than a solid body, the obscuring matter could be the long, low crests of two pinwheel-like waves of gas and dust spiraling outward from either side of the disk, viewed edge-on. As at Saturn, such spiral density waves would be triggered by the gravitational tug of a large mass—a small star, a planet, or a denser clump of disk material—orbiting unseen, starward of the waves.

    “It's fascinating,” says astronomer Ray Jayawardhana of the University of California, Berkeley. “Already by 3 million years you see clumping. It's all pointing to a lot happening in the first few million years.” Most satisfying for astronomers, things are visibly happening even now. A brightening in mid dimming has been weakening over the 6 years of observations, and the dimmings have been getting longer. Such changes in the silhouette of the disk might show theorists why newly formed planets—including most extrasolar planets found so far—seem to have migrated inward toward their stars and why some manage to stop just before being devoured by their parent stars.

  5. AGBIOTECH

    A Little Pollen Goes a Long Way

    1. Erik Stokstad

    One of the major concerns about genetically modified (GM) crops is that they might spread their genes to nearby weeds or organic crops. Some governments have responded by recommending that GM crops be planted in isolation, or by setting limits on GM material in organic or conventional crops. But they have had few data to go on. Now a comprehensive study, described on page 2386, provides some hard numbers on the movement of pollen between fields, with implications for regulators. “These are real-world data that can be used for real-world decisions,” says Paul Raymer, an agronomist at the University of Georgia, Griffin.

    A team led by reproductive ecologist Mary Rieger of the Cooperative Research Center for Australian Weed Management and the University of Adelaide in Australia reports that canola pollen can travel considerable distances but that the amount of gene flow is minimal. Although the findings reinforce the difficulty of growing GM-free crops, they also suggest that the levels of gene diffusion are below European standards for contamination of conventional food.

    Over the last decade, a handful of small experiments has indicated that a minuscule amount of pollen from engineered crops can spread up to a few hundred meters. But what happens on real farms was unclear. To find out, Rieger and her colleagues at the University of Adelaide and the University of Western Australia in Nedlands took advantage of a unique opportunity. In 2000, Australian farmers for the first time planted varieties of canola with resistance to acetolactate synthase-inhibiting herbicides. (These crops are not GM varieties but instead were created by mutagenesis.) Working in three states and under various climatic conditions, Rieger's team collected seeds from 63 nearby fields planted with conventional canola.

    The herbicide-resistance trait spread to 63% of the conventional fields, including some up to 3 kilometers away from the source. The percentage of resistance among seed samples ranged up to nearly 0.2%, but when averaged per field, the highest percentage was 0.07%. The harvests from the vast majority of fields contained less than 0.03%.

    In the air.

    Pollen from canola flowers (bottom) moved up to 3 kilometers between fields.

    CREDITS: (TOP TO BOTTOM) ALBERTA AGRICULTURE, FOOD AND RURAL DEVELOPMENT; PAUL RAYMER/UNIVERSITY OF GEORGIA

    The good news is that this level of gene flow for canola is much lower than previous studies suggested. And Rieger says it should be applicable to GM varieties of canola. If so, the contamination of non-GM canola would be less than 1%, which is the cutoff that Australian regulators have discussed as acceptable and that their European counterparts have provisionally OK'd. Rieger says that the lower gene flow should reassure consumers that the chance of transgenes getting into non-GM crops is small.

    But the study underlines a clear risk: Once transgenes are introduced, they can't be completely controlled. That's a problem for organic farmers. “It's going to be difficult with any commodity to produce a truly GM-free crop,” Raymer says. “Zero tolerance is not going to work.” Because of the long distance its pollen travels, canola might not be a good plant to engineer for growing pharmaceuticals or anything else that should stay out of the food supply, notes population geneticist Norman Ellstrand of the University of California, Riverside.

    Rieger and her colleagues also discovered a conflict with earlier studies of smaller fields, in which the amount of pollen declined exponentially with distance from its source. In Rieger's study, the frequency of herbicide resistance was relatively steady at various distances from the source. The reason could be that bigger fields produce more pollen, and that increases the likelihood that it will travel far. So size apparently matters: “This research indicates that pollen movement on a large scale cannot necessarily be predicated from small-scale studies,” Rieger says.

    With these new results in hand, however, researchers should have a better handle on gene flow when canola is modified in other ways, says herbicide physiologist Linda Hall of the University of Alberta, Edmonton. Although pollen from any crop should travel in similar ways, Hall and others note that extrapolation is tricky because crops reproduce in different ways. The flowers of wheat and barley, for example, tend to self-fertilize and are less likely to pick up foreign genes. “Canola is one of the more problematic in terms of gene flow,” says plant geneticist Rikke Jørgensen of the Riso National Laboratory in Denmark. “This is a worst-case scenario.”

  6. CANCER RESEARCH

    Nanoparticles Cut Tumors' Supply Lines

    1. Jennifer Couzin

    Tumors hungry for sustenance need new blood vessels to deliver the goods. Cancer researchers have spent years working to starve tumors by blocking this blood vessel growth, or angiogenesis, with mixed success (Science, 22 March, p. 2198). Now a team has tackled the problem of choking off tumor vessels from a novel angle: The researchers packed a tiny particle with a gene that forces blood vessel cells to self-destruct, then they “mailed” the particle to blood vessels feeding tumors in mice.

    “It is a very provocative paper, which I think will become a landmark in angiogenesis research,” says antiangiogenesis pioneer Judah Folkman of Children's Hospital in Boston. Adds Philippe Leboulch, a gene therapist at Harvard Medical School in Boston: “They achieved tumor regression—and they started with tumors [that were] quite large for mice.” Despite their enthusiasm, however, researchers are treading gingerly around the landmines in cancer treatment, where hopes have been raised and dashed many times.

    The study, reported on page 2404 and led by vascular biologist David Cheresh of the Scripps Research Institute in La Jolla, California, draws on research in a number of fields. In the mid-1990s, Cheresh and others found signatures specific to different types of blood vessels that they used as target “zip codes.” One of these, belonging to a class of membrane proteins called integrins, is apparently always present on angiogenic, or newly growing, blood vessels but rarely on established ones. The integrin, αvβ3, has another quality that would turn out to be convenient: It can propel viruses or other small particles into cells.

    Bull's-eye.

    Nanoparticles packed with targeting molecules (red) anchor to integrins (blue) on the outside of a tumor blood vessel cell before shuttling mutant DNA (green) inside.

    ILLUSTRATION: C. SLAYDEN

    Meanwhile, various teams had become intrigued by cascades of molecular signals that seem critical to new blood vessel growth. One molecule central to several of these cascades is known as Raf. Inhibiting the Raf-1 gene in mice prevents blood vessels from forming and halts embryonic development. “Our goal was to identify a common theme that all angiogenic pathways must pass through,” says Cheresh about this line of research. “That is Raf-1.”

    Cheresh's team, assisted by organic chemist and radiologist Mark Bednarski of Stanford University, designed a lipid-based nanoparticle that would target new blood vessels. The nanoparticle's surface is studded with molecules that bind to αvβ3 and embedded with copies of a mutant form of the Raf-1 gene that disrupts Raf's normal activity.

    The researchers infused a dose of these particles into the tails of mice that had been injected earlier with malignant cells. A single treatment erased tumors 400 cubic millimeters in size—1/40 the size of the mouse, or the equivalent of a 2-kg tumor in an 80-kg person—in about 6 days. Animals with metastases to the lungs or liver also saw most of their tumors disappear. In contrast, mutant mice without the αvβ3 beacon molecules to guide the nanoparticles died after a day or two.

    Examining the tumors under a microscope, the researchers saw the expected dead blood vessel cells, which self-destructed after the Raf mutant shuttled inside them. But the team also saw evidence of concentric rings of apoptosis, or programmed cell death, among tumor cells near each dead blood vessel. This illustrated a point already known, although rarely so visible: Each blood vessel cell supports 50 to 100 tumor cells, according to Folkman, and when vessel cells die, tumor cells crumble in a ring around them.

    Others agree that the work has several advantages over other antiangiogenesis approaches and experimental cancer therapies. It targets the inside of the blood vessel cell rather than its surface, as other angiogenesis inhibitors appear to do. And the mutant Raf genes are packaged in a nanoparticle, not a virus, as is common in cancer gene therapy studies. This means there's less chance that the body will develop antibodies to the treatment.

    At the same time, “one of course has to prove it,” says Leboulch. Inder Verma, a geneticist at the Salk Institute for Biological Studies in La Jolla, wonders whether the treatment does, as predicted, leave healthy cells alone. Scripps and Stanford are both applying for patents on the technology, which is currently licensed to Merck KGaA in Darmstadt, Germany, says Cheresh. In the meantime, the researchers have their fingers crossed that this cancer cure in mice won't be one of the many that, in Verma's words, “never sees the light of day”—or at least the fluorescent lights of the cancer unit.

  7. PATENTS

    NIH to Limit Scope of Foreign Patents

    1. Jocelyn Kaiser

    More than 20 years ago, the U.S. National Institutes of Health (NIH) began supporting Australian researchers who discovered two cytokines that can boost the immune system of cancer patients. These drugs, marketed by companies such as Amgen and Schering-Plough, have saved lives and chalked up more than $1.5 billion a year in U.S. sales. Yet NIH now wants to revise the policy that allowed the Australian scientists' institutions to patent and license one of the drugs on the grounds that it could put U.S. companies at a “disadvantage.” The move has sparked an uproar in Australia and even left U.S. university officials wondering how it might affect collaborations.

    A notice on NIH's Web site says that the planned change, to go into effect by the end of the year, is in “the best interests of U.S. citizens” by making sure that they benefit fully from all NIH-funded research. Posted 14 March, the notice explains how NIH plans to limit the future patent rights of all foreign recipients of grants and contracts to the awardee's own country and have NIH retain the rights elsewhere. Institutions could ask for exceptions on a case-by-case basis.

    Unhappy down under.

    Donald Metcalf and other Australian scientists are upset about NIH plan to limit patent rights.

    CREDIT: WEHI

    George Stone of NIH's Extramural Inventions and Technology Resources Branch says that the new rule is intended to address the concerns of some members of Congress and the public but that it was not triggered by any particular incident. “There has just been a heightened awareness,” he says. “We want to be proactive.”

    Few patents will likely be affected, Stone says. Only 13 of roughly 6000 inventions reported to NIH in the past 3 years included patent holders from other countries, he says, and in just two cases were the foreign grantees the only patent holders. The new policy would not have applied to the 11 joint inventorships, he says. An upcoming fact sheet will clarify the new policy, he adds.

    Some foreign research institutions are quite concerned about NIH's plans. Alan Pettigrew, CEO of Australia's National Health and Medical Research Council, has complained to Stone, as have Donald Metcalf and Nicos Nicola of the Walter and Eliza Hall Institute of Medical Research in Melbourne, whose discoveries led to the cancer drugs. Discoveries are less likely to be commercialized if NIH holds the patent rights, they suggest, which “will actually decrease the health and economic returns to U.S. citizens.” Canadian officials “are very much aware of” the NIH policy and are mulling over their response, says Janet Scholz, senior manager of the University Industry Liaison Office at the University of Manitoba in Winnipeg.

    Scholz, who is also chair of the U.S.-based Association of University Technology Managers (AUTM), says that U.S. universities are concerned that the rule will discourage international collaborations by complicating patent filings and removing commercial incentives for the foreign partners. “To some extent, there isn't a border in science,” says Scholz. The AUTM board plans to take up the matter this week.

    Scholz says AUTM members are annoyed that NIH cannot cite examples of why the new policy is needed. “I just don't understand why they think that whatever they have now doesn't work,” she says.

  8. OPTICS

    New Twist Could Pack Photons With Data

    1. Andrew Watson*
    1. Andrew Watson is a writer in Norwich, U.K.

    The humble particle of light, the photon, is beginning to show that it has surprising depth. Photons have long been known to spin, but it is also possible to give them an additional form of angular momentum, a sort of twist. A team of physicists in the United Kingdom has now devised a way to measure the twisting of single photons—a “major achievement,” according to physicist Keith Burnett of the University of Oxford. A photon's twist could be a handy information carrier: In principle, physicists could use it to load huge quantities of data onto a single photon, revolutionizing optical communications and quantum computing.

    To envision light's angular momentum, freeze time for an instant and put an imaginary sheet of glass in the path of a laser beam. For a conventional beam, the light's electric field will have the same magnitude and direction all over the spot that the beam makes on the glass. Physicists visualize this with an array of little arrows whose sizes and directions show the field strength and direction; in this case, all the arrows will be the same length and point the same way. Ratchet time forward one notch, and all the arrows in the freeze-frame will turn in unison by a small amount. Keep moving time forward, and all the arrows will make one complete turn as the beam moves forward by one wavelength of the light. This is photon spin.

    Over the past decade, physicists have realized that they can go beyond spin and add extra angular momentum to the beam, effectively imprinting a pattern onto the electric field so the arrows no longer all point the same way at the same time. In the simplest example, the arrows along a single radial line in the beam spot all point in a particular direction. Move time forward one notch again, and this “line of harmony” appears to move as an adjacent radial set of arrows snap to attention. In this way, the line of harmony sweeps around like a radar screen. This sort of rotation of the beam, which physicists call orbital angular momentum, describes a single helix in the beam as the beam moves forward. Even a beam consisting of a single photon can carry orbital angular momentum.

    Helical harmony.

    A single “line of harmony” corkscrewing along a light beam. Arrows show energy flow, which can exert a torque on objects.

    CREDIT: M. PADGETT/UNIVERSITY OF GLASGOW

    What has physicists most excited is that a lone photon can carry any number of spiraling lines of harmony simultaneously. Two lines give the familiar double helix, three lines a triple helix, and so on. These angular momentum spirals must obey quantum rules, so they bear whole-number labels that physicists can use as a bar-coding system for carrying information. The orbital angular momentum can in principle be “as high as you wish,” says Anton Zeilinger of the University of Vienna. “So an individual photon can carry much more than a single bit.”

    Extracting the information has been the problem, but Johannes Courtial and his University of Glasgow colleagues Jonathan Leach and Miles Padgett, aided by theorists from the University of Strathclyde in Glasgow, have dreamed up a way of sorting photons according to their orbital angular momentum. In the 24 June Physical Review Letters, the team members describe how they first prepared a laser beam containing photons with different amounts of orbital angular momentum. They then split the beam, giving the two branches a further twist of 180° relative to one another, and finally recombined them.

    When they come together, because of that extra twist and the symmetry properties of orbital angular momentum, photons having an odd number value of orbital angular momentum exit one way from the recombination point, and those with even values exit at right angles to it. These two sorted beams are then individually fed into a second similar splitting, twisting, and recombining setup and so on, in a cascade. Successive levels sort photons according to different multiples of 2 in their orbital angular momentum. Padgett's team made a trial two-stage cascade, enabling them to sort photons having orbital angular momentum values of 0, 1, 2, and 3. “This is equivalent to reading two bits of data from each photon,” says Courtial.

    “We will be able with this new method to process information in new ways and perhaps make more secure communications,” says Oxford's Burnett. For example, blending several quantum states onto a single photon might offer a new route to quantum computation. Although the system is unlikely to work in optical fibers, Padgett sees numerous commercial prospects in loading data onto a single photon, and he is already talking to communications companies.

  9. HIGH-ENERGY PHYSICS

    CERN Panel Calls for Cuts and Shake-Ups

    1. Giselle Weiss*
    1. Giselle Weiss is a writer in Allschwil, Switzerland.

    GENEVA—It's official: CERN must slash other research projects in order to finish the Large Hadron Collider (LHC). That's the conclusion of a group tasked with reviewing the $2 billion megaproject, under construction here at the European laboratory for particle physics, in the wake of cost overruns disclosed last fall (Science, 5 October 2001, p. 29). And non-LHC projects might not be the only sacrificial lambs: CERN is coming under pressure to shake up its senior management.

    In December, CERN's governing council, outraged by LHC's increasing price tag, appointed a nine-member external review committee (ERC) to assess how best to complete the massive proton collider. In its report, presented last week at the council's biannual meeting in Geneva, ERC praised the design of LHC and the technical competence of CERN staff. But it blasted the lab for “serious weaknesses” in cost control, contract management, and financial reporting, and it called for steps to set things right. CERN council president Maurice Bourquin says the council has accepted ERC's recommendations.

    The proposed remedies generally follow those in a medium-term plan that CERN proposed in March (Science, 29 March, p. 2341). The committee called on the lab to shift some $300 million from other operations into LHC and stretch out payments for the facility until 2010. Among numerous cost-cutting measures, ERC recommended that CERN shut down both of its existing proton colliders—the Proton Synchrotron and Super Proton Synchrotron—for all of 2005 and reshuffle staff from other accelerator projects to LHC. Finally, ERC's report laid out two models for a new organizational structure aimed at making CERN's management more efficient and accountable.

    Depth charge.

    Underground construction of the Large Hadron Collider gave CERN's governors a case of sticker shock.

    CREDIT: CERN-GENEVA

    Such changes would be “a big step in the right direction,” says Ian Halliday, a council member from the United Kingdom, adding that given the rift between CERN and its council, the negotiations that led to agreement on the report's conclusions “could have gone very badly wrong.”

    The council has given CERN's management until September to develop a short-term plan for putting most of ERC's recommendations into effect and until December to overhaul LHC's finances. The revision will include cost-to-completion estimates for LHC and a long-term budget and staffing plan for the entire lab. One key ERC recommendation—the call for a “new organizational structure”—although welcomed by council, “will take a bit longer” to implement, says Halliday. CERN director Luciano Maiani's term ends in December 2003, and particulars of the new organizational structure must be worked out in collaboration with his successor, whose name will be known in December 2002.

    With a plan in place, the council agreed to release $22 million it had held back from the laboratory's 2002 budget when it launched the ERC investigation. It also approved the lab's proposed $805 million budget for 2003.

    CERN's LHC push will hurt smaller projects such as the lab's Antiproton Decelerator, which will also be suspended for 2005. And although CERN will still provide a beamline to send neutrinos to Gran Sasso, Italy, it has withdrawn from the planned experimental portion of the project, which means a halt to neutrino physics for the lab. “Nobody likes it, that's for sure,” says Dieter Schlatter, leader of CERN's experimental physics division. Yet most researchers agree that such cutbacks are the price to pay for LHC.

    Indeed, all the good news was saved for LHC. Maiani announced that CERN is in the final stages of negotiating a bank loan for an additional $198 million toward the project's construction. He also reported happily that excavation of LHC's two new detector caverns, a major villain in the cost overruns, is now essentially complete. That puts the collider on track to begin operations in mid-2007–2 years late. That schedule is based on staffing levels that are not yet guaranteed, and it assumes that nothing else will go wrong, ERC notes.

    Although it would be “dangerous” to think that CERN's problems are solved, Maiani says, the LHC picture is in sharper view than it was a year ago. “We know pretty well how much [LHC] will cost; we know pretty well who will make it; and we are even starting to know who is going to pay for it,” he says.

  10. ASTRONOMY

    Cosmic Lenses May Be Magnifying Quasars

    1. Robert Irion

    Some objects in deep space are not quite as they appear. As their light zips across billions of light-years to Earth, the gravity of matter along the way stretches, splits, and contorts their images. Now, a new study predicts that these mirages, called gravitational lenses, are unexpectedly common for the most distant bodies that astronomers see: quasars near the fringes of the visible cosmos. Up to one-third of these remote beacons might be dramatically brightened by what Harvard University astronomer Abraham Loeb calls “natural telescopes” in the sky. The finding might help resolve a puzzle about these enigmatic denizens of the early universe.

    The farthest quasars have popped up during the Sloan Digital Sky Survey (SDSS), a multiyear effort to map the sky in exhaustive detail (Science, 25 May 2001, p. 1472). To date, SDSS astronomers have found four quasars that shone brilliantly when the universe was less than a billion years old. Cosmologists presume that black holes with billions of times the mass of our sun powered those early blazes by devouring gas at the cores of the first big galaxies. However, theories of galaxy evolution struggle to explain how such massive objects arose so soon after the big bang. Gravitational lensing might ease the problem: If some quasars are actually dimmer than they appear, then their host galaxies must be correspondingly smaller.

    Not so bright?

    This quasar, one of the four most distant known, might be magnified by an intervening galaxy.

    CREDIT: STEPHEN KENT/SDSS COLLABORATION

    To calculate how lensing affects our view of that epoch, Loeb and Harvard postdoctoral researcher J. Stuart B. Wyithe worked backward from the statistics of quasars and lenses closer to Earth. As they explain in the 27 June issue of Nature, they considered two key factors. First, it's more likely that a random galaxy will align with and magnify a distant quasar, because its light travels a much longer path. Second, lenses might allow telescopes to detect many faint quasars that they otherwise wouldn't find. This “magnification bias” could be extreme in the early cosmos, says Loeb, where modest quasars might greatly outnumber the truly bright ones.

    When Wyithe and Loeb combined both factors, they found that gravitational lensing might boost the apparent light output of 10% to 30% of the most distant quasars by a factor of 10 or more. “That's a surprisingly big fraction, and observers need to correct for it,” Loeb says. Indeed, the proportion is far higher than astronomers are used to seeing. Of the quasars that existed when the universe was 3 billion to 4 billion years old, just one in every 750 are magnified, according to a recent survey by astronomer Joshua Winn of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts, and his colleagues.

    “If Wyithe and Loeb are right, the early universe will be all that much harder for us to understand because of the distorted view,” comments Princeton University astrophysicist Edwin Turner. A test will come soon: Starting this fall, Princeton astronomer Michael Strauss and his SDSS partners will use the Hubble Space Telescope to examine dozens of quasars, including their four most distant ones, for multiple images—the signpost of a lensed quasar. Moreover, SDSS should find 10 to 20 more quasars at similar distances in the next several years.

  11. CANADA

    Few Women Win New Academic Chairs

    1. Wayne Kondro*
    1. Wayne Kondro writes from Ottawa.

    OTTAWA—Statistics can often be subtle and hard to interpret. But sometimes, says Wendy Robbins, co-founder of the women's studies program at the University of New Brunswick in Fredericton, they can slap you right in the face. That's what she hopes will happen to Canadian university administrators reading a new report showing that women are seriously underrepresented in a fledgling program to help the country retain its best academic talent.

    In October 1999 the government committed $585 million to create 2000 new posts under the Canada Research Chairs (CRC) program. The program provides $910,000 over 7 years to free up established researchers (Tier 1) from teaching duties and $325,000 over 5 years to help universities hire rising stars (Tier 2) to replace aging faculty. The fifth round of winners was due to be announced this week.

    A report looking at the first four classes shows that women, who represent 25% of the total academic pool, have received just under 15% of the 532 chairs (see graphic). The gender gap is especially wide for the Tier 2 posts, 21% of which have gone to women despite the fact that they make up 35% of the assistant and associate professors eligible for the award. CRC officials commissioned the study, done by Nicole Bégin-Heick, professor emeritus of biochemistry at the University of Ottawa, after receiving numerous complaints from female faculty members across the country.

    Seats at the table.

    Women are underrepresented in both categories of the Canadian Research Chairs program.

    SOURCE: CANADIAN RESEARCH CHAIRS

    Bégin-Heick says one possible reason for the imbalance is that women “are perhaps less ambitious than men, and they are less likely to seek these honors, if you want to call it that.” But Robbins, an English professor who's vice president of the women's issues network at the Humanities and Social Sciences Federation of Canada, points the finger at “the old boy's network of deans and academic vice presidents” that shuts out women. “Several universities have not appointed a single woman,” she notes. “One would have thought, by now, that enlightenment would have prevailed.” Robbins says that affirmative action plans and more aggressive recruitment are needed to make a real difference in the short run.

    Imposing quotas would be difficult because universities are autonomous institutions, says René Durocher, CRC secretariat executive director. “You can't give orders to these people.” But he says that CRC could seek legislative approval for such a “last resort” measure if the gender imbalance doesn't significantly improve over the coming year.

    The heads of the councils that fund social science and medical research have sent letters to all university presidents, beseeching them to redress the imbalance in future competitions for the roughly 1400 chairs still to be awarded. “I trust you will take advantage of this opportunity to reflect upon the significance of these numbers and, more importantly, what your university plans to do to address the situation,” wrote Marc Renaud, president of the social sciences granting council and chair of the CRC steering committee, who attached a table showing the gender distribution of all nominations for each participating university.

    Meeting last week in Toronto, Durocher and 100 senior university administrators proposed that institutions provide a written rationale for the gender distribution of all future nominations. They also want the federal government to create 400 additional chairs in the social sciences and humanities, in which women constitute a larger proportion of the professoriate. Those fields now get only 20% of the chairs, despite representing a majority of the professoriate, with the rest split equally between the biomedical and natural sciences.

  12. THERAPIES

    Confronting the Limits of Success

    1. Jon Cohen

    Six years ago, new cocktails of anti-HIV drugs transformed prospects for infected people in industrialized countries. Now, serious limitations have become apparent

    To veteran AIDS researchers, “Berlin” is shorthand for “gloom and doom, 1993.” “Vancouver” translates to “elation, 1996.” “Durban” means “waking up to the global crisis, 2000.” The tags refer to the field's Zeitgeist in the years these cities hosted the international AIDS conference. Next week, Barcelona, Spain, will welcome more than 10,000 participants to the XIV International AIDS Conference, and the tag line this year could well be “the limits of success.”

    In 1996, researchers first proved that new cocktails of drugs could thoroughly stymie HIV. There was even talk of cures. The 16 different anti-HIV drugs now approved by the U.S. Food and Drug Administration have indeed led to dramatic declines in AIDS-related disease and mortality—so much so that in countries where people have access to the drugs, HIV infection has changed, for many, from a death sentence to a chronic, manageable disease. But the honeymoon is over. “If we look back 6 years ago to the euphoria of Vancouver, it was appropriate, because we'd been dealing with 16 years of depression and watching people die right and left,” says Michael Saag, a clinical investigator at the University of Alabama, Birmingham. “But as this has all played out over the last 6 years, the limitations have become quite apparent.”

    In the heady days of Vancouver, prominent researchers suggested that a few years of treatment with potent drugs might eradicate HIV from a person's body. Now eradication is the E-word, something that makes researchers cringe. After Vancouver, many clinicians advocated a treatment philosophy dubbed “hit early, hit hard,” based on the assumption that infected people would fare better the earlier they started taking anti-HIV cocktails. Now, so many serious long-term side effects have surfaced with these drugs that consensus panels of experts have recommended delaying treatment until infected people are in imminent danger of symptomatic disease. And, in a vicious cycle, these side effects, combined with the psychological burden of taking a dozen or more medicines each day for months on end, have led many infected people to abandon their treatment plans because of “pill fatigue.” The result: As time passes, HIV has become increasingly resistant to existing drugs, and transmission of these resistant strains is on the rise.

    Resistance realities.

    Nevirapine (yellow balls) stops HIV's reverse transcriptase enzyme from transcribing viral RNA (gold strand) into DNA—but mutations (red) thwart the drug.

    CREDIT: ROBERT SHAFER/STANFORD UNIVERSITY/LANL

    These issues, sadly, remain of little concern for developing countries because they have yet to encounter the limits of success. Despite campaigns launched after Durban that have slashed drug prices and raised billions of dollars for AIDS treatment and prevention in developing countries—where 90% of the estimated 40 million HIV-infected people live—only a tiny fraction of the world's poor currently receive medication to protect them from the ravages of HIV (see p. 2324).

    As the euphoria of Vancouver gives way to these realities, AIDS researchers will be bringing to Barcelona some hard-headed views of the new challenges and complexities they face. “We've made tremendous strides, but we've kind of reached that plateau,” says Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases (NIAID). “When I put people on therapy and they do extremely well, I don't have any illusions that it's necessarily going to last 25 years.”

    Unnatural history

    The 1993 Berlin conference marks the low point in the search for anti-HIV drugs. Nearly a decade after HIV had been unmasked as the cause of AIDS, only three anti-HIV drugs had made it to market: AZT, ddI, and ddC, all of which attempt to cripple HIV's reverse transcriptase (RT) enzyme. None of them, either alone or in combination, packed much wallop, and huge debates roiled the field about how much benefit they truly offered. At best, they added a few years of life to people who had developed AIDS.

    By 1996, a combination of RT inhibitors and new drugs that target HIV's protease enzyme had radically changed the prospects for infected people. Various regimens of “highly active antiretroviral therapy” (HAART) could routinely drive the amount of HIV in the blood—the viral load—down below what the most sensitive tests could detect. The critical immune cells that HIV targets and destroys, CD4s, made spectacular rebounds. Hospital wards devoted to AIDS patients began to empty, and AIDS hospices closed their doors. “HAART is one of the great success stories of medicine,” says Joep Lange, a clinical investigator at the University of Amsterdam who conducts studies of anti-HIV drugs.

    But hopes that these potent drugs might entirely eliminate HIV were quickly dashed. More sensitive tests revealed that the virus hides out in various reservoirs in the body that would take decades of treatment to empty. The implication: An HIV-infected person must take medications for life. And, as with any long-term treatment, side effects and resistance are major concerns. “If people start with the right combination and they tolerate the drugs, I don't think there's any indication that there's going to be viral escape,” says Lange. “They can lead normal lives. But the big problem is that toxicities are in the way.”

    Physicians knew that the new drugs would cause nausea and anemia, but 2 years after the introduction of HAART, they began to see a new side effect in their patients: odd distributions of fat known as lipodystrophy. Other metabolic abnormalities have since surfaced that lead to diabetes-like problems, brittle bones, and heart disease. Because of these toxicities, many people switch medications or stop taking them altogether. As a result, clinicians no longer can answer one of the most common questions from patients: How much benefit do the drugs offer? “When you have multiple drugs, and each one has toxicities, it's really impossible to give people a meaningful answer,” explains leading AIDS clinician Robert Schooley of the University of Colorado Health Sciences Center in Denver.

    But some indication of long-term effects is emerging, dubbed “the unnatural history” of HIV by epidemiologist Scott Holmberg of the U.S. Centers for Disease Control and Prevention. On the positive end, Holmberg, Frank Palella of Northwestern University in Evanston, Illiois, and co-workers have shown that with the introduction of HAART, the numbers of AIDS-related diseases and deaths dramatically plummeted in a cohort of more than 1200 HIV-infected people they routinely monitor (see graphs below).

    Big bang.

    With the introduction of HAART, deaths have plummeted (top), but deciding when best to introduce HAART remains controversial. The study above shows that those with 251 to 350 CD4s who started treatment clearly did better than those who deferred.

    CREDITS: FRANK PALELLA/NORTHWESTERN UNIVERSITY/CDC

    Evidence exists, too, that—at least for some—HAART does not lose its power over time. Virologist Douglas Richman of the University of California, San Diego (UCSD), says that about half of the 33 people who participated in a landmark HAART study he helped run have tolerated the drugs and continue to fully suppress HIV. The patients began with an average of 144 CD4s per milliliter of blood (healthy people have 600 to 1200; 200 or less is considered AIDS), and after 7 years of treatment with AZT, the RT inhibitor 3TC, and the protease inhibitor indinavir, “they're doing amazingly well,” says Richman.

    But a recent analysis of a much larger study of the same three drugs in a slightly sicker population—the patients started with only 87 CD4s on average—gives a less rosy picture. Kenneth Freedberg of Massachusetts General Hospital in Boston and colleagues reported in the 15 March 2001 New England Journal of Medicine that although the treatment clearly was cost-effective, these patients' average life expectancy was only three and a half years.

    Neither of these studies is likely to reflect what happens outside clinical trials, however. In the real world, patients start HAART with every imaginable treatment history and a wide range of CD4 counts and virus levels. They might have a lot of drug-resistant virus or none at all. And, because they are less motivated to take several pills each day on a schedule, treatments often fail sooner than they do for people in trials.

    Studies that attempt to gauge the impact of HAART in real-world settings have arrived at troubling conclusions about durability. When people fail on HAART because of toxicities or side effects, they typically switch to a different cocktail of pills. But with each successive switch, says the University of Alabama's Saag, HAART works for shorter periods before another switch is required. In a study of some 400 people on various HAART regimens, Saag and colleagues found that few people could stay with a treatment plan for long. “Only about 25% of the people are on their original regimen 4 years out,” says Saag.

    Researchers stress, however, that these limits should not overshadow the obvious benefits that the new treatments provide. “Those of us taking care of patients in the early to mid-1980s” remember how people “were dying miserable deaths all around us,” says UCSD's Richman. Visit his clinic now, and “it's a no-brainer” that HAART has dramatically improved the ability to prevent AIDS and death. “The real issue,” says Richman, “is when to initiate treatment.”

    Hit when?

    In the wake of Vancouver, “hit early, hit hard” quickly became the conventional wisdom. Motivated by the dream of eradication and lessons from other branches of medicine, many physicians began giving the new drugs to all patients who had a detectable viral load. “When this started, we were still quite influenced by other fields, like oncology: The idea was if you wait to treat a cancer, you don't have any chance of a good result,” explains AIDS researcher Bernard Hirschel of the University of Geneva in Switzerland. In particular, researchers worried that if they waited too long to treat, the virus would be more difficult to control, and the immune system would have less chance to recover. Now, however, the consensus on early treatment has given way to debate.

    The shift is reflected in changing guidelines issued by the U.S. Department of Health and Human Services (HHS). In 1998, HHS recommended that HAART be offered to all patients who had 500 or fewer CD4 cells or viral loads that rose above 20,000 copies per milliliter of blood. But last year HHS took a more conservative approach, recommending that treatment be offered at 350 CD4s or a viral load higher than 55,000. Several other countries have similar guidelines. (Experts widely agree that everyone with 200 or fewer CD4s should receive treatment, as well as the minority of people who seek care within 6 months of becoming infected, as this might preserve vital immune functions that otherwise will suffer permanent damage.)

    Some support for delaying treatment has come from studies indicating that people treated later in the course of disease fare just as well in the long run. European researchers headed by Andrew Phillips of the Royal Free and University College Medical School in London, U.K., for example, saw little difference in long-term outcome in their studies of 3400 patients on HAART. They reported in the 28 November 2001 Journal of the American Medical Association that the treatment could fully and durably suppress HIV irrespective of whether a person had an initial CD4 count below 200 or above 500.

    A second study by Canadian researchers Robert Hogg, Julio Montaner, and colleagues reached similar conclusions. They found that for the 1200 patients they treated at the British Columbia Centre for Excellence in HIV/AIDS, viral load offered a poor guide for starting treatment. Only people who started HAART at less than 200 CD4s progressed to disease and death more quickly.

    These results are not persuasive to many in the field, however. “It's clear in the short term that you don't have benefit from starting treatment early, but we won't see the negative effects from delaying treatment for 10 years,” says Stefano Vella, chair of the HIV/AIDS Clinical Research program run by Italy's Istituto Superiore di Sanità in Rome. And Steven Deeks, a clinical investigator at the University of California, San Francisco (UCSF), predicts that “as we begin to understand the cause of toxicities and the ways to prevent them by using drugs more rationally, there's going to be a swing back toward treating earlier.”

    David Ho, director of the Aaron Diamond AIDS Research Center in New York City, says the pendulum has already swung too far toward deferring treatment. “I don't know where to draw the line, but I'm personally uncomfortable with 350,” says Ho. “This is a deadly virus, and unless you control it, it will take its toll on the immune system in ways that are not so apparent in routine laboratory testing.”

    “We will never have the right answer” about when to start treatment, says Vella, because “it will be too difficult” to learn it from a controlled trial. But that has not stopped NIAID from trying. In January, NIAID launched a massive study to compare the benefits of “hit early, hit hard” versus “go slow.” The controversial study, called Strategies for Management of Anti-Retroviral Therapies (SMART), plans to monitor up to 6000 people over the next 9 years. Researchers will assign participants randomly either to start HAART immediately or defer treatment until their CD4 count drops to 250. People in the go-slow group will stop taking medications whenever their CD4 count rises above 350.

    UCSD's Richman and others have strongly criticized the study, which NIAID estimates will cost up to $121 million to complete. The “design, statistics, and scientific rationale provide no hope of providing useful information,” charges Richman. But AIDS activist Mark Harrington of the New York City-based Treatment Action Group sees SMART as precisely the type of study the federal government should support, because drugmakers have little incentive to do such a complicated comparison.

    While researchers debate when best to start treatment, “the reality for many practitioners is that it's a moot point,” says Richman. The sobering reason: HIV-infected people often seek care for the first time when they end up in an emergency room with an opportunistic infection of AIDS. Saag has reported that his patients have an average of 100 CD4s at their initial visit. “I'd love to get a patient with 400 CD4s and have to make that decision about whether to recommend treatment,” says Saag.

    HAART stopping

    As the limits of HAART have become evident, AIDS researchers have begun to look into a novel strategy for making the treatment less onerous: carefully monitored drug holidays, known as structured treatment interruptions (STIs). If they work, STIs would not only provide some relief, but they would also cut the cost of treatment, which could have a major impact in developing countries. But the idea is controversial.

    Bruce Walker, Eric Rosenberg, and their co-workers at Massachusetts General Hospital have shown that STIs have promise—at least for people recently infected with HIV (Science, 19 November 1999, p. 1470). The group followed 14 patients who went on HAART within weeks of learning they were infected. After an average of 18 months of treatment, they went off the drugs and restarted them whenever their viral loads spiked. The researchers found that over the 3 years they have been tracking these patients, the periods between halting treatment and viral spikes have lengthened. Moreover, they have found that the immune system seems to gain strength: When the virus returns, it boosts the production of killer cells that target cells infected by HIV.

    Because these results are from a small, uncontrolled study, Walker is careful not to claim that STI has worked. “These people are clearly getting boosted immunity, and they're clearly controlling better with subsequent interruptions,” he says. “But there are no data that say STIs are clinically beneficial.”

    Although Walker has convinced many AIDS researchers that STI has promise for patients treated early in their infections, there's no such agreement on its use for chronically infected people. Outside the newly infected population, STIs are “sheer nonsense, absolute crap,” scoffs the University of Amsterdam's Lange. In the 2 May issue of Nature, Lange notes, a study by Daniel Douek and Richard Koup of NIAID and their co-workers suggests that STI might actually be dangerous. The researchers show that HIV prefers to infect CD4 cells that have been trained to recognize HIV. When HIV returns during an STI, they reported, this increases production of HIV-specific CD4s, thus providing HIV with more potential targets.

    View this table:

    The University of Geneva's Hirschel recently presented data from the largest study yet done of STIs in chronically infected people. At a gathering known as the Retrovirus Conference held in Seattle, Washington, in February, Hirschel reported on the Swiss-Spanish Intermittent Treatment Trial, which recruited 133 people on HAART to stop their drugs every 8 weeks for 2 weeks. At 1 year, only 67 people remained in the trial, because, for safety reasons, people could continue only if they suppressed virus each time they went back on treatment. Of those 67, only 23 suppressed their virus after completely stopping treatment. There was no evidence that the people who did better had boosted immunity from intermittent exposure to their HIV. “I wouldn't argue with those who say the results are not encouraging,” says Hirschel.

    One approach that might avoid some of the problems with STI in chronically infected people is to keep the drug withdrawal period short, so that HIV doesn't have a chance to spike. NIAID's Mark Dybul, working with Fauci, has studied a 7 day on/7 day off cycle in 10 people for 2 years, and, says Fauci, “they're doing very well.” Clinical trials of the concept are now enrolling patients in the United States. A trial called Staccato is recruiting 600 patients in Switzerland, Thailand, and Australia to compare the week on/week off approach to continuous therapy and, separately, an STI strategy of stopping treatment each time CD4s rise above 350.

    Disorganized resistance

    The combination of new toxicities, “pill fatigue,” and frequent changes in drug regimens is setting up conditions for the mother of all limitations: drug resistance.

    If any of the existing anti-HIV drugs is used in a solo attempt to thwart HIV, the virus quickly gains the upper hand by creating a mutant strain that can dodge the attack. The success of HAART rests on a concerted multipoint attack that shuts down HIV replication so effectively that it reduces the likelihood that drug-resistant viral mutants will emerge. But if a patient doesn't follow the demanding regimen and concentrations of anti-HIV drugs in the blood taper off gradually, pressure on the virus is reduced, giving resistant strains a chance to emerge and crowd out the “wild-type” virus.

    At the Interscience Conference on Antimicrobial Agents and Chemotherapy held in Chicago, Illinois, last December, Richman and Sam Bozzette of UCSD and their co-workers presented data suggesting that variants have escaped to an alarming extent. The researchers found HIV strains resistant to one or more drugs in a staggering 78% of more than 1000 blood samples from people treated during the HAART era.

    Equally disturbing, UCSD's Susan Little, a clinical investigator who collaborates with Richman, has found that resistant strains are being transmitted to new patients with increasing frequency. Little found that only 5.5% of newly infected people between 1995 and 1998 carried HIV with well-described drug-resistant mutations. But in samples taken from newly infected people in 1999 and 2000, the number had skyrocketed to 18.5%. UCSF's Robert Grant, James Kahn, and colleagues have found a similar trend. At the February retrovirus meeting, they reported that between 1996 and 2001, the proportion of newly infected people with resistant virus jumped from 16.7% to 27.6%. “San Francisco has always been the canary in the coal mine, and what happens here will happen everywhere else,” cautions Kahn.

    Frightening as these data are, many AIDS researchers hope that new and improved drugs—and a better understanding of how to use them—can cut the links between toxicities, adherence problems, and, ultimately, resistance (see sidebar on p. 2322). Yet no miracles are on the horizon. “We have made significant advances in HIV therapeutics, but we haven't cured anybody yet,” says Saag. “This is still a disease that nobody wants to have.” Success clearly has its limits.

  13. THERAPIES

    Raising the Limits

    1. Jon Cohen

    Physicians treating HIV-infected people now have a massive armamentarium at their disposal: 16 anti-HIV drugs are on the market in the United States, and more are in the pipeline. The impressive flow of new drugs—10 have been approved in the past 6 years—is giving researchers hope that they can alleviate some of the problems with current therapies (see main text).

    All 16 approved drugs target either HIV's reverse transcriptase (RT) or protease enzymes, proteins critical to the virus's ability to replicate. Different drugs home in on different regions of the target enzyme, which makes them effective in combination, and they often produce different side effects. This means that physicians can vary the mix of drugs in a cocktail to attack HIV strains that have become resistant to some drugs or to make therapy more tolerable. Some of the new drugs also combine several compounds into a single pill or reduce multiple doses to one tablet, which can simplify drug regimens. “We're seeing gradual progress on a whole series of fronts,” says Robert Schooley, who conducts clinical trials of anti-HIV drugs at the University of Colorado Health Sciences Center in Denver. But, Schooley notes, the array of choices can be bewildering for physicians: “This is as complicated as oncology.”

    No entry.

    The drugs T-20 and T-1249 interfere with HIV's gp41 as it attempts to gaff a CD4 cell and then infect it.

    CREDIT: TRIMERIS INC. AND F. HOFFMANN-LA ROCHE LTD.

    And it is only going to get more complicated. Next week, at the XIV International AIDS Conference in Barcelona, Spain, researchers will learn about several promising drugs now in clinical trials. Some attack the familiar RT and protease enzymes, but others go after new targets such as receptors that allow HIV to slip into cells or a critical viral enzyme called integrase (see table).

    Researchers are awaiting news, for example, about efficacy studies of T-20, a drug that attempts to stop the virus from entering cells by gumming up a viral protein, gp41, that's critical to the process. Although T-20 must be injected, preliminary evidence suggests that because it inhibits a novel target, the drug will work in people who have developed resistance to other antiviral compounds. Researchers hold out similar hopes for other novel compounds further back in the pipeline.

    These advances should raise some of the limits of current therapies. But they are unlikely to have the dramatic impact that protease inhibitors had when they were added to the mix 6 years ago. “We need something else in addition to antiretrovirals; otherwise we are not going to move forward in this field,” says José Gatell, a clinical investigator at the University of Barcelona, who is co-chair of the international conference. Gatell is heartened by increasing interest in immune-based treatments, such as vaccines that aim to help infected people. “We need to treat the immune system,” he says. “With antiretroviral therapy, we have reached the roof.”

    View this table:
  14. THERAPIES

    The High Cost of Poverty

    1. Jon Cohen

    A great awakening occurred 2 years ago in Durban, South Africa. Researchers, activists, caregivers, economists, and politicians at the XIII International AIDS Conference finally focused attention on an unfolding catastrophe: Tens of millions of HIV-infected people in poor countries would soon die because they had no hope of treatment. The response was swift. Drug companies slashed prices, the United Nations (U.N.) helped launch the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and an array of public and private groups began their own initiatives to shrink the treatment gap between rich and poor.

    These efforts helped, no question about it; but formidable obstacles remain. Many governments have been slow to pony up money, and disputes have broken out over how to allocate the funds that do exist. Experts are concerned that improper use of medications will spawn widespread drug resistance. And some leaders worry that poor coordination and overblown expectations might undermine progress.

    Even people at the front of the battle acknowledge that few pills have made it to the people who need them most. “It's been nearly a total failure,” says Peter Piot, director of the Joint United Nations Programme on HIV/AIDS (UNAIDS). The World Health Organization estimates that the drugs have reached only 230,000 of the 6 million residents of low-and middle-income countries who most desperately need them—and half of those who have benefited live in Brazil, where the government dispenses the medicine for free. In sub-Saharan Africa, where 70% of the world's 40 million HIV-infected people live, a mere 36,000 now receive the drugs, according to the latest estimates from Accelerating Access, an initiative spearheaded by UNAIDS that links pharmaceutical companies to the World Bank and other U.N. branches.

    Global attention.

    Protesters at the international AIDS meeting in Durban 2 years ago helped raise awareness of the disaster looming over many poor countries.

    CREDIT: OBED ZILWA/AP

    Still, there have been remarkable changes. Before the Durban meeting, the notion of offering the latest cocktails of drugs to people in developing countries was a nonstarter because treating one person costs $10,000 or more annually. Over the past 2 years, however, generic drugmakers and large pharmaceutical companies have offered deep discounts for developing countries, reducing the annual cost of treatment to as little as $300 to $400 per person. But even that's too expensive for most developing countries, Piot notes.

    The Global Fund promises to help. “The hopes of many people ride on our success,” says epidemiologist Richard Feachem, the fund's executive director designate. But the fund has money issues, too. When U.N. Secretary-General Kofi Annan first pushed to organize the fund in an April 2001 speech, he said it would need a “war chest” of $7 billion to $10 billion each year just to fight HIV/AIDS. The fund, which is supported mainly by donor nations and philanthropists, to date has raised only $2 billion.

    Feachem, founder of the Institute for Global Health at the University of California, San Francisco (UCSF), says $2 billion is “more than enough to get started.” He predicts that donors will provide more money in due time. “Large amounts of additional resources will become available when the Global Fund demonstrates results and impact on the ground,” he predicts.

    AIDS workers are joined in a fierce debate over how best to use those limited funds. In the 25 May issue of The Lancet, Elliot Marseille and colleagues at UCSF made a case for a simple, low-tech approach. They argue that prevention efforts such as promoting condom use and treating other sexually transmitted diseases are—based on a model they constructed—more than 28 times as cost-effective as even the steeply discounted drug therapies. “Over the short term, while we're way short of the $10 billion that's really needed, we should be putting the bulk of the funds in prevention,” says Marseille, a public health specialist. “The basic reality is there's not enough to do both very well.”

    Piot groans when this study is mentioned: “I find the analysis extremely simplistic,” he says. “We've got to do far more prevention, but we've got the emergency today. If we don't offer treatment to health staff, to the teachers, the whole of society is going to break down more rapidly.”

    Kevin De Cock, who directs the U.S. Centers for Disease Control and Prevention program in Kenya, cautions against setting unrealistic expectations for what AIDS therapies can accomplish in many poorer locales. “There's a real need to temper the discussion about all of the major diseases with the cold reality of technical and financial limitations,” says De Cock, who focuses largely on HIV/AIDS, malaria, and TB. “For each of those three diseases there are real unknowns about long-term impact of interventions.”

  15. VACCINES

    Monkey Puzzles

    1. Jon Cohen

    As a growing number of vaccines move through the pipeline toward clinical trials, experiments with monkeys are producing puzzling data—and doubts

    The first full-scale trial of an AIDS vaccine is scheduled to end in November, and the world soon will learn whether it works. A second product will move into a large efficacy trial this fall. Earlier in the pipeline, the array of AIDS vaccines entering human studies is more diverse than ever before (see table below). “The pipeline is dramatically improved in many ways from 5 to 6 years ago,” says Peggy Johnston, who heads the AIDS vaccine program at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. But, Johnston cautions, “significant scientific and operational challenges remain.”

    View this table:

    Foremost among those scientific challenges: Just what does it take for a vaccine to work? Almost 2 decades after HIV was identified as the cause of AIDS, researchers are still debating which immune responses are likely to provide the best protection against the virus. The answer is proving elusive in part because experiments with monkeys are coming up with puzzling, even contradictory, data. “We're so much in the dark about what we would need for a protective vaccine,” laments Ronald Desrosiers, head of Harvard University's New England Regional Primate Research Center in Southborough, Massachusetts.

    Monkeys are the favored model for testing vaccine strategies. (Researchers no longer use chimps for ethical and cost reasons.) Although HIV does not infect monkeys, a cousin simian virus, SIV, does: Some two dozen African species of monkeys are now known to harbor SIV in the wild, and it causes them no harm. But when SIV infects Asian monkeys, it causes an AIDS-like disease. In the most common type of experiment, researchers vaccinate Asian rhesus macaques and then “challenge” them with either SIV or a laboratory-made hybrid of the simian and human viruses, called SHIV.

    Although some researchers question whether the monkey model truly mimics HIV in humans, the field at large has embraced it as the best way to determine which vaccine strategies hold the most promise. But a slew of recent monkey experiments has raised questions about most of the vaccine approaches now being pursued.

    Half a loaf

    When HIV was first discovered, the way to a vaccine seemed clear: Find a part of the virus that triggers an antibody response capable of “neutralizing” HIV before it can establish an infection. The AIDS vaccine that has moved furthest in human trials—a genetically engineered version of HIV's surface protein made by VaxGen of Brisbane, California—banks on this concept.

    But monkey studies with AIDS vaccines have completely failed to elicit antibodies that can neutralize the virus. “I think the Holy Grail in the field of AIDS vaccine development is how to generate a broad, neutralizing antibody response,” says Norman Letvin, a primate researcher based at Harvard's Beth Israel Deaconess Medical Center in Boston, “but we don't know how to do it.”

    As a result, many have shifted their attention to the arm of the immune system that dispatches killer cells, tiny missiles that seek infected cells and obliterate them. Because killer cells, by definition, can do their thing only if an infection has already occurred, the goal now is not prevention of infection but of disease.

    Some monkey experiments have given heart to those taking this approach. Researchers at Merck Research Laboratories in West Point, Pennsylvania, working with Letvin, reported in the 17 January issue of Nature that two AIDS vaccines they used back to back in monkeys constrained SHIV and protected the animals from disease by triggering killer cell responses. The Merck data have buoyed spirits among vaccine researchers, and the vaccines now are in early human trials. But other monkey studies have raised doubts.

    In the same issue of Nature, Letvin, Dan Barouch of Massachusetts General Hospital in Boston, and co-workers reported that similar vaccines initially protected eight monkeys against the identical SHIV strain Merck used, whereas unvaccinated control monkeys had high levels of virus and subsequent disease. But 6 months later, one vaccinated monkey no longer could control the virus, and by 1 year it had developed AIDS-like symptoms and died. The researchers discovered that the SHIV had mutated its way around the killer-cell response. It's an ominous development, Letvin thinks, because it threatens in time to undermine every vaccine that relies on killer cells alone.

    Then again, Letvin points out, seven of the vaccinated animals are still controlling their SHIV infections, and even the animal that died fared better than the unvaccinated controls. “I'm willing to take half a loaf if that's all we have,” says Letvin.

    Immune conundrum.

    Sooty mangabeys have high viral loads of SIV, yet the virus does not make them sick.

    CREDIT: NICK GORDON/OSF/ANIMALS ANIMALS

    Experiments conducted by immunologist David Watkins of the Wisconsin Primate Research Center in Madison suggest that even half a loaf might be optimistic, however. Like the Merck team, Watkins and his colleagues used two vaccines back to back that triggered strong killer cell responses. Yet, as Watkins's team reported in the April issue of the Journal of Virology, when they challenged the animals with a famously nasty strain of SIV rather than SHIV, the virus was blunted for a time but ultimately ran wild. A growing number of researchers contend that this more vigorous challenge accurately reflects the way that HIV behaves in humans. “Watkins gets better cellular immunity than I've seen before, better than we can hope to get in humans, and it had a modest effect,” stresses Jeffrey Lifson, a virologist at SAIC-Frederick, a company that runs the National Cancer Institute's AIDS Vaccine Program in Frederick, Maryland. “I'm very depressed by these studies,” says Watkins. Killer cells by themselves, he suggests, “are not going to be protective.”

    Triple surprise

    African monkeys' impressive ability to withstand infection by SIV might provide some answers to how the immune system can keep the virus at bay. A few recent discoveries, however, have only made the puzzle seem more complex.

    In 1998, Lisa Chakrabarti, then at the Pasteur Institute, and her colleagues surprised many investigators when they reported that SIV-infected sooty mangabeys maintain terrifically high levels of the virus in their blood. If their immune system is protecting them, it's not by traditional means. Last year, Jonathan Allan of the Southwest Foundation for Biomedical Research in San Antonio, Texas, and co-workers reported that the same holds true for African green monkeys. Mark Feinberg of Emory University in Atlanta, Georgia, who collaborated with Allan and also has confirmed the French findings with sooty mangabeys, suggests that these monkeys might benefit from a sluggish immune response that keeps many immune cells—SIV's target—out of the line of fire. “More isn't necessarily better,” says Feinberg. “We don't know enough to point to what are the really good immune responses and which ones aren't so good.”

    Two experiments that have protected Asian monkeys also raise intriguing questions. A decade ago, Desrosiers's lab reported that a vaccine made from a live, weakened version of SIV offered the best protection seen to this day—and he still cannot completely explain why (Science, 18 December 1992, p. 1938).

    Another surprise has come from an experiment that resulted in substantial protection, but doesn't even involve an AIDS vaccine. Lifson of SAIC-Frederick and his co-workers, including Desrosiers, infected five monkeys with a highly lethal strain of SIV and began treating the animals the next day with tenofovir, an anti-HIV drug that also works against the monkey virus. After 28 days, they stopped all treatment. As they reported in last November's Journal of Virology, the researchers could not detect SIV in the monkeys' blood, and the animals continued to control the virus once the treatment stopped. Moreover, when the researchers challenged the monkeys with the same SIV strain more than a year later, they all beat back the challenge.

    To further test the monkeys' immunity, the researchers injected the animals with antibodies that temporarily deplete CD8 cells, the family from which killer cells originate. SIV spiked, but they quickly re-established control. The investigators also upped the ante, using a different SIV strain that should be much more difficult for the animals to recognize and contain. All five monkeys substantially controlled the new virus.

    Although CD8 cells appeared to play a role in the protection of some animals, the results perplexed many researchers because in other vaccine experiments, monkeys developed more impressive immune responses but still failed to contain the challenge virus. The animals in Lifson's study, Desrosiers says, “are as well protected as any vaccinated monkeys on Earth.”

    One lesson, says Lifson, is that blunting the initial burst of virus—whether by drugs or a vaccine-fortified immune system—is crucial, perhaps because it protects critical immune responses that otherwise would be lost for good. And he thinks this might help explain why Watkins and others could not defeat SIV with their vaccines. “None of these vaccines seem to give us enough blunting of the early viremia to allow development of an immune response that can give a good chance of solid, prolonged protection against SIV,” he says.

    Given the contradictory evidence from monkey studies, Desrosiers, the field's resident skeptic, says he has little hope that any of the vaccines now in human trials will work. “The breakthrough discovery that's going to lead to an AIDS vaccine hasn't been made yet,” he says. “And if it happens at all, it's going to be serendipitous.” Then again, many vaccines—including the one that eradicated smallpox from the world—went into widespread use long before humans had a clue how they actually worked.

  16. PLANT GENETICS

    Something to Sniff At: Unbottling Floral Scent

    1. Kathryn Brown

    Plant biologists are blending modern genomics and classic biochemistry to restore scents lost when flowers are bred for looks and long vase life

    David Weiss knows where to look for fragrant roses—and it's not the corner florist. Instead, Weiss turns to a growing rose DNA database, hunting for scent genes that could enhance future flowers. His search might mean more romantic bouquets for us all—and a bonanza for the flower industry.

    Many modern roses, bred for stunning blossoms and long vase life, have all but lost their scent. In fact, although cut roses bring in some $10 billion worldwide every year, the flowers often smell mostly of wax-paper wrapping. And these floral favorites are not alone. Carnations, chrysanthemums, and some lilacs, among other modern cultivars, lack fragrance.

    But Weiss, a plant biologist at the Hebrew University of Jerusalem, and other researchers might bring back petal perfume. Using both genomics and classic biochemistry, these scientists have begun unraveling the mechanics of scent in roses, snapdragons, and Brewer's clarkia, among other bloomers. “We now have the opportunity to go deep into this field,” Weiss says, “in a way that wasn't possible just a few years ago.”

    Unbottling the basics

    In the garden, fragrance is fickle. Blossoms can be sweet or spicy, faintly citrus, or starkly intoxicating. A plant's signature scent is a unique combination of volatile compounds: small organic molecules that evaporate off petals, filling the air with perfume to attract bee and moth pollinators. Although all flowering plants likely share some genes for floral scent, each species expresses a particular gene mix.

    For decades, floral scent was a sensual delight, difficult to measure or even describe. Perfumers have been the primary consumers of floral scent chemistry, bottling the sweetness of freesia, gardenias, and the like. But they merely require the chemical structure of a scent. Until recently, no one had tried to take a biochemical step backward—to see precisely how flowers produce scents in the first place.

    That began to change in 1994, with a study led by Eran Pichersky of the University of Michigan, Ann Arbor. Pichersky had originally been interested in evolution: How have some plant species evolved an ability to make scent when others, even close relatives, have not? Casting about the literature, however, he quickly realized that researchers didn't understand even the basics of floral scent. “We had no genes, no enzymes,” Pichersky says. “In order to see how scent evolves, we first had to learn how it's made.”

    Wildly fragrant.

    The wildflower Brewer's clarkia offered researchers the first biochemical details of floral scent enzymes.

    CREDIT: DAVID BAY/UNIVERSITY OF MICHIGAN

    Pichersky and his colleagues decided to study Brewer's clarkia (Clarkia breweri), an annual wildflower native to California that wears a strong, sweet scent and lavender blossoms. In the lab, the team trapped volatile compounds emitted by Brewer's clarkia in a plastic chamber. They injected them into a gas chromatograph, which separated the compounds, and a mass spectrometer, which identified and quantified them. In all, the team found eight to 12 major volatile compounds.

    Soon, the team accomplished a floral first: They isolated and characterized an enzyme that confers scent—linalool synthase, which helps form linalool, a common scent volatile in flowers—and its corresponding gene. Since then, the scientists have discovered three more floral scent enzymes and their relevant genes in Brewer's clarkia. “We found that almost all scent biochemistry happens in the epidermal surface of the flower—especially in the petals, where scents escape easily,” says Pichersky, who calls the system beautifully simple.

    Now, the snapdragon (Antirrhinum majus), a perennial garden favorite, is getting its day in the sun. Using a similar biochemical approach, plant biologist Natalia Dudareva of Purdue University in West Lafayette, Indiana, and her colleagues have identified and characterized the enzyme benzoic acid carboxyl methyltransferase (BAMT), which helps form methyl benzoate, a major scent volatile in snapdragons. BAMT shows up solely in snapdragon petals. “What's interesting,” Dudareva says, “is that floral scent is restricted to the areas of snapdragon petals that come in contact with pollinators, like close to the mouth of the corolla.”

    A rose to remember.

    Unlike some modern cultivars, the Fragrant Cloud rose is rich in scent—and notably volatile.

    CREDIT: DAVID WEISS/OTTO WARBURG CENTER FOR AGRICULTURAL BIOTECHNOLOGY

    Dudareva aims to sort out the snapdragon's perfume patterns. In a study published last year in The Plant Cell, for instance, she and her colleagues reported that the flowers follow a circadian rhythm, releasing four times as much methyl benzoate during the day—prime pollinating time for bees—than at night. They also found a similar circadian pattern in petunias and flowering tobacco, although these plants release maximum methyl benzoate at night, when their moth pollinators are most likely to visit. “We don't know much about this clock yet,” Dudareva says, “but it could work in many plants.”

    Like many flowers, snapdragons also turn down their scent shortly after pollination—a strategy that might steer insects toward unpollinated blossoms. To catch this scent loss in action, Dudareva's team recently hand-pollinated snapdragon and petunia flowers over several days. Within 72 hours of being fertilized, snapdragons lost 90% of their scent production; petunias lost that much in just 48 hours. The researchers zeroed in on a candidate gene that might trigger this slump in scent, Dudareva says, in work to be published later this year.

    Growing genomics

    These early scent experiments on Brewer's clarkia and snapdragons brought classic biochemistry into the garden: Researchers worked backward to characterize each scent enzyme and its gene, one at a time. The science might have stopped there. Lacking a simple way to spot subtle fragrance mutants, researchers cannot use Mendelian genetics to easily breed and test plants for scent.

    Now, however, there's a promising alternative: genomics, which enables speedy screening of plant tissue DNA for candidate genes. In Israel, Weiss heads the Petal Genomics project—a 3-year-old effort to build a database of DNA expressed in rose petals; from there, the researchers hope to identify scent genes.

    To do so, Weiss and his colleagues, including Pichersky, are cloning and sequencing active DNA from rose petals. They pinpoint candidate scent genes by searching GenBank and other databases for similar genes that encode enzymes known to help build volatiles. Finally, the team expresses those candidate genes in bacteria, analyzing the proteins' activity. “The idea is to find the volatiles produced by flowers, as well as the genes expressed by petals during different stages of scent production,” Weiss explains.

    To launch the Petal Genomics project, funded by Israel's Ministry of Science, Weiss's team chose two cultivars: Fragrant Cloud, a strongly scented red rose, and Golden Gate, an almost odorless yellow rose. When analyzed, petals from the two roses revealed strikingly different volatile compounds—and yielded more than 3000 potential genes expressed in petals, including at least 15 candidate fragrance genes, Weiss says. Already, the team has characterized four novel enzymes—including orcinol O-methyltransferases dubbed OOMT1 and OOMT2, which catalyze a common scent component in roses known as 3,5-dimethoxytoluene. The first description of a scent enzyme in rose flowers, that work will be published in Plant Physiology in August.

    Snapping in time.

    Snapdragon scent follows a circadian rhythm, spiking during the day to attract bee pollinators.

    CREDIT: FLORENCE NEGRE/PURDUE UNIVERSITY

    Ultimately, Weiss hopes to spice up floriculture by engineering more fragrant roses. “The ornamental flower industry in Israel is an important aspect of agriculture, partly because we export cut flowers to Europe during their cold, dark winters,” says Weiss, whose family owns a flower business. “I'd like to see if we can bring scent back to these modern cultivars.”

    But the work will be tricky, cautions Alan Blowers, biotechnology project manager at Ball Horticultural in Chicago. “We have an elementary understanding of floral scent at this point,” Blowers notes. “While there is commercial potential, I think we're a ways from that.”

    Indeed, early attempts to engineer floral scent have had mixed results. In the first reported effort, published last year in The Plant Journal, scientists in the Netherlands engineered petunias with the linalool synthase gene found in Brewer's clarkia. The transgenic petunias expressed linalool in many tissues but failed to actually release the scent compound. Weiss's lab recently had more success breeding the same gene into carnations, which did release linalool—although not enough for people to detect a stronger scent.

    Another tack has proved intriguing. In a study to be published next month in Molecular Breeding, Weiss and his colleagues boosted scent production in carnations by blocking the flowers' pigment. Because color compounds and scent compounds begin in the same biochemical pathway, Weiss says, blocking color likely redirects metabolic flow toward scent. Researchers might even return to carnations their rightful legacy: At one time, the flowers smelled richly of cloves and spice, thanks to heavy amounts of the volatile eugenol, a minor ingredient in today's cultivars.

    Pichersky, for one, is confident that flowers spiked with scent, or transgenic fruits with a special flavor (see sidebar), will eventually hit the marketplace, despite the current lukewarm climate for genetically modified foods. “It can happen and will happen,” he says. If so, you just might find yourself stopping to smell the roses.

  17. PLANT GENETICS

    Plants 'Speak' Using Versatile Volatiles

    1. Kathryn Brown

    Inside the garden, methyl jasmonate is the sweetest scent around. Rising off jasmine flowers, the compound's sultry perfume stops pollinators and people alike. But sweetness can be deceiving: When plants are wounded by hungry herbivores, that same scent, shot from the leaves, serves as an SOS.

    In fact, the emerging biochemistry of floral scent confirms what researchers have long suspected: Plants are versatile perfumers, flinging similar—and in some cases, identical—chemicals into the air to turn organisms on or off, depending on the situation. “Think of plant volatiles as a language,” says Jim Tumlinson of the U.S. Department of Agriculture's Agricultural Research Service in Gainesville, Florida. “If you put them together into one message, you have a scent that attracts pollinators. Put together another way, you have a scent that attracts natural enemies of herbivores threatening a plant.”

    It's been about 20 years since entomologist Jack Schultz of Pennsylvania State University, University Park, and then-student Ian Baldwin first proposed that “talking trees”—in that case, damaged poplars and maples—could signal distress to their neighbors with airborne chemicals. Scientists scoffed. But last year, Baldwin—now director of molecular ecology at the Max Planck Institute for Chemical Ecology in Jena, Germany—and graduate student André Kessler reported in Science the first field evidence for indirect plant volatile defenses against herbivores (16 March 2001, p. 2141).

    Working in southwestern Utah's Great Basin desert, Baldwin and Kessler found that tobacco plants under assault from caterpillars, leaf bugs, and flea beetles naturally release three compounds that can cut this herbivore activity by more than 90%. Now, Baldwin is looking for the genes behind these plant defense volatiles. “What is it that controls volatile release?” he asks.

    Plant scents also attract human grazers. Researchers have recently identified key volatiles that flavor sweet basil and strawberries, among other edible plants. Last November in Plant Physiology, Eran Pichersky of the University of Michigan, Ann Arbor, and his colleagues reported engineering tomatoes with S-linalool, a scent and flavor volatile also found in flowers, with the ultimate goal of improving both scent and taste. In fact, he adds, new plant volatiles—and uses—continue to emerge.

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