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BREAKTHROUGH OF THE YEAR:
The News and Editorial Staffs |
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See Web links on genes for 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.
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Jump to: Online extras on genes for mental illness Next runner-up: Climate change Top of page |
Online Extras on Genes for Mental Illness
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See Web links on climate change |
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.
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Jump to: Online extras on climate change Next runner-up: RNA Top of page |
Online Extras on Climate Change
| Papers and Articles |
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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).
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| Interesting Web Sites |
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See Web links on RNA |
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.
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Jump to: Online extras on RNA Next runner-up: Single-molecule techniques Top of page |
Online Extras on RNA
| Papers and Articles |
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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. Palatniket 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 |
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See Web links on single-molecule techniques |
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.
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Jump to: Online extras on single-molecule techniques Next runner-up: Gamma ray bursts Top of page |
Online Extras on Single-Molecule Techniques
| Papers and Articles |
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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)
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)
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| Interesting Web Sites |
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See Web links on GRBs |
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.
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Jump to: Online extras on gamma ray bursts Next runner-up: Sex cells from stem cells Top of page |
Online Extras on Gamma Ray Bursts
| Papers and Articles |
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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 |
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See Web links on stem cells |
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.
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Jump to: Online extras on sex cells from stem cells Next runner-up: "Left-handed" materials Top of page |
Online Extras on Sex Cells from Stem Cells
| Papers and Articles |
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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)
K. Hübner et al., "Derivation of Oocytes from Mouse Embryonic Stem Cells," Science 300, 1251 (2003)
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]
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| Interesting Web Sites |
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See Web links on left-handed materials |
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.
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Jump to: Online extras on left-handed materials Next runner-up: Y chromosome sequence Top of page |
Online Extras on Left-Handed Materials
| Papers and Articles |
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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 |
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See Web links on the Y chromosome |
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.
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Jump to: Online extras on the Y chromosome sequence Next runner-up: Anti-angiogenesis treatments Top of page |
Online Extras on the Y chromosome sequence
| Papers and Articles |
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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)
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 |
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See Web links on angiogenesis |
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.
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Jump to: Online extras on antiangiogenesis treatments Top of page |
Online Extras on Antiangiogenesis Treatments
| Papers and Articles |
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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)
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| Interesting Web Sites |
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Related articles in Science:
- BREAKTHROUGH OF THE YEAR:
Areas to Watch in 2004
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Science 2003 302: 2040. (in News)[Summary] [Full Text] - BREAKTHROUGH OF THE YEAR:
Scorecard 2002
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Science 2003 302: 2041. (in News)[Summary] [Full Text] - BREAKTHROUGH OF THE YEAR:
Breakdown of the Year: Space Shuttle Columbia
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Andrew Lawler
Science 2003 302: 2042. (in News)[Summary] [Full Text] - BREAKTHROUGH OF THE YEAR:
SARS: A Pandemic Prevented
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Martin Enserink
Science 2003 302: 2045. (in News)[Summary] [Full Text]
Volume 302, Number 5653, Issue of 19 Dec 2003, pp. 2039-2045.
Copyright © 2003 by The American Association for the Advancement of Science. All rights reserved.
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