News this Week

Science  19 Dec 2003:
Vol. 302, Issue 5653, pp. 390
  1. BREAKTHROUGH OF THE YEAR

    Illuminating the Dark Universe

    1. Charles Seife

    #1 The Winner

    Portraits of the earliest universe and the lacy pattern of galaxies in today's sky confirm that the universe is made up largely of mysterious dark energy and dark matter. They also give the universe a firm age and a precise speed of expansion.

    See Web links on Cosmology

    A lonely satellite spinning slowly through the void has captured the very essence of the universe. In February, the Wilkinson Microwave Anisotropy Probe (WMAP) produced an image of the infant cosmos, of all of creation when it was less than 400,000 years old. The brightly colored picture marks a turning point in the field of cosmology: Along with a handful of other observations revealed this year, it ends a decades-long argument about the nature of the universe and confirms that our cosmos is much, much stranger than we ever imagined.

    Five years ago, Science's cover sported the visage of Albert Einstein looking shocked by 1998's Breakthrough of the Year: the accelerating universe. Two teams of astronomers had seen the faint imprint of a ghostly force in the death rattles of dying stars. The apparent brightness of a certain type of supernova gave cosmologists a way to measure the expansion of the universe at different times in its history. The scientists were surprised to find that the universe was expanding ever faster, rather than decelerating, as general relativity—and common sense—had led astrophysicists to believe. This was the first sign of the mysterious “dark energy,” an unknown force that counteracts the effects of gravity and flings galaxies away from each other.

    Although the supernova data were compelling, many cosmologists hesitated to embrace the bizarre idea of dark energy. Teams of astronomers across the world rushed to test the existence of this irresistible force in independent ways. That quest ended this year. No longer are scientists trying to confirm the existence of dark energy; now they are trying to find out what it's made of, and what it tells us about the birth and evolution of the universe.

    Lingering doubts about the existence of dark energy and the composition of the universe dissolved when the WMAP satellite took the most detailed picture ever of the cosmic microwave background (CMB). The CMB is the most ancient light in the universe, the radiation that streamed from the newborn universe when it was still a glowing ball of plasma. This faint microwave glow surrounds us like a distant wall of fire. The writing on the wall—tiny fluctuations in the temperature (and other properties) of the ancient light—reveals what the universe is made of.

    Through a glass, darkly.

    Microwave data observed by the WMAP satellite (top), supernovae (middle), and galaxy clusters (bottom) all reveal a universe dominated by dark energy.

    CREDITS (TOP TO BOTTOM): NASA/WMAP SCIENCE TEAM; GSFC/NASA; SDSS COLLABORATION

    Long before there were stars and galaxies, the universe was made of a hot, glowing plasma that roiled under the competing influences of gravity and light. The big bang had set the entire cosmos ringing like a bell, and pressure waves rattled through the plasma, compressing and expanding and compressing clouds of matter. Hot spots in the background radiation are the images of compressed, dense plasma in the cooling universe, and cold spots are the signature of rarefied regions of gas.

    Just as the tone of a bell depends on its shape and the material it's made of, so does the “sound” of the early universe—the relative abundances and sizes of the hot and cold spots in the microwave background—depend on the composition of the universe and its shape. WMAP is the instrument that finally allowed scientists to hear the celestial music and figure out what sort of instrument our cosmos is.

    The answer was disturbing and comforting at the same time. The WMAP data confirmed the incredibly strange picture of the universe that other observations had been painting. The universe is only 4% ordinary matter, the stuff of stars and trees and people. Twenty-three percent is exotic matter: dark mass that astrophysicists believe is made up of an as-yet-undetected particle. And the remainder, 73%, is dark energy.

    The tone of the cosmic bell also reveals the age of the cosmos and the rate at which it is expanding, and WMAP has nearly perfect pitch. A year ago, a cosmologist would likely have said that the universe is between 12 billion and 15 billion years old. Now the estimate is 13.7 billion years, plus or minus a few hundred thousand. Similar calculations based on WMAP data have also pinned down the rate of the universe's expansion—71 kilometers per second per megaparsec, plus or minus a few hundredths—and the universe's “shape”: slate flat. All the arguments of the last few decades about the basic properties of the universe—its age, its expansion rate, its composition, its density—have been settled in one fell swoop.

    As important as WMAP is, it is not this year's only contribution to cosmologists' understanding of the history of the universe. The Sloan Digital Sky Survey (SDSS) is mapping out a million galaxies. By analyzing the distribution of those galaxies, the way they clump and spread out, scientists can figure out the forces that cause that clumping and spreading—be they the gravitational attraction of dark matter or the antigravity push of dark energy. In October, the SDSS team revealed its analysis of the first quarter-million galaxies it had collected. It came to the same conclusion that the WMAP researchers had reached: The universe is dominated by dark energy.

    This year scientists got their most direct view of dark energy in action. In July, physicists superimposed the galaxy-clustering data of SDSS on the microwave data of WMAP and proved—beyond a reasonable doubt—that dark energy must exist. The proof relies on a phenomenon known as the integrated Sachs-Wolfe effect. The remnant microwave radiation acted as a backlight, shining through the gravitational dimples caused by the galaxy clusters that the SDSS spotted. Scientists saw a gentle crushing—apparent as a slight shift toward shorter wavelengths—of the microwaves shining near those gravitational pits. In an uncurved universe such as our own, this can happen only if there is some antigravitational force—a dark energy—stretching out the fabric of spacetime and flattening the dimples that galaxy clusters sit in.

    Some of the work of cosmology can now turn to understanding the forces that shaped the universe when it was a fraction of a millisecond old. After the universe burst forth from a cosmic singularity, the fabric of the newborn universe expanded faster than the speed of light. This was the era of inflation, and that burst of growth—and its abrupt end after less than 10−30 seconds—shaped our present-day universe.

    For decades, inflation provided few testable hypotheses. Now the exquisite precision of the WMAP data is finally allowing scientists to test inflation directly. Each current version of inflation proposes a slightly different scenario about the precise nature of the inflating force, and each makes a concrete prediction about the CMB, the distribution of galaxies, and even the clustering of gas clouds in the later universe. Scientists are just beginning to winnow out a handful of theories and test some make-or-break hypotheses. And as the SDSS data set grows—yielding information on distant quasars and gas clouds as well as the distribution of galaxies—scientists will challenge inflation theories with more boldness.

    The properties of dark energy are also now coming under scrutiny. WMAP, SDSS, and a new set of supernova observations released this year are beginning to give scientists a handle on the way dark energy reacts to being stretched or squished. Physicists have already had to discard some of their assumptions about dark energy. Now they have to consider a form of dark energy that might cause all the matter in the universe to die a violent and sudden death. If the dark energy is stronger than a critical value, then it will eventually tear apart galaxies, solar systems, planets, and even atoms themselves in a “big rip.” (Not to worry; cosmologists aren't losing sleep about the prospect.)

    For the past 5 years, cosmologists have tested whether the baffling, counterintuitive model of a universe made of dark matter and blown apart by dark energy could be correct. This year, thanks to WMAP, the SDSS data, and new supernova observations, they know the answer is yes—and they're starting to ask new questions. It is, perhaps, a sign that scientists will finally begin to understand the beginning.

    Papers and Articles

    Selected Research Papers

    C. L. Bennett et al., “First-Year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Preliminary Maps and Basic Results,” Astrophys. J. Suppl. Ser. 148, 1 (2003) [arXiv.org preprint server]

    D. N. Spergel et al., “First-Year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Determination of Cosmological Parameters,”Astrophys. J. Suppl. Ser. 148, 175 (2003) [arXiv.org preprint server]

    M. R. Nolta et al., “First-Year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Dark Energy Induced Correlation with Radio Sources” (2003) [arXiv.org preprint server]

    R. Scranton et al., “Physical Evidence for Dark Energy” (2003) [arXiv.org preprint server]

    L. M. Krauss, “Implications of the WMAP Age Measurement for Stellar Evolution and Dark Energy,” Astrophys. J. 596, L1 (2003) [arXiv.org preprint server]

    M Tegmark et al., “The 3D Power Spectrum of Galaxies from the SDSS” (2003) [arXiv.org preprint server]

    J. L. Tonry et al., “Cosmological Results from High-z Supernovae,” Astrophys. J. 594, 1 (2003) [arXiv.org preprint server]

    A. V. Filippenko, “The Accelerating Universe and Dark Energy: Evidence from Type Ia Supernovae” (2003) [arXiv.org preprint server]

    News and Features

    C. Seife, “MAP Glimpses Universe's Rambunctious Childhood,” Science 299, 990 (2003)

    C. Seife, “With Its Ingredients MAPped, Universe's Recipe Beckons,” Science 300, 730 (2003)

    R. Irion, “The Warped Side of Dark Matter,” Science 300, 1894 (2003) [from Science's Dark Side special issue]

    C. Seife, “Dark Energy Tiptoes Toward the Spotlight,” Science 300, 1896 (2003) [from Science's Dark Side special issue]

    C. Seife, “Dark Energy Passes Another Test,” Science 301, 449 (2003)

    C. Seife, “Galaxy Maps Support Theory That the Universe Is Flying to Pieces,” Science 302, 762 (2003)

    Breakthrough of the Year: The Accelerating Universe (18 December 1998)

    We identified the discovery of dark energy, through observations of supernovae, as 1998's top science advance.

    Reviews and Perspectives

    Science Special Issue: The Dark Side (20 June 2003)

    Four reviews on dark matter and dark energy.

    S. L. Bridle et al., “Precision Cosmology? Not Just Yet …,” Science 299, 1532 (2003)

    A. Gangui, “A Preposterous Universe,” Science 299, 1333 (2003)

    K. C. Freeman, “The Hunt for Dark Matter in Galaxies,” Science 302, 1902 (2003)

    Interesting Web Sites

    Special Web Supplement: The Dark Side

    Collection of Web resources on topics such as the CMB and supernovae, to supplement Science's Dark Side special issue.

    Wilkinson Microwave Anisotropy Probe (WMAP)

    Site of the ongoing NASA mission includes a useful educational component, Cosmology 101, an image gallery, and more.

    Planck

    European CMB mission, slated for launch in 2007.

    Sloan Digital Sky Survey

    Web site of “the most ambitious astronomical survey project ever undertaken.”

    The Physics of Microwave Background Anisotropies

    Well-known primer on cosmology, CMB, and dark matter and energy issues by Wayne Hu of the University of Chicago.

    Supernova and Supernova Remnant Pages on the WWW

    Well-maintained selection of supernova links by Marcos Montes of the Naval Research Laboratory.

    High-Z Supernova Search

    Supernova Cosmology Project

  2. BREAKTHROUGH OF THE YEAR

    The Runners-Up

    The News and Editorial Staffs*

    1. The News and Editorial Staffs

    This year's discoveries illuminated realms as small as a single molecule and as large as a gamma ray burst.

    See Web links on genes for mental illness

    #2 Decoding mental illness.Schizophrenia, depression, and bipolar disorder often run in families, but only recently have researchers identified particular genes that reliably increase one's risk of disease. Now they're unraveling how these genes can distort the brain's information processing and nudge someone into mental illness.

    The chemical messenger serotonin relays its signal through a receptor that's a target of antidepressant drugs. The gene for this receptor comes in two common flavors, or alleles, one of which had been tenuously linked to an increased risk of depression. This year, researchers revealed why the link had been so elusive: The allele increases the risk of depression only when combined with stress. Among people who had suffered bereavement, romantic rejection, or job loss in their early 20s, those who carried the vulnerability gene were more likely to be depressed than those with the other gene variant.

    People with the high-risk allele have unusually heightened activity in a fear-focused brain region called the amygdala when viewing scary pictures. Together, these studies suggest that the gene variant biases people to perceive the world as highly menacing, which amplifies life stresses to the point of inducing depression.

    A different brain area, the prefrontal cortex, is regulated in part by a gene called COMT, one of the handful associated with risk of schizophrenia. It encodes an enzyme that breaks down neurotransmitters such as dopamine. Two years ago, one version of this gene was shown to muddle the prefrontal cortex, which is necessary for planning and problem-solving skills that are impaired by schizophrenia. Even healthy people who carry the schizophrenia risk allele have extra activity in the prefrontal cortex even when doing relatively simple tasks. The nonschizophrenia allele, which allows more efficient activity in the prefrontal cortex, appears to increase the risk of anxiety, suggesting that the two diseases lie at opposite ends of a spectrum.

    Agony antecedents.

    New work links genes, brain activity biases, and mental illness.

    CREDIT: C. ANDERSON/CHRIS ANDERSON PUBLICATIONS/CORBIS

    Late in 2002, an allele of a gene for brain-derived neurotrophic factor (BDNF) was implicated in bipolar disorder, once known as manic depression. This year the allele was found to curb activity in the hippocampus, a structure necessary for memory that is shrunken in people with mood disorders. BDNF encourages the birth of new neurons in the hippocampus; other work this year showed that antidepressants require this neurogenesis to be effective. Through these and similar insights, researchers hope to understand brain biases underlying mental illnesses well enough to correct them.

    Online Extras on Genes for Mental Illness

    Papers and Articles

    M. Neves-Pereira et al., “The Brain-Derived Neurotrophic Factor Gene Confers Susceptibility to Bipolar Disorder: Evidence from a Family-Based Association Study,” Am. J. Hum. Genet. 71, 651 (2002)

    M. F. Egan et al., “The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function,” Cell 112, 257 (2003)

    D. Hall et al., “Sequence Variants of the Brain-Derived Neurotrophic Factor (BDNF) Gene Are Strongly Associated with Obsessive-Compulsive Disorder,” Am. J. Hum. Genet. 73, 370 (2003)

    M. Egan et al., “Effect of COMT Val108/158 Met Genotype on Frontal Lobe Function and Risk for Schizophrenia,” Proc. Natl. Acad. Sci. U.S.A. 98, 6917 (2001)

    M. Akil et al., “Catechol-O-Methyltransferase Genotype and Dopamine Regulation in the Human Brain,” J. Neurosci. 23, 2008 (2003)

    A. R. Hariri et al., “Serotonin Transporter Genetic Variation and the Response of the Human Amygdala,” Science 297, 400 (2002)

    A. Caspi et al., “Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene,” Science 301, 386 (2003)

    C. Holden, “Getting the Short End of the Allele,” Science 301, 291 (2003)

    G. Vogel, “Depression Drugs' Powers May Rest on New Neurons,” Science 301, 757 (203)

    J. L. Kennedy et al., “The Genetics of Adult-Onset Neuropsychiatric Disease: Complexities and Conundra?,” Science 302, 822 (2003)

    Interesting Web Sites

    Web Supplement on Neuropsychiatric Diseases

    Supplement accompanying the 13 October 2003 Science special issue on Brain Disease.

    MEDLINEplus

    The National Library of Medicine provides links to Internet resources on bipolar disorder, schizophrenia, and depression.

    National Institute of Mental Health

    Information for the public, medical practitioners, and researchers. Resource pages on schizopherenia, depression, and bipolar disorder are provided.

    Online Mendelian Inheritance in Man

    An NIH resource on the genetics of disease. Reviews of schizophrenia and bipolar affective disorder are included, as well as entries about COMT, BDNF, and serotonin.

    National Alliance for Research on Schizophrenia and Depression

    [Top of page]

    See Web links on climate change

    #3 Is it warm in here? Climate researchers have a century's worth of temperature measurements to show that the globe has been warming. New work shows that the planet has taken notice of the change. The stream of studies suggesting global warming's impact on Earth and its inhabitants surged to a flood in 2003 with reports on melting ice, droughts, decreased plant productivity, and altered plant and animal behavior.

    Paying attention.

    Plants and animals are responding to global warming.

    CREDITS: CAMILLE PARMESAN/UNIVERSITY OF TEXAS, AUSTIN

    Among the findings this year, climate modelers linked a now fading, years-long, globe-girdling drought to unusually warm waters in the western Pacific and Indian oceans. That warm water looks to be a product of greenhouse gases. In the Arctic, river monitoring showed a 7% increase since 1936 in the flows of the six largest Eurasian rivers that empty into the Arctic Ocean. That fits climate model predictions of increased high-latitude precipitation and follows the observed warming and atmospheric circulation trends. More freshwater flooding into the far North Atlantic could slow the northward flow of heat-laden currents and thus disrupt climate around more populous parts of the North Atlantic region.

    In the biological realm, meta-analyses of studies of plant and animal behaviors strongly suggest that life has taken notice of warming, too. Plants and animals around the globe have shifted their geographic ranges or changed behaviors—such as when they bloom or lay eggs—in ways consistent with reacting to global warming. Climate change also seems to depress both corn and soybean productivity in the U.S. Midwest and plant productivity in Africa's great Lake Tanganyika.

    The growing awareness of some of the ways global warming may be altering the planet and its life has accentuated interest in learning how to adapt to these changes. Humans are getting a better idea of some of the adjustments they'll have to make in the coming centuries, such as beefing up irrigation and shifting agricultural regions. Plants and animals have yet to show how adaptable they will be.

    Online Extras on Climate Change

    Papers and Articles

    D. J. Karoly et al., “Detection of a Human Influence on North American Climate,” Science 302, 1200 (2003)

    M. Hoerling and A. Kumar, “The Perfect Ocean for Drought,” Science 299, 691 (2003)

    R. A. Kerr, “A Perfect Ocean for Four Years of Globe-Girdling Drought,” Science 299, 636 (2003)

    C. Parmesan and G. Yohe, “A Globally Coherent Fingerprint of Climate Change Impacts across Natural Systems,” Nature 421, 37 (2003).

    T. L. Root et al., “Fingerprints of Global Warming on Wild Animals and Plants,” Nature 421, 57 (2003).

    D. B. Lobell and G. P. Asner, “Climate and Management Contributions to Recent Trends in U.S. Agricultural Yields,” Science 299, 1032 (2003)

    Erik Stokstad, “Study Shows Richer Harvests Owe Much to Climate,” Science 299, 997 (2003)

    P. Verburg, R. E. Hecky, and H. Kling, “Ecological Consequences of a Century of Warming in Lake Tanganyika,” Science 301, 505 (2003).

    D. A. Livingstone, “Global Climate Change Strikes a Tropical Lake,” Science 301, 468 (2003).

    T. R. Karl and K. E. Trenberth, “Modern Global Climate Change,” Science 302, 1719 (2003)

    Viewpoint article is accompanied by a collection of Web resources on global climate change.

    Interesting Web Sites

    Global Change and Climate Change Links

    An extensive collection provided by ITAS, Research Centre Karlsruhe, Germany.

    UNEP Climate Change Portal

    Central source for research and resources regarding climate change, from the United Nations Environment Programme.

    Globalchange.gov

    U.S. government gateway to global change data and information.

    EPA Global Warming Site

    Basic information from the U.S. Environmental Protection Agency.

    U.S. Global Change Research Information Office

    An extensive collection of links to Web resources and documents.

    Carbon Dioxide Information Analysis Center (CDIAC)

    The primary global change data and information analysis center of the U.S. Department of Energy.

    Intergovernmental Panel on Climate Change

    Pew Center on Global Climate Change

    [Top of page]

    See Web links on RNA

    #4 Still hot. Science's breakthrough of 2002 kept scientists on the edge of their seats in 2003. Having sketched out the role played by miniature RNA molecules in modulating gene expression, this year biologists dove into the details, exploring how small RNAs orchestrate a cell's behavior and how harnessing their power could combat disease.

    Interference.

    Mice injected with siRNAs (right) are protected from liver disease (left).

    CREDIT: E. SONG ET AL., NATURE MEDICINE

    MicroRNAs, the runts of the RNA litter at about 22 nucleotides in length, were found to guide early development—from shaping plant leaves to mediating cell proliferation in fruit fly embryos. RNA interference (RNAi), which shuts down gene expression, also plays a critical role in development. Mice lacking an RNAi protein called Dicer lost swaths of stem cells and died before birth. Also this year, certain microRNAs in mice were found to help direct stem cells that create the embryo's blood cell system. Humans, meanwhile, are now thought to harbor as many as 255 genes that encode microRNAs—nearly 1% of the genes in the entire genome.

    RNAi also proved its worth this year as a tool to screen hundreds or even thousands of genes. RNAi offers a quick and relatively easy way of systematically inhibiting RNA molecules with a complementary sequence, preventing them from synthesizing proteins. By squelching the RNA signal of one gene at a time, researchers are beginning to outline genetic networks that govern everything from a cell's morphology to its signaling systems.

    Other RNA enthusiasts are recruiting small interfering RNAs (siRNAs), which are similar in size to their micro counterparts, in the fight against disease. They help power the RNAi machinery and thus are pros at controlling protein production—something that goes awry in many diseases. Researchers showed that siRNAs can ramp down proteins involved in HIV and protect mice from hepatitis by blocking a gene behind liver inflammation. The effort to pit these molecules against disease faces big challenges, however. Among them: getting siRNAs to the right genes and cells and steering them clear of the wrong ones.

    Online Extras on RNA

    Papers and Articles

    E. J. Finnegan and M. A. Matzke, “The Small RNA World,” J. Cell Sci. 116, 4689 (2003)

    C.-Z. Chen et al., “MicroRNAs Modulate Hematopoietic Lineage Differentiation,” Science, published online 4 December 2003 (10.1126/science.1091903)

    J. F. Palatnik et al., “Control of Leaf Morphogenesis by MicroRNAs,” Nature 425, 257 (2003)

    E. Bernstein et al., “Dicer Is Essential for Mouse Development,” Nature Genetics 35, 215 (2003)

    E. Wienholds et al., “The MicroRNA-Producing Enzyme Dicer1 Is Essential for Zebrafish Development,” Nature Genetics 35, 217 (2003)

    J. Brennecke et al., bantam Encodes a Developmentally Regulated MicroRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila,” Cell 113, 25 (2003)

    J. C. Carrington and V. Ambros, “Role of MicroRNAs in Plant and Animal Development,” Science 301, 336 (2003)

    M. Matzke and A.J. M. Matzke, “RNAi Extends Its Reach,” Science 301, 1060 (2003)

    J. Couzin, “Mini RNA Molecules Shield Mouse Liver from Hepatitis,” Science 299, 995 (2003)

    J. Couzin, “New Screen Nets ‘Hedgehog’ Genes,” Science 299, 1961 (2003)

    Interesting Web Sites

    RNA World

    Links to Internet resources on RNA-related topics, from IMB Jena.

    RNAi

    A presentation by Mary Montgomery, Biology Department, Macalester College, St. Paul, MN.

    RNAi: Interference RNA

    Lecture notes by Charles Mallory, Department of Biology, University of Miami, for a biology course.

    RNAi links

    Links to publications and labs, from Orbigen.

    miRNA Resource and RNA Interference Resource

    Information and resource pages provided by Ambion.

    The miRNA Registry

    RNA families database of alignments and CMs.

    Introduction to Micro-RNA

    From the Science Projects Web site.

    [Top of page]

    See Web links on single-molecule techniques

    #5 Single molecules groove and glow. New collaborations between biologists and physicists are detailing the busy lives of single molecules, in real time, as they buzz about their business in the cell. Work this year captured molecular motors in motion; refined long-lasting, nanoscale, Technicolor markers; and revealed some basic properties of a single enzyme bound to DNA.

    Afterglow.

    Quantum dots trace capillary networks in a living mouse.

    CREDIT: D. LARSON ET AL., SCIENCE 300, 1434 (2003)

    So-called optical tweezers exploit a laser light beam to manipulate single particles. This year, biologists remodeled optical tweezers into a minuscule force clamp to measure the stepwise motion of individual kinesin proteins—part of the cell's transportation machinery—as they chug along cellular tracks called microtubules. Kinesins move with a hand-over-hand action, it appears, rather than an inchworm gait as an earlier report suggested. Also this year, a technique exploiting single fluorescent molecules illuminated the hand-over-hand motion of another motor protein called myosin.

    Perhaps the most exciting new technique to emerge from the collaboration of physicists and biologists is the application of quantum dots to imaging. Quantum dots are tiny semiconductor nanocrystals that glow in myriad colors when excited by laser light. This year, researchers tracked the movements of individual glycine receptors within nerve cell membranes using quantum dots attached to antibodies. The glow of quantum dots endures—in this case, for 20 minutes—long after the aura of conventional organic dyes has dimmed. Quantum-dot technology for biological imaging is still in its infancy, but these versatile nanocrystals should answer some tough questions soon.

    The physics-biology highway runs in both directions, as physicists are beginning to exploit biological molecules for their own purposes. By stretching a single RNA molecule hundreds of times, researchers last year verified a thermodynamic principle called Jarzynski's equality, which concerns the energy necessary to move a system from one conformation to another. This year, researchers established the kinetics and catalytic rate of a single enzyme as it digests DNA. Expect physicists and biologists to continue bonding over their fascination with single molecules.

    Online Extras on Single-Molecule Techniques

    Papers and Articles

    C. L. Asbur, A. N. Fehr, and S. M. Block, “Kinesin Moves by an Asymmetric Hand-Over-Hand Mechanism,” Science, published online 4 December 2003 (10.1126/science.1092985)

    H. Yang et al. “Protein Conformational Dynamics Probed by Single-Molecule Electron Transfer,” Science 302, 262 (2003)

    M. Orritt, “The Motions of an Enzyme Soloist,”

    A Perspective article on the Yang et al. results.

    A. M. van Oijen et al., “Single-Molecule Kinetics of λ Exonuclease Reveal Base Dependence and Dynamic Disorder,” Science 301, 1235 (2003)

    E. A. Lipman et al., “Single-Molecule Measurement of Protein Folding Kinetics,” Science 301, 1233 (2003)

    A. Yildiz et al., “Myosin V Walks Hand-Over-Hand: Single Fluorophore Imaging with 1.5-nm Localization,” Science 300, 2061 (2003)

    C. Seydel, “Quantum Dots Get Wet,” Science 300, 80 (2003)

    Y. Sako and T. Yanagida, “Single-Molecule Visualization in Cell Biology,” Nat. Rev. Mol. Cell Biol. Suppl. SS1 (2003) [PubMed]

    M. Dahan, “Diffusion Dynamics of Glycine Receptors Revealed by Single-Quantum Dot Tracking,” Science 302, 442 (2003)

    A. E. Knight and J. Malloy, “Single Molecule Fluorescence and Optical Tweezers: Application to Molecular Motors”

    A brief introduction made available by the University of York Molecular Motors Group.

    Interesting Web Sites

    Molecular Motors Group

    Based at the University of York, this group utilizes single molecule techniques to investigate the mechanisms of molecular motors.

    Molecular Expressions

    A comprehensive resource maintained by Florida State University that includes a Microscopy Primer with tutorials on fluorescence microscopy and other single-molecule techniques, a list of microscopy web resources, and several image galleries.

    Optical Tweezers Links and Resources

    Links to recent papers and research laboratories worldwide, provided by the University of St. Andrews Optical Trapping Group.

    About Nanocrystals

    An overview of quantum dot properties, provided by Evident Technologies.

    Single Molecule Biophysics Group (at UCLA)

    Provides links to other groups around the world carrying out single-molecule spectroscopy and biophysics.

    [Top of page]

    See Web links on GRBs

    #6 Cosmic blasts.Several discoveries this year lifted veils that had shrouded the most energetic explosions in the universe: titanic blasts of energy called gamma ray bursts (GRBs). Most notably, in March, astronomers confirmed the connection between GRBs and supernovas—the death throes of massive stars—when they spotted the unmistakable imprints of a supernova in the glow of a bright GRB. Astrophysicists now believe that the burst's jets of energy spewed into space when a star's core imploded, forming a black hole or—in a minority view—a rapidly spinning neutron star with a crushing magnetic field.

    Other observations convinced researchers that GRBs confine their fiercest jets into narrow beams, perhaps just 1 to 5 angular degrees across. Only some of these flares happen to point toward Earth, making them far more common in the universe than the number of sightings would suggest. One observation sowed some dissent, however: A claimed detection of a polarized beam from a GRB sparked debate about whether the jets consist almost entirely of highly organized electromagnetic radiation, rather than a blast of particles as theorists have assumed.

    Jet sets.

    New black holes may blast narrow jets of gamma rays and fatter sprays seen in x-rays, optical light, and radio waves.

    CREDIT: DANA BERRY/SKYWORKS DIGITAL

    More solid were the conclusions by several teams that an enigmatic set of lower-energy bursts, called x-ray flashes, streams from the same kinds of stellar catastrophes that produce GRBs. Theorists think that some x-ray flashes found this year were GRBs seen from the side. Other recent collapsing stars appeared to churn out narrow cones of x-rays and wider sprays of matter that produced optical light and torrents of radio waves, but no gamma rays.

    Teamwork was the key to these advances. NASA's High Energy Transient Explorer overcame technical challenges to spot dozens of GRBs and x-ray flashes and beam their locations to astronomers on the ground, where a global network of robotic and traditional telescopes swung into action. This rapid detective work showed that a mysterious class of “dark” GRBs was visible in optical light after all, but only within minutes of the explosion.

    The field's frenzy won't subside anytime soon. NASA's Swift satellite, set for launch in mid-2004, should catch GRBs at five times the rate of any previous mission. It will tackle the field's biggest remaining riddle: the origins of GRBs that last mere fractions of a second. Today's model with the most cachet involves the merger of two neutron stars.

    Online Extras on Gamma Ray Bursts

    Papers and Articles

    K. Z. Stanek et al., “Spectroscopic Discovery of the Supernova 2003dh Associated with GRB 030329,” Astrophys. J. 591, L17 (2003)

    J. Hjorth et al., “A Very Energetic Supernova Associated with the Gamma-Ray Burst of 29 March 2003,” Nature 423, 847 (2003)

    W. Coburn and S. E. Boggs, “Polarization of the Prompt Gamma-Ray Emission from the Gamma-Ray Burst of 6 December 2002,” Nature 423, 415 (2003)

    R. E. Rutledge and D. B. Fox, “Re-Analysis of Polarization in the Gamma-Ray Flux of GRB 021206,” astro-ph/0310385 (2003) [arXiv.org preprint server]

    E. Berger et al., “A Common Origin for Cosmic Explosions Inferred from Calorimetry of GRB030329,” Nature 426, 154 (2003)

    A. M. Soderberg et al., “A Redshift Determination for XRF 020903: First Spectroscopic Observations of an X-Ray Flash,” astro-ph/0311050 (2003) [arXiv.org preprint server]

    G. Schilling, “Astronomers Nail Down Origin of Gamma Ray Bursts,” Science 300, 1860 (2003)

    R. Irion, “Gamma Ray Bursts Get Magnetic,” Science 300, 1499 (2003)

    Interesting Web Sites

    Gamma-ray Bursts

    An introduction from Imagine the Universe, a service of NASA Goddard's High Energy Astrophysics Science Archive Research Center (HEASARC).

    HETE-2 (High Energy Transient Explorer)

    HETE-2 is a small scientific satellite designed to detect and localize GRBs.

    Swift Mission

    Scheduled for launch in May 2004, Swift is a multi-wavelength observatory dedicated to the study of GRBs.

    Swift Science Center

    HEASARC hosts the science support Web site for the Swift mission.

    GRB Coordinates Network (GCN)

    2003 Gamma Ray Burst Symposium

    [Top of page]

    See Web links on stem cells

    #7 Spontaneous generation. At least one observer called the surprise discovery an “ethical earthquake”: Mouse embryonic stem (ES) cells can develop into both sperm and egg cells in culture dishes. The work hatched both scientific and ethical questions. In the short term, the discoveries should help reveal how germ cells develop. If the feat can be reproduced in human cells, it could provide a renewable source of human eggs or sperm for research. But it also opens a Pandora's box of ethical questions: Could a child be born whose genetic parent is a cell line?

    Sex cells.

    Clusters of immature (green) and maturing (red) oocytes form spontaneously in cultures of mouse embryonic stem cells.

    CREDIT: K. HÜBNER ET AL., SCIENCE 300, 1251 (2003)

    In contrast to the complex questions it raised, the discovery itself was deceptively simple. Three separate teams found that germ cells develop spontaneously in dense cultures of ES cells. The trick was identifying them. One group genetically modified ES cells to glow green if they expressed genes characteristic of developing sex cells. Once isolated, the glowing cells seemed to behave like developing oocytes, showing signs of meiosis, the specialized cell division undergone by sperm and eggs but no other cell types.

    Perhaps most surprising, after about 40 days in culture, structures that looked like early embryos appeared. The clusters may be parthenotes: embryos that sometimes develop from unfertilized eggs. (Normal mouse oocytes are known to form parthenotes in culture, but despite multiple attempts to implant them in a womb, none has ever survived to birth.) However, attempts to fertilize the lab-grown eggs have so far failed.

    Similar techniques showed that ES cells can also give rise to sperm precursors. Preliminary studies this year suggest that these immature sperm, when injected into an egg, can lead to the development of an early embryo. But none has produced a live mouse pup.

    Growing sex cells in a dish should provide insights into the molecular processes that control the formation of sperm and eggs and lead to a better understanding of some kinds of infertility. And if human ES cells can serve as a source of human oocytes, they might replace eggs from human donors, which are in short supply, in nuclear transfer experiments that might someday produce patient-specific stem cells for treating disease. Indeed, if artificial egg cells prove to be functional enough for nuclear transfer but not for production of offspring, they might blunt one of the main arguments against therapeutic cloning: that it creates embryos only to destroy them.

    Online Extras on Sex Cells from Stem Cells

    Papers and Articles

    N. Geijsen et al., “Derivation of Embryonic Germ Cells and Male Gametes from Embryonic Stem Cells,” Nature, published online 10 December 2003 (10.1038/nature02247)

    G. Vogel, “Scientists Make Sperm in a Dish,” Science 302, 1875 (2003)

    News article on the Geijsen et al. results.

    K. Hübner et al., “Derivation of Oocytes from Mouse Embryonic Stem Cells,” Science 300, 1251 (2003)

    G. Vogel, “Oocytes Spontaneously Generated,” Science 300, 721 (2003)

    News article on the Hübner et al. results.

    Y. Toyooka et al., “Embryonic Stem Cells Can Form Germ Cells In Vitro,” Proc. Natl. Acad. Sci. U.S.A. 100, 11457 (2003)

    G. Vogel, “Making Sperm from Scratch,” ScienceNOW, 16 September 2003

    G. Vogel, “An Overview of Stem Cell Research and Regulatory Issues,” Mayo Clin. Proc. 78, 993 (2003) [PubMed]

    C. Dennis, “Developmental Biology: Synthetic Sex Cells,” Nature 424, 364 (2003)

    News article on the technical and ethical minefield facing biologists trying to grow sex cells in the lab.

    Interesting Web Sites

    NIH Stem Cell Information

    Comprehensive resource about U.S. federal research policy and stem cells that includes links to recent literature, funding opportunities, and a tutorial on human embryonic stem cells.

    Nature Web Focus: Germ Cells

    A collection news and research papers on the establishment of the germline.

    The Stem Cell Debate

    Presentation from CNN covering the pros and cons of the stem cell debate; includes an animated primer about embryonic stem cells.

    Human Embryonic Stem Cells

    An animated tutorial for a general audience. (Requires Flash Player).

    Special Report: Cloning and Stem Cells

    A monthly news update on cloning and stem cell technology from NewScientist.com.

    Human Germline Engineering

    A unique compilation of opinion and commentary from specialists around the world on the scientific, social and ethical implications of altering the human germline, from the UCLA Program on Medicine, Technology and Society.

    [Top of page]

    See Web links on left-handed materials

    #8 About-face. After 2 years of debate, work this year confirmed that certain oddball materials are capable of bending light in the wrong direction. Materials bend light and other types of electromagnetic radiation according to a property known as their index of refraction. The bigger a material's index, the slower light travels through it, and the more light bends. A change in refractive index is why a straw in a glass appears to have a kink where it enters the water. In natural materials, light always bends at a positive angle with respect to the angle at which it entered.

    In 1964, a Russian physicist theorized that researchers could tailor materials to reverse the way they manipulate passing electromagnetic radiation. Two years ago, researchers created such “left-handed” materials. They beamed microwaves at a composite of copper rings and wires, which steered microwaves out at a negative instead of a positive angle. Last year other teams challenged those results, but this year definitive proof came from multiple camps.

    One group traced the path of microwaves sent through two wedged-shaped samples, one a control made from Teflon, the other an array of rings and wires. The Teflon deflected the microwaves at a positive angle, as expected, whereas the rings and wires sent them out at a negative angle. Another group reported similar results and further showed that they agreed closely with numerical simulations.

    Physicists are already finding ways to make use of left-handed materials, which have other properties besides a negative refractive index. Last month, for example, researchers reported that a set of electronic devices wired together to make a left-handed material produced an inverse Doppler effect, the reverse of the effect that causes the whistle of a passing train to drop in pitch. The new find could help researchers make cheap, compact devices useful for nondestructive testing of materials. Another team, meanwhile, snapped the first-ever image with a flat lens made from a left-handed material. Ultimately, such lenses promise to generate far less distortion than standard optics.

    Online Extras on Left-Handed Materials

    Papers and Articles

    A. A. Houck, J. B. Brock, and I. L. Chuang, “Experimental Observations of a Left-Handed Material That Obeys Snell's Law,” Phys. Rev. Lett. 90, 137401 (2003)

    C. G. Parazzoli et al., “Experimental Verification and Simulation of Negative Index of Refraction Using Snell's Law,” Phys. Rev. Lett. 90, 107401 (2003)

    P. V. Parimi et al., “Photonic Crystals: Imaging by Flat Lens Using Negative Refraction,” Nature 426, 404 (2003)

    N. Seddon and T. Bearpark, “Observation of the Inverse Doppler Effect,” Science 302, 1537 (2003)

    R. F. Service, “Inverse Doppler Demonstration Ends a 60-Year Quest,” Science 302, 1489 (2003)

    R. A. Shelby, D. R. Smith, S. Schultz, “Experimental Verification of a Negative Index of Refraction,” Science 292, 77 (2001)

    M. C. K. Wiltshire, “Bending Light the Wrong Way,” Science 292, 60 (2001)

    Interesting Web Sites

    Left-handed Metamaterials: Imaging by a Flat Lens

    A presentation by S. Sridhar's lab at Northeastern University.

    Left-Handed Metamaterials

    Research and resource page by David R. Smith, Department of Physics, University of California, San Diego.

    Negative-Refractive-Index Metamaterials

    Research presentation by George V. Eleftheriades, Department of Electrical and Computer Engineering, University of Toronto.

    “The Reality of Negative Refraction”

    Article by David R. Smith in the May 2003 Physics World.

    “Left-Handed Materials Go from Fact to Fiction and Back Again”

    1 July 2003 Web article by Alexander Hellemans on IEEE Spectrum Online.

    [Top of page]

    See Web links on the Y chromosome

    #9 The little Y that could. A sequencing tour de force revealed the genetic code of the Y chromosome this year and in the process earned new respectability for the stubby piece of DNA that makes a man a man. Half of the 59 million bases in this chromosome are jumbled, possibly useless, and virtually impossible to decipher. This “junk” suggested that the Y is slowly fading as a chromosome. But the new sequence of the other half of Y's DNA, which contains the genes, shows that it has evolved an unusual, but effective, way to take care of itself.

    Man maker.

    Insights from sequencing the Y chromosome (left) have earned it new respect.

    CREDIT: ANDREW SYRED/PHOTO RESEARCHERS INC.

    The Y's coding regions had proved difficult to unravel because there are duplicate genes throughout. The sequencers now know that most of these duplicate genes are arranged in eight palindromes, within each of which one set of genes has an identical or nearly identical mirror-image matchup. Palindromes cover up to 3 million bases and include most of the genes related to testis development and function.

    The palindromes make up for the fact that Y lacks a partner. All other human chromosomes come in pairs. When a gene on one partner goes bad, it can be replaced with a copy of the other partner's good gene. A genomic loner, Y appeared to have no way to prevent mutations from gradually destroying its genes. That's where the palindromes come in: Genes on one end of a palindrome can replace mutated twins on the other end.

    By sequencing parts of the Y chromosomes of other primates, researchers now know that at least six of the palindromes predate the evolution of humans and arose more than 5 million years ago. Thus it seems that gene swapping between palindrome arms keeps the Y chromosome's genetic makeup stable.

    Online Extras on the Y chromosome sequence

    Papers and Articles

    H. Skaletsky et al., “The Male-Specific Region of the Human Y Chromosome is a Mosaic of Discrete Sequence Classes,” Nature 423, 825 (2003)

    S. Rozen et al., “Abundant Gene Conversion Between Arms of Palindromes in Human and Ape Y Chromosomes,” Nature 423, 873 (2003)

    E. Pennisi, “Gene Researchers Hunt Bargains, Fixer-Uppers” Science 298, 735 (2002)

    News focus on TIGR's 14th International Genome Sequencing and Analysis Conference; highlights included discussions of chromosome evolution.

    M. A. Jobling and C. Tyler-Smith, “The Human Y Chromosome: An Evolutionary Marker Comes of Age,” Nat. Rev. Genet. 4, 598 (2003)

    S. Ali and S. E. Hasnain, “Genomics of the Human Y Chromosome: 1. Association With Male Infertility,” Gene 321, 25 (2003)

    D. Bachtrog and B. Charlesworth, “Towards a Complete Sequence of the Human Y Chromosome” Genome Biology 2, reviews1016.1 (2001)

    M. P. H. Stumpf and D. B. Goldstein, “Genealogical and Evolutionary Inference with the Human Y Chromosome,” Science 291, 1738 (2001)

    Interesting Web Sites

    Human Chromosome Launchpad: Y Chromosome

    Links to gene maps, sequences, associated genetic disorders, identified genes, research efforts and laboratories; provided by the Genome Programs of the U.S. Department of Energy Office of Science.

    Chromosome Y Resources

    Links to sequence-related information provided by the GDB Human Genome Database.

    The Y Chromosome Consortium

    A group involved in a collaborative effort to study genetic variation on the human Y chromosome.

    Human Y Chromosome Map

    From the National Center for Biotechnology Information (NCBI).

    Notes on Y Chromosome Variation

    Information on the use of Y chromosome variation to study the populations and their migrations, made available by the Clinical Molecular Genetics Society.

    [Top of page]

    See Web links on angiogenesis

    #10 Starving cancer. It's been a roller-coaster ride for researchers working on anticancer drugs that block development of the blood vessels that feed tumor growth. They've seen their field bounce from obscurity and skepticism to superhype—after a 1998 article in The New York Times suggested that antiangiogenesis drugs, as they are called, would cure cancer in 2 years—and then back to skepticism when early clinical trials produced unimpressive results. But this year, they've finally begun to see their efforts pay off.

    The drugs' premise is simple. As a cancerous tumor grows, it must chemically induce the growth of new blood vessels to supply it with nutrients. Antiangiogenic agents starve tumors by preventing this blood vessel growth. Numerous agents, both naturally occurring proteins and synthetic drugs, shrink tumors in lab animals, but they had not been able to meet the “gold standard” of clinical cancer trials: extending the lives of patients.

    Angiogenesis in action.

    Blood vessels grow toward a dark sarcoma tumor.

    CREDIT: L. HEUSER AND R. ACKLAND/UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE

    But this June, researchers announced that an antiangiogenesis drug, given with conventional chemotherapy drugs in a large clinical trial, prolonged the lives of patients with advanced colon cancer. The drug had failed a similar test with breast cancer patients, possibly because advanced breast tumors produce more angiogenesis-promoting factors than colon tumors do and are thus harder to control. This suggests that antiangiogenesis therapies will have to be tailored to their targets to be effective.

    Researchers have also learned that antiangiogenesis drugs work most effectively in combination, either with each other or with conventional chemotherapeutic drugs or radiation. And clinicians will have plenty of drugs to choose from. Some 60 different antiangiogenesis drugs are currently in clinical trials against a wide variety of cancers, and many more are in preclinical testing.

    Online Extras on Antiangiogenesis Treatments

    Papers and Articles

    J. Marx, “A Boost for Tumor Starvation,” Science 301, 452 (2003)

    A. Sudhaker et al., “Human Tumstatin and Human Endostatin Exhibit Distinct Antiangiogenic Activities Mediated by αvβ3 and α5β1 Integrins,” Proc. Natl. Acad. Sci. U.S.A. 100, 4766 (2003)

    Y. Sato, “Molecular Diagnosis of Tumor Angiogenesis and Anti-Angiogenic Cancer Therapy,” Int. J. Clin. Oncol. 8, 200 (2003) [PubMed]

    D. Bissachi et al., “Anti-Angiogenesis and Angioprevention: Mechanisms, Problems and Perspectives,” Cancer Detec. Prev. 27, 229 (2003)

    “Additional Study With Avastin in Metastatic Colorectal Cancer Shows Significant Increase in Progression-free Survival,”Doctor's Guide (27 November 2003)

    News update on a large clinical trial of Genentech's antiangiogenesis drug.

    M. Barinaga, “Cancer Drugs Found to Work in New Way,” Science 288, 245 (2000)

    News article on two studies that demonstrated the promise of antiangiogenesis therapy.

    Interesting Web Sites

    Angiogenesis Foundation

    Provides patients and their families with up-to-date, expert, and practical information about new angiogenesis research and medicines.

    Digest Page: Angiogenesis Inhibitors

    A collection of materials about angiogenesis inhibitors from the National Cancer Institute. Includes a fact sheet on how antiangiogenesis therapies work, an overview of active clinical trials, and Understanding Angiogenesis — an illustrated description of angiogenesis and its importance in cancer research.

    Genentech Pipeline: Avastin

    Development status of the promising antiangiogenesis agent Avastin.

    Cancer News on the Net

    Features the latest information regarding cancer prevention, diagnosis, and treatment.

    Antiangiogenesis Therapy

    Background information how antiangiogenesis therapies work, from the American Cancer Society.

    American Society of Clinical Oncology

    [Top of page]

  3. BREAKTHROUGH OF THE YEAR

    Areas to Watch in 2004

    See Web links on areas to watch

    Science 's editors prognosticate about which research and policy areas are in for big changes next year.

    Three on Mars. With luck, planetary scientists will have the equivalent of a martian traffic jam to deal with in early 2004. Three craft are expected to touch down around the turn of the year: The European Space Agency's lander Beagle 2 on Isidis Planitia and NASA's rovers Spirit in Gusev crater and Opportunity on Meridiani Planum. The oohs and ahs will come shortly after touchdown with panoramic views of new martian landscapes, but the science will dribble out during the 90-day missions and long after. Opportunity will likely find minerals that point to hot water within early Mars, but Spirit could have a tougher time figuring out how water shaped an ancient crater lake floor. The low-budget Beagle 2 is taking the big gamble, looking for signs of life, past and even present.

    Microbe militia.Biodefense research exploded in 2003, and the boom will continue in 2004. Expect advances in the basic biology of a range of little-studied pathogens that cause diseases including plague, anthrax, tularemia, botulism, and hemorrhagic fevers, as well as a torrent of newly sequenced genomes, often including multiple strains of the same bug. At the same time, look for major steps in the development of new or improved vaccines for smallpox, anthrax, and Ebola, as well as several antiviral drugs and an antidote to botulinum toxin. Meanwhile, measures to keep a lid on data that could help aspiring bioterrorists will continue to provoke debate.

    CREDIT: ILLUSTRATION BY TERRY SMITH;

    Genome data deluge.With the sequence of the human genome in hand, biologists are finding that they need much more data to make sense of it. Toward that end, several more large-scale, data-intensive projects are in the works. The SNP Consortium and Haplotype Map Project are seeking patterns in human genetic variations; microarrays are generating information on gene expression; proteomics projects are detailing the functions and interactions of proteins; and new pilot programs are working to streamline the identification of gene function. Expect a flood of information in 2004 and a plethora of new databases, software, and standards for how these data are collected and presented—but continued debate about how to use and coordinate it all. New gene discoveries and insights into how organisms are related, particularly what makes humans different from chimps, should make for an interesting year.

    Open sesame.Will 2004 be the year scientists open their hearts—and their wallets—to open-access scientific journals? A slew of publishers will launch experiments in which authors will pay publication charges and journals will make their papers freely accessible over the Internet. Advocates say that the author-pays approach will speed the flow of scientific information, but critics predict that the business model will be a flop, particularly outside the relatively flush biomedical sciences.

    Bottoms up.Recently, two “B factories” that produce particles containing the heavy “bottom” quark have been hinting at physics beyond the Standard Model. Next year may well set the physics community abuzz as the factories, one in California and the other in Tsukuba, Japan, create another swarm of B's. Unexpectedly, the decay of bottom-quark-containing particles doesn't quite match what the Standard Model predicts. This might be a sign of supersymmetry or other exotic physics. The issue probably won't be fully resolved by year's end, but new data should make the anomaly either stand in stark relief or largely disappear.

    Digging deeper. After decades of toiling to identify fungi, nematodes, and innumerable other organisms that live belowground, soil scientists have started to ask—and answer—ecological questions. Look for more studies of how microbes contribute to greenhouse gases and some plants become invasive by escaping soil pathogens. The ultimate pay dirt may be more accurate knowledge of soils' impact on climate change and better strategies for sustainable agriculture.

    Science and security.Increasingly tough antiterror measures may not be good for U.S. science. Foreign scientists continue to have trouble entering the country due to tougher visa reviews, and research leaders worry that a host of other rules—from polygraph tests for some Department of Energy scientists, to export regulations—have made science an increasingly unattractive career. Other nations are considering adopting similar rules, which may further complicate the global sharing of ideas. Look for continuing friction over the costs and benefits of tighter security—and government moves to roll back a few rules that may have gone too far.

    Online Extras on Areas to Watch

    Mars Missions

    R. Kerr, “Putting Martian Science to the Test,” Science 301, 1832 (2003)

    R. Kerr, “A-Roving We Will Go, Slowly,” Science 301, 1834 (2003)

    R. Kerr, “Eons of a Cold, Dry, Dusty Mars,” Science 301, 1037 (2003)

    R. Kerr, “Running Water Eroded a Frigid Early Mars,” Science 300, 1496 (2003)

    R. Kerr, “Iceball Mars?,” Science 300, 234 (2003)

    R. Kerr, “Scientists Pick Two Sweet Spots for Rovers on Mars,” Science 299, 326 (2003)

    NASA Mars Exploration Program Mars Exploration Rover Mission

    Engaging, information-packed sites on NASA's Mars efforts, including rovers Spirit and Opportunity.

    Beagle 2

    Site of British-led mission includes a Weblog, information on the spacecraft's scientific mission and technical story, and updates on the descent (scheduled for Christmas Day 2003).

    Biodefense

    D. Malakoff, “U.S. Biodefense Boom: Eight New Study Centers,” Science 301, 1450 (2003)

    M. Enserink, “New Biodefense Splurge Creates Hotbeds, Shatters Dreams,” Science 302, 206 (2003)

    B. Budowle, “Building Microbial Forensics as a Response to Bioterrorism,” Science 302, 1852 (2003)

    Biotechnology Research in an Age of Terrorism: Confronting the “Dual Use” Dilemma

    National Research Council report on balancing science and security.

    Countering Bioterrorism: The Role of Science and Technology

    A 2002 report from the National Academies' Institute of Medicine

    NIAID Progress Report [PDF]

    Interim report, published August 2003, about the biodefense effort at the National Institute of Allergy and Infectious Diseases.

    NIAID Biodefense Research

    Rich NIAID site on the Institute's biodefense research undertakings; includes extensive public-outreach section and a page devoted to the Institute's strategic plan for biodefense.

    Genome Data

    R. Service, “Public Projects Gear up to Chart the Protein Landscape,” Science 302, 1316 (2003)

    M. Gerstein et al., “Integrating Interactomes,” Science 295, 284 (2002)

    J. Quackenbush, “Microarrays, Guilt by Association,” Science 302, 240 (2003)

    M. Branca, “Putting Gene Arrays to the Test,” Science 300, 238 (2003)

    Microarray Gene Expression Data Society

    A society working to improve microarray standards and use.

    Spectroscopy Now: Proteomics

    Primer on proteomics with tutorials and news.

    The SNP Consortium Web site

    National Human Genome Research Institute

    NHGRI Web site has programs and online lectures on genome-related projects.

    Open Access

    D. Malakoff, News Focus: Scientific Publishing

    “Opening the Books on Open Access,”Science302, 550 (2003)

    “The Fight Over a Phrase,”Science302, 550 (2003)

    “Money Woes Force Some to Change Course,”Science302, 550 (2003)

    “House Bill Triggers Internecine Battle,”Science302, 550 (2003)

    Open Access News

    Weblog providing news and views from the “free online scholarship (FOS) movement.”

    B Meson Physics

    K. Abe et al., “Measurement of Time-Dependent CP-Violating Asymmetries in B0—> phi Ks0, K− K− Ks0, and eta' Ks0 Decays” (2003) [arXiv.org preprint server]

    BABAR

    B-factory at the Stanford Linear Accelerator Center seeking out the roots of matter-antimatter asymmetry.

    High-Energy Accelerator Research Organization (KEK)

    Organization managing and operating the KEKB B-factory at Tsukuba, Japan, the site of the Belle experiment.

    CP Violation in B meson decay: FAQ (from Kay Kinoshita, University of Cincinnati Physics Department)

    Soil Science

    C. W. Schadt et al., “Seasonal Dynamics of Previously Unknown Fungal Lineages in Tundra Soils,” Science 301, 1359 (2003)

    E. Pennisi, “Neither Cold Nor Snow Stops Tundra Fungi,” Science 301, 1307 (2003)

    W. H. Van der Putten, “Plant Population Biology: How to Be Invasive,” Nature 417, 32 (2002)

    International Society for Microbial Ecology

    Soil Ecology Society

    Soil Science Society of America

    Mycorrhiza Information Exchange

    Soils Zoo

    Brief tour of soil biodiversity, from University of Adelaide.

    Science and Security

    D. J. Galas and H. Riggs, “Global Science and U.S. Security” (editorial), Science, 300, 1847 (2003)

    D. Kennedy, “Scientific Exchange: Storm Rising?” (editorial), Science, 301, 437 (2003)

    T. Walliman, “Science and Security: A European View” (letter), Science, 301, 462 (2003)

    M. Enserink, “Panel Seeks to Balance Science and Security,” Science, 302, 206 (2003)

    D. Malakoff and M. Enserink, “Researchers Await Government Response to Self-Regulation Plea,” Science, 302, 368 (2003)

    Background Paper on Science and Security in an Age of Terrorism

    From the National Academy of Sciences Web site.

    Scientific Openness and National Security Workshop

    Web site of 9 January 2003 Center for Strategic & International Studies workshop includes text of speeches, presentations, and audio clips from various speakers.

  4. BREAKTHROUGH OF THE YEAR

    Scorecard 2002

    How accurately did our crystal ball predict this year's advances?

    Whither the ice? Watching the world's ice paid off in 2003, although it has only heightened concern among glaciologists. Satellite observations provided more evidence that mountain glaciers such as those in Argentinean Patagonia are melting rapidly. Of more concern were signs that climatic warming can get at large ice sheets quickly and easily. The breakup of more of the Larsen Ice Shelf of West Antarctica was followed by surging of the glacial ice streams that feed it, supporting the idea that ice shelves buttress glacial ice against rapid loss to the sea. The Larsen Ice Shelf has thinned so quickly that warming seawater must be the culprit, tying glacial surging to climate warming.

    See Web links on disappearing glaciers

    A sun-climate connection.Interest in whether the waxing and waning of the sun affects climate continued to grow in 2003, and researchers came up with more persuasive sun-climate connections. But the quest for an explanatory mechanism barely plodded along. The mechanism du jour—solar-modulated cosmic rays altering cloud cover—does after all involve the most poorly understood part of the climate system, its clouds. A decade rather than a year may provide a fairer assessment.

    See Web links on sun-climate connections

    Budget bust. Asia was the place to be this year for researchers seeking government support. The science budgets of China, Japan, and India all grew at healthy rates. The news from Europe was much bleaker. Cuts were the norm for Italy and France, and German scientists were forced to make do with much smaller increases than promised. The United Kingdom and Canada stood out as exceptions, with scientists enjoying significant increases. In the United States, a still-pending federal budget contains little New Year's cheer, although spending to combat bioterrorism bolstered some sectors. Science support from state governments suffered badly.

    See Web links on science budget

    R-evolutionary genomics. Comparative analyses of newly sequenced genomes or partial sequences, including those of the rat, dog, two puffers, a bread mold, and anthrax and a close relative, have stimulated new hypotheses about evolution. But questions about how organisms are related to one another on the tree of life, or even what makes chimps and humans different, remain unanswered.

    See Web links on genomes and evolution

    A different light. All in all, 2003 was a good year for astronomers tuning in to wavelengths outside the optical band. Although the Space Infrared Telescope Facility was delayed several months, the European satellite INTEGRAL is providing images of black holes and other phenomena in the gamma ray region of the spectrum. And the Wilkinson Microwave Anisotropy Probe's picture of the cosmic background radiation was such a smashing success it made Science's 2003 Breakthrough of the Year.

    See Web links on gamma-ray, infrared, and microwave astronomy

    Important matter.In 2002, two rival teams using equipment at CERN near Geneva made cold, slow-moving antihydrogen in bulk. The particles should help physicists figure out the differences between matter and antimatter. But since then, little has happened, and the antiproton decelerator at CERN is scheduled to be shut down in 2005. That means the next step—measuring the light that antihydrogen absorbs and emits—is several years away, at least.

    See Web links on antihydrogen

    Online Extras on Last Year's Picks

    Disappearing Glaciers

    H. De Angelis and P. Skvarca, “Glacier Surge After Ice Shelf Collapse,” Science 299, 1560 (2003)

    E. Rignot et al., “Contribution of the Patagonia Icefields of South America to Sea Level Rise,” Science 302, 434 (2003)

    British Antarctic Survey

    Site includes informative “topic sheets” about climate change and the Antarctic ice sheet.

    National Snow and Ice Data Center

    Center's State of the Cryosphere site provides an overview of snow and ice as indicators of climate change.

    Sun-Climate Connections

    K. S. Carslaw et al., “Cosmic Rays, Clouds, and Climate,” Science 298, 1732 (2002)

    F. S. Hu et al., “Cyclic Variation and Solar Forcing of Holocene Climate in the Alaskan Subarctic,” Science 301, 1890 (2003)

    S. K. Solanki, “Solar Variability and Climate Change: Is There a Link?” (2002) [PDF]

    Review of debate regarding the sun's influence on Earth climate, posted at the Royal Astronomical Society Web site.

    Global Change Master Directory

    Well-known NASA site includes extensive links on climate and sun-earth interactions.

    Solar Variability and Its Impact on Climate Change

    Electronic workspace for scientists from the Collaboratory for Atmospheric Science and Technology of the British Atmospheric Data Centre. Includes a public-access area.

    Science Budget

    AAAS R&D Budget and Policy Program

    Data and analysis on yearly U.S. science budget and policy priorities.

    J. Mervis, “2004 Science Budget: House Panel Backs 6% NSF Increase As Other Agencies Struggle,” Science 301, 444 (2003)

    J. Couzin, “2004 Science Budget: Congress Wants the Twain to Meet,” Science 301, 444 (2003)

    News Focus: 2004 Budget Request (7 February 2003)

    D. Malakoff, “Protecting the Homeland Sets Tone for 2004 Budget,” Science 299, 806 (2003)

    J. Mervis, “NSF Is Not Yet Seeing Double,”xy Science 299, 807 (2003)

    J. Kaiser, “NIH Shuffles Budget to Prop Up Research,” Science 299, 807 (2003)

    D. Normile, “Japan: Science Fares Well in a Tight Budget,” Science 299, 28 (2003)

    W. Kondro, “Canadian Budget: Graduate Training, Research Councils Are Big Winners,” Science 299, 1298 (2003)

    Genomes and Evolution

    B. Hoopengardner et al., “Nervous System Targets of RNA Editing Identified by Comparative Genomics,” Science 301, 832 (2003)

    E. F. Kirkness et al., “The Dog Genome: Survey Sequencing and Comparative Analysis,” Science 301, 1898 (2003)

    S. J. O'Brien and W. J. Murphy, “A Dog's Breakfast?,” Science 301, 1854 (2003)

    Science Special Issue: Tree of Life (13 June 2002)

    News and Viewpoints on charting life's evolutionary history; includes review of phylogenomics by J. A. Eisen and C. M. Fraser.

    J. W. Thomas et al., “Comparative Analyses of Multi-Species Sequences from Targeted Genomic Regions,” Nature 424, 788 (2003)

    A. G. Clark et al., “Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios,” Science 302, 1960 (2003)

    “Genome Comparisons Hold Clues to Human Evolution,”Science302, 1876 (2003)

    “Chimp Genome Draft Online,”Science302, 1876 (2003)

    Links to the Genetic World: Comparative Genomics

    Informative page on genome sequencing and genomics, with links to specific comparative genomics efforts (from the Oak Ridge National Labs Human Genome Information site).

    Roy J. Carver Center for Comparative Genomics

    Handsome site describes University of Iowa's comparative-genomics efforts, with links to similar programs around the world.

    The Tree of Life

    Ambitious Web project providing information about evolutionary relationships (including molecular ones) among Earth's diverse organisms.

    GOLD (Genomes OnLine Database)

    Comprehensive, up-to-date compendium of information on complete and ongoing genome projects around the world.

    Chimpanzee Genomics Page at Baylor College of Medicine

    Gamma-Ray, Infrared, and Microwave Astronomy

    C. L. Bennett et al., “First-Year Wilkinson Microwave Anisotropy Probe (WMAP) Observations: Preliminary Maps and Basic Results,” Astrophys. J. Suppl. Ser. 148, 1 (2003) [arXiv.org preprint server]

    ESA Integral Mission

    Space Infrared Telescope Facility (SIRTF)

    Wilkinson Microwave Anisotropy Probe (WMAP)

    Special Web Supplement: Star Formation

    Special Web Supplement: The Dark Side

    Web sites accompanying two Science special issues include links to many ground and spaceborne telescope projects and to information on the cosmic microwave background.

    Antihydrogen

    The Athena Experiment

    Web site of the CERN project that first captured antihydrogen in bulk.

    Antimatter: Mirror of the Universe

    Outstanding CERN educational site including pages on the science of antimatter and Webcasts on the theoretical and technical challenges of making antimatter.

    Antihydrogen Production

    Another CERN site, featuring QuickTime movies and information on the ATRAP antihydrogen-trapping program.

  5. BREAKTHROUGH OF THE YEAR

    Breakdown of the Year: Space Shuttle Columbia

    1. Andrew Lawler

    See Web links on Columbia

    What was to be a stellar year for NASA—continuing work on the international space station and double launches to Mars—turned into a horrible supernova above Texas. On 1 February, the space shuttle Columbia disintegrated as it returned to Earth from a science mission. The tragedy left seven dead, the shuttle fleet grounded, and NASA's future in question.

    Newly installed NASA Administrator Sean O'Keefe, a former deputy chief of the White House Office of Management and Budget, faced the klieg lights of press conferences and congressional hearings to defend the agency. Meanwhile, a blue-ribbon panel led by retired Admiral Harold Gehman pored over hundreds of thousands of pages of documents and testimony to understand both the technical failure and the management troubles that allowed the failure to occur.

    Picking up the pieces.

    Thousands of volunteers helped find debris from Columbia, which investigators used to piece together the cause of the tragedy.

    CREDIT: KENNEDY SPACE CENTER/NASA

    Gehman's panel concluded that a large piece of foam that struck the orbiter's sensitive underside during launch weakened the left wing's protective coating of tiles, allowing hot plasma to pierce the shuttle wing as it reentered Earth's atmosphere. Disturbingly, Gehman's team discovered that mission controllers at Johnson Space Center in Houston failed to heed concerns about the foam strike raised by lower-echelon NASA workers. NASA managers also vetoed a plan for U.S. spy satellites to photograph Columbia's belly in orbit to survey any damage. O'Keefe promised to fix the managerial as well as technical problems—which means the shuttle won't fly again until next fall.

    The accident has had ripple effects throughout the space program. Astronomers don't know if and when the Hubble Space Telescope will be serviced again, and international space station research has suffered while the facility has a skeleton crew and no way to launch or return large science payloads. Plans to build a next-generation vehicle to replace the shuttle became mired in a congressional debate about its design, cost, and necessity, and the White House pondered what long-term direction to give the agency in an era of war and recession. What is clear is that the breakdown of 2003 is forcing a painful reexamination of the civil space effort that is sure to take up much of 2004.

  6. BREAKTHROUGH OF THE YEAR

    SARS: A Pandemic Prevented

    1. Martin Enserink

    See Web links on SARS

    In retrospect, it almost seems like a bad dream. When severe acute respiratory syndrome (SARS) roared onto the world scene in March, the fatal, contagious disease seemed unstoppable. Experts warned that it could ignite a pandemic. And then, in early July … gone. The nightmare never became a reality.

    The outbreak was a chilling reminder that new infectious diseases are always lurking in the woodwork—and they needn't sicken a lot of people to bring economies to their knees. The episode gave the World Health Organization (WHO) new prominence and showcased public health and science at their best in response to a new challenge—and occasionally at their worst.

    In the line of duty.

    WHO's Carlo Urbani died from SARS after warning the world.

    CREDIT: GUIDO PICCHIO/AP

    SARS made its debut in November 2002, in the Chinese province of Guangdong, but the Chinese government remained silent about it for months, contributing to its spread. Officials remained in a state of denial even when SARS had started its march across the world from a hotel in Hong Kong. By sticking to a reassuring but false hypothesis—that the disease was caused by more familiar Chlamydia bacteria—and discouraging alternative views, the Chinese government prevented its scientists from playing what could have been a pivotal role in the discovery of the new virus.

    On the upside, SARS inspired intense collaboration among laboratories worldwide hunting for the real culprit. There was plenty of rivalry and the occasional squabble behind the scenes. But sharing information, specimens, and reagents definitively nailed the agent, a member of the coronavirus family, only 5 weeks after WHO had sounded a global alarm. By that time, the virus's entire genome had already been sequenced.

    But in the end it wasn't science that brought SARS under control. Centuries-old measures, such as strict isolation of patients, eventually cornered the virus after more than 8000 reported cases and 774 reported deaths. For doctors and nurses charged with that task, simply going to work took a great deal of courage. Some, including Carlo Urbani, a WHO official in Hanoi who first sounded the alarm, paid with their lives.

    Six months later, many questions remain. Perhaps the biggest ones are “Where did SARS come from?” and “Will it come back?” Apart from a Singapore scientist who became infected in the lab in August, no new cases have been reported since July, and most scientists agree that it's unlikely that SARS is going around unnoticed. But the virus's natural reservoir is still unknown, and it's unclear whether its leap to humans was caused by an extremely unlikely event—say, a freak set of mutations—or something that could happen again any day.

    Even if SARS does not return, its impact will last. The hunt for the virus set a new standard for the next emergency and helped assert WHO's leadership. The agency is fortifying its Global Outbreak Alert and Response Network—a loose affiliation of labs and institutions that have agreed to respond to emerging threats—and it's pushing hard for the adoption of the Global Health Regulations, a treaty that would oblige member states to act quickly and speak up about dangerous outbreaks within their borders. Meanwhile, the United States and several other countries are taking a critical look at often-antiquated quarantine laws and rethinking the balance between public health and civil liberties.

    Few doubt that there's more to come. An Institute of Medicine report released in March concluded that with ecological disruption increasing, populations expanding, public health breaking down, and travel and trade booming, the risk of new SARS-like outbreaks, if not of SARS itself, is only increasing.

  7. CONFLICT OF INTEREST

    Zerhouni Pledges Review of NIH Consulting in Wake of Allegations

    1. Eliot Marshall

    A newspaper report on apparent conflicts of interest among National Institutes of Health (NIH) scientists has shaken the $27 billion biomedical research center to its core. Following the publication of a four-page article in The Los Angeles Times on 7 December, detailing how a handful of employees earned millions of dollars in outside income over a decade, both Congress and NIH Director Elias Zerhouni launched reviews of how the agency oversees staffers' outside deals (Science, 12 December, p. 1875).

    The article did not directly accuse NIH officials of wrongdoing, but “our community is surprised … and angry” about the allegations, says David Korn, a former dean of Stanford University School of Medicine who is now at the Association of American Medical Colleges in Washington, D.C. “We're getting a lot of e-mail traffic,” adds Korn: People are expressing “the sort of shock you might feel on hearing that the pastor of the church was dallying with parishioners' wives.”

    Zerhouni said in a telephone interview this week that he is setting up two review groups, one to examine the allegations and produce an inventory of outside relationships going back to 1999, and a second to recommend policies for the future. He said: “There will be no stone unturned; I am going to review it from A to Z. This is too important for us not to be completely responsive.”

    The Times report focused on a memo that former NIH Director Harold Varmus issued on 3 November 1995. In it, Varmus told top NIH staff that he was removing some limits on outside activities because the Office of Government Ethics had decided that NIH's rules were then “more restrictive” than the federal norm. For example, his memo removed a $25,000 cap on permitted outside income, allowed officials formerly prohibited from consulting—such as institute directors—to do so, and gave staffers permission to take company stock as payment for work. Every outside activity was still subject to prior approval by an ethics officer.

    In an editorial, the Times argued that Varmus “demolish[ed] private-public firewalls that had served the agency well.” Varmus, who left NIH in 1999 to become president of the Memorial Sloan-Kettering Cancer Center in New York City, strongly disagrees, but he concedes that “the issues addressed by the article are very important.” NIH loosened consulting rules in large part, he says, to make working at NIH more appealing to top researchers. “I was trying to improve the intramural program and strengthen our ability to recruit” people who could earn “a hell of a lot more” from consulting if they were at a university. The aim was to encourage “useful interactions between government employees and outside groups” so NIH scientists would be “in the loop … and competitive,” Varmus says, adding: “I'm proud of it.”

    Outside interest.

    Prompted by a report alleging improper consulting by staff members, NIH Director Elias Zerhouni has begun a review “from A to Z.”

    CREDIT: ROGELIO SOLIS/AP PHOTO

    During the 1990s, NIH also won approval to hire staff under more flexible employment rules provided by Title 42 of the Public Health Service Act. Title 42 allows NIH to hire clinicians and others at higher pay rates on fixed contracts. It also bars public disclosure of certain outside-income reports. The Times claims that many NIH staffers used this provision to conceal outside income.

    That allegation may be the most upsetting to many. “Unfortunately the smell is intense,” says Korn, who doesn't see why some highly paid federal employees were allowed to keep outside income confidential while others were not. He feels that NIH may not have been as tough on itself as it has asked universities to be on their staffs.

    Federal reporting rules are “complex,” Varmus says, but “there was never any suggestion that you could hide behind [Title 42].” He claims that his staff “asked about” making it mandatory for NIH staff to list outside income on forms that could be obtained through the Freedom of Information Act, but “we were told that a statute would have to be changed.” Today, he still thinks such openness would be a good idea. But, Varmus adds, “I don't see any evidence that decisions were affected [by outside income] or that people who were consulting for companies were performing poorly.” Like Korn, however, he thinks NIH should be more aggressive in managing potential conflicts.

    Zerhouni says it is “overreaching” to suggest that anyone deliberately withheld data on outside income. Yet he says, “My philosophy is clear. … The tenets are full disclosure, transparency, and active management of [outside] relationships with peer review.” His next step will be reporting to Congress: The House Committee on Energy and Commerce, chaired by Billy Tauzin (R-LA), and the Senate Appropriations Subcommittee chaired by Arlen Specter (R-PA) are both considering holding hearings.

  8. ASTRONOMY

    Spitzer Space Telescope (né SIRTF) Sparkles in Debut

    1. Robert Irion

    After a difficult gestation, the Space Infrared Telescope Facility (SIRTF) was christened this week—and astronomers are grinning like new parents. NASA's $720 million observatory has surpassed expectations, peering through dust to see planetary nurseries and cauldrons of young stars more clearly than ever before. And in a move that is being warmly welcomed, NASA is renaming SIRTF the Spitzer Space Telescope in honor of the late astrophysicist Lyman Spitzer Jr., who first conceived of a large telescope in orbit.

    Reviewers who gathered last week at the Jet Propulsion Laboratory (JPL) in Pasadena, California, praised the observatory's smooth operation since its launch on 25 August and the quality of its early data. “I've been making infrared observations of star-forming regions for more than 25 years,” says astronomer Stephen Strom of the National Optical Astronomy Observatory in Tucson, Arizona, “and the [new] images coming back are utterly incredible. That's not hype.”

    Those words are sweet redemption for the core team of the Spitzer Space Telescope, which endured what Strom calls “an incredible number of near-death experiences” since the early 1980s. Thanks to its standing as the top-ranked project of a 1990 astronomy review panel, the last of NASA's four “Great Observatories” survived a cancellation and two redesigns as budgets plunged (Science, 6 December 2002, p. 1870). The allure of viewing the heavens in infrared light—which pierces the dust that fills galaxies like a fine fog—kept the project alive.

    Memorialized.

    Lyman Spitzer Jr. (1914–1997) at Princeton University

    CREDIT: NASA/JPL-CALTECH/W. REACH [SSC/CALTECH]

    Among the images released by NASA is a first look into a knot of gas and dust in our Milky Way, part of a nebula called IC 1396. In visible light, it's a black blob with hints of violent activity within. The infrared view reveals a brilliant nest of newborn stars. Excess infrared emission streams from a surprisingly high percentage of stars, a sure sign of dusty disks orbiting them. And when the Spitzer Space Telescope peered at a known disk around the nearby star Fomalhaut, it saw warm dust orbiting close enough to form Earth-like planets.

    Beyond the Milky Way, the observatory took a striking image of clumps of stars forming within the sweeping arms of M81, an iconic spiral galaxy. “Dust has always blocked our view of the true stellar distributions and morphologies of galaxies,” says Giovanni Fazio of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts, who leads an instrument team. “Breaking down galaxies into old and new stars is the only way to show how these building blocks of the universe formed.”

    The Spitzer Space Telescope already has found a galaxy that was churning out complex prebiotic molecules at a far greater distance than any yet seen: about 3.25 billion light-years away. Infrared spectral patterns reveal water ice and carbon-based ices, as well as polycyclic aromatic hydrocarbons (“basically diesel exhaust,” as one astronomer puts it). “We expect to look for these compounds much farther out in the universe with deeper exposures,” says project scientist Michael Werner of JPL.

    In the midst of taking data, Werner's colleagues put the telescope through its paces and found that all critical systems are A-OK. Most importantly, the supply of liquid helium—which cools the optics to 5 kelvin, so they can register faint traces of heat—is being consumed more slowly than mission scientists dared hope. That makes the nominal 2.5-year mission a snap, says Werner. “We can now be confident of a 4-year lifetime and talk seriously about a 6-year lifetime,” he notes happily.

    Womb with a view.

    Newborn stars in this dusty globule in IC 1396 show up in infrared light but not in visible light (inset).

    CREDIT: DENISE APPLEWHITE/PRINCETON PLASMA PHYSICS LABORATORY

    The reviewers in Pasadena did discuss glitches that will force astronomers to modify a few programs. For instance, cosmic rays from deep space trigger more electronic noise than expected in the instrument sensitive to the longest wavelengths. Other detectors have “ghost images”: They retain partial imprints of bright sources from previous exposures. However, scientists will learn to adapt, says review chair Michael Hauser, deputy director of the Space Telescope Science Institute in Baltimore, Maryland. “In all of the major characteristics, this is a spectacular technological success,” he says.

    Astronomers hope that the Spitzer Space Telescope's tenure will mirror the career of its namesake, a longtime Princeton University astronomer who died in 1997 at age 82. Lyman Spitzer catalyzed much of the century's research on the matter between stars, the dynamics of star clusters, and hydrogen fusion as a potential power source. His 1946 report on optical space telescopes led to the eventual flight of the Hubble Space Telescope, a project that Spitzer championed tirelessly.

    Colleagues recall Spitzer as a graceful, deeply modest man. “He was a towering scientist and a great human being, whom we would want all of our children to emulate,” says astrophysicist John Bahcall of the Institute for Advanced Study in Princeton, New Jersey. “It's a great day for NASA. They needed some great days.”

  9. ECOLOGY

    Too Much Crunching on Rainforest Nuts?

    1. Erik Stokstad

    As a child in Belém, Brazil, Carlos Peres would watch boats heaped with Brazil nuts plying the Amazon River. Many were headed for warehouses of his father, who at one time held a virtual monopoly on the nut trade. Even then, Peres suspected that such intense harvesting of nuts from the rainforest couldn't be sustainable—a source of arguments with his father. “He never believed me,” recalls Peres, a wildlife biologist at the University of East Anglia in Norwich, U.K. “It took me 25 years to prove him wrong.”

    On page 2112 of this issue, a team led by Peres shows for the first time that Brazil nut exploitation is preventing many natural stands from reproducing, which is leading to ever older populations of trees that could eventually cause the Brazil nut trade to crash. The finding is important because Brazil nut harvesting is a major part of the rainforest economy—and has been thought to be a sustainable way to prevent more-destructive activities such as ranching. The lesson is simple, says Charles Peters of the New York Botanical Garden in New York City: “You can't just go into the forest, pick up all the nuts, and assume that the forest will magically regenerate.”

    Even if not magic, Brazil nut trees (Bertholletia excelsa) are a wonder. They're the stoutest trees of the Amazon, with girths of up to 16.5 meters. They're remarkably fertile, too, dropping vast quantities of nuts, packaged inside hard pods the size of grapefruit, for 3 months a year. At least 45,000 tons of nuts are harvested each year from the Amazon.

    About 10 years ago, Peres started to investigate the impact. He first surveyed relatively untouched stands of Brazil nut trees in the remotest parts of the Amazon. Then he struck up collaborations with 16 specialists from Brazil, Peru, Bolivia, Europe, and the United States. At 23 sites across the Amazon, they measured trunk diameters—a proxy for tree age—and assessed the history and intensity of harvesting through public records and interviews with local collectors. The researchers also compiled data on other relevant factors, such as amounts of rainfall and soil nutrients.

    Easy pickings.

    Extensive harvesting of Brazil nuts has led to a dearth of young trees, threatening the future of this crop.

    CREDIT: C. PERES

    The best predictor of population health, according to several statistical analyses, was the exploitation of nuts. In sum: The more harvesting, the fewer younger trees in the forest. In some of the most heavily harvested areas, all the Brazil nut trees are mature—and aging. That's the bad news.

    The good news is that the solutions may be simple, and most of the mature trees still have at least a few decades of productivity left. Peres says that harvest quotas, or temporary no-take areas, could help establish a next generation. Planting nursery-grown seedlings might also make a difference. Brazil nut trees don't seem to grow as well in monoculture plantations, however, so these strategies require protection of primary forest, Peres notes. According to Ghillean Prance, former director of the Royal Botanic Gardens, Kew, “The most serious threat to the species and the production is deforestation.”

    In the long term, however, it may take more than just a hands-off approach to produce a healthy population of Brazil nut trees, says Daniel Nepstad, a tropical ecologist at the Woods Hole Research Center in Massachusetts. The trees may need football field-sized clearings, not just the occasional tree fall, to get enough sunlight to thrive, he says. He notes that young Brazil nut trees are much more common in gardens and farms, where they are tended and get more sunlight, than in shady forests. Indeed, Amerindians long cultivated Brazil nut trees this way, Nepstad contends, pointing out that they are commonly found with medicinal plants growing amid archaeological artifacts.

    Peres says that overharvesting is the culprit and that, given the chance, Brazil nut trees can regenerate just fine on their own in the forest. Whatever the reasons for the current predicament, everyone agrees that the trees are facing a reproductive crisis. Says Peres: “This paper will ring some alarm bells.”

  10. CELL BIOLOGY

    In Sex Reversal, Protein Deterred by Nuclear Barrier

    1. Aparna Sreenivasan*
    1. Aparna Sreenivasan is a writer in Pacific Grove, California.

    SAN FRANCISCO, CALIFORNIA—Each year, a few babies are born with a male set of chromosomes and female sexual organs. This sex reversal, called Swyer syndrome, can happen when changes in a protein called SRY impair its function. Previously reported SRY mutations interfere with the protein's ability to bind to DNA. But recent data, including some presented here this week at the annual meeting of the American Society for Cell Biology (ASCB), show that in some cases, the altered protein has trouble entering the nucleus of fetal male gonadal cells. Thus, genes that should be turned on by SRY to make testes remain off. “We now show a completely different mechanism as to how someone can become an XY female,” reports cell biologist David Jans of Monash University in Victoria, Australia.

    Getting certain proteins in and out of the nucleus is important for normal cellular functions. But Jans, Vincent Harley of Prince Henry's Institute of Medical Research in Victoria, Australia, and colleagues were the first to directly link a defect in nuclear import with a human syndrome. They reported this summer that SRY molecules engineered to have the same changes found in some sex-reversed people seemed to have problems getting into the nucleus of cells. Normal SRY slips into the nucleus readily.

    A closer look revealed that a portion of the protein could no longer latch onto importin β, a factor that helps certain molecules slide into the nucleus through pores in the nuclear membrane. Most proteins use a sequence called a nuclear localization signal (NLS) to attract escort molecules such as importin β. SRY has two NLS segments, and if the one that binds importin β is bungled, Jans and Harley reported earlier, not enough SRY gets into the nucleus.

    Denied entry.

    Normal SRY, labeled in green, hastens into cell nuclei (left). Some mutated SRY can enter the nucleus (right), but much of the protein lingers in the surrounding cytoplasm.

    CREDIT: D. JANS

    In some sex-reversed people, however, the NLS recognized by importin β is normal, but the other NLS sequence is mutated. What this NLS recognizes was not well known, but it apparently interacts with the calcium-binding protein calmodulin. Jans and colleagues modified the second NLS in SRY molecules as it is mutated in some sex-reversed people. The engineered protein failed to bind calmodulin. And when the researchers repressed calmodulin activity in cells with normal SRY, the protein could no longer easily enter the nucleus, Jans reported at the ASCB meeting.

    Whether calmodulin, a protein that has many functions in the cell, facilitates movement into the nucleus has been a controversial subject. The new findings solidify its role in somehow helping SRY inside. This first demonstration that a clinical syndrome can be caused by a molecule's inability to get into the nucleus is likely “just the tip of an iceberg” of diseases with similar mechanisms, says John Hanover, a cell biologist at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.

    “It's important to understand SRY because it's the master trigger for maleness: With SRY one becomes a male, and without it one becomes a female,” says geneticist Eric Vilain of the University of California, Los Angeles. The Jans team hopes to follow defunct SRY molecules in growing mouse fetuses to learn more about how the protein affects the regulation of genes and the formation of male sex organs. “Sex determination is still very poorly understood,” Vilain adds.

  11. GENOME SEQUENCING

    Cow Ambles to the Sequencing House

    1. Jennifer Couzin

    The U.S. Department of Agriculture (USDA), normally loath to back big-budget genetics projects, is offering $11 million to help sequence the cow genome. The funding, announced last week, comes after months of lobbying from bovine enthusiasts and ensures that the project, estimated to cost at least $50 million, will go forward. Four countries—the United States, Canada, New Zealand, and Australia—have contributed a total of $53 million. Proponents claim that the cow genome will help elucidate human diseases and identify gene variants important for agriculture, such as those that promote milk production.

    Bovine supporters have been eyeing USDA's coffers since last summer, when the last of the other contributions were announced. The National Human Genome Research Institute in Bethesda, Maryland, forked over $25 million; the state of Texas, $10 million; the Canadian government, $5 million; and the governments of Australia and New Zealand, $1 million each. Two-thirds of New Zealand's contribution came from the cattle industry.

    Rounding up support.

    Funding is in place to sequence the cow genome.

    CREDIT: NHGRI

    Until now, USDA had balked at a big donation: “There's never been enough money in the USDA budget to support large-scale sequencing,” says Harris Lewin, director of the Institute for Genomic Biology at the University of Illinois, Urbana-Champaign. In 2003, USDA's extramural research program totaled a mere $166 million out of its $74 billion budget. The agency has helped fund smaller sequences, such as the honeybee's 200 million base pairs. Researchers credit Joseph Jen, the USDA undersecretary for research, education, and economics, with helping convince the agency to contribute to the roughly 3-billion-base-pair bovine sequence.

    A Montana Hereford has been anointed the lucky cow. The project will begin at Baylor College of Medicine in Houston, Texas, in the next few months and should be completed within 3 to 4 years.

  12. ASTROPHYSICS

    Gamma Ray Satellite Sees Out First Year With a Bang

    1. Govert Schilling*
    1. Govert Schilling is an astronomy writer in Utrecht, the Netherlands.

    A year ago this week, the European Space Agency (ESA) released a picture of a fuzzy-looking white blob against a mottled blue background. It may not have looked like much, but this image of Cygnus X-1, a possible black hole, was the first output of ESA's new flagship gamma ray observatory, Integral (see figure). Since then, Integral has continued to peer into the most violent and energetic events in the universe: annihilating antimatter, black holes, supernovas, and the titanic explosions of gamma ray bursts (the latest on 3 December). Last month, Astronomy and Astrophysics Letters marked Integral's anniversary with a special issue containing 75 papers on its discoveries, and on 6 November ESA decided to extend the mission for 4 years, until late 2008. “It's a great success, and I'm extremely happy,” says Giovanni Bignami, the new chair of ESA's Space Science Advisory Committee.

    In a busy first year, Integral spotted seven gamma ray bursts (massive exploding stars in remote galaxies), detected a new class of black holes, mapped antimatter in the center of the Milky Way, and found tantalizing evidence for radioactive iron atoms in supernovae. And in that time, Integral has already improved upon the sky maps that NASA's Compton Gamma Ray Observatory took 9 years to make.

    Not that gamma ray astronomy is easy. These highest-energy photons—millions of times as energetic as photons of visible light—are hard to catch and study, and they are very rare. “The number of sources is limited, and the photon flux is extremely low,” says Integral project scientist Christoph Winkler of the European Space Research and Technology Centre (ESTEC) in Noordwijk, the Netherlands. “Many observations take days or even weeks to complete.”

    Integral was conceived in 1993 and launched on 17 October 2002. Along with a small optical telescope and two identical x-ray telescopes, Integral sports a sensitive Italian-French gamma ray camera and a high-resolution French-German gamma ray spectrometer. Instead of using lenses, which don't work on gamma rays, the camera works like a pinhole camera, creating images with tungsten grids known as coded masks, and the spectrometer determines the energy of every gamma ray photon entering the instrument. Apart from a slight degradation in the detectors of one of the x-ray telescopes, all instruments are working flawlessly. “My job has been quite easy,” says mission manager Arvind Parmar of ESTEC.

    In fact, the most significant setback so far was a temporary delay in instrument calibration. Once Integral had been launched and checked out this time last year, it took a couple of months before it could observe the Crab Nebula, a well-known gamma ray source chosen to calibrate the instruments, because of the satellite's orbit and the position of the Crab in the sky. It wasn't till last summer, Parmar explains, that researchers at the Integral Science Data Centre (ISDC) in Versoix, Switzerland, were regularly churning out fully calibrated data. Nevertheless, Integral turned up many surprises during its setup period early last year.

    Gamma hurrays.

    Starting with a black hole candidate in Cygnus (bottom), the Integral orbiting observatory has racked up a host of discoveries.

    CREDITS: ESA

    So far, Winkler says, Integral's most exciting discovery is IGR J16318-4848, first detected on 29 January in the constellation Norma. To the gamma ray eyes of Integral, it looked like a typical point source in the central plane of the Milky Way. Most such sources are neutron stars or black holes that suck matter from a nearby companion star into a swirling accretion disk that blazes with high-energy x-rays and gamma rays. Surprisingly, however, x-ray telescopes had never spotted the new source, and follow-up observations by ESA's XMM-Newton x-ray satellite revealed only a feeble glow.

    A team led by Roland Walter of ISDC concluded that the new object is shrouded in a thick cocoon of cold gas, which absorbs all but the very highest-energy radiation. The cocoon, about as wide as Earth's orbit, probably results from a strong stellar wind, ejected by the massive companion star. Of the 12 new sources Integral has discovered, three or four show a similar lack of x-rays, says Winkler: “These hidden black holes constitute a new class of astronomical objects.” They might explain a large part of the observed high-energy background radiation in the Milky Way galaxy.

    Integral will also shed light on galactic nucleosynthesis, the formation of new elements. In particular, astronomers wonder why interstellar space contains relatively large amounts of aluminum-26, a radioactive isotope with a half-life of about a million years. Possible sources include supernovas, dense associations of young stars, and strong stellar winds from unstable giant stars. Al-26 produces gamma rays of a specific energy as it decays to magnesium. Integral's spectrometer is mapping its distribution in the cosmos, along with the much weaker gamma ray signature of another radioactive isotope, iron-60, which is produced only in supernovas. The results should reveal how much aluminum is produced in supernovas, Winkler says.

    Bignami says that Integral is also producing the first real maps of the distribution of antimatter in the galactic center. No one yet knows where the antimatter comes from, but when electrons and their antiparticles (positrons) collide and annihilate, they produce gamma rays with a very specific energy. Integral's spectrometer has shown that the annihilation occurs in a wide, diffuse region surrounding the core of the Milky Way, suggesting that the antimatter does not come from the smaller supermassive black hole at the galactic center.

    Finally, Integral is tracking the rapidly evolving drama of gamma ray bursts. So far, it has spotted seven of these titanic explosions and in most cases flashed their locations to other observatories across the globe within seconds, enabling astronomers to search for telltale afterglows at x-ray, optical, or radio wavelengths. “Integral's handling of gamma ray bursts is much better than expected,” says Bignami.

    With more gamma ray photons entering its sensitive detectors every day, Integral will slowly but surely unravel the mysteries of the high-energy universe, especially given the 4-year extension of the mission. For its second year of observations, astronomers have sent in eight times as many proposals as the satellite can handle, and mission manager Parmar expects a stronger and closer cooperation with XMM-Newton. In the coming years, Integral will be joined by NASA's Swift satellite, which will begin a dedicated search for gamma ray bursts in the summer of 2004, and in February 2005 by the Japanese-American Astro-E 2, which focuses on a slightly different range of gamma ray and x-ray wavelengths. But Parmar doesn't think they will steal Integral's thunder: “In the field of nucleosynthesis, there's no real competition.”

  13. ECOLOGY

    Bye, Bye Biosphere 2

    1. Jeffrey Mervis

    After 19 years, desert ecologist Tony Burgess is trying to come to terms with the fact that he'll probably never work again on Biosphere 2. And he's not the only one. This week Columbia University is pulling out of the unique and controversial eco-experiment in the southern Arizona desert, uprooting some 150 scientists and educators who ran its affiliated programs and leaving Biosphere 2's fate in the hands of billionaire owner Edward Bass.

    Tourists will still be able to pay as much as $23 to visit the 1.3 hectare, glass-enclosed facility that once housed eight “bionauts.” But unless a white knight appears soon, its days as a research-based enterprise will be over. “I'm not sure that there are any options out there relating to science,” says Martin Bowen, vice president of Decisions Investments Corp. (DIC), Bass's Fort Worth, Texas, company. “The government talks about the need to understand climate change, but there's not a lot of new money available. And DIC won't fund anymore research or education activities.” DIC plans only a crew of 50 to 60 people “to keep the apparatus in good shape” while it entertains offers, says Bowen.

    Biosphere 2 was supposed to test whether humans could thrive in a closed environment that replicated miniecosystems—from rainforests to desert climates to oceans—on Earth (Biosphere 1). But that 2-year experiment fizzled in the early 1990s after organizers were forced to intervene to maintain safe oxygen and carbon dioxide levels. In 1996 Columbia decided to take the $150 million facility under its wing, hoping that its academic pedigree would attract top-notch researchers interested in running controlled experiments on the impact of global change on the living planet. It also offered an “Earth semester” for up to 80 undergraduates interested in environmental studies and a smaller “universe semester” for astronomy majors.

    Last January, however, Columbia's new president, Lee Bollinger, announced that the university was “reviewing” its relationship with Biosphere 2. That led to a suit by DIC that accused Columbia of failing to live up to its contract to operate the facility through 2010. On 8 September, as part of an out-of-court settlement, Columbia announced that on 22 December it would walk away from Biosphere 2.

    The news was a staggering blow to Barry Osmond, an Australian-born plant physiologist, who was removed immediately as Biosphere 2's president and executive director. “I came [in 2001] based on the university's offer of a $35 million investment through 2005 that included hiring six professors” who could take full advantage of the unique facility. Those positions were never filled, Osmond says, and “we've been in limbo” for the past year.

    Home alone.

    Columbia has given pink slips to most Biosphere 2 researchers and educators.

    CREDIT: CHRISTOPH BOSSHARD

    Osmond, who says he's still “licking his wounds,” is negotiating a separation agreement with the university that would require him to hold his tongue. But Joseph Berry, a plant physiologist at the Carnegie Institute of Washington's laboratory in Palo Alto, California, and a collaborator on a recently completed Biosphere 2-based study of the biochemical mechanisms of photosynthesis, faces no such constraints. “I'm really pissed off,” says Berry, who accuses Columbia of “having a bad business plan” predicated on a false hope that the Department of Energy (DOE) would take on the site as a national user facility. In May a DOE panel concluded that Biosphere 2 was “a facility in search of questions” and gave it a lower priority than existing projects.

    For many members of the scientific staff, the demise of Biosphere 2 as a research facility means more than the loss of a job. Burgess—who designed Biosphere 2's desert ecosystem and who teaches students about the interaction of its geological, chemical, and biological components—admits that Biosphere 2's attempt to support humans was “too much, too fast, too forced … and exceeded our skills as managers.” But what he really regrets is the loss of “a sustained commitment to environmental stewardship” that is rare in academia.

    Wylie Cox, a former government field biologist who oversees the Earth semester program, says that the blend of eco-active students and a unique curriculum “has spoiled me to teach anywhere else.” Katy Garmany, who ran the universe semester, says that it was a rare program in a discipline that doesn't normally allow students to deviate from a rigid sequence. Garmany is one of a dozen or so people with Columbia contracts that run until June 2005.

    For Rebecca Reider, being at Biosphere 2 as a Harvard University junior was a “life-changing experience” that gave focus to her interest in the environment. Now a graduate student in environmental management at Yale University, she says she's not surprised by Columbia's decision. “It was a totally unsustainable program about sustainability,” she laughs. But Reider is sad that other students won't be able to enjoy the camaraderie and natural beauty of the place. “Columbia administrators never quite understood why such general lessons needed to be taught out in the desert,” she says. “But to my fellow students, it always made perfect sense.”

  14. SCIENTIFIC COMMUNITY

    The Trials of Thomas Butler

    1. Martin Enserink,
    2. David Malakoff

    Thomas Butler was a sought-after plague expert, with a clinical trial in Tanzania that promised important results for biodefense. Then he was charged with mishandling plague samples and lying to the FBI. This month, a jury convicted him of financial wrongdoing. Who is Thomas Butler, and what lessons do his trials hold?

    Sitting on an airplane preparing to take off from Dar es Salaam, Tanzania, American microbiologist Thomas Butler had some time to reflect on his rising fortunes. Stowed in the plane's belly was a footlocker containing carefully packed specimens from more than 60 Tanzanian bubonic plague victims. His journal was full of data—painstakingly hand copied from hospital records—that detailed how the patients had responded to a new antibiotic. The 2002 clinical trial was a scientific coup, and Butler believed that the results, once published in a top-tier medical journal, would help solidify a nervous nation's defenses against bioterror. Not incidentally, they would also send his 30-year career in an exciting new direction.

    In 1969, as a young Navy researcher in Vietnam, Butler had become fascinated by plague—the “Black Death” that had once decimated European populations but was now largely confined to remote, impoverished parts of the world such as Tanzania. He soon moved on to other diseases. But now, Butler, 60, was reunited with his first scientific love.

    After three visits to Tanzania, Butler was on the verge of becoming perhaps the United States' hottest plague scientist. The work would confirm his reputation as a can-do researcher known for getting results under even the most primitive conditions. Other scientists were increasingly interested in his efforts, and the U.S. Food and Drug Administration (FDA) was practically begging him to apply for a $700,000 research grant. “How many people have a world expert in plague just an e-mail away?” Butler had bragged in a message to an FDA official.

    The demand for Butler's talents couldn't have come at a better time. After 15 years at Texas Tech University Health Sciences Center in Lubbock, Butler was feeling frustrated and exhausted by an increasingly bitter battle with school administrators over his clinical research and financial dealings. The idea of leaving Lubbock had crossed his mind, and the results of the Tanzanian trial promised to make him more attractive to other institutions.

    Yet, as he stared at other jets taxiing on the tarmac on the morning of 14 April 2002, the veteran clinician also mulled some potential problems, he noted in his journal. Among them were the “challenges of getting organisms back” into the United States, he wrote. The rules had tightened drastically since Butler had last encountered plague in Brazil in the late 1970s. A British colleague had even warned him “that in the U.K. you can be arrested for bringing in pathogens,” Butler wrote.

    Butler would soon learn that U.S. authorities could be just as aggressive as their British counterparts. On 15 January, 2 days after reporting that 30 vials of plague bacteria were missing from his lab, Butler was shackled and thrown into a Lubbock jail, charged with lying to federal agents about the fate of the vials and illegally importing the Tanzanian samples into the country. At that moment, “my stomach froze in my chest,” Butler said later.

    Seven months after his arrest, the government indicted Butler on 69 charges. In addition to allegations that he had mishandled the plague samples, prosecutors accused him of defrauding his university of clinical trial fees and cheating on his taxes. Butler's prosecution became a cause célèbre for those who felt that the government was using him to scare scientists into obeying strict new bioterror-prevention laws. They urged the government to drop the case, predicting that it would drive researchers out of biodefense research and undermine national security. But on 1 December, a jury convicted Butler on 47 counts. He faces up to 240 years in jail and millions of dollars in fines.

    CREDIT: JIM WATKINS/LUBBOCK AVALANCHE-JOURNAL/AP

    How Butler went from hot property to convicted felon is a tangled tale. It reveals a scientist who was able to pull off what others couldn't, as well as one whose penchant for cutting corners ultimately ruined his career and fortune. The jury's sometimes puzzling verdict, however, sends anything but a clear message.

    To reconstruct Butler's path, Science sent two reporters to Lubbock to attend his trial, review court documents, and conduct interviews. Unless otherwise noted, all direct quotes in this story come from trial testimony or documents entered into evidence. Many of those most knowledgeable about the case, including Butler himself, have been silenced by a court-imposed gag order. But their testimony provides a detailed, if sometimes disputed, record of an extraordinary career and its controversial demise.

    A calming hand

    Lubbock, Texas, has two industries: cotton and college students. And although the seemingly endless, pancake-flat farm fields that surround the drab town are still its soul, it is the sprawling campus of Texas Tech University that is its heart. The school's 30,000 students and staff pump more than $1 billion a year into the local economy, and thousands of fans avidly follow the fortunes of its sports teams. Texas Tech graduates and faculty also figure prominently in the community: The judge in Butler's case, “Maximum Sam” Cummings, is an alum, for example, and the lead prosecutor, U.S. Attorney Richard Baker, teaches at Texas Tech's law school.

    Butler became part of that cozy community in 1987, when the Tennessee-born physician and his Swedish wife, Elisabeth, arrived from Case Western Reserve University in Cleveland, Ohio. As head of the health center's infectious-disease division, Butler quickly became known as an excellent doctor and teacher. A former assistant, Kimberly Bethune, testified that the tall, snowy-haired physician could put patients at ease simply by placing a hand on their shoulder. And although other doctors might resent having residents bug them on weekends, Butler graciously answered calls at all hours. He was also adept at enrolling patients in clinical trials for drug companies—a significant source of cash for the health center.

    But 3 years ago, one of those trials placed Butler on a collision course with Barbara Pence, the health center's associate vice president for research. The confrontation would ultimately cause a university panel to withdraw its approval for him to perform human research, and it would trigger financial investigations that prosecutors claim caused him to instigate a bioterror scare.

    Pence, a slight, middle-aged pathologist, is a Texas Tech graduate who has spent her entire career at the university. She holds one of the health center's most sensitive jobs, overseeing its burgeoning research budget and its Institutional Review Board (IRB). The government-mandated IRB—composed of a shifting cast of researchers, nurses, clergy members, town folk, and sometimes even ex-convicts (prisoners are often study subjects)—is responsible for protecting patients who participate in clinical studies. No trial can start without its blessing.

    Pence testified that in late March 2001, the IRB expressed serious concerns about one of Butler's trials. Together with more than 150 other doctors across the nation, Butler was testing the efficacy of a drug developed by Chiron Corp. of Emeryville, California, to treat sepsis, a massive blood infection that often results in death. Butler had told the IRB that he expected up to 50% of the severely ill patients enrolled in the study to die. But during a routine review, IRB members noted that about 70% of Butler's first small group of patients had died and that some paperwork appeared to be missing. The panel decided to suspend the trial and ask for more information. A month later, after Butler complied, it allowed the study to resume.

    Still, Butler was upset. In particular, he was angry at Pence, believing that she was at least partly responsible for the “very abrupt and disrespectful” suspension of the trial—the first of his career. The “terrible experience,” he testified, damaged his reputation and “essentially ruined” his relationship with Chiron. It also triggered a time-consuming review by the FDA; the agency ultimately cleared him.

    In mid-2001, Butler filed a grievance against Pence, who tried unsuccessfully to convince university officials that his beef was with the IRB, not her. The opponents picked two faculty mediators to examine the issue, and in February 2002 they issued a report that criticized both Pence and Butler for missteps. And although Pence disagreed with some of the findings, she and Butler eventually signed a settlement statement.

    The matter didn't end there, however. Pence, who said she was unaware that FDA had given Butler's sepsis trial a clean bill of health, was still worried about the study, which had ended some months earlier. Four days after receiving the mediators' report, she asked health center auditors to investigate whether Butler had improperly billed some medical tests to the government or patients. Then, 9 days later, she asked Stacey Pugh, her clinical trials administrator, to review Butler's reporting of trial deaths and his adherence to the study's scientific protocol, according to court records. Butler considered the studies “retaliation” for his grievance, he testified. But Pence insisted that she was “just doing my job. … There were dead people we couldn't account for.”

    Destructive force.

    Yersinia pestis bacteria, the cause of Black Death.

    CREDIT: GARY GAUGLER/PHOTO RESEARCHERS INC.

    Butler was decidedly uncooperative with both investigations, Pence and other health center officials testified. And Pugh's report, delivered in late summer of 2002, was highly critical of Butler. “I found a number of problems, some of which I thought were quite serious,” Pugh testified. For instance, she alleged that Butler had improperly filed patients' consent forms, ordered tests before obtaining their consent, and then billed the patients instead of the study's sponsors. In September, acting on Pugh's report, the IRB wrote Butler that he had apparently violated federal regulations and Texas Tech policies in the sepsis study. It asked for an explanation—and fast.

    In the meantime, Pence's office stumbled onto another serious matter. In late July 2002, during a routine telephone conversation about a paperwork problem, an employee of the Pharmacia-Upjohn (now Pfizer) pharmaceutical company in Kalamazoo, Michigan, mentioned to one of Pugh's staffers that the company had an unusual way of paying Butler for his clinical trial work. Typically, a Pharmacia official testified, the firm completed a single contract with each of its trial investigators, spelling out the payment for each enrolled patient. The money was generally sent to a special account at the investigator's university.

    In Butler's case, however, Pharmacia had twin contracts with the scientist for several trials involving a diabetes drug. One of the contracts was signed by both Butler and a university official and specified a fee to be sent to the university. The other, signed only by Butler, specified a second, identical fee that was sent directly to Butler. Together, the split fees added up to the company's usual payment, about $6000 per patient.

    Pence testified that she was stunned to learn of the arrangement and that it violated health center rules requiring all trial funds to go through the university. Pugh also “felt pretty stupid,” she admitted, because it explained an oddity she had not understood in one of Butler's previous contracts. In that case, she noticed that Pharmacia was paying Butler only half of what it was sending to another health center researcher involved in the same trial. “I became a little angered with Pharmacia,” she testified. “I thought they were trying to take advantage of Dr. Butler.” But when the administrators contacted Butler and suggested that they might be able to double his fee, he told them “to butt out of it,” said Pence.

    When the split contracts came to light, it all made sense, Pence testified. She immediately turned the matter over to university investigators.

    Into Africa

    Within the small world of plague science, however, few scientists knew of Butler's troubles at Texas Tech. They saw only a researcher on a roll—and returning to his roots.

    Butler's first brush with plague came in 1969 in South Vietnam, where the disease was common. After completing his Navy service, he returned several times as a civilian researcher at Johns Hopkins University in Baltimore, Maryland. But the work ended when Saigon fell to Ho Chi Minh's forces in 1975—Butler, in fact, was on one of the last planes carrying Americans out of the city. His last close encounters with plague came in Brazil in the late 1970s.

    MAP: J. MOGLIA/SCIENCE

    However, Butler kept up with the literature and published several book chapters and reviews—enough to retain his standing as an expert. That reputation propelled him back into the field in the late 1990s, when the threat of bioterrorism again made plague a hot topic. Experts had begun sounding the alarm after Kenneth Alibek, a former Soviet bioweapons researcher, revealed that the former superpower had mass-produced the microbe, which can kill in days when inhaled. Concerns deepened in 1995 when the U.S. government arrested microbiologist Larry Wayne Harris, who had links to extremist groups, for ordering plague microbes from a culture library under false pretenses. (The incident triggered Congress's 1996 creation of the first stringent rules for transferring dangerous microbes, which Butler allegedly violated.)

    In 1999, Butler gladly accepted an invitation from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, to help produce a training video on how to recognize and treat a plague attack. As Butler and a group of experts huddled over a simulated victim, they began debating the best treatment, he recalled. A variety of antibiotics had been used to treat plague, but nobody knew which worked best or had the fewest side effects. A trial in humans would be the ideal way to answer the questions. But the logistical and ethical obstacles were daunting. Exposing healthy people to plague was out of the question, and most cases of the disease occur in the developing world. There are fewer than a dozen plague cases a year in the United States.

    But Butler wasn't deterred. After studying several options, he rejected a return to communist Vietnam and decided that French researchers had the inside track in Madagascar. So Butler contacted researchers in Tanzania, and “they burst forth with enthusiasm,” he said.

    In 2001, Butler took a yearlong leave from Texas Tech to lay the groundwork for a Tanzanian trial, which he jump-started with his own funds. Early that year, he arrived in Dar es Salaam laden with medications, syringes, and cotton balls—a goodwill gesture to his collaborators—and met with Eligius Lyamuya, a well-known investigator at the Muhimbili Medical Center. Butler traveled to the mountainous Tanga region in northeastern Tanzania, where plague is endemic. There, using a spartan clinic as a base, he and his Tanzanian partners arranged for a side-by-side comparison of two antibiotics, doxycycline and gentamicin.

    The team members agreed that the study would include drawing fluid samples from the “bubos,” or hideously swollen lymph nodes, of the patients to confirm the presence of Yersinia pestis, the plague bacterium. Butler would then isolate the microbes—and share his cultures with the Tanzanians. The Tanzanian government had approved the study, whereas the Texas Tech IRB had exempted it from its review because Butler said he was just a consultant to the Tanzanian principal investigators (see sidebar, p. 2056).

    After a long delay, the clinical trial finally began in early 2002. In Lubbock, Butler received word that his principal Tanzanian collaborator, William Mwengee, had enrolled the first of what would eventually become more than 60 patients.

    By then, the 11 September terrorist attacks and October anthrax letters had moved bioterrorism to the top of the political agenda. Butler smelled new opportunities: “Idea in AM. Go after bioterrorism moneys for grant to work on plague,” he wrote in one of his notebooks not long after 9/11. Indeed, scientists at three government agencies were eager to work with him; the uncertainty about plague antibiotics suddenly loomed large as a gap in national security.

    FDA soon decided to fund his work by “buying” data from the Tanzanian trial, which one agency official at the time called a “truly unique asset.” Plague researchers at the Centers for Disease Control and Prevention (CDC), meanwhile, agreed to confirm Butler's Tanzanian plague samples at their lab in Fort Collins, Colorado, the only lab in the U.S. certified to do so. And USAMRIID researchers were eager to add Tanzanian plague to their microbe collection. “We really want these strains,” USAMRIID plague expert Russell Byrne would later e-mail Butler.

    In April 2002, Butler returned to Tanzania on a 10-day trip to reap his scientific harvest. He hand copied patient records and then packed the fluid samples in dry ice and dropped them into his footlocker for the flight home. Despite the worries penned in his journal, however, Butler testified that he did not ask U.S. or U.K. officials for transport permits before boarding the plane—although he did have a letter from Tanzanian authorities. But he had no trouble clearing British customs when he arrived for a layover in London, where he checked into a hotel near Gatwick Airport.

    At some point during his stay, Butler met on a London sidewalk with microbiologist John Wain, the Imperial College researcher who had once warned him about the U.K.'s increasingly aggressive enforcement of pathogen-transport rules. Butler popped open his trunk, he testified, and Wain gave him fresh dry ice to keep the vials cold. The next day, Butler flew into Dallas, Texas. As he passed through U.S. Customs, he did not declare his plague samples as “commercial merchandise,” customs forms show. That act, the federal government later alleged, constituted smuggling.

    More transport violations ensued, court documents show. On 23 June 2002, Butler drove 1200 kilometers from Lubbock to CDC's Fort Collins lab to get his samples tested—without the required government permits. On 9 September, he sent another set of plague isolates back to Tanzania in a FedEx box labeled “laboratory materials”—and without a needed export permit. And on 1 October, Butler flew from Lubbock to Washington, D.C., carrying a third set of samples. He then drove to the nearby USAMRIID—again without the necessary paperwork.

    Nobody objected to how he had moved his samples, Butler later testified. Indeed, at least one government scientist had congratulated him on his plan to hand carry them (see sidebar at left). And USAMRIID researcher Patricia Worsham would e-mail Butler that his Tanzanian study “was nothing short of miraculous.”

    Institutional harassment

    By the time Butler returned from USAMRIID last fall, however, the IRB and auditors investigating his contracts were beginning to bear down. But the researcher wasn't returning phone and e-mail messages—it was “institutional harassment,” Butler testified. And when two university auditors showed up at his laboratory on 10 October, Butler literally shut the door in their faces, one of them testified. Butler said he didn't know the duo and had never heard of their office. “They could have walked in from the street,” he said. Butler's boss, meanwhile, was pressuring him to cooperate. “It is crystal clear to me that you will have to submit,” internal medicine dean Donald Wesson wrote Butler on 9 October.

    Again, Butler was upset at Pence, blaming her for the investigations and the IRB's letter. Pence, meanwhile, had fallen seriously ill in August 2002 and wouldn't return to campus until mid-2003. Still, on 15 October 2002, Butler vented his frustration in a blistering draft letter to a senior administrator that he penned in his journal, which was entered into evidence. (He later sent a revised version.) Titled “Smoking gun of Pence's retaliation,” Butler alleges that Pence had “manipulated” the IRB by asking a friend of his to recuse himself from the panel. And he complains that the IRB's membership had created a situation in which “nonphysicians” were “rendering judgment on me.”

    On 6 November, the IRB delivered its heaviest blow. It told Butler that he could no longer work with human subjects. For the prolific researcher, the suspension was a disaster. It not only imperiled a follow-up to his Tanzanian study, but it also could cut off the bulk of his income and torpedo his chances of winning an FDA grant. On 9 January the IRB, still dissatisfied with Butler's lack of cooperation, sent him another e-mail confirming his suspension.

    The mystery of set 5

    Two days later, on a crisp Saturday morning, Butler went to his narrow, cluttered lab to perform some routine chores. That's when, Butler testified, he noticed something odd: A bright blue rack was missing its 30 tubes of Y. pestis cultures. “Set 5 missing!” Butler scrawled in his journal. Puzzled, he returned home for some family obligations, but he returned on Sunday to conduct a thorough search. “Can't explain other than intentional removal, suspect theft,” he wrote.

    Center stage.

    Butler has worked at Texas Tech's Health Sciences Center since 1987.

    CREDIT: JIM WATKINS/LUBBOCK AVALANCHE-JOURNAL/AP

    On Monday morning, Butler reported the missing vials to chemist Michael Jones, the health center's biosafety officer at the time. After touring Butler's lab together, the two men decided that they would contact their superiors. But there was no “sense of urgency,” Jones testified.

    That would change the next day, after Butler broke the news to Donald Wesson, his department chair. “I was flabbergasted,” Wesson testified about his 1 p.m. meeting with Butler. By 4 p.m., Wesson and Butler were huddled with senior health center officials. Butler opposed plans to inform the police and health authorities about the missing samples, several participants testified. But the group overruled him; this was a serious matter that the university could not handle on its own, the others decided. They asked Butler to call the local health department, while Wesson called the police.

    As darkness fell that Tuesday, 14 January, the investigation moved into high gear. Lubbock police called in the FBI, which pulled out all the stops, including informing the White House of a possible bioterror threat. The press got wind of the story, and it became a leading item on CNN.

    Through it all, Butler remained remarkably calm. The researcher, who once gave a talk titled “Pneumonic Plague: Delight of Terrorists,” explained to agents how a skilled microbiologist could convert his cultures into a bioweapon in just 4 days. His description was “like he was reading ingredients off of a cereal box,” one FBI agent testified.

    FBI's smooth operator

    Among the investigators hurrying to Lubbock that night was Dale Green, an agent in the FBI's Dallas office. An interrogator with training in psychology and a law degree—he is licensed to practice in three states—prosecutors described Green as an “expert questioner” able to draw out key information from witnesses and suspects. As Butler put it, “he had a very smooth manner to him.”

    At the trial, Green described himself as “trained to listen to what [people are] saying and how they are saying it. I'm looking for what I call red flags.” His skill, he said, is to tell “when the truth is the truth is the truth.” Green, however, couldn't tell jurors one truth: He is, in fact, a polygraph examiner—and the judge had excluded all mention of the machine from the trial.

    When Green arrived at the police department just after 11 p.m. on Tuesday, investigators had already spent several hours questioning Butler. Initially, he was considered a victim and a witness, one FBI agent testified; the agents theorized that the missing vials might be the work of a disgruntled employee. But as information about Butler's IRB suspension and the financial investigations streamed in, they began to suspect that “the disgruntled employee might indeed be Butler,” said FBI agent Miles Burden.

    Around midnight, Green asked Butler to take a polygraph test. The researcher agreed, waiving his right to an attorney in the process. By the end of the exam, Green was convinced that Butler was lying. But he didn't confront the researcher with his doubts; instead, he sent him home around 2:15 a.m. “Neither of us were spring chickens, … [and] I felt that the threat of the plague was very remote,” Green testified.

    Not that Butler got much sleep: Eleven agents accompanied him and then searched his modest, suburban ranch-style home for several hours. They also questioned his wife.

    When FBI agents returned to the house the next morning around 10 a.m., they were surprised to find Butler heading for work. Instead, he agreed to accompany them to the Lubbock police station. There, in a small room, Butler again waived his right to a lawyer. Then, Green confronted Butler with the polygraph results. “I used an empathetic approach,” Green testified, telling Butler that ‘we all make mistakes.’” Maybe Butler had accidentally destroyed the samples, Green suggested. “I'm trying to give him a way to save face. … Do I think he accidentally destroyed [the samples]? No. I'm giving him an out.”

    Butler soon confirmed Green's scenario by smiling, Green said. “This wasn't a ‘That's a good joke’ smile. … This was ‘I got caught with my hand in the cookie jar,’” he testified. Then, Green asked Butler to write a statement. In it, the researcher admitted to “accidentally” destroying the vials and making a “misjudgment” by reporting them missing.

    At the trial, the two men differed sharply over how the admission was crafted and what it was intended to accomplish. Green said he wanted Butler to reassure the public that it was not in danger, and that he suggested only a few specific phrases. But Butler testified that Green essentially dictated large chunks of the document. The two men went “back and forth,” Butler testified, until the handwritten note (see graphic above) became a “composite effort which fit what he wanted and what I felt comfortable with.”

    Among the things Green wanted was a sentence saying that investigators had made “no threats or promises” to obtain the statement, the researcher testified. But Green “tricked and deceived” him, Butler told the television news show 60 Minutes in August, just hours before the gag order was imposed. And he testified that the FBI agent had assured him that if he recalled destroying the vials, “we'll both walk out of here and nobody will be investigated.” Green disputed that claim.

    After the statement was finished, Butler was given a second polygraph, which agents claim confirmed his new account. Next, Butler answered more questions and then cooled his heels while the agents met in another room. At about 8 p.m.—barely 24 hours after the investigation started—Butler learned that he was under arrest.

    The news sparked confusion and outrage among scientists and friends. In the 10 months between his arrest and the start of his trial, several scientific organizations and individuals rallied to Butler's defense. Some, including a quartet of Nobelists, loudly denounced how the government had treated him—including 6 days in jail, the yanking of his passport, and house arrest with an electronic anklet. “Tom Butler is not a criminal,” says laureate and longtime Butler friend Peter Agre of Johns Hopkins. “He's a fine and honorable physician-scientist working for the good of mankind.” He and more than 50 others have donated to Butler's defense fund.

    Others predicted that Butler's case might discourage scientists “from embarking upon or continuing crucial bioterrorism-related scientific research,” as two presidents of the U.S. National Academies put it in an August letter to Attorney General John Ashcroft. And the “seemingly selective prosecution raises extremely serious concerns,” the New York Academy of Sciences' human rights committee added in September. Both groups pressured the government to drop the charges. But after several delays, Butler's trial finally began on 3 November.

    On trial in Lubbock

    It didn't have to happen. Prosecutors offered Butler a plea bargain that included 6 months in prison and a fine, if he agreed to plead guilty to several charges, according to media reports. But Butler, who friends say can be stubborn, balked at any deal involving jail time. He decided to roll the dice.

    Paper chase.

    Texas Tech medical school dean Richard Homan reassures the public at a press conference held soon after Thomas Butler signed a statement that he had destroyed the 30 missing vials of plague bacteria. Butler later recanted the statement, saying it had been coerced by FBI agents.

    CREDIT: JIM WATKINS/LUBBOCK AVALANCHE-JOURNAL/AP

    It was a big gamble. Texas Tech has a tradition of settling work-related disputes with employees, says Victoria Sutton, a bioterror law expert at the university who advised the prosecution. The dual contracts, which the FBI investigated thoroughly in the weeks after Butler's arrest, would not normally have gone to court, let alone been prosecuted as a federal crime. Now, the government added them as 54 new charges to Butler's original 15-count indictment. Internal Revenue Service agents also delved into what they claimed were huge, nonexistent expenses on Butler's 2001 tax return that saved him almost $40,000 in taxes. All told, Butler was facing 69 counts that carried a maximum of 469 years in jail and $17 million in fines.

    Defense attorneys filed a barrage of unsuccessful motions to soften the blow. District Judge Cummings rejected their plea to suppress Butler's 15 January “admission.” He also shot down requests to recuse himself because of his Texas Tech ties; to move the trial out of Lubbock, where the case was front-page news for months; and to separate the plague and fraud counts into separate trials. The defense team did win motions to suppress the polygraph results and to introduce heaps of e-mail evidence.

    For 16 days, Butler would stroll into the George H. Mahon Federal Building—just off Buddy Holly Avenue—looking sober and composed. The courtroom was a high-ceilinged, wood-paneled affair that was often so cold that everyone bundled up. One reporter wore gloves, and a juror huddled under a blanket. Butler's wife always sat stoically behind her husband, often accompanied by her eldest son Thomas, a recent Stanford graduate in biology. The youngest, a 5-year-old son, wasn't allowed in the courtroom. Family friends took turns providing support.

    From the trial's opening moments, prosecutors painted Butler as a man desperate to extricate himself from a hole he had dug with his own hands. Butler had reported the vials missing to distract attention from his IRB troubles and the financial investigations, they alleged. “The wagons were circled … and he had a plan to lash out,” prosecutor Robert Webster told the jury. “He wanted to throw a monkey wrench in the internal affairs of [the university].” But he didn't expect Texas Tech officials to contact the police. Instead of starting “a bonfire,” Butler lit “a wildfire that [got] out of control,” said Webster, who looked like a tall cousin of Mark Twain and could be graciously polite and devastatingly sarcastic in the same breath.

    Prosecutors also heaped scorn on Butler's claim that he didn't understand the pathogen-transport rules. His journal entry about the “challenges” of importing samples showed that he knew enough to know better, they argued, as did his downloading of the rules from CDC's Web site. Butler even warned other researchers about the stringent requirements, one scientist testified.

    Butler's hand transport was also reckless, they claimed. Plague is “in its own way as serious as the atomic bomb,” argued prosecutor Michael Snipes, a master of hyperbole with the physique of a linebacker. One of the trial's most dramatic moments came when biosafety expert Barbara Johnson of Science Applications International Corp. easily crushed with one hand a plastic petri dish just like those that Butler had used to carry some plague cultures to USAMRIID. The dishes were a disaster waiting to happen, she warned.

    The defense never disputed that Butler broke the transport laws but argued that he did so unknowingly and in good faith. Nobody was ever harmed by Butler's bacteria, defense attorneys repeatedly reminded the jury. And the scientist was only “doing what the government wanted him to do,” said attorney Chuck Meadows, a seasoned fraud defender who favored flamboyant ties and spoke in a folksy Louisiana drawl. Three government agencies, including CDC, had encouraged Butler to go to Africa and then praised his achievements. “And now they charge him with a felony for not having a piece of paper from another branch of the CDC?” he asked. “Give me a break, folks!”

    The defense had a much harder time explaining Butler's financial dealings, which prosecutor Webster pounded on for hours during his daylong cross-examination of the defendant. Butler claimed that his private payments from Pharmacia and Chiron, totaling more than $350,000 since 1996, were not for clinical work but were “companion consultancies” for his help in designing the studies, analyzing data, and writing papers. “They wanted me to be part of an inner circle of advisers,” said Butler. Butler donated much of the money back to the university to fund his research, the defense suggested. But a Texas Tech auditor testified that the donations accounted for just $65,757 of the total.

    Pharmacia and Chiron officials, meanwhile, disputed the consulting claim and noted that Butler was the only investigator involved in the trials who had twin contracts. Susan Stevens, a former contract negotiator for Chiron, even checked with her legal department when Butler asked for one split. “It set off some bells and whistles in my head,” she said. But the lawyers told her it wasn't the company's problem.

    Webster also questioned how a meticulous scientist could repeatedly botch his tax returns. Butler had claimed expenses for “professional and legal services” on his 2001 filing that exactly equaled the fees he earned from Pharmacia and Chiron. Similar deductions appeared on every filing going back to 1996. As a result, Butler's consulting business appeared to lose tens of thousands of dollars year after year. “Dr. Butler, did it ever occur to you to get out of the medical consulting business?” Webster mocked.

    Prosecutors raised another odd incident to undermine Butler's credibility. On the morning of 14 January, just hours before the investigation began, a colleague in Butler's department diagnosed the researcher with possible chronic fatigue syndrome. The physician then signed a letter, drafted by Butler, to the department administrator, recommending that Butler be granted medical leave. Butler might seek care “out of town,” it said. Butler never mentioned the diagnosis to the FBI, and his defense didn't bring it up at the trial.

    Together.

    Butler and his wife, Elisabeth, as the trial winds down.

    CREDIT: JIM WATKINS/LUBBOCK AVALANCHE-JOURNAL/AP

    That's because the letter was “an incredibly bogus, ridiculous diagnosis,” prosecutor Snipes snapped in a withering final argument. He portrayed Butler as an arrogant liar who refused to take responsibility for his actions. Butler had everything, Snipes said: a successful career, international prestige, a nice family. “He blew it all,” Snipes said. “Because he's greedy, he had to have all the money, and he simply wouldn't listen to anybody.”

    The defense team fired back. Why would Butler destroy his own career by bringing the investigators down on his head? And although he may not have had the proper paperwork, the veteran microbe hunter knew what he was doing when he transported his samples. “The world's leading expert is gonna put you in danger? He's gonna put himself in danger?” thundered Floyd Holder, the bald, baritone 69-year-old local legal legend who led Butler's defense. “Tom did what it took, and he did it as best as he could.” And now, he said, the government was punishing him for it.

    A puzzling split verdict

    For the nine men and three women on the jury, sorting through such arguments was heavy going. At the beginning of the trial, prosecutor Webster had promised them that they would “become amateur biologists and chemists” by the end of the case. Defense attorneys added that they'd have to become accountants, too. And after hearing from more than 40 witnesses, it seemed they had mastered the material. After deliberating for 3 hours, then taking 5 days off for Thanksgiving, they needed just 6 hours more to deliver their verdicts.

    Butler looked straight ahead as District Judge Cummings announced the string of convictions. As they mounted, he closed his eyes, clenched his jaw, and became flushed, apparently near tears. His wife Elisabeth and son Thomas sat sober and silent behind him.

    In delivering its judgment (see sidebar), the jury steered a middle course between the Jekyll-and-Hyde portraits of Butler painted by the dueling attorneys. Most notably, it blew a gaping hole through the heart of the prosecution's original case by acquitting Butler of the most sensational charge: lying to the FBI about the fate of his samples. And it backed Butler's claim that he acted in good faith by acquitting him of lying to his university about possessing plague bacteria, of lying on his tax returns, and of 15 of the 18 charges related to transporting his samples.

    But the jurors clearly didn't buy Butler's explanation of the split contracts, convicting him on 44 of the 54 fraud counts. And it decided that he should have known he needed an export permit when he shipped plague cultures back to Tanzania in a FedEx carton marked “laboratory materials.” The three convictions related to that mistake could prove particularly costly, prosecutors say: The export violation alone carries a maximum sentence of 10 years. (Ironically, a Department of Commerce biosecurity expert testified that Butler probably would have gotten the permit, had he applied.)

    The fraud verdicts have puzzled attorneys on both sides, however. That's because, in several instances, the jury convicted Butler of accepting one payment associated with a single contract but not a similar payment made a few weeks later. Similarly, it found him innocent of receiving certain payments but guilty of the attached mail fraud charge. “It's hard for us to understand,” Meadows says. And Texas Tech law professor and former prosecutor Larry Cunningham says that the verdicts bear the hallmarks of a divided jury that split the difference to avoid a lengthy deliberation. On the other hand, he says that the contradictions are largely academic under criminal law: “Juries aren't required to be consistent.”

    No sentencing date has been set. Butler remains at home. His lawyers have already filed a pro forma request for a retrial. If it is rejected, as expected, they will appeal on grounds that may include Cummings's denial of a change of venue and his refusal to recuse himself. Texas Tech, meanwhile, is moving to fire Butler, who had been on paid leave.

    Butler's supporters are delighted that he was acquitted of most of the charges that started the drama. Some are confident that ultimately he will be cleared of the financial charges, too. Microbiologist William Greenough, a former teacher and prominent ally at Johns Hopkins, says that he suspects Butler used the money from the split contracts for work overseas that the university was unwilling to fund.

    Beyond Butler's close allies, however, reaction has been muted. Many have rejected the image of Butler as victim of a Justice Department run amok. Butler's case just isn't that simple, they say; it raises too many questions. The 42,000-member American Society for Microbiology, for instance, never took a stand on the case, and some members had trouble making sense of it, says Janet Shoemaker, the group's policy director. But the government has sent a clear signal that scientists must follow the rules, says Texas Tech's Sutton.

    Still, even after the exhaustive investigation and expensive prosecution, many remain perplexed. The weeks of testimony never solved the case's biggest mystery: What really happened to the plague bacteria that Butler says went missing that Saturday morning? The jury signaled that it believed Butler: He was manipulated by the FBI and has no idea where the plague cultures are. That brings the case full circle. Thirty vials of deadly microbes are still unaccounted for—and nobody is looking for them.

  15. SCIENTIFIC COMMUNITY

    African Study Raises Ethical Issues

    1. Martin Enserink

    Last year, 37 children and 26 adults in one of the poorest nations in the world acquired something that made them priceless to the U.S. government: They came down with plague. Research among these rural Tanzanians could help officials decide which antibiotics to stockpile for use if bioterrorists were to use the bug against a U.S. city.

    The study's aftermath would land Thomas Butler in jail (see main text). But over the past year, the research itself has become mired in controversy. Prosecutors alleged that Butler violated ethical rules by not obtaining informed consent from the patients or their legal guardians. The defense has suggested that the Food and Drug Administration (FDA) broke federal rules when it supported the work financially.

    Although Butler was not charged with offenses directly related to the study, the case is now under investigation by the Office for Human Research Protections (OHRP) within FDA's parent agency, the Department of Health and Human Services. Mary Faith Marshall, a prominent ethicist at the University of Kansas Medical Center in Kansas City, says it raises questions about biodefense studies in the developing world. “Oh, oh, oh. … Big trouble,” Marshall reacted when given a summary of court testimony about FDA's role.

    Butler's study sought to address a gap in U.S. biodefense. A 2000 “consensus statement” published in the Journal of the American Medical Association (JAMA) recommended two antibiotics for treating plague based on a review of scant test tube, animal, and human data. One, streptomycin, is an old, FDA-approved standby for plague that has been used for decades. But only one company makes it, supplies are limited, and it can cause serious side effects. The other, gentamicin, is widely available and is considered safer. But it's not approved to treat plague.

    In Tanzania, Butler hoped to gather data that would help FDA give gentamicin its blessing. The study would compare the drug with doxycycline, an antibiotic that is standard in Tanzania.

    The trial was carried out in the Tanga region in early 2002 by Butler's local collaborators, led by regional medical officer William Mwengee. When Butler arrived in April to collect samples and copy patient records into his notebook, he added the note “No consent” to the records of 42 patients. When he later sent copies of the pages to FDA, however, the words were whited out. Prosecutors seized on the changes, accusing Butler of violating an ethical cornerstone of human research and then trying to cover it up.

    Butler disputed the allegation. The notes only indicated that the patients hadn't signed consent forms, he said. But all had given their verbal consent, Mwengee told him. So Butler deleted the notes, which were “no longer truthful,” he said. Mwengee could not be reached for comment.

    FDA's role in the study trial came under scrutiny as well. Although primarily a regulatory agency, FDA funds research on drugs that aren't commercially viable but could be used to counter bioterrorism. It became interested in Butler's Tanzanian collaboration in February 2001, said Dianne Murphy, director of FDA's counterterrorism office.

    The human toll.

    Butler's fluid samples came from massively swollen lymph nodes, which signal the presence of plague.

    CREDIT: CDC

    But there was a problem: Although approved by an ethics panel at the Tanzania Ministry of Health, the trial had not passed the Institutional Review Board (IRB) at Texas Tech University. (The IRB gave Butler an exemption because he was officially a trial consultant and not the principal investigator.) Nor did Butler obtain the so-called Investigational New Drug (IND) status for gentamicin from FDA. Without IRB approval and an IND, the study was “untouchable with federal dollars,” Murphy said.

    After extensive internal discussions, however, FDA found a way to acquire the data, Murphy said. Federal regulations say that researchers don't need IRB approval if they collect already existing data, documents, or specimens rather than create new ones. After talking to Butler in February 2002, FDA officials believed that he would return to Tanzania to collect existing data and specimens from a completed trial involving 26 to 30 patients, Murphy said. Based on this premise, FDA gave Butler $24,500 to purchase the results. It hoped he would then get his paperwork in order and apply for a $700,000 follow-up grant.

    As it turned out, however, the trial was not finished; the last patients were enrolled in early April. Murphy testified that she became aware of this fact only later. But Butler said that the agency told him early on that he would need about 60 patients.

    Either way, says Marshall, Butler should have obtained approval from his own IRB. She also questions FDA's decision to buy the study's results. “It looks like they were gaming the system,” she says, adding: “We need to be careful that, in our efforts to protect national security, we're not trodding on the rights and well-being of vulnerable populations.”

    A spokesperson for OHRP, which monitors compliance with human-subjects regulations, confirmed only that the case is under investigation. FDA also declined comment.

    The study showed that gentamicin and doxycycline were equally effective, Butler testified. But the fate of a manuscript describing those results, which he has submitted to The Lancet, is uncertain. The journal has asked Butler for clarifications about consent procedures, says William Greenough of Johns Hopkins University, who helped Butler assemble the manuscript after Butler's computer was seized.

    Meanwhile, during the Butler trial, one prosecution witness raised new questions about the results. Donald Wesson, Butler's department chair, said he reviewed Butler's records and noticed discrepancies between his notebooks and the final report he sent to FDA. In particular, he said, Butler told FDA that patients on gentamicin had received twice-daily doses of 2.5 milligrams per kilogram of body weight—the dose recommended in the 2000 JAMA consensus paper. But Butler's field notes appeared to show doses averaging just 1.8 milligrams per kilogram.

    The gap, if true, could be problematic for several reasons, experts say. It could lead to faulty recommendations for plague treatment. And trial participants who received 30% less of the antibiotic than is recommended could have been exposed to unnecessary risk.

    Butler is barred from discussing the issue. Greenough says that he was unaware of the discrepancy, but he assumes there's a good explanation. “Thomas Butler is an extremely meticulous researcher,” he says.

  16. SCIENTIFIC COMMUNITY

    Butler's Samples Spelled Trouble for U.S. Agencies

    1. David Malakoff

    Thomas Butler may be headed to prison for mishandling his plague paperwork. But testimony at his recent trial (see main text) raises potentially embarrassing questions about whether some government scientists followed all the rules.

    Six weeks after Butler's arrest, Michael Jones, then the safety officer at Texas Tech University Health Sciences Center in Lubbock, sent e-mails to the Centers for Disease Control and Prevention (CDC) laboratory in Fort Collins, Colorado, and to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, asking a set of questions, including how their scientists received Butler's samples.

    “Congratulations again and I like your plan for testing. The hand carriage of specimens to FC [Fort Collins] bespeaks of your ‘real’ field experiences. I've had some sad experiences with field materials in the past. … The work you completed so far should position you better than anyone for the anticipated FDA grant.”

    CDC's David Dennis to Butler on 9 May 2002

    Behind the scenes, Jones's query sparked concerns. CDC plague expert May Chu—who had overseen testing of Butler's samples—warned colleagues in an e-mail that “there are some legal unknowns here. … We need to know what the answers to these questions are meant for.”

    Initially, both agencies said that they didn't know that Butler had hand carried the bacteria to their labs. “We don't know the method of conveyance to CDC,” the lab's director, Duane Gubler, e-mailed Jones. But at the trial, CDC medical entomologist Kenneth Gage testified that he believed Gubler had been less than forthcoming. “I think they knew the method of transport,” Gage said after reviewing an extensive e-mail exchange in which Butler and several CDC scientists discussed the hand-delivery plan. One scientist, David Dennis, even commended it, telling Butler it “bespeaks of your ‘real’ field experiences.” That wasn't “very good judgment on his part,” Gage testified. Dennis, now retired, told Science that he had assumed Butler had the proper permits. CDC didn't respond to repeated requests for comment.

    “I know this sounds terrible, as someone who just wants to get the job done, but things are changing and not for the better.”

    CDC's Dennis to Butler on 16 May 2002

    At USAMRIID, plague researcher Patricia Worsham testified that she “would have run from the room screaming” if she had realized that Butler had lacked permits for his samples, some of which he delivered to her office on 1 October 2002. But she never confronted Butler. Later that month, Butler realized that Texas Tech hadn't sent CDC a transfer form, which it was required to submit within 36 hours of his delivery. To solve the problem, Worsham and USAMRIID's safety officer agreed to back the idea of putting a later delivery date, 29 or 30 October, on the form. “Safety officer says that you can tell us the ‘best’ dates and we will comply,” she wrote Butler. In a statement to Science, USAMRIID officials last week said that their scientists followed proper procedures and that “the record shows that Texas Tech provided incorrect shipping dates [to CDC]. … No one at USAMRIID signed the form after it was dated.”

    “Safety officer says that you can tell us the ‘best’ dates and we will comply.”

    USAMRIID's Patricia Worsham to Butler in mid-October 2002

    Worsham also briefly described a “face-to-face” meeting that she and other USAMRIID staff members had with a senior lab officer to discuss the “unclear guidance” they had given Butler. She didn't consider the talk a reprimand, she said. When Science asked USAMRIID if any employees had been disciplined due to the incident, it replied that “the performance and behavior of personnel involved with Butler were reviewed and corrective action taken.”

    The record also shows that government scientists moved to put their own files in order after Butler's troubles became public. Worsham testified that on 15 January, the day Butler was arrested, she refiled a computer record of adding Butler's samples to her lab's microbe collection, after discovering that an earlier registration hadn't “taken.” And at CDC, Gage testified that a report on Butler's testing results that should have been completed earlier was added to a file about 3 weeks after the researcher was arrested.

  17. SCIENTIFIC COMMUNITY

    The Final Score: 47 to 22

    1. Martin Enserink,
    2. David Malakoff

    Guilty on

    • Eighteen counts of theft, fraud, and embezzlement related to 18 “shadow” payments Butler received between 1998 and 2001 for work on three clinical trials sponsored by Pharmacia-Upjohn and Chiron. The funds should have been funneled through the Texas Tech University Health Sciences Center.

    • Thirteen counts of mail fraud, relating to 13 paper checks that Chiron and Pharmacia mailed to Butler.

    • Thirteen counts of wire fraud, relating to 13 electronic payments Chiron wired to Butler's bank.

    • Three counts of unauthorized export, making a false statement on a shipping bill, and illegal transportation of hazardous materials related to a single FedEx box of plague samples sent from Texas to Tanzania.

    CREDIT: PHOTODISC

    Not guilty on

    • Four counts of theft, fraud, and embezzlement related to payments for the clinical trials sponsored by Pharmacia and Chiron.

    • Six counts of wire fraud, related to six electronic payments FDA wired to Butler's bank.

    • Three counts of illegally importing and smuggling plague bacteria, related to Butler's carrying of plague samples into the United States from Tanzania in April 2002.

    • Two counts of transportation of hazardous materials relating to plague samples brought into the United States and taken to an Army laboratory in Maryland.

    • Three counts of transporting smuggled goods, related to Butler's carrying of the imported plague samples to the Army lab and a CDC center in Colorado, and mailing vials back to Tanzania.

    • One count of making a false statement to Texas Tech biosafety officer Michael Jones about the status of Yersinia pestis in his lab.

    • Two counts of making false statements to the FBI regarding the missing 30 vials of plague and his understanding of U.S. pathogen-transport rules.

    • One count of filing a false tax return regarding $114,000 in business expenses in 2001.

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