# News this Week

Science  10 Sep 2004:
Vol. 305, Issue 5690, pp. 1135
1. STEM CELL POLITICS

# California Debates Whether to Become Stem Cell Heavyweight

1. Gretchen Vogel

President George W. Bush may end up doing California stem cell researchers a huge favor. Spurred by the Bush Administration's restrictions on funding for human embryonic stem (ES) cells, patient advocates, venture capitalists, and research leaders have launched a campaign to persuade California voters to pass an unprecedented ballot proposal, called Proposition 71, that would allocate $3 billion for the field over the next 10 years. If the measure passes in November—and early polls say it's still too close to call (Science, 27 August, p. 1225)—California would spend nearly$300 million a year on human ES cell research, almost 50% more than the $214 million the National Institutes of Health (NIH) spent on all human stem cell research—both embryonic and nonembryonic—in 2003. “It will change the landscape of where this work is done,” says Douglas Melton of Harvard University, who because of the White House's restrictions has had to set up a privately funded lab to derive new human ES cell lines. “California will become a hotbed of stem cell research.” Supporters of Proposition 71 have raised more than$11 million from donors such as Microsoft's Bill Gates and eBay founder Pierre Omidyar and his wife, Pamela. In the coming weeks, they plan to make their case for the measure with television, radio, and newspaper ads arguing that the investment will speed discovery of cures for dozens of diseases, cut health care costs, and boost California's economic recovery.

But some skeptics, including supporters of public funding for human ES cell research, say the plan is too expensive for a state facing multibillion-dollar budget deficits. A group called Doctors, Patients and Taxpayers for Fiscal Responsibility has led opposition to the measure, objecting to its cost as well as its focus on embryo-derived cells.

While Proposition 71 proponents say the opportunity for citizens to vote directly for science funding is an unprecedented chance for outreach, others worry that the political slogans could mislead voters and raise unrealistic expectations for miracle cures. “The argument that they use is that it's going to save lives. That's a good argument, politically, but in reality that's nuts,” says George Annas, a bioethicist at Boston University. “Someday, hopefully, that's going to happen, but not in the next year or 2 or 10.”

Proposition 71 is the brainchild of real estate developer Robert Klein II, whose son with juvenile diabetes and mother with Alzheimer's disease inspired his support for stem cell research. Following the decision that NIH funding for human ES cell research would be limited to cell lines created before 9 August 2001, California, like several other states, passed a bill explicitly allowing the derivation and use of new ES cell lines. But proponents soon realized that the measure meant little without any funding attached, says cell biologist Lawrence Goldstein of the University of California, San Diego.

Going further than the previous law, Proposition 71 would change the state's constitution, giving researchers the explicit right to conduct research with pluripotent stem cells, including cells created from embryos generated by couples undergoing fertility treatments or by somatic-cell nuclear transfer (SCNT). It would also authorize the state to issue $3 billion in bonds to establish the California Institute for Regenerative Medicine, a funding body that would disburse grants for buildings and research projects—an average of$300 million per year for 10 years.

The money would go to stem cell research that NIH cannot fund—namely, deriving or studying new human ES cell lines and working on human SCNT. It would potentially boost medical research funding in the state by 10% a year. (California scientists received about $3 billion from NIH last year, according to Goldstein.) “I know these numbers seem immense,” says Irving Weissman, a stem cell biologist at Stanford University and one of the initiative's main backers. “I'll just say that it shocked me” on first hearing, he says. But building buildings and conducting clinical trials—two of the tasks spelled out in the Proposition 71 proposal—can quickly consume tens of millions of dollars a year, he says. “Now it doesn't shock me at all.” The sums still stun some observers. “I think [$3 billion] is excessive in a state that is broke and cutting health services for their poor,” says Annas, who notes that he nonetheless wholeheartedly supports federal funding for such research.

With respect to Annas's concern that the potential of stem cells is being oversold to voters, Weissman agrees that the nuances of the complicated field can get lost when distilled into a political slogan. “I say it all the time: ‘Don't expect any cures from this in the next 5 years,’” he says. “Every time a public relations sort of person tries to talk about cures, I tell them you can't say that without qualifications. It's just not right.”

What most excites scientists is hard to sell in a 30-second ad spot, says Fred Gage of the Salk Institute for Biological Studies in La Jolla. Although transplant therapies aren't likely to be ready within a decade, he says, stem cells will provide insights into many diseases. “Stem cell biology, and particularly human embryonic stem cells, will be a tool that every lab interested in biological sciences in the world will have to have” to test whether animal-based observations are true for human cells, says Gage. “We are asking the public of California to recognize the value that basic scientific discovery has on their lives. That's pretty ‘out there.’ We are giving the Californian voter credit for being smart enough to understand this.”

View this table:

Proponents of Proposition 71 also tout the potential economic boost the funding could give the economy. Cures for chronic diseases such as juvenile diabetes would save $1 billion a year in health care costs in the state, Goldstein says. And he and others argue that tax revenues and royalties from companies spun off from new discoveries will help offset the$6 billion it will cost to pay off the bonds over 30 years. “You could think of it as an intellectual stimulus package,” Gage says.

But even if scientists develop a stem cell-based cure for diabetes, counters Annas, it would likely be so expensive that overall savings would be minimal.

The potential involvement of industry worries other observers. Richard Hayes of the Center for Genetics and Society in Oakland says that his group is concerned about the prominent role that industry representatives may have on the Institute for Regenerative Medicine's Independent Citizen's Oversight Committee. According to the proposition, the panel will include representatives from patient advocacy groups, universities, research institutes, and at least three biotech companies. “We're pro-science, pro-choice, and support public funding for stem cell research,” he says. “But we're concerned that Prop 71 gives interested parties enormous power over a huge sum of public funds and restricts public accountability.”

Whether voters will really understand such details before the election is far from clear, says Annas: “My guess would be that no one who is not directly involved will have read this initiative, and not more than a tiny percentage of voters really understand what this is about.”

One wildcard is California's governor, Arnold Schwarzenegger. The state Republican party has come out against Proposition 71, but the pro-choice Republican governor has stayed quiet. The governor's support of either camp could decide the race, Weissman predicts.

2. AIDS VACCINES

# HIV Dodges One-Two Punch

1. Jon Cohen

In what has become a depressingly familiar story line, a leading AIDS vaccine strategy has failed to live up to expectations in human studies.

An international team led by Andrew McMichael, an immunologist at Oxford University in the U.K., reported last week at an AIDS vaccine meeting in Lausanne, Switzerland, that only 20% of 205 participants in the study had had the critical immune response the researchers had hoped to elicit. Like many who attended the meeting, Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), says the meager response surprised him. “It was dreadfully low,” says Fauci.

The 4-year-old study, funded by the New York City-based International AIDS Vaccine Initiative (IAVI), is taking place in five countries, but these preliminary results are from the United Kingdom, Kenya, and Uganda. Although many AIDS vaccines have focused on triggering production of antibodies that prevent HIV from infecting cells, this trial tested whether two vaccines in combination could stimulate the so-called cellular arm of the immune system, which clears cells that the virus manages to infect. The study built on provocative evidence from HIV-exposed but uninfected sex workers in Nairobi and the Gambia. McMichael and other researchers found that these subjects had developed cellular immune responses to the virus (Science, 23 June 2000, p. 2165).

The closely followed study has broad implications because several other research groups are pursuing similar approaches. Both vaccines rely on harmless vectors to shuttle an HIV gene (gag) and other small pieces of the virus into the body. The “priming” vaccine splices the viral components into a ring of bacterial DNA, and the researchers follow it with a “boost” that delivers the same HIV ingredients by means of an experimental smallpox vaccine called modified vaccinia Ankara (MVA).

The McMichael team measured the ability of the prime-boost vaccination to turn up production of the biochemical messenger interferon γ in response to HIV, an indicator that the immune system has launched a cellular attack against the virus. The negative, preliminary results led IAVI to scotch plans to expand the MVA/DNA trials to other countries, but the researchers will complete those that are under way.

McMichael says their results may be disappointing in part because the team was very stringent in how it defined a positive interferon γ response. But he also suspects that the DNA prime, which works well in mouse experiments, didn't do its job. “I think DNA is a poor primer in humans,” says McMichael, who notes that it has performed badly in other human studies. Yet there's no denying the new data call into question the worth of MVA. “Is this the death knell for all MVAs?” asks Cornell University's John Moore, a member of NIAID's AIDS Vaccine Research Working Group. “If other MVAs are no more immunogenic than McMichael's, this has major strategic impact.”

“Before we throw away the platform, I think it's worth doing more studies with MVA,” says IAVI's Emilio Emini, who formerly headed the AIDS vaccine program at Merck & Co., noting that IAVI has two new MVA projects in the works. “By this time next year, we'll know whether the whole platform is in trouble.”

McMichael urges people to keep his group's data in perspective. “People have unreal expectations that a vaccine is just around the corner,” says McMichael. “Getting the vaccine is going to be a slow building process. If something doesn't work, you have to reshape it. We want to regroup and keep going. And I don't think someone else is going to solve it in the next 3 months.” His lab also plans to continue a small “therapeutic” study of the vaccines, intended to boost immune responses in HIV-infected people who are receiving antiretroviral drugs.

Seth Berkley, the head of IAVI, says it's critically important to pull the plug when confronted with disappointing results—a step that is all too often delayed in AIDS vaccine research. “The hardest decisions are going to be dropping things, not keeping things alive,” says Berkley. “I'm quite proud that we took an idea that has been on the agenda since 1993 and got what would appear to be a definitive answer in a short period of time.”

3. JAPAN BUDGET

# Science Ministry Puts In for Big Increases

1. Dennis Normile

TOKYO—Operating on the principle that it doesn't hurt to ask, Japan's Ministry of Education, Culture, Sports, Science, and Technology has submitted requests for sizable spending increases in next year's budget. That strategy, combined with the government's repeated promise to bolster research, helped make science one of the few winners in this year's budget. And policymakers predict it will work again.

“I don't know that [the overall 2005 science budget] will increase, but it may not decrease,” says Reiko Kuroda, a chemist at the University of Tokyo and a member of the Council for Science and Technology Policy, which will vet the requests before they go to the Finance Ministry. That would be quite an achievement, she says, as “all other [spending categories] are likely going down” as the government tries to reduce a ballooning deficit. The ministry's current budget is $33 billion, and the council staff is still reviewing the 2005 requests submitted at the end of last month. Those requests, for the fiscal year starting in April, include increases of 32% for life science research, 23% for environmental studies, and 46% for nanotechnology. The ministry also wants to pump up spending on competitive grants in a last-ditch effort to fulfill a promise to double such research over 5 years. Among the life sciences, the ministry is seeking a 48% boost, to$36 million, for a project headed by geneticist Yusuke Nakamura of the University of Tokyo to link single-nucleotide polymorphisms to diseases and adverse drug reactions, as a step toward tailoring medical treatments to an individual's genetic characteristics. It has also asked for an 18% hike, to $97 million, for the fourth year of a 5-year effort to resolve the structures of 3000 proteins in order to improve understanding of protein function and identify possible drug targets. “So far we have produced more than the promised number of protein structures,” says Shigeyuki Yokoyama, a biophysicist at the RIKEN Genomic Sciences Center in Yokohama, who leads the project. Japan's current 5-year science and technology plan pledged to double (from roughly$2.7 billion in 2000) the amount of money disbursed through competitive grants (Science, 27 June 2003, p. 2027). Although the government may get only halfway to that goal, planners at the Education and other ministries are emphasizing competitive grants in their 2005 requests. The bulk of the boost for nanotechnology and materials sciences, for example, would go to a $56 million competitive grants program, and the only major new program in the life sciences would provide$88 million to address emerging diseases (for example, SARS and avian influenza), molecular imaging, and other “social needs.”

4. CLIMATE CHANGE

# Changes in Planktonic Food Web Hint At Major Disruptions in Atlantic

Land plants and animals are already responding to global warming. Cherry trees in Japan are blossoming ever earlier in the spring, for example, and some birds in northern Europe lay their eggs sooner than they used to. The oceans appear to be warming as well, and several groups are studying how the changes might be affecting marine organisms. Now two papers provide the most comprehensive, longest-term look at the impact of rising temperatures on ocean ecosystems.

On page 1609, Anthony Richardson, a numerical ecologist at the Sir Alister Hardy Foundation for Ocean Science (SAHFOS) in Plymouth, U.K., and marine ecologist David Schoeman of the University of Port Elizabeth in South Africa show that the abundance of plankton in the northeast Atlantic has shifted with water temperature over the past 45 years. And in the 19 August issue of Nature, Richardson and SAHFOS marine ecologist Martin Edwards reported that the timing of seasonal abundance of plankton has shifted in ways that already may have radically disrupted the food web. “These changes in the plankton will almost certainly have huge impacts on commercial fisheries and so will have accompanying economic implications,” comments marine ecologist Graeme Hays of the University of Wales, Swansea.

Both sets of findings come from a unique monitoring effort called the Continuous Plankton Recorder survey, run by SAHFOS. Since 1931, researchers have hitched small sampling devices behind freighters that ply the North Atlantic, and since 1997, in the North Pacific as well. Every unit contains a long roll of silk that collects plankton as it slowly spools into an internal chamber. Each 10 centimeters of silk harvests about 18 kilometers' worth of plankton, which are identified in the lab. More than 9 million kilometers have been towed over the past 70 years. “It's only with data sets like this that we're going to be able to understand the impact of climate change,” says biological oceanographer Charles Greene of Cornell University.

Using these data, SAHFOS researchers have previously discovered biological changes, such as the northward shift of some plankton species in parts of the northeast Atlantic (Science, 31 May 2002, p. 1692) and changes in the abundance of a few species. The new Science paper expands that effort by looking at more than a hundred taxa, including phytoplankton, such as diatoms and dinoflagellates; herbivores, such as crustaceans called copepods; and carnivorous plankton, including arrow worms and voracious crustaceans called amphipods.

Comparing the counts with changes in sea surface temperatures in 20 regions of the northeast Atlantic, Richardson and Schoeman found two patterns. Phytoplankton tended to become more abundant when cooler regions warmed, probably because higher temperatures boost metabolic rates. But they became less common when already warm regions got even warmer, possibly because warm water blocks nutrient-rich deep water from rising to the upper layers, where phytoplankton live. That variable response suggests that climate change will have regional impacts on fisheries, Hays says.

Richardson and Schoeman also demonstrated effects further up the planktonic food chain. When phytoplankton bloomed, both herbivores and carnivores became more abundant. The pattern indicates that the planktonic food web is controlled from the “bottom up,” by primary producers, rather than from the “top down,” by predators. That means climate effects on primary producers could reach all the way to fisheries. “To date, we are not very good at detecting the consequences of plankton changes for fisheries production or for the rest of the marine ecosystem,” says fisheries scientist Keith Brander of the International Council for the Exploration of the Sea in Copenhagen, Denmark.

In the Nature paper, Richardson and Edwards charted shifts in the timing of seasonal plankton blooms over the decades. Each species has an annual cycle, and herbivores and carnivores have evolved to exploit the phytoplankton bloom. Since 1987, however, the cycle's peaks have shifted out of synch. In places where waters have warmed, the peak bloom of phytoplankton occurs 3 weeks earlier, but zooplankton grazers peak only 10 days earlier. If the discrepancy causes herbivores to go hungry, they could provide less prey for fish larvae and carnivorous plankton. “These effects at the base of the food web are so dramatic that they're bound to have an effect on the whole North Atlantic ecology,” Edwards says.

Measuring that impact will take a lot of work, Greene says, because marine food webs are extremely hard to untangle. Still, he says, ecologists should be concerned, because much more northeast Atlantic warming is predicted. Brander expects further changes in plankton abundance and timing as warming continues. Although some species should adapt, Edwards says, new communities will also likely emerge.

SAHFOS and others will be watching.

5. SCIENTIFIC PUBLISHING

1. Jocelyn Kaiser

The National Institutes of Health (NIH) has released a draft policy aimed at increasing public access to the results of NIH-funded research. The proposal issued 3 September in the NIH Guide* would require grantees to deposit copies of their papers in NIH's free PubMed Central archive once they have been accepted by a journal. Manuscripts would be posted online 6 months after publication.

In July, a congressional spending panel recommended that NIH post NIH-funded manuscripts within 6 months of publication, or immediately if NIH grants were used to pay publication costs. The language, part of NIH's pending 2005 budget, triggered frenzied lobbying on all sides. Librarians, patient organizations, and scientists who think taxpayers should have easier access to NIH-funded research urged NIH to follow the House language. Commercial publishers and many scientific societies lobbied against a mandatory plan, saying it could bankrupt many journals.

NIH Director Elias Zerhouni, who has held meetings recently with interested groups, told scientists last week that 6 months was “reasonable” (Science, 3 September, p. 1386). The draft policy is similar to the House language: Investigators will submit their final, peer-reviewed manuscript to PubMed Central. Journals can ask NIH to replace the manuscript with the published paper, sooner than 6 months if they wish. NIH plans to take comments for 60 days and will also post the draft policy in the Federal Register.

“We're strongly behind it,” says Richard Johnson of the Scholarly Publishing and Academic Resources Coalition. His group “would have preferred immediate access, but we see this as an important step forward.”

Scientific societies had a mixed reaction. Alan Leshner, executive director of AAAS (which publishes Science), calls the policy “a reasonable compromise” but says it “could pose significant risk for some scientific societies.” And Martin Frank, executive director of the American Physiological Society, calls the plan “an unnecessary expenditure of federal funds for a redundant repository of peer-reviewed literature.” He notes that most journals already provide back articles for around $5 to$30, or for free after a certain period. Frank also wonders how PubMed Central will keep track of manuscripts submitted separately by co-authors of the same paper. “It could be chaos out there,” he warns.

The Association of American Publishers (AAP), which is also worried about the policy's impact on free markets, plans to take its objections to senators Arlen Specter (R-PA) and Tom Harkin (D-IA), chair and ranking member, respectively, of the Senate appropriations committee for NIH, which will take up the spending bill once it passes the House. “We think there are a lot of questions that should be answered,” says Allan Adler, AAP vice president for legal and governmental affairs. However, last week Specter told The Washington Post that he does not intend to intervene.

6. NUCLEAR PROLIFERATION

# South Korea Admits to Laser Enrichment Program

1. Charles Seife

Another secret nuclear program on the Korean Peninsula is in the news, but this time it's the work of South Koreans that's drawing criticism. The International Atomic Energy Agency (IAEA) announced last week that South Korea had used a covert isotope-separation program to create a few hundred milligrams of highly enriched uranium. The technology, potentially an energy-saving way to separate bomb-worthy uranium-235 from its less dangerous sibling uranium-238, was tried and abandoned in the United States and Russia over the past few decades.

Few details about the nature of the program are available. However, faced with IAEA inspections, the Republic of Korea (ROK) admitted that several years ago its scientists had produced small quantities of near-weapons-quality uranium by using lasers, apparently at a nuclear facility in Taejeon, South Korea. Although the ROK government is claiming that the laser- separation project was run by a handful of rogue scientists, proliferation experts believe that the program must have been sanctioned by higher-ups.

“It's their main nuclear research site,” says nuclear proliferation expert David Albright, president of the Institute for Science and International Security in Washington, D.C. “The scientists worked for a government-owned agency, and they had to report to their bosses.” Furthermore, nuclear experts say, the technology is too costly and intricate for a small group of rogue scientists to have pursued on its own.

The method in question is known as atomic vapor-laser isotope separation (AVLIS). AVLIS exploits a subtle difference in how uranium-235 and uranium-238 absorb light. Because the two atoms have different masses, they absorb very slightly different colors of light. By shining a laser of precisely the right color on a beam of mixed-isotope uranium vapor, scientists can induce the uranium-235 in the beam to absorb a photon of light and fly in one direction while the uranium-238 in the beam remains unaffected. That's the theory, anyway.

In practice, though, AVLIS hasn't proven useful for separating uranium on a large scale. “There are no commercial programs” that use lasers to separate uranium isotopes, says Thomas Cochran of the Natural Resources Defense Council in Washington, D.C. A diplomat who is knowledgeable about nuclear proliferation issues says the countries that have tried it concluded “it was too expensive; you could not produce enough [enriched uranium] quickly.” In 1999, the United States killed its own AVLIS program, developed at Lawrence Livermore National Laboratory in California and run by a private firm based in Maryland.

Iraq and Iran also worked on laser-separation technologies, often with help from vendors in other countries. “Laser enrichment is not simple,” says Kenneth Luongo, executive director of the Russian-American Nuclear Security Advisory Council in Washington, D.C. “In the Iranian case, they once had a deal with the Russians. In [the South Korean] case, it's not clear where the technology would have come from or whether it was developed indigenously.”

Albright says he would be disturbed if the United States had been involved. “But I'd be even more worried if they'd made it themselves,” he says, because it would mean that the technology isn't prohibitively difficult to develop. “It shows that, at the laboratory level, you can make nuclear materials.”

The few hundred milligrams of enriched uranium are orders of magnitude less than what's needed to build a bomb. But producing even that amount is a serious violation of the nuclear nonproliferation treaty. “It's not so much the quantities but the fact that it wasn't declared,” says the knowledgeable diplomat.

7. EUROPEAN UNION

# The Commissioner Who Listened

1. Martin Enserink

BRUSSELS—Things didn't look auspicious for physicist Philippe Busquin when he was nominated for Europe's top science post in 1999. European scientists—many of whom equate Brussels with bureaucracy—knew next to nothing about the Belgian socialist and career politician. During a stormy confirmation hearing, conservative members of the European Parliament mounted a fierce attack, alleging that Busquin was tainted by corruption scandals in the party he chaired and unfit to be a credible manager. Busquin survived, but one thing was certain: The new European Commissioner for Research would have to work hard to make his term a success.

Now that his 5-year tenure has come to an end—Busquin is stepping down this week to take a seat in the European Parliament, ahead of the departure of the rest of the European Commission on 1 November—the skepticism has evaporated. “He really has done a remarkable job,” says Thomas Östros, Sweden's minister of science and education. Östros credits Busquin with a skillful campaign to get science to the top of Europe's political agenda, crowned by an agreement, signed in Barcelona in 2002 by E.U. member states, to drive toward spending 3% of national income on research and development by 2010.

Busquin also launched the notion of a European Research Area (ERA)—Europe's scientific equivalent of a free trade zone—and maneuvered it into the text of the proposed European Constitution. He fought hard to fund stem cell research and threw his weight behind the creation of a European Research Council (ERC), which would fund basic research using no other criterion than excellence. “For the first time, we had a commissioner who was listening and who was responsive,” says Kai Simons, director of the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden.

Busquin had far better relations with the European Parliament than did Edith Cresson, his controversial predecessor, whose alleged fraud triggered the downfall of the entire commission in 1999. In part, this is because he's a “modest and unassuming man,” says Eryl McNally, a former British member of the European Parliament. “Sometimes, it's the quiet ones who get things done.”

In an interview with Science in his partly packed-up office last week, Busquin said he was proud of his tenure and a bit sad to leave a post that satisfied his passions of science and politics. He relished seeing top-notch research up close, he says, from the vast particle smashers near Geneva to Europe's mountaintop astronomical observatory at Paranal, Chile. And the European Molecular Biology Laboratory in Heidelberg is a “phenomenal place,” he says. He devours its annual research report: “It's one of the most interesting books I know.”

Busquin worries, however, that many Europeans fail to see science's beauty, let alone its potential to foster economic growth. Investment in research and development is lagging, compared to the United States and Japan, as young European researchers are moving overseas. At the same time, China is on the way to becoming a new scientific superpower. With Europe's aging population and few natural resources, the continent's survival is at stake, he warns, and only science and innovation will keep it competitive.

One response championed by Busquin is the ERA: It aims to forge a Europe-wide science policy, coordinate national funding agencies, and remove barriers between E.U. states that prevent researchers from relocating. Lining up political support among European leaders for an overall increase in spending was another. “The 3% really was his own idea,” says Robert-Jan Smits, who heads a directorate under Busquin. But each country is responsible for its own R&D spending, and even Busquin acknowledges that many won't meet the target. Still, he says, using periodic scorecards produced by his staff, “we can now point the finger at countries that have not done their homework.”

ERC was not one of Busquin's ideas. But once it arose in the scientific community, he was a skillful enough politician to sense its importance and embrace it, says Enric Banda, a former head of the European Science Foundation and director of the Catalan Research Foundation.

Still, there were problems that Busquin could not solve. Scientists often gave him an earful about the inescapable bureaucracy that comes with applying for grants from the E.U.'s gargantuan Framework research programs. Busquin acknowledges the problem but says it's difficult to amend, for various reasons. However, he agrees that the new ERC should keep paperwork to a minimum.

Another disappointment for Busquin was his failure to win support for using Framework money to fund research on human embryonic stem cells. Countries such as Germany, Austria, and Ireland, which have banned work that requires the destruction of embryos, fiercely opposed spending a single euro on such controversial studies and threatened to sink the entire $17.5 billion 6th Framework Program to make their point. “He took a very firm stand in the interest of science,” says Peter Gruss, president of the Max Planck Society. The battle ended in a deadlock last year; for the moment, studies can be funded only after review by a special committee (Science, 12 December 2003, p. 1872). Although he launched new initiatives to boost biotech, Busquin also acknowledges that the deep-seated public resistance to genetic engineering in Europe is hard to overcome—even though he finds it troubling sometimes. “When I see people uprooting trial fields, I find it completely unacceptable. And I think Europe should be a bit more clear and courageous in saying: ‘No. Scientific progress is an important value for us.’” Less glamorous times lie ahead. Busquin says he would have loved to stay on, but the Belgian government did not renominate him; instead, he was elected in June as one of the 730 members of the European Parliament, which sits a stone's throw from his current office. But because McNally and several other science experts have just stepped down, Busquin will stand out as the unrivaled heavyweight on science issues, and he says he will return to the fight with enthusiasm. Janez Potocnik, the Slovenian economist nominated to succeed him at the commission (Science, 20 August, p. 1089), is lucky, says McNally: “He has a very good legacy to work with.” 8. SCIENCE POLICY # The Man Behind the Memos 1. Jocelyn Kaiser* 1. With reporting by Jon Cohen. U.S. official William Steiger has been criticized for making life harder for scientists in international health research and policymaking. He says he has strengthened the field It's not often that scientists at the bench or in the field battling diseases such as AIDS and malaria take note of a special assistant to the Secretary of Health and Human Services. But William R. Steiger, the point person on international health for HHS Secretary Tommy Thompson, has made a name for himself everywhere—from the National Institutes of Health (NIH) to the Centers for Disease Control and Prevention (CDC) to the halls of academia. Then again, not many bureaucrats would want the kind of attention he's received. Steiger, 34, a political appointee who has close ties to the Bush family, has brought an unprecedented level of oversight to HHS's international activities—and it has made him a lightning rod for critics. When HHS clamped down on foreign travel by its scientists, Steiger began personally approving each trip. When industry groups criticized a World Health Organization (WHO) report on nutrition, Steiger slammed it as scientifically flawed. When the department declared that it would choose which U.S. scientists WHO could invite as expert advisers, Steiger signed the memo. The critics complain that Steiger, who has a doctorate in Latin American history and is fluent in Spanish and Portuguese, has politicized a position traditionally held by an expert in public health. His command-and-control management style is demoralizing, they say. “I see an increasing and pervasive squeezing of academic freedom by bureaucratic control,” says Gerald Keusch, who left as director of NIH's Fogarty International Center last December and recently endorsed a Union of Concerned Scientists critique of the Administration's science policy. In a telephone interview with Science, Steiger brushed off the criticism, arguing that he has led a “major expansion” of HHS's international activities. His Office of Global Health Affairs' (OGHA's) management changes—part of Thompson's efforts to unite the department as “one HHS”—have shaken up the status quo; the scientists who complain, he says, “have axes to grind.” He says too that “no HHS secretary in history has been as devoted to global health” as Thompson, who has traveled to 35 countries to see health problems firsthand and chairs the Global Fund, the international AIDS relief program. ## Inside track Steiger grew up in Washington, D.C., the son of Representative William A. Steiger from Oshkosh, Wisconsin, a moderate Republican who gave Vice President Dick Cheney his first political job. Representative Steiger died in 1978. Godson of former President George H. W. Bush, the younger Steiger completed a dissertation on Brazilian history in 1995 before he was tapped to be education policy adviser to then-Wisconsin governor Thompson. When Thompson became HHS secretary in 2001, he brought his protégé to Washington as part of his management team and gave him the job of overseeing international affairs. Steiger was soon named Thompson's representative to the WHO board, the World Health Assembly, despite his lack of health experience. HHS also revamped the entire U.S. delegation, which in previous years had included representatives from the American Medical Association (AMA) and the American Public Health Association (APHA). They were not invited, although a nurse from the National Right to Life Committee was added. (Steiger explains that AMA and APHA “go anyway” on their own, and Thompson wanted to “include real people who might not have had a chance to go in the past.”) Meanwhile, scientists from CDC and NIH who took part in U.S. government delegations on specific health topics such as tobacco and nutrition were instructed to leave the talking to HHS officials, says Derek Yach, a former WHO chief of noncommunicable diseases and mental health who left for Yale earlier this year. “They weren't allowed to speak up.” Within WHO, Steiger's approach was to resolve disputes not by discussion but “by throwing [U.S.] power and authority around,” charges Howard University College of Medicine senior associate dean Mohammed Akhter, a former executive director of APHA. Steiger advocated new policies that critics quickly labeled pro-industry. In May 2001, for example, he instructed Thomas Novotny, an epidemiologist and HHS career civil servant negotiating the U.S. position on a global treaty designed to curb tobacco use, to change course. Instead of endorsing a total ban on advertising, Novotny (now at the University of California, San Francisco) says he was told to oppose these restrictions, as well as proposed new tobacco taxes. This U.S. position caused an uproar among public health experts. Nutrition research sparked another flap. Experts convened by WHO and the United Nations Food and Agriculture Organization (FAO) drafted a report on diet and disease that suggested that countries restrict junk-food ads. After the sugar industry tried to block the final April 2003 report, last January Steiger's office issued a scathing critique charging that the report was scientifically flawed, mixed science and policy, and departed from the U.S. position favoring “personal responsibility” for curbing unhealthy habits. Although the critique included some valid scientific points, says Harvard epidemiologist Walter Willett, its emphasis on personal responsibility “is a political philosophy statement coming from Washington.” Steiger says all HHS scientists involved with the nutrition report “agreed with the message,” and that the United States helped push through the tobacco treaty and an obesity strategy, yielding final WHO documents that were “strong” and “feasible.” ## Tough on travel Steiger's aggressive style also has ruffled feathers in the AIDS research community. He has been a hard-nosed enforcer of the Administration's controversial emphasis on sexual abstinence in HIV prevention programs and its prohibition on using generic AIDS drugs for treatment until they are approved by the U.S. Food and Drug Administration. A decision to pull the plug on a proposed CDC AIDS partnership with Myanmar, claiming that Myanmar would not allow nongovernmental groups to perform voluntary testing and counseling, also rankled (Science, 19 September 2003, p. 1654). This spring, Steiger ruled that HHS would send only 50 U.S. staff to the 2004 world AIDS conference in July in Bangkok, down from 236 sent to the previous meeting in Barcelona in 2002—keeping home many scientists scheduled to give talks (Science, 23 April, p. 499). HHS also slashed its support for the meeting to$500,000, compared to \$3.6 million for Barcelona. The reason, Steiger says, is that “the scientific value of this conference is nowhere near what it used to be.”

In April, Steiger decided that for the first time in 30 years HHS would not contribute funding for the annual meeting of the nonprofit Global Health Council, after conservatives complained that two participating groups supported abortion. HHS spokesperson William Pierce claimed the council could not ensure that the money would not be used to lobby Congress.

Steiger's crackdowns on travel have gotten attention in the scientific community. HHS's deputy director for management, Ed Sontag, announced in March 2001 that all foreign trips had to be cleared through the Secretary's office. Weeks-long delays and last-minute approvals have led some researchers to miss meetings, scientists say; in other cases, Steiger vetoed overseas trips and postings of CDC staff, overriding decisions made by scientific managers. Under orders from Steiger, NIH has trimmed staff participation in international meetings (Science, 23 July, p. 462). Even visits to offices of WHO and other United Nations agencies in downtown Washington now have to be cleared as foreign travel to help ensure “accountability,” says Pierce.

## Order in the ranks

Steiger's oversight, some critics suggest, is motivated more by political ideology than fiscal prudence. “He's been given far too much power without experience,” says one former HHS scientist. “He feels like he's doing the bidding of the Administration, and he tends to overinterpret.”

Keusch cites an example: Last fall, he says, he received a peremptory e-mail from Steiger as NIH was gearing up to co-host a November conference called Globalization, Justice, and Health. Steiger wrote, “I am very, very uncomfortable with this conference and our sponsorship of it, and I would like to discuss it with you.” Steiger explains that some speakers, such as Columbia University economist Jeffrey Sachs, “were taking a particular point of view, which is not the department's point of view,” on generic drugs and access to medicine. OGHA also asked to see Keusch's remarks in advance; he sent them afterward. “I didn't see any reason other than censorship,” says Keusch, who now heads global health programs at Boston University.

This spring, Steiger's office tightened the screws, scrutinizing staff involvement in WHO's scientific activities. In April, Steiger wrote WHO that invitations for HHS researchers to be consultants to WHO must go through his office, because WHO's choices “have not always resulted in the most appropriate selections.” The letter drew angry editorials in the Los Angeles Times, the Boston Globe, and The Lancet, as well as criticism from health experts including smallpox expert D. A. Henderson and former CDC director Jeffrey Koplan, who called it a political move meant to suppress agency scientists.

WHO Assistant Director-General Denis Aitken at first challenged HHS's new position but has since reached a détente: WHO will send nominations to Steiger's office but will not accept substitutes. If HHS rejects WHO's choices, “there will be fewer and fewer requests for government scientists,” says William Foege, a former CDC director now with the Gates Foundation in Seattle. Steiger's actions add up to a “tragedy,” says Yach. “CDC and NIH are organizations like none other, and to have an Administration actively working to control how they work internationally is a loss to the U.S. and the world.”

Steiger fiercely disagrees that he has suppressed HHS scientists. OGHA wants to weigh in on WHO consultations, he explains, because WHO may not identify some top experts and they needed to be briefed on related HHS activities. “Almost never are we going to say ‘You've picked the wrong person,’” he says. His oversight of travel and overseas assignments, he says, has uncovered abuses and helped “our investments match a set of strategic priorities.”

Moreover, such criticism overlooks what's been accomplished, Steiger says. OGHA has been elevated to a division at HHS, increasing its influence. More staff members are working overseas, including new “health attachés” added at embassies in places such as Beijing and South Africa. Steiger hopes to establish a “defined career path” for HHS staff interested in international health, like the State Department's Foreign Service.

A former Wisconsin Democratic leader, Thomas Loftus, says Steiger may have had a steep learning curve at WHO, but now he “knows this stuff.” Loftus, special adviser to the WHO director-general, says, “He's a very valuable guy. And he's become more diplomatic with every meeting.”

Even some of Steiger's fiercest critics say he is smart, can be likeable, and may mean well. But they also say his attempts to manage from the top down and enforce Administration priorities may do the opposite of what he intends by stifling scientists who have devoted their careers to international health.

9. ENDANGERED SPECIES ACT

# Can California Ranchers Save the Tiger Salamander?

Scientists hope a very unusual conservation decision could preserve salamander habitat, but they worry that it might harm the most vulnerable populations

For some 5 million years, the California tiger salamander (Ambystoma californiense) has lived in grasslands surrounding pools that fill with water in the spring. Once a year, the salamanders emerge from burrows to lay eggs in these vernal oases. Over the past 150 years, however, three-quarters of the salamander's habitat has been lost, converted to housing tracts, vineyards, and row crops. Now, if the U.S. Fish and Wildlife Service (FWS) is correct, the 20-centimeter-long amphibians will have a new ally: ranchers.

On 4 August, FWS announced that it was protecting a vast swath of salamander habitat in the state. At the same time, the agency decided not to restrict what ranchers can do on that habitat—an unusual accommodation. That's because ranchers own the majority of salamander habitat—often prime real estate—and they maintain cattle ponds that the salamanders have adopted for breeding.

But although most scientists agree with FWS officials that a rancher-friendly approach could be crucial to preserving the habitat, they worry that some activities require closer scrutiny, especially where populations are most in jeopardy. The blanket exemption for ranching is “not scientifically based and may be harmful,” says attorney Kassie Siegel of the Center for Biological Diversity, an environmental group that intends to take FWS to court over its August announcement in the Federal Register. At the same time, an industry group is challenging another aspect of that decision.

The California tiger salamander has been at the center of a political battle for more than a decade. In 1992, Bradley Shaffer, an evolutionary biologist at the University of California, Davis, and others began urging FWS to put the animals on the endangered species list. But the agency didn't move forward until environmentalists sued. Despite opposition from developers, in 2000, FWS declared a salamander population in Santa Barbara County to be in grave peril from loss of habitat and listed the animals as endangered. Shaffer's genetic studies showing that this group is a “distinct population segment” bolstered the rare, emergency listing. Three years later, facing another court- ordered deadline, FWS did the same for an even smaller salamander population in Sonoma County.

The listing status matters. Under the law, “endangered” means that any activity that might harm the salamanders or their habitat requires a permit and a conservation plan. The requirement can be a paperwork headache. However, if a species is listed only as “threatened,” FWS can exempt certain activities from permits. So it was a relief to ranchers when FWS exempted “routine ranching activities” in listing as threatened the state's largest population of the salamanders, spanning 20 counties.

The decision was based on the idea that ranching can be more compatible with salamander conservation than can other land uses, such as vineyards or housing. Like salamanders, cows need open grasslands and ponds. There's even evidence that grazing helps natural vernal pools persist, where grasslands are dominated by invasive grasses, ecologist Jaymee Marty of the Nature Conservancy has found.

But there are risks, too. Some routine ranching activities, such as creating firebreaks, may be deadly. The central population is a good place to examine those variables and determine proper guidance for ranchers, Shaffer says, because salamanders and their habitat are less critically endangered there. “We have more room to maneuver and more time to try creative solutions,” he asserts.

That's not the case in Santa Barbara and Sonoma counties, Shaffer cautions. These populations are particularly vulnerable, he and others say, because they are small and face intense development pressure. And as genetically unique lineages, they're extremely valuable for conservation. “It seems obvious that they deserve more protection,” says Carlos Davidson, a conservation biologist at California State University, Sacramento.

To exempt ranching statewide, FWS had to downgrade the populations in Santa Barbara and Sonoma counties from endangered to threatened. Normally, such an action only happens when populations are recovering and threats diminishing. Scientists say that's not the case with the two salamander populations. “There's no biological basis for downlisting,” says Lawrence Hunt, a consulting herpetologist in Santa Barbara.

Some scientists also worry that the exemption could make it easier for ranchers who want to rid their land of salamanders—and the development restrictions that come with them—to do so through excessive use of routine practices. “It's basically a license to kill,” says herpetologist Samuel Sweet of the University of California, Santa Barbara. Although scientists admit that there may be no way to eliminate cheating, they say the government should require permits to keep a closer eye on habitat in Santa Barbara and Sonoma counties.

Shortly after FWS issued its decision, environmentalists told the agency they plan to sue in federal court this fall to reverse the downlisting and remove the ranching exemption from Santa Barbara and Sonoma counties. And with industry challenging the listing of the central California population, the controversy over the tiger salamander seems certain to continue burning bright.

10. BRIAN FAGAN PROFILE

# Archaeologist Leaves an Imprint on His Field--Without Research

1. Michael Balter

Popularizer Brian Fagan argues that spreading the word about archaeological research is as important as doing it

SANTA BARBARA, CALIFORNIA—During the 1960s, archaeologist Brian Fagan was excavating at the Zambian site of Ingombe Ilede, famed for its gold-laden skeletons. Fagan was asked to date the burials and used indirect methods to place them around 1000 C.E. A few years later, however, another excavator showed conclusively that the skeletons had actually been laid to rest in the 16th century.

That miscalculation convinced Fagan of something he had long suspected: He was only a second-rate excavator. Reluctantly, he decided to abandon field research. But he did not give up archaeology. Instead, he traded in his trowel for a typewriter and later a computer, and launched an exceptional career as an academic popularizer.

Today British-born Fagan is arguably the best-known archaeologist in the United States, his adopted country, and the author of more than two dozen books, including an introductory archaeology textbook that has gone through 11 editions since its first printing in 1972. This year, Fagan, 68, won the Society for American Archaeology's public understanding of archaeology award for his latest book, Before California, and he is now finishing up his next book, on the archaeology of Chaco Canyon, New Mexico.

Last year Fagan retired from the faculty of the University of California, Santa Barbara (UCSB), where he had taught for 36 years. Unlike almost all other academics, however, Fagan has based his career entirely on general textbooks and popular archaeology books rather than on original research. He strongly defends his choice to be a generalist, and to do it from within the boundaries of academia. “Much of what we do in archaeology today is so arcane that it's of interest, at the most, to half a dozen people. We've forgotten that archaeology is of startling relevance to a contemporary society wrestling with issues of human diversity. We should take public outreach seriously—and do something about it,” he says.

Many other academics, such as Jared Diamond and the late Stephen Jay Gould, have written popular books—but they usually have done so in addition to a successful research career. Some successful popularizers of science have even seen their scientific standing suffer as a result; the late Carl Sagan, whose nomination to the National Academy of Sciences was rejected in 1992, is the best-known example.

Perhaps surprisingly, Fagan's decision to eschew original research has not diminished his stature in the eyes of his colleagues. “He has been a very important person in the field,” says anthropologist Margaret Conkey of UC Berkeley. “He is an excellent communicator of the fundamental principles, issues, and practices of the discipline.”

Archaeologist Jeremy Sabloff, who recently stepped down as director of the University of Pennsylvania Museum in Philadelphia, agrees, adding that the kind of writing Fagan does is “part of our collective academic responsibility. Who better to explain the cutting edge of archaeological research than archaeologists themselves?”

It took a series of lucky breaks before Fagan found the popularizing path. He was considering working in his family's publishing business when an offer arrived from the University of Illinois, Urbana-Champaign, to teach for a year. This led to a tenured position teaching introductory archaeology at UCSB. Upon arriving, Fagan was surprised to find that there were no good introductory textbooks. So he wrote one himself.

During the earlier years of his career, Fagan says, his popular writings sometimes were not valued as highly as research papers. Skeptical promotion review committees wanted to see original contributions to archaeological journals—papers Fagan no longer produced. But most of this resistance came from “beyond the department,” notes archaeologist Michael Glassow, the current chair of UCSB's anthropology department, adding that Fagan's anthropological colleagues gave him such strong support that he eventually rose to the university's “highest ranks” in terms of pay and prestige.

Fagan readily acknowledges this support and also credits the more experimental philosophy that existed at the relatively new Santa Barbara campus when he arrived there in 1967. “If I had gone to Berkeley or the University of Chicago, it would have been much harder to be a generalist,” he says.

Nowadays, young archaeologists are often discouraged from following in Fagan's footsteps, says Sabloff. “Such activities don't help when it comes to tenure and promotion and might even count against them,” he says. “Most scholars don't realize how strong one's grasp of relevant theory, method, and substance of a topic must be to produce a truly useful popular interpretation.”

Fagan argues that popular writing should be considered a valid academic endeavor, especially because the preservation of often-threatened archaeological sites around the world requires public understanding of their importance. “You can define research many ways, but it's myopic to assume that it's all specialized inquiry,” he says. “Startlingly few archaeologists are concerned with the big issues of early human history and diversity.”

He adds that today most digs are not university-supported research expeditions but “rescue” excavations of endangered sites, often reluctantly funded by developers. “Unless we take communicating with the wider audience seriously,” he says, “there may be no archaeology for our grandchildren to study.”

11. OCEAN ECOLOGY

1. Dan Ferber

Scientists debate how best to revive the Gulf of Mexico's oxygen-starved waters

Every summer, death stalks the waters of the northern Gulf of Mexico. A New Jersey-size swath of sea becomes depleted of oxygen, suffocating millions of crabs and other denizens of the sea floor. In 1999, the federal government diagnosed the cause of this seasonal dead zone: The hypoxia arises largely because of nitrogen pollution from the fertilizer-drenched farms in states along the Mississippi River. Two years later, the government released a plan to reduce nitrogen runoff and revive the gulf. Now a new government report says that because the original diagnosis was wrong, the costly prescription will fail.

Released last month to little public notice, the controversial report, issued by the Atlanta office of the U.S. Environmental Protection Agency (EPA), places increased blame for the dead zone on phosphorus pollution from factories and cities along the Mississippi River and recommends focusing the cleanup on phosphorus as well as nitrogen. Farm-industry groups seeking to delay the national plan have seized on an early draft of the report that challenged the use of any nitrogen reduction. Marine scientists have given the report, which has not yet been peer reviewed, a cooler reception. “I think it has some really serious deficiencies,” says Donald Boesch, president of the University of Maryland Center for Environmental Science.

Scientists agree that factories, cities, and farms in the Mississippi River watershed have jacked up both phosphorus and nitrogen levels in the river. Each spring, those nutrients pour into the northern Gulf of Mexico and trigger blooms of phytoplankton, minuscule plants that float in the water. That sets off population booms in zooplankton, the tiny animals that consume them. Then sea-floor bacteria, which feed on dead zooplankton and their waste, multiply wildly and use up oxygen in the bottom waters.

In 1999, the National Oceanic and Atmospheric Administration (NOAA) released a comprehensive assessment of the causes and consequences of hypoxia in the gulf. It concluded that phytoplankton growth in the dead zone was primarily limited by the availability of nitrogen. Relying on that report, a state-federal partnership, the Task Force on Gulf Hypoxia, developed a national action plan with a single overarching goal: reduce nitrogen coming down the Mississippi River by 30% by 2015.

That prescription seemed simplistic to Howard Marshall, a veteran water-quality scientist at EPA's Atlanta regional office who was assigned to help implement the plan. By reexamining available data on dissolved nitrogen and dissolved phosphorus concentrations, Marshall and other EPA scientists determined that the lower Mississippi River contained a large excess of dissolved nitrogen relative to dissolved phosphorus. Although growing phytoplankton need more nitrogen than phosphorus—they usually accumulate the nutrients at a 16:1 ratio—the amount of nitrogen so exceeded the quantity of phosphorus that the latter nutrient had most likely limited the growth of phytoplankton there, the EPA group concluded. The same also held true for the northern gulf in the spring, when the dead zone typically forms, according to the group. “Wouldn't it be better to reduce phosphorus and starve the bastards?” Marshall asks.

That's “pretty naïve,” argues biogeochemist Robert Howarth of Cornell University, who chaired a National Research Council committee in 2000 that examined hypoxia in coastal oceans. Last week, Howarth, Boesch, and Donald Scavia of the University of Michigan, Ann Arbor, sent EPA a letter criticizing the new report. They argue, for example, that the nutrient ratios in water don't necessarily reveal what's available to phytoplankton, because phosphorus is resupplied from organic debris in the sediment.

But other oceanographers who have seen the report say that the EPA team has a point. “There's been this focus on nitrogen as the major culprit, even though we knew from early on that phosphorus played a role,” says biological oceanographer Steven Lohrenz of the University of Southern Mississippi in Hattiesburg. And oceanographer Michael Dagg of the Louisiana Universities Marine Consortium in Cocodrie, who's worked in the gulf since the 1980s, says that Marshall “has done an extremely important service by scrutinizing these issues as intensely as he did. It should have been done 10 years ago.”

Indeed, several recent lines of evidence support the idea that phosphorus can control phytoplankton growth in the gulf. In results presented in January at the American Geophysical Union's Ocean Sciences meeting, James Ammerman of Rutgers University and colleagues reported that nitrogen-to-phosphorus ratios greater than 380 occurred over the entire Louisiana continental shelf in the spring and early summer of 2001, indicating that phosphorus supplies may well constrain the plants' growth. Moreover, adding phosphorus but not nitrogen stimulated phytoplankton growth in bottles containing seawater from many of those locations. And phytoplankton from much of the shelf had high levels of an enzyme that they turn on to scavenge phosphorus when supplies are tight.

Overall, the data suggest that “there's this huge slug of water going into the gulf that's phosphorus-limited at its fresh end and nitrogen-limited at its salty end,” says coastal ecologist Hans Paerl of the University of North Carolina, Chapel Hill. What remains unknown, he says, is how much phytoplankton growth at the fresh end contributes to hypoxia.

At last week's meeting of the gulf hypoxia task force, farm-industry interests lobbied to redo the NOAA-led science assessment and delay expensive efforts to reduce fertilizer runoff from farms. EPA's Ben Grumbles, acting assistant administrator in the Office of Water, says the task force is “committed to doing an independent peer review” of the new EPA report, and that the reviewers should include “fresh faces” who weren't involved in the 1999 NOAA assessment. But he emphasizes that the agency plans to continue its efforts to cut nitrogen pollution while exploring how to cut phosphorus. For the gulf, that may be just what the doctor ordered.

12. AMERICAN CHEMICAL SOCIETY MEETING

# Finding Reactions in a Haystack: Try 'em All, See What Works

1. Robert F. Service

PHILADELPHIA, PENNSYLVANIA— More than 10,000 chemists, physicists, and materials scientists gathered here from 22 to 26 August for the 228th national American Chemical Society meeting.

For synthetic chemists, improving on nature is, well, second nature. For over 150 years they have used new types of chemical reactions to craft molecules never seen before. “That strategy is very effective, particularly when you know what you're trying to make,” says David Liu, a synthetic chemist at Harvard University in Cambridge, Massachusetts.

But is this goal-oriented approach the best way to find all the different types of possible chemical reactions under the sun? Liu suspected not. So he and his team set out to find new types of reactions by harnessing biology's prowess for synthesizing a diverse set of compounds. In Philadelphia, Liu unveiled an approach that shepherds molecules together with strands of DNA. The group has already spotted one new reaction with the technique and is casting its net wider to see what other reactions may be lying in wait.

Liu's talk was “pretty cool,” says Kenneth Suslick, a chemist at the University of Illinois, Urbana-Champaign. “I was really taken with it.” A chief goal of the new work is to discover novel reactions that chemists can then use in DNA-directed synthesis or with their traditional methods. But Suslick notes that not all reactions discovered by the new technique will make the jump: The DNA approach might prevent side reactions that would spoil the recipe in a conventional synthesis. So far, the technique has been used only to search for reactions that take place in water, but Liu says his team is expanding its search to include reactions in organic solvents.

Over eons of evolution, biological organisms generate a diversity of compounds and simply select those that work best. Liu and colleagues brought that kaleidoscopic approach to bear on the small organic molecules that synthetic chemists favor. They started with two flasks of small organic molecules, each tethered to a unique DNA snippet. Each DNA strand in flask A was designed to identify its own small-molecule cargo (A1, A2, and so on) and to attract a complementary DNA identity tag attached to one of the small molecules in flask B (B1, B2, etc.). Each B molecule also sported a molecular “hook” called biotin.

When the researchers poured the contents of the two flasks together, the complementary DNAs paired up, bringing their small molecules into close contact with one another in every possible combination of A's and B's. In the few cases in which conditions were right, the small molecules reacted to form larger molecules. To find which compounds had combined, the researchers weeded them out in several steps. First, they dropped in iron beads studded with streptavidin, a molecule that binds to biotin. The researchers then pulled the beads out again, dragging with them B molecules snagged by their biotin hooks, as well as other molecules entangled by their DNA, and washed the compounds in a solution that unzipped the intertwined DNA strands. Lone A molecules that had not reacted fell off and were washed away, leaving unreacted B molecules and the newborn AB compounds attached to the beads (see figure).

The researchers then used the polymerase chain reaction (PCR) to amplify trailing DNA strands containing a certain nucleic acid sequence—a sequence found only in the A strands. Because all the unattached A molecules had been left behind in a previous step, only the A strands that had formed new molecules survived to be amplified by PCR. The researchers read the amplified DNAs with a standard gene chip, which identified their full sequences and thus revealed which A and B molecules had paired off.

Liu reported that in one experiment, with 168 possible small-molecule products, his group found a new reaction that uses a palladium catalyst under mild conditions to link simple hydrocarbon molecules called alkenes and alkynes into a more complex group called a trans-enone. Using the setup, Liu says, a single researcher can scan thousands of possible combinations of small molecules and reaction conditions for new reactions in just days.

13. AMERICAN CHEMICAL SOCIETY MEETING

# Enzyme Deactivates Heart-Friendly HDL

1. Robert F. Service

PHILADELPHIA, PENNSYLVANIA— More than 10,000 chemists, physicists, and materials scientists gathered here from 22 to 26 August for the 228th national American Chemical Society meeting.

Not all “good” cholesterol in your bloodstream keeps good company. In patients with coronary artery-clogging plaques, as much as half of the high density lipoprotein (HDL), which carries the “good” cholesterol, is chemically altered, blocking its normal ability to combat the buildup of cholesterol deposits, researchers reported at the meeting. The new work, led by chemist and physician Stanley Hazen and graduate student Lemin Zheng of the Cleveland Clinic Foundation in Ohio, is expected to lead to novel drugs that help prevent atherosclerosis by blocking the damage to HDL. It may also spur better diagnostics for heart disease: At the meeting, another group reported preliminary progress on one such test.

“This is pretty exciting,” says Ian Blair, a disease biomarker expert at the University of Pennsylvania in Philadelphia. “[They] seem to have a biomarker that is far better than existing biomarkers for cardiovascular disease.” For the first time, he adds, the new work lays out a clear molecular mechanism that explains how HDL can become “dysfunctional” and why high HDL cholesterol levels may not always ward off heart disease.

The research grew out of efforts to find better ways to track risk for heart disease. Last year, Hazen's team identified two new inflammation markers that were far better than existing tests for assessing a person's cardiac risks. The first of these was myeloperoxidase (MPO), an enzyme that immune cells use to fight bacterial and fungal invaders. MPO levels helped pinpoint the near-term risk of heart attacks, bypass surgery, or death among patients seeking emergency care for chest pain.

The second marker was a protein modification called nitrotyrosine, a byproduct of oxidative damage triggered by MPO and other compounds. At the time, however, Hazen's group didn't know whether MPO slapped nitrotyrosine groups on proteins indiscriminately or whether it had a primary target.

Using standard protein-tracking techniques, Hazen's group discovered that MPO targets apolipoprotein A1 (apoA1), the primary protein component of HDL, for oxidation. When the researchers looked at blood samples from 90 patients, half with cardiovascular disease and half without, they found that individuals with high levels of MPO-modified apoA1 had a 16-fold higher risk of heart disease. By contrast, patients with high levels of currently used clinical markers—total cholesterol and C-reactive protein—have less than double the risk. “This may help explain why not all persons with high HDL levels are protected from getting heart disease,” Hazen says. He suggests that when MPO reacts with apoA1, it modifies the protein at one or more key sites, interfering with the protein's ability to ferry cholesterol out of cells and eventually leading to atherosclerosis. The findings also appear in the August Journal of Clinical Investigation. Hazen says his team's results have already prompted drug companies to work to develop compounds aimed at blocking MPO's ability to bind and react with HDL.

Last year Hazen's team also showed that patients at high cardiac risk have high levels of MPO in circulation, presumably released at sites of inflamed coronary vessels—a result that has spurred other researchers to track MPO levels to gauge heart attack and stroke risk.

At the meeting, for example, Alexei Bogdanov, a radiologist at Harvard Medical School in Boston, reported creating a new MPO-binding compound that can be used as a contrast agent for MRI tests. Bogdanov reported that the contrast agent gave off a clear MRI signal when added to petri dish materials designed to simulate real plaques. The contrast agent is now being tested in animals, Bogdanov says. Tracking high MPO levels in clots, Bogdanov explains, should show which atherosclerotic clots are at greatest risk of breaking apart and leading to a heart attack or stroke. If the test works in humans, it could give patients advance warning of a pending heart attack or stroke—a signal that could save thousands of lives.

14. AMERICAN CHEMICAL SOCIETY MEETING

# Breaking a Barrier to New Brain Images

1. Robert F. Service

PHILADELPHIA, PENNSYLVANIA— More than 10,000 chemists, physicists, and materials scientists gathered here from 22 to 26 August for the 228th national American Chemical Society meeting.

For more than 20 years, physicians have relied on magnetic resonance imaging's ability to peer inside tissues throughout the body to help them diagnose everything from torn ligaments to cancer. An offshoot of the technology, known as functional MRI, enables them to track the general metabolic activity level of tissues.

MRI researchers have beefed up the technique by developing MRI contrast agents that give off a strong MRI signal only when they bind to specific targets in the body—such as calcium, which indicates neuronal firing, or certain proteases, which are common in cancer cells. Tracking such processes in the brain could open new windows into brain development and point the way to diagnostics for depression and other brain diseases. Unfortunately, MRI contrast agents haven't been able to find their way across the protective membrane that surrounds the brain—until now.

At the meeting, chemist Thomas Meade of Northwestern University in Evanston, Illinois, reported that his student Matthew Allen synthesized a standard MRI contrast agent linked to stilbene, a small organic compound used to ferry radioactive compounds into the brain for positron emission tomography, another popular brain imaging technique. The Northwestern scientists then teamed up with chemist Russell Jacobs of the California Institute of Technology in Pasadena to test the compound on mice bred to serve as models for Alzheimer's disease. When the researchers injected the compound into the tail veins of mice, the stilbene-toting contrast agents found their way inside the brains of their mice and bound to amyloid plaques, which are typically found in the brains of Alzheimer's patients. If the new work pans out in further animal tests and humans, doctors might one day use noninvasive MRI imaging to track brain development and diseases from Alzheimer's to schizophrenia.

“It's a very exciting development,” says Daryl Busch, a chemist at the University of Kansas, Lawrence. “You'll be able by [MRI] to see how the brain functions over a range of different conditions,” he says. “That's heavy-duty.”

Meade and colleagues are still studying how the stilbene-tethered compounds work. Meanwhile, they are seeing whether other contrast agents attached to stilbene will cross the blood-brain barrier as well.

15. AMERICAN CHEMICAL SOCIETY MEETING

# Snapshots From the Meeting

1. Robert F. Service

PHILADELPHIA, PENNSYLVANIA— More than 10,000 chemists, physicists, and materials scientists gathered here from 22 to 26 August for the 228th national American Chemical Society meeting.

Dendrimer splits water. Researchers from the University of Tokyo in Japan reported creating a starburst-shaped molecule called a dendrimer decorated with light-capturing compounds capable of splitting water molecules to make hydrogen gas, a valuable fuel. Previous water-splitting dendrimers were insoluble in water and therefore of little use. The new water-soluble dendrimers still can't match the water-splitting prowess of inorganic compounds, but because organic molecules are far easier to tailor, the Tokyo researchers expect the efficiency of the dendrimers to rise.

Heart failure help. Johns Hopkins University (JHU) researchers reported creating new compounds for treating heart failure. Nitroglycerin and other current heart failure medications deliver nitric oxide (NO), which helps the heart muscle relax. But the JHU researchers found in preliminary tests on dogs that novel compounds that deliver nitroxyl, or HNO, provide much the same benefit without the side effect of reducing the heart's ability to pump.

Cleaning water. Researchers at the University of Illinois, Urbana-Champaign, reported that cheap fibers made from polymer-coated fiberglass are eight times more effective at removing the herbicide atrazine from water than commercially available activated carbon. The new fibers could help combat increasing atrazine pollution. The popular herbicide contaminates the drinking water of millions of Americans.