News this Week

Science  08 Feb 2002:
Vol. 295, Issue 5557, pp. 36
  1. HIGH-ENERGY PHYSICS

    Troubled by Glitches, Tevatron Scrambles to Retain Its Edge

    1. Charles Seife

    Scientists working on the newly refurbished Tevatron accelerator are struggling to overcome serious technical problems. If the setbacks aren't resolved soon, researchers warn, the effort to get the accelerator running properly could drain scientific expertise from other projects, and the Tevatron may even fail to meet some of its scientific goals.

    Particle accelerators often have trouble when they first start up, so it's no surprise that the Tevatron—which smashes together highly energetic beams of protons and antiprotons—has run into difficulties in the 10 months since its $260 million refit. Scientists are confident that they can eventually fix the Tevatron's problems, but “we wanted to be farther along than we are now,” says Mike Witherell, director of the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, the Tevatron's home. “Things are not going swimmingly,” Steve Holmes, head of Fermilab's Beams Division, told a meeting of the High Energy Physics Advisory Panel last week in Washington, D.C.

    The amount of scientific data that an accelerator produces is related to its integrated luminosity, a combination of the beam's luminosity (the “brightness” of the particle beam) and the amount of time it runs. According to Tevatron scientists' latest projections, the Tevatron is scheduled to have 2 inverse femtobarns (fb−1) of integrated luminosity by the end of 2004 and, after a change in configuration, 15 fb−1by the end of its run in 2008. Since March 2001, however, the accelerator has produced only 0.02 fb−1. Although accelerators tend to get most of their data near the end of a run, the severity of the problems is worrisome, scientists say. Holmes told the advisory committee that under certain conditions some of the magnets that accelerate and guide the protons and antiprotons have tended to “quench": The superconductor in the magnet has been heating up and losing its superconducting ability. In particular, when Tevatron technicians want to get rid of the beam, they quickly switch the magnetic field at a specific point in the ring to guide the particles into a “beam dump.” However, particles were getting into the wrong part of the ring at the wrong time, fouling the switching process and quenching the magnet. “We lost the month of July due to magnet failure for various reasons,” says Holmes. “But we're almost out of the woods on that.”

    Out of the loop.

    Tevatron's main injector (top) is losing too many particles.

    CREDITS: (TOP TO BOTTOM) ULLRICH AND HAHN/FERMILAB; FRED ULLRICH/FERMILAB

    Unfortunately, there are many more problems left to troubleshoot. For example, the machine loses a potentially ruinous 70% of its antiprotons as it moves them from the accumulator, where magnets store the newly created antiprotons and focus them into a tight beam, into the main injector, which speeds particles up before guiding them into the main ring. It also loses 20% of the particles while transferring them from the main injector to the main ring of the Tevatron, where the collisions take place. The losses seem to indicate that the particles take on a wider-than-expected range of speeds, which effectively makes the beam wider than the pipe it is supposed to travel through. In addition, the protons and antiprotons, which travel in opposite directions in the same tube, affect each other more than is healthy, causing the beam to spread. “We have to work on a lot of things in parallel,” says Mike Church, deputy head of the Beams Division.

    Witherell says that Fermilab already has “its proper share of resources,” so it will probably not need more money. But scientists at Fermilab are being diverted from other projects to whip the ailing accelerator into shape. Some physicists who are supposed to be designing a major jump in luminosity in 2005, for example, are instead busy putting out the current fires.

    And the fires must be put out if the Tevatron is to meet many of its scientific goals, such as accurately determining the properties of the top quark and a force carrier known as the W particle. “The performance requirements are quite demanding, especially on precision measurements,” says Daniel Froidevaux, a physicist at the CERN accelerator near Geneva, Switzerland. “For the top quark, an integrated luminosity of a few hundred inverse femtobarns is not sufficient. They need to meet the 2 fb−1 target.” Measurements of the W particle will be even more difficult, he adds.

    Unless the machine can be brought up to peak capacity, the Tevatron will be relegated from a long shot to a noncontender in the race to find the Higgs boson: a huge, undiscovered particle that theory claims is the source of mass. Some physicists are hoping that the Higgs boson will be just within the Tevatron's reach and that the machine can snatch it before CERN's Large Hadron Collider comes online in 2007. “If we push to the limit, and the mass is low, we can get there,” says Witherell. But even if CERN prevails, he adds, “there will be terrific scientific progress without the Higgs—on W physics, top [quark] physics, and supersymmetric searches.”

    Although scientists are nervous, they still believe that the Tevatron will hit its stride. “I'm sure this thing will take off,” says Froidevaux. “I really hope so. I really hope so.” So does Church. “I'll worry in 6 months if we haven't made significant progress,” he says. “If by summer we're still struggling, I don't know.”

  2. STEM CELLS

    German Researchers Get Green Light, Just

    1. Gretchen Vogel*
    1. With reporting by Sabine Steghaus-Kovac in Bonn.

    BERLIN AND BONN— German scientists are thankful for small mercies after their country's parliament last week approved some of the world's strictest regulations covering work with human embryonic stem (ES) cells.

    The new measure, approved on 30 January, prohibits scientists in Germany from deriving human ES cell lines and “fundamentally bans” the import of these controversial cells. However, the Bundestag left an opening: Researchers can import ES cells if they can demonstrate that there are no feasible alternative ways to conduct the research. But even that comes with a catch: No imports can be approved until the Bundestag passes a new law establishing a national commission to review all import proposals, and the soonest such a commission could be in place is early summer.

    Still, researchers are looking on the bright side. “This is a positive signal to scientists, biomedical research, and in the end also to patients,” says developmental neuroscientist Oliver Brüstle of the University of Bonn, although he had hoped for a less restrictive vote. “It is the best we could hope for under the circumstances,” agreed Rüdiger Wolfrum, a law professor at the University of Heidelberg and vice president of the DFG science funding agency.

    Many scientists hope human ES cells, which can in theory transform into any of the body's cell types, might someday produce treatments for dread diseases such as Parkinson's or diabetes. But the cells have stirred controversy because they are derived from week-old human embryos. In Germany, scientists and politicians have argued that the country's embryo protection law, which forbids research on human embryos, does not bar work with stem cell lines that were derived outside the country. Debate on the issue has raged for more than a year, ever since Brüstle proposed importing human ES cell lines from Israel (Science, 14 December 2001, p. 2262).

    The art of compromise.

    German Bundestag members vote to allow restricted import of human embryonic stem cells.

    CREDIT: MARKUS SCHREIBER/AP

    For four and a half hours, Bundestag members debated three proposals, ranging from a complete ban on any import of human ES cells to few import restrictions. The winning compromise follows a formula established by President George W. Bush in August, when he permitted U.S. government-funded researchers to use only cell lines that had already been established (Science, 17 August 2001, p. 1242); German researchers will be allowed to import only cell lines established before last week's vote. “Killing of embryos for research purposes must remain illegal,” argued Maria Böhmer of the Christian Democratic Union, one of the co-authors of the winning motion. But “we cannot cancel” the fact that embryos were already killed for existing cell lines, she said.

    Legislators on all sides of the debate called for generous funding for research into alternatives to ES cells, including stem cells derived from umbilical cord blood and adult tissues.

    A day after the Bundestag vote, DFG announced that it would fund Brüstle's work as soon as the national commission is in place to give its stamp of approval. DFG had agreed several times to delay its funding decision until the Bundestag had debated the issue. Asked whether he regretted waiting, DFG president Ernst-Ludwig Winnacker said the result of the debate “shows that it was right to be patient and cautious in this sensitive field. Freedom of research [enshrined in Germany's constitution] is not absolute but is restricted by other rights.”

    Bundestag leaders have said they hope to have a draft of a new law ready in a few weeks, with final passage possible in a few months. But several scientists warn that this will not be the end of the debate in Germany. Molecular biologist Detlev Ganten of the Max Delbrück Center for Molecular Medicine in Berlin-Buch, a member of the National Ethics Council, said he will push for a review of the embryo protection law after national elections in September. “The discussion will not end here,” he says. “From my point of view, import is a step in the right direction, but it leaves a double standard in place.” For now, it seems to be a double standard that a majority of German lawmakers can agree on.

  3. CANCER RESEARCH

    Leukemia Protein Spurs Gene Silencing

    1. Jean Marx

    Researchers have identified hundreds of genes that can, when mutated, cause uncontrolled cellular growth and other changes that underlie cancer. But in the past few years, increasing evidence has suggested that mutations aren't the only genetic changes that lead to cancer. The addition of certain chemical groups to genes or their associated proteins can also alter gene activity patterns in ways that result in malignancy, without disrupting gene structures. Exactly how cancer-related genes acquire these so-called “epigenetic” alterations hasn't been clear, however.

    Now, a team led by Luciano Di Croce and Pier Giuseppe Pelicci of the European Institute of Oncology in Milan, Italy, provides a possible answer for a blood cancer known as acute promyelocytic leukemia (APL). On page 1079, they report that a mutant oncogenic protein involved in APL development recruits enzymes that attach methyl groups to DNA, in this case to a possible tumor suppressor gene called RARβ2. The addition of these methyl groups silences the gene, and that in turn contributes to the malignant transformation of the leukemia cells, the researchers report.

    This finding could lead to better APL therapies aimed at blocking methylation of RARβ2 and other targets of the oncogenic protein. “The implications of the work range all the way from the basic to potential clinical applications,” says Stephen Baylin of Johns Hopkins University School of Medicine in Baltimore, Maryland, whose own work focuses on gene methylation.

    Gene lock-up.

    On binding to its target promoter, PML-RAR attracts an enzyme (HDAC) that removes acetyl groups from histone proteins and also enzymes (Dnmt) that add methyl groups to the DNA. The actions of these enzymes, together with the proteins (MBDs) attracted by the added methyl groups, eventually shut down the gene.

    CREDIT: ADAPTED FROM L. DI CROCE ET AL.

    On the basic side, the discovery helps resolve a paradox concerning gene methylation in cancer cells. The genomes of cancer cells usually carry fewer methyl groups than normal, but particular genes—including several tumor suppressors whose loss or inactivation contributes to excessive cell growth—often have more than their share of the chemical additions. This presumably shuts down the genes' activity. “The big question is what targets methylation to [those] specific sites,” says Peter Jones, a methylation expert at the University of Southern California in Los Angeles.

    To address that question, Di Croce, Pelicci, and their colleagues turned to APL cells. They carry an oncogenic protein, named PML-RAR because it's the product of an abnormal gene formed by fusing two genes, one encoding the α form of the retinoic acid receptor (RAR) and the other encoding the so-called promyelocytic leukemia protein (PML). Normal RAR, when bound to retinoic acid, alters gene expression in immature white blood cells, causing them to mature and stop dividing. PML-RAR has the opposite effect: It blocks the development of immature white blood cells, which consequently grow out of control. The protein apparently does this by suppressing gene activity, and the Milan team wanted to find out whether it might do so by facilitating methylation of its target genes.

    Several lines of evidence suggest that it does. For example, the researchers found that in immature white blood cells, PML-RAR binds to a DNA segment needed for the expression of one of its targets, the gene for the β form of the retinoic acid receptor (RARβ). And once the protein binds to the regulatory site, Pelicci says, “we see hypermethylation of this target promoter.” This in turn silences the gene.

    Further work indicated that PML-RAR triggers hypermethylation by drawing in two methylating enzymes. The enzymes bound to the RARβ promoter only when PML-RAR is present. “It's the first example in a human tumor where a genetic change [formation of the PML-RAR fusion gene] is setting up an epigenetic change,” Baylin says.

    What's more, that epigenetic change seems to be what holds the cells in the immature, dividing state seen in APL: Di Croce and his colleagues showed that once the epigenetic changes were established, the fusion protein was no longer necessary. They did this by setting up the experiments so that the PML-RAR gene was expressed in the white cell precursors only in the presence of zinc ions. If they turned off PML-RAR production after 48 hours by removing the zinc, the cells remained locked in their undeveloped condition.

    Conversely, the team found, treatments known to return APL cells to a more normal behavior demethylate the RARβ gene and increase its activity. This can be done, for example, by treating the cells with both retinoic acid, which makes PML-RAR behave more like normal RAR, and the drug 5-Aza-dC, which removes methyl groups from DNA.

    Although intrigued by the findings, some researchers want to see more evidence of PML-RAR's ability to recruit methylating enzymes to its target genes. “I would be more convinced if they had been able to show that for more than one gene,” says Jean-Pierre Isse of the University of Texas Southwestern Medical Center in Dallas. “RARβ is methylated in a lot of cancers without PML-RAR.”

    Still, Baylin says, researchers interested in epigenetic events in cancer now have a new line of investigation to follow. He points out that many leukemias and lymphomas feature both fusion proteins and hypermethylated tumor suppressor genes. The question now is whether any of them work the same way that PML-RAR does in transforming cells to malignancy.

  4. GENETICS

    DNA Mutations Linked to Soviet Bomb Tests

    1. Richard Stone

    CAMBRIDGE, U.K.— For survivors of the atomic bombs dropped on Japan at the end of World War II, the disfiguring burns and radiation-induced illnesses were all too real and agonizing. Now researchers have strong new evidence of a more insidious effect in other people blighted by nuclear weapons: unexplained DNA mutations from atomic tests in Kazakhstan in the early days of the Cold War.

    On page 1037, researchers led by geneticist Yuri Dubrova of the University of Leicester, United Kingdom, describe a compelling connection between radioactive fallout and elevated mutation rates in families living downwind of the Semipalatinsk nuclear facility, the Soviet equivalent of the Nevada Test Site. The mutation rate of minisatellite DNA—short, repeating sequences that pepper the genome—challenges the conventional view that radiation inflicts its punishment on DNA solely by directly corrupting the nucleic acids. Some other mechanism must be at work amplifying the effect of the chronic low-dose radiation, because the number of mutations is “orders of magnitude too large for such an explanation,” says Dudley Goodhead, director of the U.K. Medical Research Council's Radiation and Genome Stability Unit in Harwell. At the same time it's unclear whether such mutations are—or could ever be—linked to health effects.

    Wasteland.

    Researchers from the International Atomic Energy Agency visited the Semipalatinsk nuclear facility last year.

    CREDIT: WACLAW GUDOWSKI

    The findings bolster a controversial 1996 report by Dubrova and a different group of colleagues that linked germ line mutations to fallout from the 1986 Chornobyl explosion. That study, published in Nature, described double the usual mutation rate in the children of men living in a region of Belarus heavily contaminated with cesium-137. The study was a revelation, as the Japanese bomb survivors and their families had showed no such mutations. But the study drew skepticism because Dubrova's team could not eliminate some other environmental factors and the researchers used British families as controls, as they were unable to obtain blood from nonirradiated Belarusans.

    In the findings reported this week, Dubrova's team collected blood from three generations of 40 different families in the Beskaragai district of Kazakhstan, a desert region hit particularly hard by four atomic surface tests between 1949 and 1956. In each subject they examined eight minisatellite DNA regions that are prone to mutations. The naturally high mutation rate in this DNA allows researchers to detect statistically significant increases in mutation rates in small populations.

    When the data came back, “I couldn't believe my eyes,” says Dubrova. Compared to control families in a nonirradiated part of Kazakhstan, individuals exposed to fallout had a roughly 80% increase in mutation rate, and their children showed an average rise of 50%. Probing further, Dubrova's group found an apparent dose-related effect in the children: evidence that the radiation, not some other environmental factor, was inducing the mutations. The correlation “was the icing on the cake,” says Dubrova. His group is now following up its Chornobyl findings with an improved study under way in Ukraine.

    What these germ line mutations mean for health is a mystery, says Bryn Bridges of the Medical Research Council's Cell Mutation Unit in Brighton. “Is this just a biomarker or more?” he asks. Although minisatellites were once dismissed as “junk DNA,” evidence is mounting that they affect gene transcription and are linked with disease predisposition. But looking for radiation- induced health effects in Kazakhstan would be fruitless, says Dubrova, because there are not enough people affected by the fallout who are still alive.

    The germ line mutations are unlikely to become merely a Cold War footnote. “They present a potential challenge to the current paradigm used for assessment of genetic risk,” says Goodhead, who notes that screening for such mutations might offer a new tool for monitoring radiation exposure. Indeed, says William F. Morgan, director of the Radiation Oncology Research Laboratory at the University of Maryland School of Medicine in Baltimore, the findings are relevant to the current debate over how to protect people from chronic low-dose radiation near some of the Department of Energy sites that represent the U.S.'s nuclear legacy.

  5. NANOTECHNOLOGY

    Nanowire Fabricators Earn Their Stripes

    1. Robert F. Service

    Electronics makers love a good sandwich. By layering sheets of semiconductors, researchers have learned to control electrons and photons precisely enough to build everything from ultrafast transistors to ultrasmall lasers. Now three groups report that they have carried this sandwichmaking ability down to one dimension by creating tiny wires, each of which resembles a stack of pancakes composed of different semiconductors. The work could open the door to a host of new devices that would boost progress toward long-sought technological goals such as molecular-based computers, quantum computers, and chips that automatically cool themselves.

    “These are very nice results,” says Paul Alivisatos, a chemist and nanotech expert at the University of California, Berkeley. The ability to layer materials into two- dimensional sheets has been so important for research and applications, Alivisatos says, that “the ability to do it in one dimension has to be very important. There will undoubtedly be a lot of work in the next few years on this.”

    Nanowires have already generated considerable attention. Over the past few years, numerous groups have grown a variety of different semiconducting wires and have even managed to turn them into components of electronic devices, such as transistors. These early nanowires, however, lacked a key ingredient: variety. Although researchers made wires from various materials, each single wire was chemically uniform. If researchers could change that makeup, they would likely gain control over the movement of electrons and photons within individual wires, setting the stage for integrating devices right into the wires themselves—a development that could further shrink electronic circuits.

    Nanowhisker.

    Gold-capped wire of indium arsenide and indium phosphide.

    CREDIT: M. T. BJORK ET AL., NANO LETTERS 2 (2002)

    The three groups hit on the same solution. One team, led by Charles Lieber of Harvard University, reports its results this week in Nature. The other two—one led by Peidong Yang of the University of California, Berkeley, and a second led by Lars Samuelson of Lund University in Sweden—report their results in the February issue of Nano Letters.

    To pull off the feat, all three groups tweaked the method for making single-composition nanowires. In each case they started with tiny gold particles—each just tens of nanometers across—which they placed on a surface inside a vacuum chamber. They then used either lasers or chemical methods to vaporize the semiconductors that were to make up the first segment of the wire. The semiconductor vapor condensed around the gold particle and began to crystallize out between the gold particle and the surface in a tiny cylinder that eventually raised the particle off the surface. To change the composition of the next bit of wire, the researchers simply fed the chamber a different precursor semiconductor, which was deposited between the gold particle and the previous semiconductor. Together the three teams showed that the process works for several of the most important types of semiconductors, including silicon, silicon-germanium, gallium arsenide, gallium phosphide, indium arsenide, and indium phosphide.

    The striped wires could prove handy in molecular electronics, the effort to fabricate computer chips by assembling individual molecules into complex circuits. Striped nanowires are likely to make that assembly easier because they can create transistors and other devices within current-carrying wires, says Mark Gukiksen, a Harvard graduate student and first author on the Nature paper. Yang adds that striped nanowires should do wonders as well for thermoelectrics, materials that can use electricity to pump heat. Thermoelectrics are layered materials whose efficiency is expected to rise as their size gets smaller, a property Yang's team is now testing. Finally, Samuelson believes that the technique can be used to grow wires composed of numerous electron-trapping quantum dots. Because these dots are the basis for many quantum-computing schemes, striped nanowires could propel research in this area as well. With so many possible applications, Samuelson says, “it might quickly become a very crowded field.”

  6. NEUROSCIENCE

    Drugs and Placebos Look Alike in the Brain

    1. Constance Holden

    Researchers in Sweden and Finland say they have finally shown what scientists have long suspected: that a placebo activates the same brain circuits as painkilling drugs. This first brain imaging study of placebo analgesia, reported online this week by Science (http://www.sciencexpress.org/), graphically illustrates the principle that higher brain functions help control how humans perceive pain, say the researchers, headed by neuroscientist Predrag Petrovic of Stockholm's Karolinska Institute.

    Psychoneurologist Pierre Rainville of the University of Montreal describes the finding as “really great news.” There is already considerable evidence that placebos harness the same endogenous painkilling circuits as do opioid drugs. But the evidence is all indirect, drawn primarily from studies showing that compounds that block opioid action also block a placebo's analgesic effect. “For at least 5 years we've been waiting for a good functional imaging study of placebo effects,” says Rainville.

    To provide such images, Petrovic and his colleagues used positron emission tomography to scan the brains of nine men while a 48°C metal surface was pressed to the backs of their hands. The team compared brain responses after subjects were given intravenous injections—by a doctor in a white coat—of either an opioid painkiller or a placebo.

    Painless.

    This is your brain on placebos.

    CREDIT: P. PETROVIC ET AL.

    Both the genuine analgesic and the placebo led to increased blood flow in areas of the brain known to be rich in opioid receptors: the brainstem and the rostral anterior cingulate cortex (ACC), which exchanges information with a network of brain regions, including the orbitofrontal cortex, a relatively sophisticated part of the brain known to process emotions. Furthermore, those people who responded most to the placebo—according to their ratings on a scale of 0 to 100 of how much it reduced their pain—also showed more rostral ACC activation from the drug. This, the authors write, provides new fodder for the hypothesis that “high placebo responders have a more efficient opioid system.”

    Jon-Kar Zubieta of the University of Michigan, Ann Arbor, who has tracked the function of the opioid receptor system implicated in the new study (Science, 13 July 2001, p. 311), suspects that those people who respond robustly to the placebo have increased concentrations of opioid receptors. However, he says the small number of subjects prevents any of the study's findings from being definitive.

    Nevertheless, by showing the intimate relation between placebo and drug effects in the brain, the work fits with the theory that the placebo response is deeply embedded in all analgesic treatments, says neuroscientist Fabrizio Benedetti of the University of Turin, Italy. For instance, one of his recent studies shows that a painkilling injection is more effective when the patient is watching than when the drug is administered covertly.

  7. MEXICO

    Cuts Add to Turmoil Over Research Spending

    1. Jocelyn Kaiser*
    1. With reporting by Marina Chicurel, a writer in Santa Cruz, California.

    Mexican scientists are in an uproar over a surprise decision by the country's leading research agency to sharply cut research awards. The government of President Vicente Fox says the cuts have been blown out of proportion and are part of a major reshuffling that will result in a larger science budget. But scientists are skeptical, pointing to a series of recent actions that have raised doubts about the government's commitment to basic research.

    The reformist Fox began his 6-year term a year ago promising to double the budget of the National Council for Science and Technology (CONACYT), which funds research in all disciplines. But what followed was a string of financial problems. Last fall, the agency ran out of money for graduate scholarships and halted grants to visiting scientists and to attract scientists back from abroad. More recently, salary payments to researchers were delayed for several weeks.

    The last straw for many scientists was the news last month that CONACYT will spend only $56 million on basic research grants and fellowships in its 2001 round of awards, a drop of 34% from the $84 million disbursed in 2000. The cut reflects a decline in the number of grants funded from roughly 1000 per year since 1996 to just 656 in 2001. “Last year was disastrous,” says René Drucker, president of the Mexican Academy of Sciences. “It was one of the worst years in the history of Mexican science.”

    More than praise.

    Mexican researchers want a greater commitment from President Fox, left.

    CREDIT: NOTIMEX

    Officials at CONACYT, which oversees about 15% of the government's investment in science and technology, have tried to put the best face on these events. They say grant funding declined only slightly last year compared to the late 1990s and that 2000 was an “atypically” good year. In meetings, however, officials have explained that the agency overspent its budget in 2000 and then had to take money from 2001 funds, according to Jaime Urrutia, director of the Institute of Geophysics at the National Autonomous University of Mexico (UNAM), Mexico City. More recently, the delay of a customary $32 million end-of-the-year payment from the Ministry of Education for operating expenses forced CONACYT to borrow from the 2002 budget, says CONACYT spokesperson Armando Reyes.

    The agency is also in “transition,” adjunct director for scientific research Alfonso Serrano has told national media, and it plans to tap research budgets from the health, agriculture, and other federal ministries to fund new programs aimed at attacking practical problems that reflect “the country's needs.” The new pot will restore some of the $28 million shortfall in the 2001 grants competition, says Reyes, and it will also reflect a 24% increase in CONACYT's 2002 budget, to $477 million.

    The new programs are to begin accepting proposals this month. But that's little comfort to hundreds of scientists and students, who must now stretch existing grants for several more months or get by on personal funds. Some also worry that CONACYT's new focus on practical problems could mean less funding for basic science, says Antonio Peña of the Permanent Forum for Science and Technology, a group that advises the president. CONACYT officials, however, say there will be more money for basic research, not less.

    Some scientists are hopeful that the Fox plan could eventually benefit Mexican science. “It's a new government, and we need to give them time to show what they can do,” says structural biologist Lourival Possani of UNAM, Cuernavaca. But Possani and others remain concerned about the dearth of information coming from officials. “There isn't much clarity at all,” Drucker says.

  8. CLINICAL RESEARCH

    Cancer Study Lawsuit Dismissed in Oklahoma

    1. Eliot Marshall

    A federal judge has dismissed a high- profile lawsuit claiming that a clinical trial at the University of Oklahoma violated patients' human rights under international law. The ruling derails—at least temporarily—a legal juggernaut driven by New Jersey lawyer Alan Milstein. Milstein has taken four respected clinical centers to court claiming that their research projects violated the Nuremberg Code, a set of medical rules established half a century ago in reaction to Nazi experiments. Last week, federal Judge H. Dale Cook of Oklahoma City cast doubt on that legal strategy by ruling that the Nuremberg Code can't be used as the basis of a civil suit in U.S. courts.

    Milstein began testing the Nuremberg argument 2 years ago. A partner in a Pennsauken, New Jersey, firm, he made headlines when he sued the University of Pennsylvania in Philadelphia on behalf of the family of Jesse Gelsinger, a patient who died in a gene therapy trial. The university settled for a large but undisclosed sum in 2000.

    Since then, Milstein has sued the Fred Hutchinson Cancer Research Center in Seattle, the University of Oklahoma Health Sciences Center in Oklahoma City, the Ohio State University Medical Center in Columbus, and Penn, this time over a second patient in the Gelsinger gene therapy trial. In all cases, the suits accused researchers and others of violating the patients' human rights under the Nuremberg Code and other international standards.

    Rebuffed.

    Attorney Alan Milstein plans an appeal.

    CREDIT: A. MILSTEIN

    The Oklahoma case was one of Milstein's largest. Federal authorities had closed down a trial of an anticancer vaccine, and the university dismissed some of the staff members who were involved (Science, 4 August 2000, p. 706). Milstein filed a complaint on behalf of 19 patients, alleging that the doctors had engaged in “careless, negligent and reckless conduct,” violating the patients' dignity and privacy. By invoking international standards, Milstein elevated the case from a local to a national matter, suitable for trial in a federal court.

    In throwing out the federal case, Cook reasoned that no “fundamental” constitutional rights were at stake. He said “there is no private right of action for an alleged violation of international law,” such as guidelines for the conduct of research. He also argued that the “right to be treated with dignity” enshrined in the Nuremberg Code is too “vague” to serve as the basis for a civil suit.

    Milstein says he has already filed an appeal with the federal appeals court in the 10th Circuit. “We believe we can show that the American people believe it is a fundamental right not to be treated as a guinea pig,” he says, adding that Cook's opinion “assumes that these people gave their consent when in fact there was no informed consent.”

    Arthur Caplan, director of the Center for Bioethics at Penn, says he isn't surprised by the decision. He calls the Nuremberg argument “a balloon that would burst anytime it got near a judge.” (Caplan himself was named, and later dropped, as a defendant in Milstein's first Penn lawsuit.)

    Milstein's three other human-rights lawsuits are still in preliminary stages; no trial dates have been set. Paul Lombardo, associate professor of law and medicine at the University of Virginia in Charlottesville, calls Milstein's argument “creative” but predicts it will be “very tough” for him to prevail.

  9. FRANCE

    CNRS Under Fire From Government Auditors

    1. Michael Balter

    PARIS— France's mammoth basic research agency has come under blistering attack from the nation's government accounting body. In a report issued last week (http://www.ccomptes.fr/), the Cour des Comptes took the Centre National de la Recherche Scientifique (CNRS) to task for a variety of alleged faults, including a lack of overall research strategy, organizational rigidity, and lackadaisical efforts to recruit young scientists and encourage them to become independent. But CNRS officials argue that the report did not take into account recent initiatives or the organization's prodigious scientific output.

    With a $2.2 billion annual budget and 11,400 researchers, CNRS is often a target of the Cour des Comptes' annual scrutiny of government operations. But the report for fiscal year 2001 is particularly harsh. “The recent history of the CNRS is marked by the incapacity of the organization … to get beyond the stage of collective reflection and working group discussions to launch strategic orientations,” the auditors declared. They also complained that many labs were pursuing their own research strategies with too little guidance from CNRS administration. The Cour des Comptes was particularly alarmed about the “aging” of CNRS's scientists—nearly 30% of whom are due to retire between 2008 and 2010—and concluded that current recruitment is too slow to fill the looming gap.

    Chief defender.

    CNRS head Geneviève Berger.

    CREDIT: CNRS

    CNRS director-general Geneviève Berger dismissed most of these complaints. “Having a strategic vision does not mean stifling the researchers,” she says. Others also reject the complaint that labs have too much autonomy. “The Cour des Comptes did not understand that the CNRS can't be run like the post office,” says Anne-Marie Duprat of the Center for Developmental Biology in Toulouse. “You can't do whatever you want, but the labs must have a certain amount of freedom.” Berger says the agency does think strategically, such as in its efforts to commercialize its research, a primary reason why Berger, a medical researcher, was tapped to run CNRS (Science, 8 September 2000, p. 1667). Since 1994, annual license and royalty income from the agency's scientific patents has soared to $26 million, a 10-fold increase.

    Berger also argues that the report “hardly mentions” the scientific output of CNRS, whose researchers are authors or co-authors of more than 70% of all scientific papers published in France. She does agree, however, with the auditors' criticisms that CNRS needs to encourage more interdisciplinary research and collaborate more with other European countries.

    The Cour des Comptes saved much of its fire for CNRS's treatment of young researchers, who—under the hierarchical French system—often find it difficult to set up their own labs. The auditors complained that most so-called new units were the result of reshuffling old ones and few truly new teams were being created. But Berger and other CNRS researchers counter that this critique does not take into account measures begun last year to set aside funds for young scientists. “That is really starting to work well,” says Duprat. “The young teams are starting to take off.”

  10. GENETICS

    Germany's Elite Tie Knot With Big Pharma

    1. Gretchen Vogel

    MUNICH — Germany's top research organization, the Max Planck Society, took a leap into the unknown this week when it inked a multimillion dollar deal to form a joint institute with one of the world's largest pharmaceutical companies. GlaxoSmithKline (GSK) will establish a new Genetic Research Center on the campus of the Munich-based Max Planck Institute of Psychiatry, dedicated to finding genetic links to common diseases.

    GSK will buy and install the sequencing machines and computers needed to process the genetic data from patients, pay rent for a whole floor of the institute's lab building to house the center, and employ the center's technical staff. The Max Planck Institute, in turn, will provide clinical data and scientific expertise on collaborative projects. Institute scientists will have access to 15% of the center's sequencing and data-crunching capacity for their own projects.

    Such a close alliance with big pharma is a first for the organization, but it mirrors a trend in Germany. The society has been aggressively establishing new biotech spin-offs on or near its campuses. In contrast, few academic scientists had any connections to industry 7 years ago, says molecular biologist Axel Ullrich of the Max Planck Institute for Biochemistry in Martinsried, near Munich. Ullrich, who helped found Genentech in the 1970s, calls the new center “a hybrid between a Max Planck Institute and a pharmaceutical company … that promotes the interests of both parties.”

    Dealmakers.

    Officials announce Max Plank- GlaxoSmithKline collaboration.

    CREDIT: GLAXOSMITHKLINE

    GSK is eager to tap into the huge repository of patient tissue samples and clinical data available through the institute's scientists and doctors, whereas Max Planck scientists hunger for advanced sequencing and computing power. The Bavarian government will contribute $3.5 million over the next 3 to 5 years. Max Planck scientists will retain the right to patent any discoveries from projects they initiate, but GSK will have first refusal on whether to license them from the Max Planck Society.

    The center will focus on finding patterns of genetic variations in patients with a variety of common diseases. These variations, called single-nucleotide polymorphisms (SNPs), represent a change in a single base pair in the human genome that can help scientists home in on disease-related genes.

    The first target will be unipolar depression. It's a tall task, says Kenneth Kidd of Yale University School of Medicine, who is not involved in the project. Although having a family member with depression is a risk factor for the disorder, no one has been able to pin down genes that might play a role. Most doctors believe depression has multiple causes that vary among patients. “Diagnosing depression is as precise as diagnosing a headache,” agrees Florian Holsboer, director of the psychiatry institute. But he hopes that comparing patterns of tens of thousands of SNPs in 1000 depressed patients with those in healthy controls will provide clues about what triggers the disease and why patients respond differently to treatment.

    Whereas psychiatry institute scientists will focus on central nervous system disorders, GSK will join other scientists—each of whom will negotiate intellectual property rights—to investigate a range of diseases. Ullrich, for one, will lead a group developing a large-scale screen for genes related to cancer development.

  11. MOLECULAR COMPUTING

    DNA-Based Computer Takes Aim at Genes

    1. Dennis Normile

    TOKYO— Olympus Optical Co. surprised computer scientists last week by announcing the development of the “world's first DNA computer for gene analysis.” But experts disagree about whether Olympus's machine is really a computer.

    “I think they've got a device for genetic analysis,” says University of Tokyo biochemist Kensaku Sakamoto, who works on DNA computing. “But to function as a general-purpose computer, it still has a ways to go.” Takashi Yokomori, a computer scientist at Waseda University in Tokyo, is more generous. “If you take a broad view of information processing, then what Olympus has developed is a splendid DNA computer,” he says.

    Researchers around the world have been working on DNA computing since the mid-1990s in hopes of harnessing the molecule's ability to store huge volumes of information and to react in many ways simultaneously for use in massively parallel computations. Efforts have focused on problems in Boolean logic, in which statements are linked by “and” and “or” into formulas, such as ((a = 1) OR (b = 1)) AND ((a = 0) OR (b = 1)). The goal is to find a set of variables that satisfies the formula. Researchers have devised ways of representing such expressions as strings of DNA. They create molecules representing each possible solution to the formula and then, using restriction enzymes and other tricks of DNA manipulation, eliminate the molecules representing unworkable solutions.

    DNA computing has solved simple problems in math, logic, and even chess (Science, 18 February 2000, p. 1182; 19 May 2000, p. 1152). The technology has remained a laboratory curiosity, however, because creating a molecule for each possible solution can demand literally tons of biochemical material to solve complex problems, and all of the chemical shaking and baking must be done by hand.

    Real thing?

    Akira Suyama says his machine for analyzing gene expression is the first practical DNA computer.

    CREDIT: D. NORMILE

    University of Tokyo biophysicist Akira Suyama, whose work led to the Olympus machine, says he has found a simpler way. First, he uses an algorithm that solves the problem in steps, building more and more complex DNA “formulas” as it goes and chemically weeding out failed solutions at the end of each round. That approach cuts the number of dead-end molecules by orders of magnitude, but at the cost of more chemistry. So Suyama automated the process, adding an electronic computer to control sample handling and processing. As a “killer application” for his machine, Suyama chose gene-expression profiling, a procedure increasingly used in research and drug development to study which genes are expressed in the course of diseases, among other problems. The work led to a partnership with Olympus, which hopes to both sell DNA computers and offer analytic and diagnostic services.

    Sakamoto praises his colleague's work on automating DNA computing as having “big long-term potential.” But he thinks gene-expression profiling is so specific a task that the device doesn't qualify as a general-purpose computer. Suyama acknowledges that his pride-and-joy algorithm doesn't come into play in the Olympus machine. But he says that whether it is addressing Boolean logic problems or analyzing gene expression, “it is the same hardware, with just a change in the source program.”

    Semantics aside, potential users are eager to see what Suyama's machine can do. Sumio Sugano, a molecular biologist at the University of Tokyo's Human Genome Center, says one “extremely important” advantage is that the Olympus machine promises to measure absolute levels of gene expression in a sample. Current technology can only compare whether a particular gene is expressed more or less than other genes. Also, for limited numbers of genes, the Olympus machine returns results in just hours, instead of the day or more required by DNA arrays. And researchers can select a different set of genes for profiling with a bit of reprogramming instead of developing a new array.

    Olympus researcher Nobuhiko Morimoto says the machine will be put through its paces at NovusGene Inc., a new Olympus subsidiary gearing up to offer genetic analysis services to research labs and clinics. “Our target is to offer gene-expression profiling for about half of current prices,” which run about $5000 to check expression levels of 500 or so genes in a sample. If all goes well, Morimoto says, Olympus may use the machine to offer profiling services or even sell DNA computers in 2003.

  12. 2003 BUDGET

    War Effort Shapes U.S. Budget, With Some Program Casualties

    1. David Malakoff*
    1. With reporting by Martin Enserink, Constance Holden, Jocelyn Kaiser, Andrew Lawler, Jeffrey Mervis, Charles Seife, Robert F. Service, and Erik Stokstad.

    The president wants to finish doubling NIH's budget, but significant growth in basic research elsewhere may hinge on a stronger economy

    The bark proved worse than the bite. After months of warning that government research spending could become a casualty of the war against terrorism, the Bush Administration this week unveiled a budget proposal for 2003 that would significantly increase spending on bioterrorism, nanotechnology, and space science, while taking nibbles out of some defense, environment, and energy research programs.

    Overall, the $2.1 trillion blueprint sent to Congress on 4 February calls for an 8% rise in research spending, to $112 billion, in the fiscal year that begins 1 October. It includes an additional $2.4 billion in research-related efforts to combat terrorism, led by $1.7 billion for the National Institutes of Health (NIH) and $420 million for the Department of Defense (DOD). The budget is “a good story” for most scientists, says White House science adviser John Marburger, given the constraints imposed by a slumping economy and increased security demands.

    But not everybody is thrilled. By preserving NIH's place as the dominant player —spending two-thirds of the government's investment in basic research—the president's budget “gives short shrift to everything except the life sciences,” laments Michael Lubell of the American Physical Society. And legislators seem likely to object to several provisions, including those that transfer three research programs to the National Science Foundation (NSF) and reshuffle NASA's planetary research program.

    Here are research highlights from the president's spending plan:

    Biomedical research: A 16%, $3.7 billion boost to $27.3 billion would complete a 5-year campaign to double the NIH budget (Science, 1 February, p. 785). More than half of the increase would go to bioterrorism and cancer research mainly at two institutes. NIH's other 25 institutes would see increases averaging 9%. New and competing grants would rise by 477 to 9854, with the average grant jumping 4% to $369,500. For the first time, NIH could fully fund multiyear grants in the first year.

    NIH's AIDS budget would increase 10% to $2.8 billion, part of which will fund DOD's $23 million AIDS research program that otherwise was slated for termination. “We're on the verge of what I'm terming an acquisition merger,” says Col. John McNeil of the program, which is headquartered in suburban Maryland.

    At the Atlanta, Georgia-based Centers for Disease Control and Prevention (CDC), spending is up 35% from 2001, to $5.8 billion, but down by $1 billion from this year because of a one-time shot of cash after 11 September and the anthrax attacks. About $1.6 billion is reserved for bioterrorism preparedness, including $400 million more to stockpile vaccines and drugs against a bioterror attack and $120 million for new labs and training facilities in Atlanta and Fort Collins, Colorado, home to CDC's insect-borne diseases lab. At the same time, the Bush Administration would end a $68 million campaign to promote healthy teenage lifestyles and take 3% off a $355 million budget for “ordinary” infectious diseases.

    NSF: Director Rita Colwell got most of what she wanted—but at a price. A 5% increase, to $5.04 billion, would allow NSF to start two long-awaited projects, fund larger grants, increase graduate student stipends, add $30 million to a mathematics initiative, and expand a program to upgrade the skills of elementary and secondary school teachers. NSF's 1550-person workforce would also grow by about 5% to meet the demands of managing more interdisciplinary and complex science. But the trade-offs are significant, including a negligible rise in the number of new awards and cuts to several core research and education programs.

    NSF's research account would increase by $184 million. But $76 million of that would come from running programs transferred from other agencies (see sidebar on p. 954). A 10% jump in the average grant size, to $125,000, will force NSF to hold nearly constant the number of awards it makes annually at 10,500. Astronomers are hailing a $30 million request to continue building the $660 million Atacama Large Millimeter Array in Chile but not the 3% cut in bread-and-butter research programs. EarthScope, a collection of geophysical instruments to probe the North American continent, would debut with $35 million, and a 10-site National Ecological Observatory Network would get $12 million to develop two locations.

    Within NSF's education programs, the $40 million boost for the $160 million Math and Science Partnerships program more than eats up an overall increase of $33 million. That would mean cuts in programs to help states become more competitive, as well as efforts to strengthen undergraduate science and to reform local and state school districts. Graduate students also got mixed news. Colwell says she is “delighted” about the proposed $3500-a-year boost, to $25,000, in stipends for three graduate fellowship programs, although the number of students served will remain flat.

    NASA: New Administrator Sean O'Keefe made a splash by canceling two planetary missions and proposing development of nuclear systems for spacecraft. The moves are sure to spark a heated battle among lawmakers and researchers over the future of solar system science.

    The most dramatic gesture in the $15 billion budget, up 1.4%, is to wipe clean the outer planetary program, which has been mired in controversy (Science, 4 January, p. 32). O'Keefe canceled the mission to Jupiter's moon Europa now being planned by Pasadena, California's Jet Propulsion Laboratory, as well as a competed Pluto flight being prepared at Maryland's Applied Physics Laboratory for which Congress earmarked funds in the 2002 budget. Costs were “going out of control,” says Marburger. In their place is a program of competitively selected missions, costing up to $650 million apiece, that would take no more than 4 years to develop. Marcus Peacock of the White House Office of Management and Budget says that the choice of missions for this New Frontiers program likely will hinge on the results of a National Academy of Sciences study due out this spring of priorities for solar system exploration.

    A second controversial move is to pump some $125 million into developing nuclear electric propulsion systems and nuclear electric power generation systems. O'Keefe and space science chief Ed Weiler argue that nuclear systems are the best choice for long-term missions to Mars and beyond, allowing for longer operation and enough power for a more complex array of instruments. But antinuclear activists worry that such systems could pose a threat to Earth during launch or flybys, and some researchers are wary that missions will be delayed until the new technologies are mature. Indeed, the budget plan also postpones a Mars smart lander and mobile laboratory from 2007 to 2009 to take advantage of new nuclear power systems. However, Michael Drake, an astronomer at the University of Arizona in Tucson who chairs NASA's solar system exploration advisory subcommittee, says that the move to push technology is “basically right.” The Administration rejected NASA's request to begin work on new earth science missions, pending a review of the government's climate change program. The budget request calls for the White House and NASA to come up with “clear, high-priority, affordable science objectives” which can be accomplished soon aboard the space station; it also calls for NASA to study the effect of space radiation on biological systems.

    View this table:

    Defense: The Pentagon would get a 14% boost to $379 billion, but little of the new money would trickle down to research. The military's basic research account—a major source of funding for university math, engineering, and computer science studies—would remain flat at about $1.3 billion, and its overall science and technology budget would drop 2%, to $9.7 billion, well below the $11 billion sought by a coalition of academic and science groups.

    Energy: A $21.9 billion overall budget holds the Office of Science at current levels, with some reshuffling. Fermilab's Tevatron collider picks up $6 million from cuts made to the fixed-target facility at Brookhaven National Laboratory, and the RHIC collider at Brookhaven gets approximately $14 million extra to double its run time. Fusion research gets a 4% increase to correct an “underutilization” of facilities, says acting science director James Decker. There are also plans to construct a $69 million compact stellarator, a variation of the classical tokamak-shaped fusion facility, at the Princeton Plasma Physics Laboratory. DOE also plans to spend $35 million to open one new nanoscience center and start planning three others.

    National Institute of Standards and Technology (NIST): A proposed 42% cut in the ever-controversial Advanced Technology Project (ATP), which funds high-risk industrial research, would bring its budget down to $108 million. But “what you see and what we end up with are often two different things,” says one NIST budget watcher. The Administration says it wants to boost university participation in ATP, limit large-company involvement, and require firms whose ATP ventures turn a profit to reimburse the government's investment as much as fivefold. Elsewhere, the Administration would boost funding for NIST's core labs by 9%, to $362 million, and provide $50 million to complete the agency's Advanced Measurement Laboratory in Gaithersburg, Maryland, plus $35 million for equipment.

    Agriculture: The Administration is taking another stab at boosting funds for competitive grants: It has proposed doubling the National Research Initiative, to $240 million. “That's phenomenal,” says Karl Glasener of the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. On the other hand, the department has not even asked to fund the Initiative for Future Agriculture and Food Systems—a $120-million-a-year legislatively mandated program that's long been a political hot potato.

    Geological Survey: Once again the survey would suffer under the president's budget proposal, with an 8.7% cut, to $867 million. Much of the decline, not including a 9% reduction in the National Water-Quality Assessment, to $57 million, is the result of eliminating congressional earmarks. The $14 million Toxic Substances Hydrology Research program would disappear, although $10 million of it would be shifted to NSF.

    Environmental Protection Agency (EPA): Some 60% of a requested $200 million increase for the $7.5 billion agency would go for antiterrorism initiatives, including figuring out how to clean up buildings contaminated by biological agents. EPA's scientific core, the Office of Research and Development, would lose ground: A proposed $75 million for cleaning up contaminated buildings more than erases a $35 million hike, to $626.9 million. Administrator Christine Todd Whitman also has requested $8 million for “computational toxicology": using data from the Human Genome Project to do risk assessment of compounds. “We tried to come up with a sexier name, but when you're dealing with scientists that's a tough thing to do,” she says. EPA's budget also includes $8 million to keep water out of South Dakota's Homestake gold mine, the proposed site of an underground neutrino laboratory.

  13. 2003 BUDGET

    NSF Shines Brightest in New Good-Government Scorecard

    1. Jeffrey Mervis

    The National Science Foundation (NSF) manages its $4.8 billion budget better than any other federal agency, according to the foundation's overseers at the White House Office of Management and Budget (OMB). In fact, OMB this week awarded NSF the only “green light” in the executive branch, praising its ability to instantaneously tell scientists the status of their research proposal or how much grant money is left in their account. The exercise is part of a new ratings system tied to the president's 2003 budget request (see main text).

    In a bid to improve government operations, OMB has assigned every agency a red, yellow, or green light in each of five categories: human resources, competitive sourcing, financial management, electronic commerce, and integrating budget and performance. The grading initiative extends a 1993 law (Science, 6 January 1995, p. 20) that forces agencies to look inward, set consumer-oriented goals, and then track how well they are meeting them. “It should be no surprise that 80% of [this year's] ratings are red,” says OMB's Marcus Peacock, because officials wanted to highlight the need for improvements. Even NSF's top mark in financial management, for example, is offset by three reds and one yellow in the other areas. Still, Peacock says other agencies should seek “to emulate” NSF's budgetary prowess.

    CREDITS: RYAN MCVAY/PHOTODISC

    What is NSF's secret? Its electronic grants management system, called FastLane, helps investigators and program managers keep close tabs on the agency's research efforts. Using peer review to award 94% of its research dollars also helps—although the Department of Health and Human Services, parent of the National Institutes of Health, also scores a commendable 83%. (The Department of Energy, in contrast, peer reviews just 24% of its research.) The extensive use of upfront funding to avoid tying up its budget in long-term commitments also gets good marks.

    In addition, it probably doesn't hurt that NSF's former chief financial officer, Joseph Kull, now oversees the OMB review of federal financial management systems. “I've taken a lot of ribbing for that,” Kull admits. “But when my boss learned about everything that NSF has done, he totally agreed with the [top] rating.”

  14. 2003 BUDGET

    White House Wants to Shuffle, But Will Congress Dance?

    1. Jeffrey Mervis

    National Science Foundation (NSF) director Rita Colwell laced up her political track shoes and ran for cover this week. She was anxious to avoid getting caught in the middle of an upcoming clash between the White House and Congress over a controversial presidential proposal to transfer three research programs from other agencies to NSF.

    “I have no opinion” on the proposed moves, Colwell told a group of journalists and science lobbyists assembled to hear her analysis of the agency's proposed budget for 2003. “We will do whatever we are assigned to do, well.” But her comments, unusually frank for an agency head, suggest that her real preference would be to see the issue vanish.

    Sea change.

    White House wants to move some marine science programs to NSF.

    CREDIT: OAR/NURP

    The proposal, by the White House Office of Management and Budget (OMB), would give NSF responsibility for the $57 million Sea Grant program currently run by the National Oceanic and Atmospheric Administration, a $10 million water-quality program at the U.S. Geological Survey (USGS), and a $9 million environmental education program at the Environmental Protection Agency. OMB officials say that the three programs would benefit from being part of an open, NSF-run research competition, implying that they currently suffer from lax management. “The idea is that if the work is competed, it could end up back at USGS or somewhere else” that proposes a better way to do it, says OMB's Marcus Peacock.

    It's hard to find anyone who thinks the transfer will happen, however. Federal budget officials, congressional aides, and lobbyists all say that the proposals are dead on arrival at Congress, as congressional committees are expected to fight to keep the programs in the agencies they oversee. OMB has already bowed to pressure and withdrawn a similar plan to give NSF $35 million from three research centers run by the Smithsonian Institution, settling instead for a feasibility study. At the same time, nobody expects OMB to abandon its underlying message: Agencies must earn the right to manage a research program.

  15. CIRCADIAN CLOCK

    How the Brain's Clock Gets Daily Enlightenment

    1. Marcia Barinaga

    Researchers have discovered a new class of light-sensing cells in the mammalian retina that send their information to the circadian clock

    Like a watch that runs a bit fast or slow, an animal's internal clock must be reset every day. The circadian clock regulates 24-hour patterns of behavior and physiology; it controls body temperature, schedules sleep and activity, and protests when we cross too many time zones at once.

    Daylight sets this clock, and researchers have long known that in mammals, circadian photoreceptors—the neurons that detect light and send its signal to the clock—are located in the eyes. But the identities of the photoreceptors and the photopigment chemical within them that reacts to light have remained elusive.

    In a burst of papers published in the past 2 months, culminating with two in this week's issue of Science, researchers report their discovery of a new class of light-detecting retinal cells that send their signals to the brain's clock; the cells also contain a molecule that may be the long-sought circadian photopigment.

    “This is spectacular,” says clock researcher Joseph Takahashi of Northwestern University in Evanston, Illinois. “It is the biggest break yet in the question of what is the photoreceptor in mammals.”

    The papers, from five different labs, mesh seamlessly, says clock researcher Martin Zatz of the National Institute of Mental Health in Bethesda, Maryland. “They've gone at it from a molecular perspective, from an anatomical perspective, from functional, electrophysiological, and immunocytochemical perspectives,” he says. “It all fits.”

    Indeed, Zatz adds, the new work describes an entirely independent light-detection system in the mammalian eye. It is intermingled with the neurons that serve vision but has unique characteristics. These are suited for detecting the level of illumination, known as luminance or irradiance, rather than the contrasts and details in which the image-forming visual system specializes. What's more, this system appears to send its signals not only to the clock, but also directly to other brain areas that use irradiance information, such as the area that controls light-activated pupil constriction.

    “It looks like there is a generalized irradiance-detecting system that is regulating a variety of different non-image-forming responses to light,” says photopigment researcher Russell Foster of the Imperial College of Science, Technology, and Medicine in London.

    The impact of this light-sensing system may go far beyond pupil size and the clock. In humans, light levels can modulate mood and performance. “This photoreceptor system may be incredibly important in our general physiology and well-being,” says Foster.

    The eyes have it

    Unlike other vertebrates, which have light sensors in multiple tissues, mammals detect light only with their eyes. Researchers initially assumed that mammals rely on the retina's visual photoreceptor cells—the rods and cones—for all their light sensing. But in 1999, Foster's team showed that mutant mice lacking all rods and cones still have light-responsive clocks. Some other cells in the eye had to be sensing light, perhaps using a unique photopigment to do so. Indeed, the photopigments in the rods and cones are optimally activated by light wavelengths of 500 and 506 nanometers, respectively, whereas recent unpublished results from Foster's group show a different optimal wavelength for resetting the clock of the mice that lack rods and cones.

    Photopigment contender.

    These mouse retinal ganglion cells contain melanopsin.

    CREDIT: ANA CASTRUCCI AND I. PROVENCIO

    In 1998, a protein found in the eye and called cryptochrome briefly looked like a hot candidate for the circadian photopigment. But while attention was focused on cryptochrome, another molecule, melanopsin, quietly entered the scene.

    Ignacio Provencio, Mark Rollag, and Guisen Jiang of the Uniformed Services University of the Health Sciences in Bethesda, Maryland, had set out to clone the photopigment in frog melanophores, skin cells that redistribute their stores of light-absorbing melanin in response to light. Their effort yielded a previously unknown member of a class of proteins called opsins, many of which act as photopigments. Provencio dubbed the protein melanopsin. And, although it hadn't been proven to respond to light, its presence in the melanophores suggested it was their light sensor.

    The team went on to find melanopsin in the frog's retina as well, and that was when “a light bulb went off,” says Provencio. If melanopsin were in mammalian retinas, it might be the circadian photopigment. He and his colleagues cloned the mouse melanopsin gene and, as they reported in the Journal of Neuroscience in January 2000, found melanopsin in the mouse retina, in a small subset of retinal ganglion cells (RGCs).

    RGCs are well known to vision researchers not as light-sensing cells, but as the neurons that receive signals from rods and cones and pass them to the brain via the optic nerve. Most RGCs send their long connecting axons to brain areas involved in vision. But a few, about 1% or 2% of those in a rodent's retina, go to other parts of the brain, including the suprachiasmatic nucleus (SCN)—the home of the circadian clock.

    Clifford Saper of Harvard Medical School in Boston runs a lab that studies the RGC-SCN link. Last May, Josh Gooley, a first-year graduate student, approached Saper with an idea for a rotation project: He wanted to see if the RGCs that contain melanopsin connect to the SCN.

    Gooley injected the SCN of rats with a dye that marks neurons by traveling backward along their axons to their cell bodies, thus labeling the small fraction of RGCs that link to the circadian clock. He then stained the retinas with a DNA probe for melanopsin RNA. By September, Gooley had his answer: It marked the very same cells.

    Meanwhile, members of Jens Hannibal's team at the University of Copenhagen took a different path to the same result. They had shown that RGCs that link to the SCN contain a peptide called PACAP. When they double-stained for both PACAP and melanopsin, they found melanopsin in the PACAP-containing cells.

    The Saper group published its work in December 2001 in Nature Neuroscience; the Hannibal team, in the online January 2002 issue of the Journal of Neuroscience. The two papers confirm what many suspected when they saw Provencio's paper 2 years ago: The neurons that connect to the clock contain melanopsin.

    Lighting the path

    Neurophysiologist David Berson of Brown University in Providence, Rhode Island, didn't need to hear that before making his move. Provencio's paper, Berson says, made it “absolutely plain” that these RGCs were “the prime candidate for the missing photoreceptor.” Normally, RGCs are activated indirectly by light signals from the rods and cones. It would be “completely revolutionary” for them to respond directly to light, Berson says. “I just had to find out if they did.”

    Berson was well positioned to do that. His team specializes in recording the electrical activity of RGCs. The researchers injected a dye into the SCNs of rats to label the RGCs that connect there, then they removed the rats' retinas and recorded the electrical responses of the labeled RGCs.

    “We knew we were onto something” right away, Berson says, because the cells fired in response to light. Clearly, they weren't being triggered indirectly by the rods and cones, because in Berson's preparation, the rods and cones are incapacitated. That meant the RGCs must be responding directly to the light.

    Seen the light.

    This rat retinal ganglion cell fires in response to light.

    CREDIT: FELICE DUNN AND D. BERSON

    To confirm this, Berson's team added drugs to block all neuron-to-neuron signaling in the retinas, making it impossible for the RGCs to be activated by other neurons. When light hit the retinas, the cells still fired.

    For a final check, the researchers removed individual RGCs from the rat retinas, and the isolated cells responded to light. Those results, published on page 1070, “are definitive,” says Zatz. “They clearly demonstrate that this subset of ganglion cells is directly photosensitive.”

    Researchers had now shown that melanopsin is in a small set of RGCs that connect to the clock, and that RGCs linked to the clock respond directly to light. To close the circle and show that the melanopsin-containing and light-sensitive cells are one and the same, Berson and his postdoc Motoharu Takao teamed up with King-Wai Yau of Johns Hopkins University in Baltimore and his student Hsi-Wen Liao, who had made antibodies to melanopsin.

    Takao labeled the RGCs that send axons to the SCN and confirmed that they were light responsive, then Liao used the antibodies to show that those same cells contain melanopsin. That finding suggests that melanopsin is the photopigment that allows some RGCs to register light, a signal those RGCs then send to the circadian clock.

    Beyond the clock

    In their paper, which appears on page 1065, Yau and colleagues report another intriguing result. Using mutant mice engineered by postdoc Samer Hattar, they traced the axons of the melanopsin-containing RGCs and found that they don't all go to the SCN. Some connect to other brain areas involved in circadian function or the part of the brain that constricts the pupils in response to light. The neurons seem to communicate with still other regions that remain to be studied closely. “It looks to be a single population of ganglion cells, namely, those that contain melanopsin, that go to all these different targets,” Yau says.

    Apparently, the light-sensitive RGCs make their information about luminance levels available to multiple brain systems that can use it. Pupil constriction is one, and Berson has evidence suggesting that the RGCs contribute to that system: His team found that the best wavelength of light for activating the melanopsin-containing RGCs is the same as the optimal wavelength that Foster and his colleagues Robert Lucas and Ronald Douglas reported for triggering pupil constriction in mice without rods and cones.

    These special RGCs are well suited to the job of detecting irradiance, a mission quite different from that of the rods and cones. Rods and cones relay details about the light coming from individual points in the visual scene; to do this, each rod or cone cell responds only to light shone on a very small spot. But the RGCs Berson studied respond to light striking a broad expanse of the retina.

    That complements what Provencio and his team found when they stained RGCs for melanopsin. They reported in the 31 January issue of Nature that the melanopsin-containing RGCs have large melanopsin-filled networks of receptive endings, called dendrites, that cover large patches of retina. “This looks like a net that is spread out through the whole retina to catch photons,” says clock researcher Michael Menaker of the University of Virginia in Charlottesville.

    Berson and his colleagues found other ways in which the light-responsive RGCs are particularly tuned to detect luminance. The neurons are not as sensitive to light as the rods and cones are, and they do not change their sensitivity in response to changes in luminance. Rods and cones need to turn down their sensitivity when the ambient light brightens suddenly, for example, or we would be blinded.

    The light-responsive RGCs are slow to react to luminance changes but then respond continuously without adapting for at least 20 minutes. That ensures a stable reading of average light levels—just what the circadian system needs, says Provencio, to weed out “photic noise” and prevent the clock from being shifted, for example, by a brief flash of lightning. “The properties of this particular subset of retinal ganglion cells are just perfect for the job,” says Menaker.

    Although researchers generally agree now that some RGCs are photoreceptors, they are reluctant to bestow the title of circadian photopigment on melanopsin just yet. “Melanopsin is clearly the best candidate we have, because it is turning up in the right place,” Foster says. But unlike other opsin molecules, melanopsin has still not been proven to react to light.

    Light messenger.

    Blue-stained axons of melanopsin-containing retinal ganglion cells reach the suprachiasmatic nucleus (dark blue) via the optic nerve.

    CREDIT: S. HATTAR AND K.-W. YAU

    The gold standard for proving that a molecule is a photopigment is to make a lot of the protein in cultured cells, reconstitute the protein in its natural state, shine light of various wavelengths on it, and measure its absorbency. Researchers have done this with the opsins from rods and cones and other closely related opsins. But it's tricky to get the protein to fold correctly, and researchers have not been able to achieve this with either cryptochrome or melanopsin.

    Until melanopsin is shown to be a photopigment, says Foster, researchers must consider that there may be some other photopigment in the RGCs that project to the SCN. Some still view cryptochrome, which is found in some RGCs, as a candidate. Saper's team at Harvard is using cryptochrome probes from Aziz Sancar of the University of North Carolina, Chapel Hill, to see if the cryptochrome-containing RGCs link to the SCN.

    Meanwhile, those studying melanopsin will soon have another tool: mutant mice that lack the pigment. “I think there is a high probability they are going to see some defect” in those mice, says Northwestern's Takahashi. A defect would be further evidence that melanopsin has a light-sensing role.

    But it may be too much to expect the clocks in the mutant mice to be totally unresponsive to light. The circadian clock is too important for survival to rely on just one photopigment, Takahashi says. Although melanopsin may be the clock's main light detector, most researchers expect that there are other sources of light information—perhaps from the rods and cones, or from cryptochrome-containing cells—that may fill in if melanopsin is knocked out.

    “It is very satisfying that everything has come together this way,” says clock researcher Greg Cahill of the University of Houston about the recent progress. After years of learning which cells and molecules are not the circadian photoreceptors, he says, “now, we have really nice information about what they might be.”

  16. PRIMATOLOGY

    Homeland Defense in the Wild

    1. Dennis Normile

    INUYAMA, JAPAN— The 100 participants in “Research on Long-Lived Animals” held here 15 to 18 January discussed the driving force behind male territoriality in chimpanzees, the behavior of gibbons toward long-lost relatives in need, and a successful effort to protect muriquis in Brazil. But they also explored the sociability of primates, with both welcoming and farewell parties and a trip to a traditional Japanese pub.

    Territorial Motives

    Are male chimpanzees after food or sexual favors when they seek to expand their territory? An analysis of 25 years of data from the Kasakela chimpanzee community at Gombe National Park in Tanzania suggests that both reasons apply, with nutrition taking the lead in this long-running debate among primatologists.

    The Kasakela community may be the best studied group of primates on Earth thanks to the pioneering work of primatologist Jane Goodall in the early 1960s. Although Goodall is still involved, most of her efforts now go into conservation. Local workers have continued tracking individual animals from nest to nest, recording their movements, diet, weight, companions, and interactions, with both group members and neighboring communities. But their notebooks were accumulating dust in Goodall's house in Dar es Salaam until 1990, when Anne Pusey and colleagues at the department of ecology, evolution, and behavior at the University of Minnesota, Twin Cities, shipped them to the university's Jane Goodall Institute.

    Using computers to tease out a number of subtle changes over time, Pusey presented evidence here that male territoriality is aimed at gaining access to food rather than attracting mates, as many believed. At the same time, a copious food supply has the added benefit of enticing more females. “This is really something of a merger of the two theories,” says Pusey. A report on a portion of these results is in press at Animal Behavior.

    Chimpanzee communities consist of roughly equal numbers of adult males and females and their offspring. Males stay with the natal group for life. Interactions with male chimps from neighboring groups are always hostile, usually fiercely so. Juvenile females typically migrate to a different group. Once they become adults, however, females usually remain with a community and tend to stay near the center of the community's territory.

    Banana bait.

    A treat lures Gombe chimps onto scales to be weighed.

    CREDIT: A. PUSEY

    Pusey's analysis refines that observation by showing that adult females modified their roaming pattern in accordance with changes in the community's boundaries, which varied over time from 5.5 to 13 square kilometers. When the group's territory grew, the core area covered by adult females also expanded. When the group's territory shrank, adult females restricted their movements to a smaller core to avoid being at the edges of the territory.

    When the Kasakela group expanded its territory, males were not rewarded with more females, Pusey says, presumably because females in the neighboring community also restricted their movements to a smaller core area as their group's territory shrank. Indeed, when adult females did occasionally wander into the fringes of Kasakela territory, Kasakela males drove them away. “So we don't think access to females is the prime motivating factor in defending territory,” Pusey concludes.

    Instead, the analysis supports the hypothesis that males defend a feeding range for themselves, resident females, and their offspring. Signs of better nutrition followed an increase in the group's territory: Average body weight climbed, resident females were more likely to show the swelling of the rump indicating fertility, and their babies were born closer together.

    Even so, an expanding empire may eventually pay off in the mating game. Pusey's team also found that juvenile females were more likely to join the Kasakela community when its territory was at its maximum. Perhaps they recognized that the group commanded a good food supply, Pusey speculates, or were attracted to heavier, better fed males. “One of the benefits of long-term studies is that you can answer questions you might not even have thought of when you started the study,” says Jan van Hooff, a primatologist at the University of Utrecht, the Netherlands. “And these results from Gombe are a good example.”

    Why the size of a community's territory waxes and wanes so much remains a puzzle, however. Pusey says recent studies of chimp groups adjacent to the Kasakela community suggest that groups expand their range when they outnumber their neighbors. But more long-term data are needed to understand what triggers these growths and declines in population, data that might yet be found in the Gombe notebooks.

    Set Out Another Plate, Ma

    A crisis often brings families closer together. That adage is as true for gibbons as for humans, according to new work by Teruki Oka, a primatologist at the Forestry and Forest Products Research Institute in Morioka, Japan.

    Oka began studying gibbons in the Bukit Soeharto Education Forest of Mulawarman University in East Kalimantan, Indonesia, in 1995. He followed 21 individuals in six family groups as part of an effort to develop conservation plans for the region. His work took a surprise turn in the spring of 1998, however, when a forest fire swept through the study area. Although many larger trees were left standing, the loss of ground cover and smaller trees dramatically affected the animals' food supply and disrupted normal territorial patterns.

    Fireproof friendships.

    Gibbons in East Kalimantan reestablished familial ties after being uprooted by forest fires.

    CREDIT: LUIZ GUSTAVO DIAS

    A number of sociological characteristics distinguish gibbons from other apes, Oka says. They form monogamous couples that defend a home territory for the exclusive use of themselves and their family. And both male and female offspring leave the group at sexual maturity, find mates, and stake out their own ranges. Although other adults are not welcome in a pair's territory, unrelated juveniles occasionally join family groups, apparently as part of the search for a mate.

    Six of the 21 animals Oka had been tracking disappeared after the fire, presumably either killed or driven away. Seven more had moved from their home ranges, he found. One adult male who had lost his mate and home base moved to a neighboring territory with his male child and formed a new family group with the resident female, apparently chasing away the spouse, who was spotted roaming alone in another part of the forest.

    Much to his surprise, Oka also found that two gibbon pairs displaced by the fire had joined family groups whose territories had not been so badly burned. Why would these gibbons suddenly tolerate competing adults in their ranges, he wondered. On a hunch, Oka analyzed the DNA of fecal samples to see if there might be a family connection. He was right.

    The host couple were the parents of one member—male in one case, female in the other—of each intruding pair. In effect, at a time of crisis, the children and their mates were welcomed back home. “A family in need is a family indeed,” Oka concludes. Minnesota's Pusey is intrigued by the findings: “It had always been thought that familial groups needed regular contact to continue to recognize kin.” Toshisada Nishida of Kyoto University says that he's struck by the gibbons' ability to be flexible in an emergency.

    But the welcome mat may not stay out forever. As the forest began to recover, Oka noticed that the parents grew less tolerant of sharing their fruit trees, sometimes to the point of chasing away a youngster. It was, he says, as if the parents were telling the younger couples that it was again time, now that the crisis had passed, to find their own piece of the forest.

    A Conservation Success Story

    Scientists have helped broker a deal between the Brazilian government and a local landowner that provides hope for the survival of a highly endangered New World monkey.

    The northern muriqui of Brazil is one of the world's 25 most endangered species, with most of its woodland habitat having been cleared over the past century for farming. But last fall, the muriquis got a new lease on life when a 957-hectare patch of privately owned forest that hosts more than half of the 300 remaining monkeys was turned into a reserve. “Now we have the forest secure,” says Karen Strier, a behavioral ecologist at the University of Wisconsin, Madison, whose studies of the muriquis focused attention on their plight and helped build a case for the reserve.

    Muriquis had received scant attention before Strier began studying them in 1982. She found them to be a curious breed. Unlike many other primate species, there is virtually no aggression among the males of a troop, and females mate with as many males as possible. “These findings suggested a greater diversity in behavioral options for primates,” Strier says.

    Fast friends.

    Karen Strier's studies of muriquis helped build a case for preserving their Brazilian habitat.

    CREDIT: JONATHAN HEAD/AP

    But the century-long expansion of agricultural activity in Brazil's Atlantic Forest, which hosts muriquis and dozens of other species, threatened to foreclose further exploration of those options. Fewer than 10% of the forest remains, mostly as isolated fragments too small to sustain wildlife populations. One of the largest chunks is at Caratinga, about 560 kilometers north of Rio de Janeiro, where the Abdala family kept a sizable chunk of the forest intact to provide humidity for nearby coffee groves.

    Studies by Strier and her colleagues in the 1990s concluded that the Caratinga muriquis are the only known population with sufficient numbers, genetic diversity, and habitat to be viable for the long term, and that enlarging the forest would allow more animals to survive. Armed with those data, researchers and conservationists added some 100 hectares to the forest by persuading some landowners to let surrounding pastures grow wild. But the biggest conservation victory came in September with a deal that will keep it in a natural state for perpetuity. Under the agreement, the Abdala family maintains title to the land and the Brazilian government agrees to watch over it.

    The deal demonstrates the positive role that scientists can play in conservation efforts, according to Strier. “Long-term studies have so much to contribute, not only to understanding the biology and ecology of endangered primates,” she says, “but also helping to tailor conservation efforts on their behalf.”

    Caratinga shows that “people with a long-term interest in conservation at a particular site can make a difference,” says Marina Cords, a behavioral ecologist at Columbia University in New York City. But she cautions that not all conservation campaigns will be as easy to mount. Preserving the Caratinga forest was an obvious step to take, she says, because it is the only viable remaining habitat for a highly endangered species. “But someone trying to conserve a forest in Africa or Southeast Asia couldn't claim that it was nearly the only patch of forest left [for a certain species].”

  17. VERA RUBIN PROFILE

    The Bright Face Behind the Dark Sides of Galaxies

    1. Robert Irion

    Vera Rubin has raised four scientists, measured the rotations of galaxies, and advanced the cause of women in astronomy—usually in that order

    Vera Rubin's first press clipping was a doozy. “Young Mother Figures Center of Creation by Star Motions,” gasped The Washington Post on 30 December 1950. “A young mother, in her early 20s, startled the American Astronomical Society today with a daring report—so daring, in fact, that most astronomers think her theories are not yet possible.”

    More than 4 decades later, her friends concocted another headline: “Old Grandmother Gets National Medal of Science.” It marked a real honor bestowed upon her by President Bill Clinton in 1993: a tribute to her victory over rebukes and dismissals in forging one of the most distinctive careers in 20th century astronomy.

    To celebrate that career, a constellation of noted astronomers gathered here last month for a symposium* at the Carnegie Institution of Washington. Rubin, now 73, listened to presentations on the nature of galaxies, nearly all of them influenced by her pioneering studies on how galaxies revolve within massive shrouds of “dark matter.” Every astronomy text describes her evidence: a methodical analysis of how stars move in the outskirts of galaxies, research that she continues today.

    Just as important to Rubin's success, many noted, are the deep curiosity, unbiased eyes, and unabashed joy that she brings to her work. “She retains a child's wonder at it all,” said astronomer Donald Lynden-Bell of Cambridge University, United Kingdom. “The originality of her research programs is matched only by her ability to recognize the importance of the unexpected whenever it turns up.”

    Other comments praised Rubin for improving the lot of women in the male-dominated field of astronomy, or for raising four Ph.D. scientists with her husband of 53 years, chemical physicist Bob Rubin. The combination of stellar career and brilliant family is “amazing,” says astronomer Sandra Faber of the University of California (UC), Santa Cruz. “I'm totally blown away by that.”

    Rubin wears her fame lightly, welcoming even first-time visitors with genuine warmth and lack of pretense. In a field where collisions between senior astronomers are common, she radiates kindness. “She is utterly down to earth,” Faber says. Sitting in her tidy office at the Carnegie Institution's bucolic campus in northwest Washington, D.C., Rubin shrugs when asked about the harsh receptions some of her ideas have received. “I just thought to myself, 'These astronomers are very cross people,'” she says of her 1950 presentation. “I was reasonably pleased that I had chosen to do something no one had ever done.”

    What Rubin did, for her master's thesis at Cornell University, was to analyze the motions of 109 galaxies. She subtracted the known expansion of the universe and plotted the leftover motions on a globe. The pattern was consistent with spin around a common axis. Rubin's talk, boldly titled “Rotation of the Universe,” featured statistical methods that wouldn't hold today. But she was on to something, namely, that the unexpected motions of stars and galaxies were hiding cosmic secrets.

    Island universes.

    Rubin's love of galaxies has driven her career, from Vassar College in 1947 (top) to the present day.

    CREDIT: (TOP TO BOTTOM) COURTESY OF V. RUBIN; RICK KOZAK

    Her curiosity about such motions dates from her childhood in Washington, D.C., when she watched the sky turn at night outside the north-facing window at her bedside. It sounds apocryphal, she admits, “but it's absolutely true. I became an astronomer because of looking at the sky.” Her father, an electrical engineer, helped her make a crude telescope, but Vera did the rest. “I faked my way through high school. Every report I had to write was related to astronomy.”

    The young Vera Cooper received scarce encouragement along the way. Her physics teacher, upon learning that she had received a college scholarship, had these words: “As long as you stay away from science, you should do OK.” An admissions officer at Swarthmore College in Pennsylvania suggested that she become an astronomical artist, advice that her family turned into a running joke whenever anyone encountered a hurdle: “Have you ever thought about going into painting?” Instead, she chose Vassar College in Poughkeepsie, New York, because Maria Mitchell—the first nationally known woman astronomer—had worked there.

    Vera Cooper and Bob Rubin, soon to be a graduate student in chemistry at Cornell, met on a summer break and married after her graduation from Vassar in 1948. Her new status led her to turn down an offer from Harvard University for the then relatively unknown astronomy program at Cornell. Thus began a series of tough decisions familiar to two-career couples. “We made a number of compromises over the years, depending on where the options were most promising for each of us,” Bob says.

    Bob's first job was at the Applied Physics Laboratory of Johns Hopkins University, then located in Silver Spring, Maryland, where he worked with physicist Ralph Alpher. He introduced the Rubins to his colleague, astrophysicist George Gamow of George Washington University. Gamow became Rubin's adviser even though she was attending Georgetown University, which had the area's only Ph.D. program in astronomy. Her 1954 thesis on the large-scale distribution of galaxies broke new ground on a topic that remains hot today. In the meantime, Rubin fell in love with the wood-paneled library of Carnegie's Department of Terrestrial Magnetism (DTM) where she and Gamow used to meet. She joined the Georgetown faculty but did little observing, instead focusing on her family. “It took me a long time to believe I was a real astronomer,” she says.

    The turning point came in 1963. Bob Rubin took a 1-year fellowship in La Jolla, California, so that Vera could collaborate with noted astrophysicists Margaret and Geoffrey Burbidge of UC San Diego. The Burbidges invited her to observe at the McDonald Observatory in Texas. Using an 82-inch telescope, Rubin measured the rotation of a galaxy for the first time.

    Beyond experiencing the thrill of collecting such data, Rubin felt a new sense of professional accomplishment. “The Burbidges' interest in what I had to say made it seem possible that, yes, I could be an astronomer,” she recalls.

    Returning to Washington, Rubin walked into DTM and asked for a job. Director Merle Tuve agreed to hire her at two-thirds of her Georgetown salary—allowing Rubin to get home in time to welcome her children from school. “Vera owes everything to DTM,” says UC's Faber, noting that researchers there don't teach and rarely apply for grants. “It was just the kind of place where she could flourish and catch up. If she had gone to a university, she would have been inundated with other things to do. Carnegie was a garden in which she could grow.”

    One bountiful collaboration involved physicist Kent Ford, inventor of the image-tube spectrograph, a device for electronically amplifying starlight. The technical advance brought dim parts of the universe into view for the first time. The partnership lasted until Ford retired in 1990. The duo's observing trips, by themselves or with a succession of postdoctoral researchers at DTM, took them to Kitt Peak and Lowell Observatory in Arizona and to Cerro Tololo in Chile. In 1965, Rubin became the first woman legally permitted to use the 17-year-old Palomar Observatory in Southern California. She loved to plan telescope pointings, prepare photographic plates, set up heavy equipment, and guide the telescope through the cold nights—often accompanied by The Pirates of Penzanceor more tranquil music.

    She also enjoyed scrutinizing the data, which she still does today. Indeed, the Monday morning after her recent symposium found her back in her office, measuring spectra. “That's the nitty-gritty work, and she does most of it herself,” says astronomer Stacy McGaugh of the University of Maryland, College Park. “She's all about the science. She just loves getting into it.”

    Geologic explorers.

    The Rubins in Rocky Mountain National Park, summer 1961: Karl, David, Allan, Vera, and Judith (left to right).

    CREDIT: BOB RUBIN

    Rubin's joy washed over her family, both at home and on summer sabbaticals, often in the southwestern United States. “We lived in a household where being a scientist looked like so much fun,” says daughter Judith Young, an astronomer at the University of Massachusetts, Amherst. “How could we possibly want to do anything else?” Evidently, her siblings felt the same way: older brother David, a geologist with the U.S. Geological Survey in Santa Cruz, and younger brothers Karl, a mathematician at Stanford University, and Allan, a geologist at Princeton University.

    At DTM, Rubin and Ford's early work focused on quasars, distant and energetic points of light discovered in 1960. The team also detected an apparent large-scale motion of many galaxies toward one part of the sky, a phenomenon soon called the “Rubin-Ford effect.” Both the quasars and the galaxy motions, however, proved too competitive and controversial for Rubin's tastes. She returned to the topic she broached with the Burbidges in 1963.

    “Lots of people were working on the centers of galaxies, but I got curious about the outsides,” she says. “I wanted to know how galaxies ended, which is not a question anyone ever talked about.” The spectrograph allowed Rubin and Ford to examine rotation in those wispy outer reaches as never before. That search formed the heart of Rubin's career. The team compiled an exhaustive set of spectra of spiral galaxies. Each spectrum revealed the speeds of hydrogen gas and stars around the galaxy's center via the Doppler effect. Astronomers expected to see the most distant stars move slowly, just as the outer planets in our solar system orbit the sun at a snail's pace, compared to the inner planets. However, nearly all of Rubin and Ford's spectra were flat: Stars moved at a constant speed, out to the edges of the galaxies. The strange but unavoidable consequence was that unseen matter—and a lot of it—enshrouded the entire visible disks of the galaxies and added enough mass to accelerate the outermost stars.

    Rubin's careful work earned her election to the National Academy of Sciences (NAS) in 1981. She was the second woman astronomer chosen—after Margaret Burbidge in 1978. Still, Rubin readily acknowledges that she did not “discover” dark matter, as some popular accounts over the years have implied. Other evidence, including data from radio astronomy, was more convincing to some observers. Rubin neither knows nor cares what role history will assign her in the unraveling of this basic cosmic mystery.

    Away from the telescope, Rubin's advocacy for women has earned her great respect. She and Burbidge have been outspoken in calling for more women in the NAS, on review panels and program committees, and as serious candidates in academic searches. She has seen a lowering of the most egregious barriers—excluding women from graduate programs and observatories and actively discouraging them from entering the field. However, pervasive problems remain. Salaries for women are lower, faculty positions are hard to come by, and honor societies are still male bastions.

    “My daughter has had normal academic problems for a woman; it's terrible to call them 'normal,'” Rubin says. “I have fought with the NAS, and I am outraged at the small number of women elected each year. It's the saddest part of my life. Thirty years ago, I thought everything was possible.”

    When Rubin talks with girls and young women considering careers in astronomy, she urges them to persist in the face of adversity. That was the key for her generation, says a friend, Nancy Grace Roman, who had a distinguished career at NASA headquarters: “We were stubborn. We never seriously wanted to do anything else.”

    The 1950 Washington Post article hints at that resolve. “The astronomers were not complimentary,” the reporter concluded. “They politely and persistently questioned [Rubin's] figures, because there are not enough sure observations to substantiate them. She replied that it was worthwhile to try.” A half-century later, her fellow astronomers let her know how glad they are that she never stopped trying.

    • *“Galaxies: Mind Over Matter,” 10-11 January.

  18. A Space Age Vision Advances in the Clinic

    1. Eliot Marshall

    The total mechanical heart is making headlines, but many say a less radical technology—the heart assist device—is leading the revolution

    After barely surviving for nearly 2 decades, efforts to build a “total artificial heart” have gained a new lease on life. Surgeons in Louisville, Kentucky, removed the failing heart of a 59-year-old man last July and replaced it with a machine. Indeed, they implanted a whole network of machines: a 1-kilogram pump, a computer, a battery, a power converter, and cables to link them all together.

    It was a dramatic procedure, the first total heart implant in the United States since the mid-1980s. The patient, Robert Tools, had been facing certain death and was too sick for a donor heart. He agreed to be the first to try a new mechanical replacement heart made by Abiomed Corp. of Danvers, Massachusetts. And it was a success, at least in some respects: Tools survived the implantation at Louisville's Jewish Hospital and later gained enough strength to venture outdoors a couple of times. But he suffered a stroke—caused possibly by a clot that formed in the artificial heart. On 30 November he died after 151 days on the machine.

    Tools's experience was certainly better than that of his famous predecessor—Barney Clark, the Seattle dentist who in 1982 was the first to receive the celebrated “Jarvik-7” heart, named for its designer Robert Jarvik. Clark lived 112 days tethered to an external power unit the size of a washing machine, never able to leave the hospital room. In news clips he appeared miserable and uncomfortable. Even though another patient with a Jarvik-7 lived for 620 days, the artificial heart became linked in the public mind with Barney Clark's ordeal.

    Hoping to erase those memories, Abiomed took a different tack. It created a more user-friendly device, called AbioCor, in which the pumping components are fully implanted, powered by radio-frequency energy transmitted through the skin. Doing away with connector lines may lower the risk of infection and frees the patient to walk around for several hours with batteries. Company president and CEO David Lederman also sought to protect patients' privacy and limit harsh publicity: Hospitals agreed not to give daily reports on medical details. And he lowered expectations, telling reporters that they should consider it a success if the first patients lived 60 days. At this writing, four of six had passed that mark and three were still living. Time magazine dubbed AbioCor “the invention of the year.”

    The AbioCor trials have gone “remarkably well” considering how sick the patients are, says John Watson, the senior official at the National Heart, Lung, and Blood Institute (NHLBI) who oversees this area. But that success has rekindled a debate about the best way to meet the needs of the estimated 100,000 people in the United States who, like Tools, face heart failure each year yet have little prospect of obtaining one of the 2200 donor hearts available for transplant.

    AbioCor's comparative success has led supporters to argue that it could eventually be an alternative to transplantation. But critics dismiss the totally implantable heart as “obsolete,” a hugely expensive technology that may never deliver an acceptable quality of life. Many experts, including Watson, believe that, at least in the near term, desperate patients are more likely to be helped by machines known as ventricular assist devices (VADs). These mechanical pumps, in use since the early 1990s, boost rather than replace the ailing heart by increasing blood flow through a single chamber, or ventricle, and may even help the heart get stronger.

    Heart of the heart.

    The AbioCor pump is controlled by a small computer and power supply system, all implanted.

    CREDIT: ABIOMED INC.

    All these devices are now just stopgaps. The U.S. Food and Drug Administration (FDA) has approved them only as a “bridge to transplant,” not as a permanent solution. But supporters of AbioCor and VADs are both hoping to gain FDA's blessing for far more extensive use of these ultimate bionic devices.

    Aerospace baby

    The U.S. effort to build artificial hearts began in 1964 when NHLBI established the first R&D program, with a budget that rose to $10 million a year by 1970. Contracts, mainly with aerospace firms, yielded several test devices, including the Jarvik-7. Developed at the University of Utah under the direction of Willem Kolff, it was the first artificial heart implanted in a human with FDA's approval. Kolff recruited Utah heart surgeon William DeVries to lead the clinical work and in 1982 won FDA's consent to treat five patients. DeVries and others reported results in 1988. An accompanying editorial in the Journal of the American Medical Association noted “many complications” that “seem to be related specifically to the design of the Jarvik-7,” such as blood clots and infections along the skin-penetrating power lines.

    Three months later, NHLBI director Claude Lenfant announced that he was ending the total artificial heart program because NHLBI couldn't afford it, and many clinicians believed that VAD systems then under development were closer to practical use. But two powerful senators—Edward Kennedy (D-MA) and Orrin Hatch (R-UT)—got NHLBI to reverse that decision and renew funding.

    Over the years, NHLBI has spent about $100 million on the total artificial heart, Watson estimates. By the late 1990s, however, only two competitors remained: Abiomed and a group led by William Pierce, Walter Pae, and Gerson Rosenberg of Pennsylvania State University's Hershey Medical Center. Penn State lost the race to the clinic, Rosenberg says, when its industrial backer, 3M Corp., pulled out. In 2000 the university sold the “Penn State Heart” to Abiomed, which plans to develop it.

    Survivor

    What makes AbioCor exceptional, says company vice president Edward Berger, is that the system fits within the body. Unlike predecessors, it doesn't require a line into the body for pressure relief or power supply. It relies on a quiet centrifugal electric pump that shuttles hydraulic fluid alternately between two chambers that press on blood sacs corresponding to the left and right sides of the heart. In addition to reducing infection risks, according to Abiomed, this should enable the patient “to remain mobile and continue a productive lifestyle.”

    The AbioCor has not been priced yet, Berger says, although many predict that it will cost about $75,000. Berger notes: “Our goal is to eventually sell it for less than half that amount,” assuming manufacturing can be improved. The implantation procedure might cost $150,000, observers say. The heart would be offered to patients with moribund left and right heart chambers who could not be saved by a VAD. No one is sure how many people might be candidates; Abiomed estimates “many thousands” per year in the United States, whereas an executive at a VAD manufacturing firm doubts that the number would reach 3000. VADs, by contrast, are thought to have a potential market of 30,000 to 100,000 per year.

    Pioneers.

    Robert Jarvik (left) and Barney Clark, the patient who received the first Jarvik-7 heart, in 1982.

    CREDIT: BETTMANN/CORBIS

    Before Abiomed can sell this product, however, it must demonstrate to FDA that its device will extend and improve a patient's life. Jarvik thinks this will be hard. The AbioCor system “represents old technology,” Jarvik argues. It uses a displacement diaphragm pump that requires artificial heart valves, he adds, making for a complex system that's likely to cause clots and infections. Jarvik predicts that fiscal managers will balk at total replacement hearts: Because they are intended for the sickest heart patients, Jarvik predicts that implanting them will often be traumatic, leading to “million-dollar patients.”

    Abiomed's Berger rejects this skepticism, noting in an e-mail that “reliability testing in the laboratory leads us to think … we may already have an AbioCor that will sustain a patient for more than a year.” It is too early to tell whether blood clots will be a problem for the first-generation AbioCor, he says, although results so far suggest that “the issue is addressable through anticoagulation management” similar to that already given to patients with artificial heart valves. Recently Abiomed announced that it is removing an outer “cage” to lower the risk of clots in future trials. Eventually, 5 to 10 years from now, Abiomed hopes its device will run for 5 years and be an alternative to heart transplantation.

    Reversing field

    As Abiomed seeks to prove that its device can replace a failing heart, others—including Jarvik—are pursuing a different strategy. “Removing the natural heart is an obsolete approach,” Jarvik says today. His own company in New York City is developing small, simple pumps that go inside the heart and potentially salvage it. He calls his new device the Jarvik 2000, or the “flowmaker,” to suggest something as routine as a pacemaker. Jarvik argues that the risk of infection is greatly reduced because his device is one of several new models powered by a miniature rotary pump that generates no pulse and requires no artificial valves. The entire mechanism sits in the ventricle immersed in blood, an environment hostile to bacteria.

    One surgeon pioneering the use of Jarvik 2000, Stephen Westaby of John Radcliffe Hospital at Oxford University, U.K., seconds Jarvik's views. “The total artificial heart puts us back 30 years,” Westaby says. Instead, he praises the “thumb-sized” Jarvik 2000 because it is easy to sew inside the patient's left ventricle—and it can be removed just as simply if the natural heart improves. Already, Westaby says he is using the Jarvik 2000 experimentally as a permanent prosthesis: “I've had three in the community for 7 to 19 months now, and they're all doing terrifically well.” The 19-month patient, Peter Houghton, who according to Westaby was “within a couple of weeks of death” before surgery, recently flew across the Atlantic Ocean on a commercial plane to see relatives and brief NHLBI on his health.

    Researchers are surprised to discover that the use of VADs enables some patients' hearts to regain strength by resting the muscle. Westaby says he and colleagues at the Texas Heart Institute in Houston and the Cleveland Clinic in Ohio have all seen this phenomenon. This is “my biggest interest” now, Westaby says. “I intend to spend a lot of time on it.” He imagines that it may be possible someday to routinely use small pumps, drugs, and cell therapy to restore sick hearts.

    Many other VAD designers are also developing miniature rotary pumps. The biggest U.S. company in the field, Thoratec Corp. in Pleasanton, California, is working on several generations of VADs simultaneously. The newest, called HeartMate II and HeartMate III, will include small rotary pump devices. Terumo Corp. of Tokyo was among the first to use a levitating magnet system to eliminate bearings and friction that can damage blood cells, and similar designs are being developed by Thoratec and the Berlin Heart company in Germany.

    Next generation.

    Robert Tools (left), with doctors; Tools lived 151 days on the AbioCor device but suffered a stroke and fatal bleeding.

    CREDIT: AFP PHOTO/JEWISH HOSPITAL

    Keith Grossman, CEO of Thoratec, claims that the HeartMate II VAD pump is designed to run for 5 to 8 years and HeartMate III, for up to 10 years. These goals are twice the design life of Thoratec's current standby, the HeartMate XVE. Grossman expects that a growing number of patients who cannot get donor hearts will use VADs as a permanent solution. Indeed, Thoratec has asked FDA for permission to begin marketing VADs as a therapy for heart disease, and FDA has already scheduled an advisory panel review for 4 March.

    Thoratec and others plan to cite the REMATCH trial,* reported last November, as proof that mechanical hearts are robust enough now to be used as standard therapy. This trial of 129 patients showed that those with VADs were more likely to survive over a 2-year period, and to enjoy a good quality of life, than those on standard drug therapy. Eric Rose, lead author of the REMATCH study at Columbia University in New York City, predicts that an FDA policy change could come as early as this summer.

    The major task after the FDA review, Rose says, will be to argue that Medicare should reimburse medical centers for VADs even if patients are not waiting for a transplant. Rose is already consulting with the Department of Health and Human Services about costs. If Medicare gives a green light, the artificial heart-makers will enter a brave new world.

    • *E. A. Rose et al., “Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart Failure,” New England Journal of Medicine 345, 1435-1443 (2001).

  19. Not Blood Simple

    1. Erik Stokstad

    Compounds that act like blood to deliver oxygen are in the final stretch of clinical trials after decades of setbacks due to the complexity of hemoglobin and its sometimes surprising effects on humans when it's not ensconced in red blood cells. A handful of companies have persevered, however, predicting an ever greater need for blood substitutes as growing numbers of elderly patients needing blood-intensive surgery such as hip repairs or replacements strain the existing donor supply.

    Not Blood Simple

    Erik Stokstad

    After decades of setbacks, compounds that act like blood to deliver oxygen are in the final stretch of clinical trials

    Until March 1998, Baxter Healthcare Corp. thought it had a sure-fire winner. The Deerfield, Illinois, company was in phase III trials of HemAssist, an oxygen-carrying solution designed to treat patients in shock from massive bleeding. Analysts were excited because blood substitutes—more accurately known as oxygen therapeutics—could be stockpiled and given to anyone regardless of blood type.

    But after enrolling about 100 people who had been knifed, shot, or critically injured in car accidents, Baxter discovered that the patients given HemAssist were more likely to die than those given regular blood. “They pretty much had a disaster,” says Reuven Rabinovici, chief of trauma and surgical critical care at Yale University School of Medicine. Baxter called off the trial. And although the problem may have been faulty trial design rather than HemAssist itself, the company soon ditched its decade-long development effort.

    Most clinical testing involves disappointments, but blood substitutes have had a particularly tortured history. Four decades after research began, the U.S. Food and Drug Administration (FDA) has approved only one blood substitute—for treating anemia in dogs. Longtime researchers say the main reason for the delay is the complexity of hemoglobin and its sometimes surprising effects on humans when it's not ensconced in red blood cells. Also contributing to the rocky progress are the challenges of regulating a novel type of material, as well as ups and downs in Wall Street enthusiasm. A handful of companies persevere, predicting an ever greater need for blood substitutes as growing numbers of elderly patients needing blood- intensive surgery such as hip repairs or replacements strain the existing donor supply.

    Scientists began working on artificial blood in the 1960s, trying to see whether iron-rich hemoglobin molecules extracted from red blood cells would be able to pick up oxygen molecules and deliver them to tissues when transfused into a patient. Those early compounds ran into problems with kidney toxicity. Work took off in the 1980s, with the realization that HIV, the virus that causes AIDS, had contaminated the blood supply. “The urgency was such that industries tried to bypass basic research and proceeded immediately into development and clinical trials,” recalls blood substitute pioneer Thomas Chang of McGill University in Montreal. This generation of compounds constricted blood vessels and capillaries, which can limit circulation to oxygen-starved tissue.

    Half of the companies with compounds in advanced trials still report vasoconstriction. The reason is not entirely clear, but many researchers suspect that these compounds penetrate the lining of the blood vessels and scavenge nitric oxide (NO), a molecule that would otherwise relax the muscular walls surrounding blood vessels. Others believe that excessive diffusion of hemoglobin within the vessel is the key. In any case, scientists have reduced this problem—in animal studies and early human trials—by modifying or clumping hemoglobin molecules to make them larger. Meanwhile, Baxter is working on recombinant human hemoglobin that doesn't scavenge NO.

    Harvey Klein, chief of transfusion medicine at the National Institutes of Health's (NIH's) Clinical Center in Bethesda, Maryland, says he is less worried about vasoconstriction than he is about the incomplete understanding of why the side effect occurs: “It's telling us that something is happening at a basic level that might cause other problems.” Other experts stress that more needs to be known about how modified hemoglobin delivers oxygen to tissue before an ideal substitute can be designed.

    The novelty of blood substitutes has also raised questions about how to test them for efficacy and safety. “There is no golden standard to compare blood substitutes to,” says Konrad Messmer, a professor of experimental surgery at Ludwig Maximilians University in Munich, Germany. (FDA uses surrogate endpoints, such as a decreased need for transfused blood.)

    Another concern is the source of the hemoglobin. Most products in advanced trials purify hemoglobin from collected human blood that has passed its expiration date. In contrast, Hemopure, made by Biopure Corp. in Cambridge, Massachusetts, is made from cow blood. Biopure says it uses only U.S. cattle bound for slaughter and controls their feeding and care. The company says its manufacturing process removes any infectious agents that might slip through, such as the prions implicated in bovine spongiform encephalopathy, or mad cow disease. Last April, Hemopure was approved for anemia during surgery in South Africa.

    CREDIT: BIOPURE

    For products further upstream, investment capital is harder to come by now that the blood supply is more safe from HIV. “Fifteen years ago, there was almost a bottomless well of capital,” says Robert Winslow of Sangart Inc. in San Diego. “The capital markets for this have almost dried up.” Sangart relies heavily on NIH funding and is planning a phase I trial in Sweden for a hemoglobin molecule modified with strands of polyethylene glycol, designed to protect the molecule and prevent vasoconstriction. The Defense Advanced Research Projects Agency is also in the game, funding research into freeze-dried blood products, for example.

    Any new products that reach the market will have to compete with actual blood, Winslow notes, which is now very safe. If blood substitutes are approved in the United States for human use, they're likely to fetch a premium over blood, which can cost hospitals $200 or more per unit. Biopure hasn't set a price yet but estimates that each unit will sell for perhaps $700 to $1000. Whatever the cost, researchers and clinicians want to have supplies of blood substitutes stocked for emergencies—including the discovery of new infectious agents in donated blood.

    View this table:
    • *In the United States.

    • †Dose-dependent.

    • ‡All transient.

  20. Wanted: Pig Transplants That Work

    1. Jennifer Couzin

    A shortage of human organs spurred researchers to look for replacements from animals. They're still struggling to cross the species barrier successfully

    In the early 1960s, Keith Reemtsma, a surgeon at Tulane University in New Orleans, transplanted chimpanzee kidneys into six patients and launched the modern era of xenotransplantation. One person survived for a startling 9 months, sparking worldwide enthusiasm for a potentially limitless supply of lifesaving organs and tissue.

    Since then, the field of xenotransplantation—the transfer of organs, tissues, and cells from one species to another—has been humbled by a string of false starts and failed procedures. Nearly 4 decades after Reemtsma's transplants, no human recipient of a whole animal organ is known to have survived for as long as that early kidney patient. Twelve-day-old Baby Fae, for instance, received a baboon heart in 1984 but died 3 weeks later. Whole-organ transplants into humans have been largely abandoned in industrialized nations due to massive immune rejection and other safety worries, although researchers hope they may someday be practicable. Clinical trials of cell and tissue xenotransplants, meanwhile, are under way in Europe and the United States, where they are tightly regulated. Thus far, results have been mixed.

    Since abandoning chimpanzees as donors, scientists have turned to pigs, whose organs resemble those of humans in size and function. The one animal-to-human transplant routinely performed worldwide employs pig heart valves. Because the valves are chemically treated to kill living cells, most nations do not regulate their use as xenotransplants.

    But living pig tissue is another story. Scientists have known for years about deadly immune responses generated by intact pig organs. So-called hyperacute rejection occurs when human antibodies swoop in on a porcine sugar called α-galactose (α-gal) that studs the surface of pig cells. The antibodies also trigger acute vascular rejection, whereby the host attacks introduced porcine blood vessels. T cells and possibly macrophages also work to thwart the organ, as can happen in same-species transplants.

    In January, researchers reported one advance toward preventing hyperacute and vascular rejection: They engineered piglets with just one gene for α-gal instead of the usual two (Science, 4 January, p. 25). Pigs with both genes missing, which researchers hope to breed from these animals, could make organ xenotransplants more viable. But “there's a spectrum of opinion” on the subject, says Fritz Bach, a professor of surgery at Harvard Medical School in Boston, who suspects that other antibodies and mechanisms may play a role in immune rejection.

    Desperate measures.

    A baboon heart beat in Baby Fae until she died 3 weeks after receiving it.

    CREDIT: LOMA LINDA UNIVERSITY MEDICAL CENTER

    Foreign cells and tissues are considered less risky to transplant. Unlike whole organs, they lack blood vessels and can evade some of the immune system's revolt. One convenient target for such xenotransplants is the brain and spinal cord, which are not subject to the same immune system scrutiny as the rest of the body. In clinical trials since 1995, Diacrin, a company in Charlestown, Massachusetts, has implanted porcine neurons into the brains and more recently spinal cords of more than 40 people with neurological disorders; results so far are equivocal. A study on stroke victims was halted after two suffered seizures. Perhaps Diacrin's greatest success emerged from autopsies of two volunteers whose deaths were unrelated to the study: Millions of pig cells that had been implanted in the central nervous system had survived long term. A Swedish study of porcine islet cell implants into the pancreas, however, found that few endured.

    Another approach to using animal tissue is to avoid transplants altogether. At hospitals in Germany, Italy, the Netherlands, Spain, Belgium, and the United States, patients with acute liver failure have been hooked up to a device that uses porcine liver cells to treat the patient's blood. A phase II/III study of 171 patients recently ended; Circe Biomedical, the Lexington, Massachusetts, company running the trials, reported in November that the treatment prolonged survival for a majority of the patients, buying them more time to find a human donor.

    Now, get to work.

    Pig nerve cell fibers (white threads) survived in the brain of a patient with Parkinson's disease.

    CREDIT: JONATHAN H. DINSMORE

    At least as daunting as immune rejection is the concern—fueled by mad cow disease and the apparent emergence of HIV from a primate virus—that xenotransplantation of any type could transmit viruses harmless to pigs but deadly to humans. For instance, all pigs carry porcine endogenous retrovirus (PERV), but its potential effects on people are unknown. Repeated testing, including a 1999 study of 160 xenotransplant patients, has turned up no sign of PERV. Still, no one can prove that PERV or another virus won't jump to humans and cause disease, and health regulatory agencies have reacted accordingly.

    The U.S. Food and Drug Administration (FDA) will permit xenotransplant trials on a case-by-case basis, but it requests consent forms warning patients of troubling unknown risks. “The patient consent form makes it sound like they're on the verge of unleashing some plague on the world,” says Thomas Fraser, CEO of Diacrin. For instance, the FDA asks that consent forms warn subjects of potential risks to their family, particularly during sexual contact, and inform patients that they must submit to lifelong monitoring (although the agency lacks the legal means to enforce this).

    Although stringent, FDA offers more leeway than many other countries. Italy and Germany allow animal tissue to be used outside the body but forbid implants. Japan bans xenotransplants outright, and rules in France and England are so strict that study applications are rarely submitted. Norway and the Netherlands have moratoriums in place. “I find it excessive,” says Henri Bismuth, a liver transplant surgeon at Paul Brousse Hospital in Villejuif, France, of the French situation. The intergovernmental Council of Europe is working to establish common standards and include countries such as Russia and China, where cell xenotransplants may have been performed with little government oversight.

    Xenotransplantation research continues in labs worldwide, but many agree that stem cells and bioengineering hold at least as much promise. Annika Tibell, chair of transplantation surgery at Huddinge Hospital in Stockholm, Sweden, hopes to see “several different solutions to the organ problem.”

  21. Tending Tender Tendons

    1. Elizabeth Pennisi

    What do a skate egg case and a tendon have in common? Cross-links that make them strong—an observation that propelled Thomas Koob on his quest to build a bionic tendon

    Gazing at an aquarium tank almost 20 years ago, Thomas Koob made an observation that would eventually change the course of his research. While reflecting on the remarkable properties of a skate egg case, he realized it might hold the secret to an artificial tendon.

    Bidding farewell to his studies of human and shark reproduction, Koob, a biochemist at Shriners Hospital for Children in Tampa, Florida, joined the then-very-small ranks of scientists trying to build a bionic tendon. He now has plenty of competition: The field is quite “huge,” says Albert Banes, a cell biologist at the University of North Carolina, Chapel Hill, and another bionic-tendon pioneer.

    If any of these contenders are successful, they will have a hot commodity. Tendons are the ropes that tie muscle to bone, enabling the former to maneuver the latter quickly and efficiently. Some, such as the Achilles' tendon, act as springs. Others get the body moving and, for example, help turn the open hand into a clenched fist. But when they break, “our ability to repair tendons is limited,” laments Richard Gelberman, an orthopedic surgeon at Washington University School of Medicine in St. Louis, Missouri. He estimates that surgeons try to fix some 300,000 tendons a year—and that doesn't include those in the legs and feet. Recovery can take months, notes Adam Summers, a comparative physiologist at the University of California, Irvine, and at best the restored tendon is about 60% functional.

    In their first attempts to create replacement tendons, researchers tried polyesters or other synthetic materials. But more recently, several research teams, including Koob's and Banes's, have gone after biologically based materials that might be less prone to immune rejection.

    Inspiration.

    A skate egg case is one of many natural “body” parts to inspire bionic ones.

    CREDIT: THOMAS J. KOOB

    Koob and others are grappling with how to replicate the complex structure of the tendon. A substitute must be strong, stiff, and resilient, and it should be able to change its properties—such as its stiffness—as real tendons do. Contrary to the common view of them as elastic cables, “tendons are very much alive,” explains Banes.

    Industrial strength.

    Cross-links between collagen strands impart strength to tendons.

    CREDIT: THOMAS J. KOOB

    Viewed one way, the cells within a tendon look like boxcars along tracks of collagen. “But it's really more like a spider web. The cells are highly interactive and intertwined with the collagen,” says Banes. This network includes molecular bridges that reach across and set up cross-links between nearby collagen strands, thereby preventing the collagen from slipping as the tendon is pulled by a contracting muscle.

    Collagen helps make the tissue strong, but the tendon cells are equally important, because they react to loads, activate genes, and change the properties of the tendon itself. Any replacement tendon must either provide new cells or recruit new ones into the artificial tissue if it is to function as well as the original, says Banes, who thinks he has solved this problem.

    Koob is tackling a different issue first: how to make a biological material strong enough to temporarily take a tendon's place as it heals. That's where the egg cases came in. Skate eggs emerge white and pliable from a large gland in the reproductive tract; over the next few hours, they darken and become leathery. Made of collagenlike materials, the egg cases are tough enough to persist in the ocean for months, and so are its enzymes. Koob was intrigued by the chemistry underlying this transition and stability. Further study suggested that these enzymes form bonds that are the cross-links between the case's collagenlike fibers. He wondered whether that process could be mimicked to make biosynthetic tendons and began looking for a way to cross-link human collagen fibers.

    After much searching, Koob found a chemical called NDGA, derived from a shrub called creosote, that could do just that in his lab. As he reported at a recent meeting,* the collagen-NDGA combination is very compatible with rabbit tissue and does not trigger immune reactions. (The Food and Drug Administration requires this test for biomaterials to be used in humans.) For that reason, notes Summers, this “natural” tendon material might be safer than a synthetic.

    Not that this new tendon material is ready for use. Koob still needs to find a way to glue in the artificial tendon—something that can already be done with a woven polyester tendon material, notes Bahaa Seedhom, a bioengineer at the University of Leeds, U.K., who helped develop the polyester substitute. And even though Koob's material has the necessary strength and stiffness, he needs to demonstrate that it can withstand the multiple stresses to which it will be subjected, notes Robert Ker, another Leeds tendon expert.

    The ideal tendon material, all these tendon contenders recognize, would need to contain or recruit cells that could help the tendon develop the right set of properties and repair small tears as needed. Because his material accumulates cells only on the outside, Koob is now working on making it less dense and more like a real tendon. Meanwhile, Banes and those working on gel-based substitutes have materials that already come with their own tendon cells or, in one case, stem cells. These groups plan to add genes to these cells that would enhance their ability to work like natural tendon cells. At this stage, however, no one can predict which approach will yield a tendon that is almost as good as the real thing.

    • *Society for Integrative and Comparative Biology 2002 Annual Meeting, 2-6 January, Anaheim, CA.

  22. New Prospects for Putting Organs on Ice

    1. Jocelyn Kaiser

    After a lull, scientists are again exploring vitrification and other techniques for deep-freezing tissues and organs

    In the movie Vanilla Sky, Tom Cruise has his broken body frozen in the hope that he'll someday be revived and healed. In reality, cryonics, as this practice is known, remains the most speculative science fiction. Researchers have failed for decades to deep-freeze and thaw most tissues—let alone organs or animals—without damaging them, often seriously. But recently, a few cryobiologists have celebrated successes with ovaries and complex tissues like vascular grafts.

    The work has sparked hope that donated organs can eventually be banked for longer than the current few days, which would buy time for distributing them and finding recipients who are good immunological matches. And as progress is made engineering artificial livers, bladders, and other tissues containing living cells, the need for better preservation techniques is expected to grow (see Viewpoint on p. 1009). “Each company at some point will need to store and transport their product,” says Mike Taylor of Organ Recovery Systems in Charleston, South Carolina.

    Currently, transplant surgeons perfuse whole organs with a special solution that enables them to be banked just above 0°C for up to a few days. Ideally, they would like to preserve organs at -196°C, the boiling point of liquid nitrogen—so cold that molecular motion virtually stops and tissues cease to decay. Half a century ago, that seemed within easy reach. Scientists found that blood and sperm could survive such deep freezing if mixed with glycerol. The glycerol lowers the cells' freezing point and keeps them from getting lethally salty when they do freeze and water diffuses out. And since 1972, embryos have been frozen with liquid nitrogen and later successfully implanted.

    Organs, however, don't hold up so well below the freezing point. Water leaked from cells during freezing forms ice crystals in the space between cells, and this ice destroys fragile structures such as ducts and blood vessels. Sometimes pieces of organs, such as pancreatic islet cells, work adequately after freezing. But larger, more complex organs such as kidneys don't function properly when sufficiently ravaged.

    As a way around this problem, some researchers turned to vitrification, or “ice-free” cryopreservation. The idea is to fill the organ with a viscous fluid that turns into a glassy (not crystalline) solid at low temperatures. This reduces the problems of ice, but toxicity of the cryopreservant can still damage organs. And ice crystals tend to form as vitrified tissue—especially large pieces—is warmed. Partial success came in the 1980s, when Red Cross scientist Greg Fahy showed that rabbit kidneys could withstand the high concentrations of cryoprotectants needed to vitrify these organs. They worked when reimplanted, but Fahy had only cooled them to -3°C. Many experiments later, it's clear that “vitrification is very, very complicated,” says cryobiologist David Pegg of the University of York, U.K., and in most labs vitrification of large organs has been on hold.

    Recently, cryobiologists have had better luck studying vitrification on a smaller scale. For example, fine-tuning the solutions that are injected into the organs, as well as heating and cooling rates, minimized injury to 2- to 3-centimeter-long pieces of rabbit veins, Taylor's team at Organ Recovery Systems reported in the 18 March 2000 issue of Nature Biotechnology. The vessels retained 80% of their function when dosed with drugs that cause them to contract, compared to 20% following simple freezing. When implanted in rabbits, the grafts appeared to work normally. “We're the first to demonstrate [that vitrification works better than freezing] in reasonably complex tissue,” Taylor says. Two other groups have recently shown that they can vitrify corneas, getting much less damage than from freezing. But the scientists have yet to show whether these corneas function in vivo.

    Roger Gosden and colleagues at McGill University in Montreal have had success even with conventional freezing with a small organ, they reported last month in Nature. They froze rat ovaries, fallopian tubes, and attached blood vessels in liquid nitrogen and transplanted them into genetically identical rats whose ovaries had been removed. The animals ovulated. Some ice damage occurred, so vitrification might be even more successful, suggests Gosden, now at the Jones Institute for Reproductive Medicine in Norfolk, Virginia.

    Several groups are tackling problems that thwart both vitrification and conventional freezing. Pegg's group at York, for instance, is working on how to thaw tissues and avoid ice crystal formation. The team has developed a technique that Pegg says can evenly and quickly heat pingpong ball-sized clumps of cells embedded in gelatin to simulate large tissue. Taylor's group, meanwhile, is collaborating with Carnegie Mellon scientists on dosing tissues with iron compounds that are then excited with magnets to generate heat.

    Taking a cue from nature, researchers are also using natural antifreeze proteins to help mop up crystals formed during freezing and thawing. Many organisms, from carrots to fish to beetles, produce proteins that latch onto and isolate growing ice crystals. The one drawback is that at temperatures well below 0°C, this system can backfire by causing ice crystals to form spikes that disrupt cells. Several companies are developing improved synthetic versions of these “ice blockers"; for example, Taylor's company hopes to produce smaller molecules that attach to ice crystals at the base as well as the face, which could prevent spike formation.

    Fahy, meanwhile, has never given up trying to vitrify large organs. “He has soldiered the way on this for years and years,” Pegg says. Now at a company called 21st Century Medicine in Rancho Cucamonga, California, Fahy has tested hundreds of vitrification solutions and patented the most promising ones. “Greg has always been tantalizingly close to getting it to work,” says cryobiologist William Rall of the National Institutes of Health. The company Fahy works for receives funding from the Life Extension Foundation, which supports cryonics. Fahy says his work is strictly limited to cryopreserving organs. But he adds, “If I'm successful, perhaps it will remove some of the [cryonics] controversy.”

  23. Part Man, Part Computer: Researcher Tests the Limits

    1. Gretchen Vogel

    Kevin Warwick plans to connect a computer chip to the nerves in his arm to see if a computer can read and communicate signals directly from his nervous system. Are computer-controlled humans next?

    By the end of this month, Kevin Warwick hopes to be a cyborg. If all goes as planned, in late February the University of Reading, U.K., professor of cybernetics will have surgery to connect nerves in his arm with wires leading to a “smart card"-sized collection of microprocessors. The wires will pick up signals from his central nervous system and relay them via a radio transmitter to an external computer that will record the patterns. Warwick hopes the device will pick up discrete signals from the nerves depending on his movements, his sense of touch, and even his mood, and then send those signals back to his nerves to see if they can mimic the movement or the sensation. Warwick's wife plans to have a similar implant so the two can try to communicate through computer-mediated signals.

    For decades, science fiction writers have imagined beings who are part human, part machine—Robocop, for instance. In the nonfiction realm, cochlear implants have restored hearing to deaf patients, and computers that sense brain waves have enabled paralyzed patients to communicate (Science, 29 October 1999, p. 888). But as far as Warwick knows, this is the first time anyone has attempted to computer-enhance the nervous system of a healthy human. Some scientists doubt Warwick will succeed, and others call the effort unethical. But Warwick says the potential benefits of computer enhancement outweigh the risks, and he is eager to debate just how far the technology should go.

    Warwick first made headlines in 1998 when he had a much simpler device implanted into his arm. Like a built-in security badge, this computer chip allowed sensors in his lab building to detect his location and movements. With the new device, Warwick is aiming for much more. He hopes the computer will detect patterns of electrical signals that correspond to movements or sensations: the bending of his index finger or the pain of a pinprick, for example. In one experiment, Warwick hopes to send those signals to a robot. By trial and error, he hopes he can learn to remotely control the robot by simply moving his finger.

    Animal experiments suggest that goal is realistic. Several groups, including those of neuroscientist Miguel Nicolelis at Duke University in Durham, North Carolina, and Andrew Schwartz at the Neurosciences Institute in San Diego, have been able to program robot arms to crudely mimic the movement of a monkey's arm based on patterns in the animal's brain waves. Warwick is curious to see whether the computer chip can “play back” such signals, triggering his arm to move involuntarily or tricking him into thinking his finger has been stuck.

    The bundle of nerves that runs down the arm, called the median nerve, also communicates with the body's limbic system—for example, making our palms sweat when we're nervous. Warwick will attempt to record the signals produced by shock or anger, then have a colleague try to send them back to the implant when he is calm—and unsuspecting—to see if they have an effect.

    If the initial experiments go well, Warwick's wife, Irena, will receive her own implant a few weeks later. The pair will then attempt to send nerve-mediated messages—emotional or otherwise—through their computer connection. If Warwick cuts his finger while slicing a bagel, for instance, the chip should record the signal from his medial nerve and then send it to a computer that communicates with his wife's implant, adding new meaning to the phrase “I feel your pain.”

    Warwick and others in the cybernetics community envision a world in which humans are able to expand their senses to hear ultrasonic sounds or see infrared wavelengths. “It's tremendously exciting. Can we in the future link extra memory into our brains? Why shouldn't we do something like that?” he asks.

    Such questions are premature, says Peter Fromherz of the Max Planck Institute for Biochemistry in Martinsried, Germany. “Warwick is a very interesting person. But what he's doing is scientifically crazy,” he says.

    For 15 years, Fromherz has been working on experiments that join single neurons and computer chips, with the goal of enabling researchers to build better computer-enhanced prosthetic devices. In a paper published l November in the Proceedings of the National Academy of Sciences, his team described a nerve-computer circuit consisting of snail neurons and a computer chip. The circuit was able to send a discrete signal from a computer chip to a neuron, from that neuron to a second neuron in a network, and from the second neuron back to the computer chip. On a cellular scale, Fromherz's work is state of the art, but it is a long way from computer-synthesized emotions, he notes.

    Others think Warwick's experiment should not be allowed to proceed. (It does not require permission from a formal ethics board, as Warwick is experimenting on himself.) Political scientist Langdon Winner of Rensselaer Polytechnic Institute in Troy, New York, for one, calls the experiment “profoundly amoral. Enhancing one's information-processing ability by connecting chips to the nervous system marks a very fundamental change in what human beings are.” Should it become possible, he says, “then it is a matter for theologians, politicians, and citizens to address.”

    And that's the debate Warwick hopes to spark, much as the birth of Dolly fueled the debate over cloning. Although he sees great benefits from computer enhancement, left unchecked, the technology also has great potential for harm, he says. For example, if the computer is able to prompt Warwick to move his arm involuntarily, then that suggests that a computer could someday remotely control a person instead of the other way around—a troubling prospect, he concedes. “If you're creating superhumans,” Warwick says, “that could mean the end of humanity.” And even this cyborg hopeful thinks that's a question that humans, not computers, should decide.

  24. The Confusing Mix of Hype and Hope

    1. Jon Cohen

    Despite promising leads and publicity galore, restoring vision through bionic eyes remains a distant dream

    On 3 December 1999, media around the world reported that music icon Stevie Wonder had said he might be able to see someday, thanks to an artificial retina being developed at Johns Hopkins University in Baltimore, Maryland. Wonder made the remark at a funeral, where, according to press accounts, the mourners jumped up and cheered. Many researchers in this small, high-risk field had a decidedly different reaction. Two weeks later, their disbelief turned to dismay when ophthalmologist Mark Humayun of Hopkins's Wilmer Eye Institute appeared with Wonder on the television newsmagazine 20/20.

    “There is the possibility that Stevie Wonder could see?” host Barbara Walters asked.

    “Certainly, there is the possibility,” said Humayun, cautioning that he had yet to complete his exams of Wonder's eyes. “We believe that something could be available for patients in the next 2 to 3 years.”

    Humayun and his colleague, ophthalmologist Eugene de Juan Jr., now both at the Doheny Retina Institute at the University of Southern California (USC) in Los Angeles, have yet to implant their artificial retina in a single patient. “It was basically just hype,” charges rival Alan Chow, a pediatric ophthalmologist in Chicago, Illinois. Chow's company, Optobionics, is developing a similar artificial retina now being tested in six patients—the only clinical trial of a permanently implanted device under way. Chow also emphasizes that Wonder, who became blind shortly after birth, would not be a good candidate for prosthetic eyes, as he likely has substantial damage to his retinas.

    Wonderland.

    A TV interview raised hopes-false, some say-that Stevie Wonder might see, thanks to an artificial retina.

    CREDIT: ALEXANDER SIBAJA/GETTY IMAGES

    But Humayun and others have accused Chow, too, of overstating his results. “He hasn't shown any data, and it remains a mystery why,” says Humayun, who attended a Vitreous Society meeting last November where Chow claimed that his six patients had shown “substantial visual function improvements.” Before discussing details, Chow says he wants a scientific journal to publish his data.

    Welcome to the contentious, competitive world of research on the bionic eye. Bionics —be it restoring vision by implanting a silicon chip or replacing a damaged heart with a plastic one—lends itself to hyperbole. Researchers work at the extreme edges of biological knowledge, attempting feats that were earlier the things of myths. Many also have commercial ties and hope to profit from their research.

    Restoring vision, in particular, has a unique appeal, says ophthalmologist Eberhart Zrenner, who is working on an artificial retina with colleagues at the University Eye Hospital in Tübingen, Germany (see Viewpoint on p. 1022). And success would offer a unique triumph, he notes. You could say: “I'm the one who, like Jesus, made a blind man see again.”

    A dozen research groups are attempting to create artificial vision by either stimulating the visual cortex in the brain, the optic nerve, or, the most popular approach, the retina. The retina is a collection of rods, cones, ganglia, and bipolar cells sandwiched together. Retinal devices are silicon chips that surgeons can place on either side of that sandwich—the “subretinal” or the “epiretinal” space. The hope is that the retinal cells will transmit the signals to the optic nerve. Chow's device, which he invented with his brother Vincent, resembles a fly's eye and has solar cells that convert light into electrical signals. The USC group and others are placing arrays of electrodes on their chips, which receive electronic signals from a miniature camera mounted on glasses that the person wears. Others use cameras to send signals through wires implanted on the optic nerve or in the visual cortex.

    To date, however, results have been mixed. Most human experiments have simply tested the effects of surgically delivering temporary electrical stimulations to the retina. Even so, Humayun is enthused that he has helped prove wrong several once-common beliefs, such as that there is no safe way to place an electronic device on a retina without damaging it.

    But John Wyatt, an electrical engineer at the Massachusetts Institute of Technology, says his work on a retinal implant with Harvard neuroophthalmologist Joseph Rizzo has shown how difficult it is to create meaningful vision. In their experiments, what patients “saw” often did not correlate with the stimulation pattern, and none has recognized shapes or letters, as reported by Humayun and colleagues. “Let's aim for small successes for now,” implores Wyatt. “To impart a coarse level of vision that would expand a blind person's autonomy is an ambitious but plausible goal.”

    Overstating the promise comes at a steep price, says Wyatt, noting that the blind and their families can suffer mightily. Harvard's Don Eddington, a biophysicist who develops cochlear implants, says hype also “reduces the credibility of this work in the minds of serious scientists.” Eddington says this, in turn, “not only affects the individuals working in retinal prostheses but neural prostheses in general.”

    Humayun strongly denies that he hyped anything. And Gerald Chader, chief scientific director of the Foundation Fighting Blindness near Baltimore and a former official at the National Eye Institute (NEI), agrees: “I think [Humayun] tried to be very evenhanded.”

    Humayun points out that the story became news because of what Stevie Wonder, not Humayun, said. And although he agrees that Wonder is not an ideal candidate for this device, he doesn't think he provided false hope to the public or to Wonder, as no one knows enough to state definitively what will or won't work. The USC group hopes to launch clinical trials of its device later this year.

    The Stevie Wonder publicity had an upside, too, Chader argues. It sparked a flow of philanthropic donations and, he suspects, may have influenced NEI's decision to fund a multimillion-dollar consortium effort that includes the USC researchers as well as Wyatt, Rizzo, and others.

    When and if this research will pan out is anyone's guess. Says Zrenner, “That's like someone asking us when will we arrive at the moon when we've just begun to build a rocket.”

  25. The Quest to Reverse Time's Toll

    1. Constance Holden

    Scientists and entrepreneurs are optimistic to varying degrees about prospects for extending the human life-span

    Tom Johnson has a way to get rich quick, if he wants to: Go into the business of grinding up his worms for snake oil. Johnson studies aging at the University of Colorado, Boulder; his work with nematodes has revealed that changing a single gene can dramatically increase the worm's life-span. Some years ago a clinic in Guadalajara, Mexico, proposed that he supply them with extracts from long-lived nematodes to rejuvenate elderly patients. “I get two or three similar offers a year,” says Johnson.

    Aging research is hot these days. And so is a commercial “antiaging” movement that is being fueled by demographics as millions of baby boomers hit their 50s. “Aging is probably the process that humans have most tried to conquer for our entire history,” says Johnson. The difference today is “we now know that we can alter aging.”

    Scientists have known for decades that a very low calorie diet extends life in some species. Recently they have begun to directly manipulate the mechanisms of aging with gene alterations that substantially extend the life-span of fruit flies, nematodes, and mice. Using markers generated by the Human Genome Project, researchers expect to come up with a flood of new candidates for genes influencing the processes of aging. These discoveries, and the promise of more to come, have spawned a host of new companies dedicated to reversing aging's toll.

    George Roth, chief of molecular physiology and genetics at the National Institute on Aging (NIA), counts about 40 recent scientist-run start-ups, most of them looking for life-extending genes—and many of which have already fallen by the wayside. There's also bustling commerce in antiaging products ranging from vitamin supplements to potentially dangerous hormone preparations that purport to reverse diseases of aging. Some merchants try to give their products a veneer of plausibility by citing recent research with telomeres, antioxidants, or hormones. Scientists such as zoologist Steven Austad of the University of Idaho in Moscow are wary. When groups interested in life extension ask him for advice, “I tend to avoid them like the plague. … I don't want to end up on their Web site.”

    Researchers as entrepreneurs

    But nowadays everybody's in the game. “I would be surprised if any legitimate biogerontologist did not have some commercial affiliation,” says pioneering aging researcher Leonard Hayflick, now a consultant to Genentech in South San Francisco.

    One way they hope to make money is by looking at those who survive to extreme old age. Centenarians seem to be healthier than most old people: Witness Frenchwoman Jeanne Calment, the oldest person on record, who died in 1997 at 122. Last year, Thomas Perls of Beth Israel Deaconess Medical Center in Boston, director of the New England Centenarian Study, with molecular geneticists Louis M. Kunkel and Annibale A. Puca of Children's Hospital, Boston, founded a company called Centagenetix that is scanning the genomes of his subjects to find genes that set them apart.

    Leonard Guarente of the Massachusetts Institute of Technology is coming at the problem from a different starting point: yeast. Several years ago he found a gene called Sir2 that, when its expression was increased, extended yeast's life-span. Guarente believes different organisms may share some universal survival-promoting mechanisms—and Sir2 may be one of them. He's so optimistic that he has founded a company, in partnership with Cynthia Kenyon, a nematode researcher at the University of California, San Francisco, called Elixir, to see if they can make an aging retardant from the gene product.

    Roth of NIA is looking for a guaranteed blockbuster. He's involved in a company called GeroTech, the goal of which is to make a “calorie restriction mimetic”—a drug to make your body think you're starving even while you're eating normally. Roth says he already has encouraging results from restricting monkeys' calories: One of his subjects has lived to 38 instead of the usual 25.

    Seeking youth.

    Oscar Wilde's The Picture of Dorian Gray represents an eternal human goal.

    CREDIT: CORBIS

    The biggest player in the antiaging research industry is Geron Corp. in Menlo Park, California, which has numerous patents on telomerase, the enzyme that restores telomere length. Telomeres shorten as cells age and lose their ability to divide. Calvin Harley, chief scientific officer, says Geron's researchers have shown that they can transplant aging human skin cells, the telomerase in which has been activated, onto immunocompromised mice, where they behave like young cells. The company is also working on both gene and drug therapies for telomerase activation in age-related diseases.

    Despite the heady possibilities, some researchers caution that longevity probably comes with a downside. “We evolved in a high-hazard environment with disease, food shortages, droughts, accidents—enormous selective pressure to get the job done fast,” observes George Martin of the University of Washington, Seattle. “You have genes to make you develop rapidly, have progeny early. There was no need to develop robust quality-control mechanisms allowing you to live beyond reproduction.”

    Mechanisms that serve the youthful organism may precipitate aging or disease later on, notes Martin, who is also editor-in-chief of the Science of Aging Knowledge Environment (Science's SAGEKE, sageke.sciencemag.org). Human growth hormone, for example, a favorite of antiaging hucksters, affects metabolism and physiological indicators such as muscle mass. But it also creates undesirable side effects, such as raised glucose levels, and may even shorten life. Other mechanisms are also two-edged. Telomerase is implicated not just in cell renewal but cancer. Even the cancer-fighting p53 gene, when up-regulated, has been found to hasten aging in rats (Science, 4 January, p. 28). “It's difficult to retard aging without affecting something else,” says Austad. “Genes evolve in a certain context because they do something well at that level of expression. If you soup them up, there's always a price to pay.”

    On the edge

    S. Jay Olshansky, a biodemographer at the University of Illinois, Chicago, cautions that researchers should be careful of the company they keep. “There is so much money to be made,” he says, that he and others are “really concerned” that some scientists “have either crossed the line or are about to cross the line.”

    That line is not always clear, and reputable scientists may differ on where it should be drawn. For example, the Life Extension Foundation (LEF), based in Fort Lauderdale, Florida, sells a vast assortment of products from vitamins to a product called pregnenolone that is said to contain “brain-boosting nutrients that function via a variety of mechanisms to correct the molecular devastation that aging inflicts on the brain.” It had a long-running battle with the Food and Drug Administration over its claims. (A court eventually ruled in LEF's favor.)

    LEF also funds research, including tests of possible longevity compounds on mice by Richard Weindruch of the University of Wisconsin, Madison, and Stephen Spindler of the University of California (UC), Riverside. Spindler, who is still at UC, is now chief technical officer of a LEF-founded company called LifeSpan Genetics, which uses gene chips to study the ability of compounds to mimic genomic effects of calorie restriction.

    Former NIA researcher Richard Cutler has an association with a company that Olshansky and Austad, at least, find distinctly problematic. Cutler, who studies antioxidants, compounds that prevent damage to cells from byproducts called free radicals, now works at Kronos, a reputable nonprofit in Phoenix, Arizona, devoted to uncovering some of the secrets of aging. He also advises a company called Youngevity in Carrollton, Texas, which touts products containing a mix of “miracle minerals” captured from the waters of Vilcabamba, Ecuador, whose denizens “live their lives in a state of youthfulness.” The Youngevity Web site cites his research as evidence that antioxidants can “significantly extend our health span,” although Cutler readily acknowledges that antioxidant supplements would benefit only a minority of people with oxidative stress from circumstances such as infectious diseases. “Youngevity makes a strong sell, that's true,” he says. “I've been asked [by Kronos] to quit. I probably will.” He told Science he will ask Youngevity to use more accurate wording. Cutler's boss at Kronos, Mitch Harman, was distressed when he learned that Cutler's name was still on the Youngevity Web site: “I'm trying to do legitimate research and get tarred with the same brush.”

    Special genes?

    Oldest documented human, Madame Calment, at 122.

    CREDIT: STR/AP

    Cutler stands firmly with his scientific colleagues, however, in distancing himself from the 7-year-old American Academy of Anti-Aging Medicine, founded by physician Ron Klatz. “Practical immortality”—that is, living maybe a few hundred years if we want—is the group's ultimate goal, according to Klatz, who told Science that “antiaging medicine has been smeared by the gerontology establishment, [which is] perfectly comfortable with the concept that aging is immutable.” The group, which claims to have 10,000 physician and scientist members, refers the public to antiaging clinics and products and offers physicians certification in “antiaging medicine.” Olshansky says he goes to the annual convention in Las Vegas “to collect information on the latest antiaging quackery.”

    If it's “antiaging,” he notes, it's quackery by definition. Some potions and elixirs may indeed have some effect on aging's manifestations, but they don't touch the still-mysterious processes at the core. Figuring out those processes will drive research—and many commercial endeavors—for years to come.

  26. Cracking the Secrets of Aging

    1. Constance Holden

    It's hard to fight senescence, scientists admit, because “we still don't know how to define aging per se,” says former National Institute on Aging head Robert Butler, now director of the U.S. branch of the International Longevity Center in New York City. Theories abound, however, including the accumulation of cell damage (from oxygen free radicals and environmental toxins) and glycation (stiffening of tissue with formation of sugar-protein bonds). Another is the progressive shortening of telomeres, the tips of chromosomes, as cells divide. Scientists are still not sure whether aging is a unitary phenomenon—the result, perhaps, of a predictable pattern of altered gene expression—or “a set of processes that happen to occur in rough synchrony,” says Richard Miller of the University of Michigan Institute of Gerontology in Ann Arbor.

    Meanwhile, the life-extending effect of calorie restriction offers researchers tantalizing clues. It's been replicated in a number of species, including spiders: Those fed about two-thirds of their regular diet lived longer, and dogs and rodents experienced later onset of diseases of aging, including arthritis and cancer. Scientists speculate that calorie restriction triggers a mechanism that probably evolved at times of food shortage, changing a variety of gene functions that affect parameters such as glucose levels and body temperature so the body goes into a conservation mode. Some believe it works by slowing down energy utilization and its “wear and tear” on cells.

    Even if researchers can figure out ways to slow the aging process, opinion varies on the ultimate limits to human life-span. S. Jay Olshansky, a biodemographer at the University of Illinois, Chicago, says that “anything past 130 is ridiculous.” But William Haseltine of Human Genome Sciences in Rockville, Maryland, thinks stem cells will ultimately prove the route to virtual immortality. In an interview last year with Fool.com, Haseltine predicted that it will one day be possible to “reseed the body with our own cells that are made more potent and younger, so we can repopulate the body.”

    Nematode man Tom Johnson of the University of Colorado, Boulder, is also optimistic. There are no “aging” genes, he notes, because natural selection washes its hands of an organism once it has passed the age of procreation. “The very absence of an evolutionary reason to die makes it relatively easy to manipulate life-span,” he says. “If humans are as malleable as worms, we could see life-spans of 350.”

    But the picture is obscured because there are no “biomarkers” for aging—such as a biochemical that predictably changes in level with age—as there are for, say, cancer or diabetes. Gray hair, which correlates about 0.7 with age, is still “as good as you could do” for a marker, says gerontologist Leonard Hayflick. At this point, the most reliable biomarker for aging is death.

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