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ScienceWeek
SCIENCEWEEK
June 8, 2007
Vol. 11 - Number 22
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No one of us really will ever know very much. This is why we shall have to find comfort in the fact that taken together we know more and more.
-- J. Robert Oppenheimer (1904-1967)
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Contents (full text below):
1. Physiology: Sister Act
2. Geophysics: Listening to Subducting Oceanic Plates
3. Climate Change: Pushing the Scary Side of Global Warming
4. Genomics: Guilt by Association
5. Stem Cells: Recycling the Abnormal
6. Astrophysics: Gravitational Waves Constrained
7. Determinism: Chaos Tamed
8. The Stem-Cell Market and Patents
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1.
Science 8 June 2007: Vol. 316. no. 5830, pp. 1436 - 1438 DOI: 10.1126/science.1144837
Physiology: Sister Act
David D. Moore
All biologists know that the myriad enzymatic pathways that extract energy from metabolites and convert them to essential products are literally the biochemical basis for life. Many also view these reactions as an indigestible list of obtuse facts, which makes it all the more impressive that the late Dr. Robert Atkins, creator of the popular high-protein, high-fat, low-carbohydrate diet, was able to pass on a relatively obscure aspect of this process to a substantial fraction of the public--namely, that ketone bodies, produced from metabolizing fat, accumulate when you fast, allowing the body to use fat instead of carbohydrates for energy. Like all metabolic processes, the production of ketone bodies from fat (a process called ketogenesis) is regulated. As Atkins stressed, "burning" of fat is blocked by insulin in response to eating carbohydrates but is activated by starvation and also by a low-carbohydrate "ketogenic" diet. Two recent papers in Cell Metabolism (1, 2) have identified a remarkable and unexpected role for an obscure growth factor in this process. A third paper in the Proceedings of the National Academy of Sciences (3) reveals how another protein facilitates this growth factor's effect on metabolism.
The human genome encodes 22 members of the fibroblast growth factor (FGF) family (4). Most function in diverse processes such as development and wound healing. But three members--FGF19 (FGF15 in the mouse), FGF21, and FGF23--have recently emerged as metabolic hormones. FGF19 modulates bile acid biosynthesis, and itself is regulated by farnesoid X receptor (FXR), a nuclear receptor that is activated by bile acids (5). FGF23 regulates phosphate and calcium homeostasis, and its expression is controlled by the vitamin D receptor (6, 7). FGF21 has a variety of beneficial effects on undesirable metabolic parameters. For example, treating obese mice (genetically engineered to lack leptin, a hormone that controls appetite) with FGF21 decreases the concentrations of serum glucose and triglycerides and increases insulin sensitivity (8). Similar results were observed in obese rhesus monkeys (9). Inagki et al. (1) and Badman et al. (2) now show that FGF21 expression in the liver of fasted mice is activated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha, also known as NR1C1).
Like other nuclear hormone receptors, PPARalpha directly regulates gene expression in response to low molecular weight signaling molecules. But unlike the well-known nuclear receptors that respond to endocrine hormones, PPARalphabelongs to a new group of metabolic receptors that respond to common metabolites (10, 11). In the case of PPARalpha, fatty acids can function as endogenous signaling ligands, and it is well documented that PPARalpha functions in the liver to induce the expression of enzymes that promote fatty acid oxidation. This represents an elegantly simple regulatory circuit in which the presence of the energy source activates an enzymatic pathway that causes its own combustion.
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2.
Science 8 June 2007: Vol. 316. no. 5830, pp. 1439 - 1440 DOI: 10.1126/science.1141921
Geophysics: Listening to the Crackle of Subducting Oceanic Plates
Andreas Rietbrock
Areas called subduction zones occur under the ocean where one section of Earth's crust (the lithosphere) collides with another and descends into the mantle (see the figure). Although these zones are of substantial scientific interest, they also have great social and economic importance. Most of the world's disastrous earthquakes and volcanoes take place at subduction zones, as well as geological processes that generate many of the ore deposits on Earth.
We can map the path of the descending lithospheres by measuring the abundant seismic activity in the subduction zone. Since it was first observed in the early 1930s, however, the precise nature and cause of this seismicity has been debated. On page 1472, Brudzinski et al. report a major step forward in our understanding of the geophysical and geochemical processes at work in these seismic regions (1).
The deep layers of seismic activity in subducting regions are called Wadati-Benioff zones (WBZs) and can be found as deep as 700 km. Originally, WBZs were believed to be single layers of seismic activity, but they have turned out to be more complex. The first convincing observation of a double WBZ beneath northern Honshu, Japan, was made by Hasegawa et al. (2), and they reported a separation distance between the two layers of about 30 to 40 km. Since then, the geoscience community has been puzzled by the relative rarity of double WBZs.
Recently, as a result of a huge increase in seismological data collected and the availability of new data-processing tools, hints of double WBZs with much smaller separation distances (<10 km) have been found in many different subduction zones (3). Brudzinski et al. have taken these observations further and propose that double layering of seismicity is an inherent feature of WBZs in the depth range between 50 and 300 km (which they refer to as double Benioff zones, or DBZs).
The origin of WBZ seismicity has been controversial for several reasons. Brittle failure or, more precisely, sudden slip along a preexisting fault or plate interface is the cause for most of the earthquakes in Earth's crust (<50 km depth). However, due to the high temperature and pressure at the depth level ofWBZ seismicity the material will instead undergo ductile deformation, which inhibits earthquake faulting. Therefore, different processes are necessary for the generation ofWBZ seismicity.
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3.
Science 8 June 2007: Vol. 316. no. 5830, pp. 1412 - 1415 DOI: 10.1126/science.316.5830.1412
Climate Change: Pushing the Scary Side of Global Warming
Richard A. Kerr
Greenhouse warming might be more disastrous than the recent international assessment managed to convey, scientists are realizing. But how can they get the word out without seeming alarmist?
Climate modeler James Hansen knows all about sounding the alarm. In the summer of 1988, drought wracked the country, fire was consuming Yellowstone National Park, and the nation's capital sweltered. Even the Senate hearing room where Hansen was testifying was warm and stuffy--the Democrats had opened the windows the night before. Then Hansen, dubbed NASA's top climate scientist by the media, shouted "Fire!" in the crowded theater: "With a high degree of confidence," he declared, greenhouse warming had arrived. Although many of his colleagues agreed, none chimed in with support; they could not share his high degree of confidence. Still, Hansen's lone authoritative voice was enough to send the media into a years-long brouhaha over global warming.
That uproar quieted within a few years, but Hansen, still the director of NASA's Goddard Institute for Space Studies (GISS) in New York City, finds himself at the head of an informal movement to again rouse the public and policymakers. This time he worries that sea level could rise several disastrous meters by the end of the century, as the warming he heralded sends the great ice sheets rumbling toward the sea. If nothing is done to rein in greenhouse gas emissions, he says, "I just can't imagine that you could keep sea-level rise under a meter." Then the sea would flood many kilometers inland along the world's low-lying coasts, from Florida to Bangladesh.
That was Hansen's warning to Congress in late April, but it's not the message that came out of the U.N.'s Intergovernmental Panel on Climate Change (IPCC) in early February. Many news reports gave the impression that the prestigious international assessment actually downgraded the risk of imminent sea-level rise to a small fraction of a meter.
So Hansen seems to be out on a limb, again. This time, however, he's got company. No longer reticent, other scientists are going public about how bad things might get by the end of the century. "The IPCC has been overly cautious in not wanting to give any large number to [future] sea-level rise," says climate researcher Stefan Rahmstorf of the Potsdam Institute for Climate Impact Research in Germany.
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4.
Nature 447, 645-646 (7 June 2007) | doi:10.1038/447645a
Genomics: Guilt by Association
Anne M. Bowcock
In a tour-de-force demonstration of feasibility, a consortium of 50 research teams uses 500,000 genetic markers from each of 17,000 individuals to identify 24 genetic risk factors for 7 common human diseases.
Mr Woodhouse, the comical hypochondriac of Jane Austen's Emma, takes great comfort in blaming his various ailments on the rain, the cold and an unfortunate piece of wedding cake. He would, no doubt, have been greatly surprised to learn that even his most rudimentary ailments resulted, at least in part, from genetic factors. Reporting on page 661 of this issue1, a consortium of more than 50 British groups, known collectively as the Wellcome Trust Case Control Consortium (WTCCC), asserts just that. In the largest study of its type so far, the WTCCC has examined the genetic underpinnings of seven common human diseases: rheumatoid arthritis, hypertension, Crohn's disease (the most common form of inflammatory bowel disease), coronary artery disease, bipolar disorder — also known as manic depression — and type 1 and type 2 diabetes.
The WTCCC study is groundbreaking in various respects. It not only confirms the involvement of some genes for which disease association has previously been reported, but it also identifies several novel genes that affect susceptibility to common diseases. Moreover, it models a successful and instructive approach to large-scale genomic scans of this type, showing that a set of common controls can be used for a variety of diseases with relatively little loss of analytical power. Its success also provides strong grounds for performing such studies on an even larger scale.
The WTCCC investigators examined genetic variation at 500,000 different positions within the genomes of 17,000 individuals living in Britain using a genome-wide association scan (Fig. 1). This statistical approach compares the frequencies of genetic variation in disease cases and in healthy controls from the same population. Using the signal from each position as an indicator for the DNA sequence that surrounds it, genome-wide association scans examine the relationship between each DNA position and a particular trait (such as diabetes). Strong 'association' between a DNA position and a trait marks the general locale of the offending alteration, even if it is not itself the cause.
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5.
Nature 447, 649-650 (7 June 2007) | doi:10.1038/447649a;
Stem Cells: Recycling the Abnormal
Alan Colman & Justine Burley
Using human eggs in the quest to make donor-specific embryonic stem cells is controversial. A method developed in mice, if applicable to humans, could eliminate the need to obtain eggs for this purpose.
On page 679 of this issue, Egli et al.1 describe a promising method for generating embryonic stem-cell (ESC) lineages using the technique of somatic-cell nuclear transfer (SCNT). Conventional SCNT involves replacement of the nuclear genetic material of an unfertilized egg (oocyte), with that of a somatic (non-germ) cell. After 'fertilization', which is induced by chemical or electrical triggers, the embryo undergoes several rounds of cell division and, after implantation into a foster mother, may develop to term. So far, this technique has been used successfully to clone 12 species. It also has been used in mice to generate ESCs from a 3.5-day-old mouse embryo2 — a blastocyst.
Since Dolly the Sheep was cloned by SCNT more than ten years ago3, it has been hoped that this technique would serve to create patient-matched ESCs for therapy, and human-disease-specific ESC lines for use in basic research and drug development. However, in contrast to SCNT in mice, the use of this technique in humans has been thwarted by technical difficulties, as well as logistical and ethical concerns about obtaining oocytes. Now, Egli and colleagues1 describe a different approach to produce donor/disease-specific ESC lines that may well revolutionize the field of human stem-cell research, and that removes one of the main ethical objections to such work. The crux of their contribution is the use of fertilized eggs, instead of oocytes, as SCNT recipients.
Historically, fertilized mouse eggs at the one-cell stage — the zygote — have been successfully used as recipients of nuclear genetic material4, but only when the donor cells were also zygotes and not from later developmental stages5. Possible reasons for this limitation include loss of essential non-DNA factors with the removed genetic material6, and inadequate time for the reprogramming of the donor's genetic material in its new environment5.
Egli et al. reasoned that the loss of the crucial factors could be minimized or eliminated if nuclear transfer is conducted when both the recipient zygote and the donor cell are temporarily arrested at the mitotic cell division. To test this, they used the drug nocodazole to arrest mitosis in mouse zygotes at the stage when chromosomes condense. Replacing nocodazole with another inhibitor allowed chromosome alignment along the mitotic spindle, but prevented further cell-cycle progression. The spindle could then be seen using optical devices, and removed mechanically.
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6.
Nature 447, 651-652 (7 June 2007) | doi:10.1038/447651a;
Astrophysics: Gravitational Waves Constrained
Michele Maggiore
Cosmic gravitational waves could provide unprecedented information on the early Universe. The effects that are of interest are small, but experiments are gradually achieving a sensitivity that will test cosmological models.
Gravitational waves are tiny disturbances in space-time. They can be triggered during cataclysmic events involving stars or black holes, and they could even have been generated in the very early Universe, well before any star formed, merely as a consequence of the dynamics and expansion of the Universe. In the latter case, these waves should provide a 'background' signal of gravitational waves coming from all directions in space — if indeed they can be spotted. One particularly sensitive experiment recruited to the search for gravitational waves is LIGO, the Laser Interferometer Gravitational-Wave Observatory. It has just published the results from its fourth bout (S4) of data-taking in The Astrophysical Journal1.
Gravitational waves are not the only known source of cosmic 'noise'. Most famously, the Universe is filled with a background of electromagnetic radiation left behind by the hot Big Bang; it has now cooled to its present temperature of about 2.7 kelvin by the subsequent expansion of the Universe. The discovery of this 'cosmic microwave background' by Arno Penzias and Robert Wilson in 1964 is a milestone in the history of modern cosmology, and its detailed study provides some of our best information on the early Universe. In 1992, NASA's Cosmic Background Explorer (COBE) satellite reported its measurement of the spectrum of the microwave background and found it to have a perfect 'black-body' form with a characteristic temperature that has tiny variations across the sky — the 'seeds' for galaxy formation2. Subsequent experiments, in particular NASA's follow-up WMAP (Wilkinson Microwave Anisotropy Probe) mission, have provided a more detailed picture, and ushered in an epoch of precision cosmology, in which the agreement between experimental data and theoretical models can be at the level of a few per cent.
The discovery of a cosmological background of gravitational radiation would arguably be even more fundamental. Any background of relic particles provides us with a snapshot of the Universe at a very definite time: the time at which these particles decoupled from the primordial plasma. For the photons of the cosmic microwave background, this happened when the Universe was just 270,000 years old. The photons we see today in the cosmic microwave background are a true photograph of the Universe at that age.
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7.
Nature 447, 643 (7 June 2007) | doi:10.1038/447643a
Determinism: Chaos Tamed
Kees Wapenaar & Roel Snieder
Even though our view of the physical world has shifted from that of determinism to randomness, randomness itself can now be exploited to retrieve a system's deterministic response. DeterminismChaos tamed
In the nineteenth century, the world of physics was one of order. Pierre-Simon Laplace was a key proponent of the deterministic Universe. In this model, the future is completely predictable if one knows the forces between all particles as well as their positions and velocities at any one moment. Take, for instance, a ball kicked into a forest. The ball bounces repeatedly off the tree trunks, but if you know the original position of the ball, its velocity and the trees' locations, you can determine the future motion of the ball from the player's initial kick.
In the twentieth century, Heisenberg's uncertainty principle shattered the deterministic dream. In the quantum world, only the probabilities for events are constrained by the laws of quantum mechanics. So for an atom-sized soccer ball kicked into the forest, the trajectory is not determined, but the probability for every imaginable trajectory is.
Even for macroscopic systems, determinism did not survive into the twentieth century. At that point Henri Poincaré, in a visionary anticipation of chaos theory, showed that even tiny uncertainties in initial conditions can grow exponentially with time to make motion at a later time indeterminable, for all practical purposes. So, when the soccer ball is kicked a number of times in slightly different directions, it hits the same trees during the first few bounces at slightly different positions; but over time the trajectories diverge, and after a few bounces the ball may move in completely different ways between the trees.
So much for particles: waves behave completely differently. If a referee blows her whistle in the same forest repeatedly at slightly different positions, the sound waves scattering between the trees change much less than the motion of the ball. One reason is that waves have an intrinsic length scale, the wavelength, and any perturbations affecting the waves over this length scale are effectively smoothed out.
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8.
New England Journal of Medicine Volume 356:2341-2343. June 7, 2007. Number 23
The Stem-Cell Market -- Patents and the Pursuit of Scientific Progress
Fiona Murray
University of Wisconsin researcher James Thomson and his colleagues wowed the scientific community when they reported in November 1998 that they had isolated and cultured human embryonic stem cells.1 They also precipitated intense debate. Although moral dilemmas and federal funding of stem-cell research have received the most media attention, behind-the-scenes concern has centered on the market for stem cells — the ownership, control, pricing, and availability of stem-cell lines. For many academic researchers hoping to build on Thomson's discovery, the difficulty of obtaining stem cells was immensely frustrating.
This difficulty arose because not only did Wisconsin have material rights to the cell lines its researchers generated, but Thomson had filed U.S. patent applications on his discoveries, resulting in intellectual property rights. These latter rights, owned by the University of Wisconsin and managed by its technology-transfer office, the Wisconsin Alumni Research Foundation (WARF), encompassed both Thomson's stem cells and the core techniques used to develop them. For this reason, these rights governed research on almost all available human embryonic stem-cell lines.
These patents have now been reexamined by the U.S. Patent and Trademark Office, thanks to a challenge brought by a consumer watchdog group. The preliminary decision of the Patent Office, issued in April 2007, is that the patents should be revoked, on the grounds that Thomson's invention was not a significant advance beyond already published work. Whatever is ultimately decided, this case provides important lessons about universities' use of material and intellectual property rights to shape the future of scientific research.
Traditionally, there have been two separate markets for scientific knowledge.2 Knowledge generated in academia has been governed by norms facilitating full and rapid publication, disclosure, and sharing: in addition to publishing, academic scientists are generally expected to comply with requests for their materials and methods, and few restrictions are placed on colleagues after materials are shared. In return, scientists receive recognition for scientific priority and rewards for publishing their findings. In contrast, knowledge generated in the private sector has been governed by property rights protected by patents. Knowledge is disclosed in patent applications in exchange for temporary monopolies, whereby scientists prohibit others from using their materials while they, through commercialization, capture the value created. If private-sector scientists choose to share their materials or methods with colleagues outside their organization, they can craft a contract allowing them to reap part of any future profits.
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