Clinical Trials and Tribulations
Special Online Collection

To move a therapy from the research lab to the doctor’s office requires a huge investment in clinical trials, which are growing more costly and more complex every year. In a special section of the 10 Oct 2008 issue, a series of News stories reported on the challenges besetting clinical trials in the United States, including spiraling costs, complicated guidelines, and poor management; the promise and pitfalls of clinical trials overseas; efforts to make clinical data more accessible and to ensure that government-sponsored trials in the United States are balanced by gender; and some surprising results from trials involving drugs designed to prevent heart disease by controlling cholesterol. Online, a video presentation discussed progress in regulating and testing medicines for children, and a podcast segment highlighted some of the reasons why trials are becoming more expensive and more complicated as well as ongoing efforts to make them run more efficiently.


Control and Conspiracy

Why do people form superstitions, create conspiracy theories, and see patterns where none exist? In a Report in the 3 Oct 2008 Science, Whitson and Galinsky suggest that the answer may be because people are in situations where they do not have control. That is, when individuals are unable to gain a sense of control objectively, they will try to gain it perceptually. In a series of experiments that used multiple methods to induce a lack of control in participants, the team found that subjects in the lack-of-control condition were more likely to perceive a variety of illusory patterns, including seeing images in static, forming illusory correlations in stock market information, perceiving conspiracies, and developing superstitions (see the related ScienceNOW story by G. Miller). Interestingly, when these participants first did a self-affirmation exercise designed to make them feel more psychologically secure, they were less prone to seeing illusory patterns. The researchers point out that the beneficial effects of this sense of security are commonly tapped into by psychotherapy, which attempts to give patients a sense of control over their lives to reduce compulsive or other distressing behaviors. Lead author Jennifer Whitson discussed the work in a related podcast interview.


Genes, Dopamine, and Obesity

What are the biological factors that increase an individual’s risk of future weight gain? Results from a new study by Stice et al. reported in the 17 Oct 2008 Science suggest that for some individuals, abnormal dopamine signaling may be a contributing factor. The brain’s dorsal striatum releases the neurotransmitter dopamine in response to eating, and the amount of dopamine released corresponds to the degree of pleasure that the food brings. It has therefore been hypothesized that obese individuals may have an underactive reward circuitry, which leads them to overeat in order to compensate for a sluggish dopamine reward system. To test this hypothesis, the researchers used functional magnetic resonance imaging (fMRI) to monitor the brains of subjects while they partook in a tasty chocolate milkshake or a tasteless control solution. Consistent with their hypothesis, the researchers observed that the dorsal striatum was less active in obese individuals than in lean individuals during the taste test. Moreover, individuals bearing the A1 allele of the dopamine D2 receptor gene -- which is associated with reduced dopamine transmission in the striatum --had the most blunted brain activity in response to the milkshake and were also more likely to gain weight over the course of the next year. In a related podcast interview, lead author Eric Stice commented on how behavioral or pharmacologic interventions aimed and correcting a blunted striatal response to food may assist in the prevention and treatment of obesity.


Deconstructing Signaling Networks
Special Online Collection

Complicated biochemical signaling pathways regulate the function of living cells. To fully understand these regulatory systems and exploit their potential as targets of therapeutic strategies, researchers need quantitative information on the flow of signals through a pathway and on the timing and location of signaling events within cells. In a special section in the 17 Oct 2007 issue of Science, and a companion issue of Science Signaling published on 21 Oct, a series of papers explored recent advances in addressing these challenges. In Science, three Review articles examined the ways in which regulatory feedback loops shape signaling responses in space and time, how mathematical modeling and quantitative experimentation are providing new insights into signaling during development, and the use of light to probe and control signaling proteins in cells. In Science Signaling, an original research paper described an engineering approach to identifying the weakest links in cellular signaling networks, while Perspective articles looked at new techniques that take advantage of chemistry to investigate signal transduction mechanisms, how scaffolding molecules can determine the graded or switchlike response of a pathway, and how oscillating input signals are used to understand the dynamic behavior of a signaling system in yeast.


Fat Cell Origins

The intertwined epidemics of obesity and diabetes have heightened interest in the developmental origin of adipocytes or fat cells. Despite the importance of fat cells in human health and disease, little has been known about the identity or location of the progenitor cells that give rise to them. Now, in a Report in the 24 Oct 2008 Science (published online 18 Sep), Tang et al. describe their use of cell lineage tracing in mice to hone in on the long-sought progenitor cells. The team found that most adipocytes originate from a pool of proliferating progenitors that reside within the walls of the blood vessels that feed fat tissue -- but not in the vasculature of other tissues. These progenitors appear to commit to the adipocyte lineage either prenatally or shortly after birth. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development. Further characterization of this niche and isolation of fat cell progenitors may help establish whether intervention in adipose lineage formation can be an effective therapeutic approach for obesity and diabetes. An accompanying Perspective by C. R. Kahn highlighted the study.


Tackling the Wheat Genome

As the staple food for 35% of the world’s population, wheat is one of the most important crop species. Despite its broad socioeconomic importance and the challenges facing agriculture today, wheat genomics and its application to crop improvement are lagging behind efforts involving other important crops. The wheat genome’s enormous size (17 gigabases, five times larger than the human genome), its large share of repetitive sequences (>80%), and the presence of three sets of chromosomes in each cell nucleus all pose daunting challenges. Now, in a Report in the 3 Oct 2008 Science, Paux et al. report a major step forward. Using a "divide and conquer" approach, the researchers isolated the largest wheat chromosome (chromosome 3B) and made a physical map of it, placing more than 1400 molecular markers along its 995 million bases. The study demonstrates the feasibility of constructing physical maps in large, complex, polyploid genomes using a chromosome-based approach. As noted in a related ScienceNOW story by E. Pennisi, "[t]he map will not only assist in sequencing but also help researchers more easily find genes important to increasing yields and dealing with drought and disease."


Making Sense of Glia

Sensory organs are the main conduit by which an animal perceives its environment; they are composed of neurons, which convert environmental stimuli to electrical signals, and glial cells. Although glial cells comprise the largest cell population in the vertebrate nervous system, their specific functions are not well understood. In a Report in the 31 Oct 2008 Science, Bacaj et al. investigated the role of glial cells in the amphid -- the major sensory organ of the nematode worm Caenorhabditis elegans that mediates responses to chemical, thermal, and tactile stimuli. The team found that lack of glia in this organism results in altered neuronal morphology, sensory deficits, and ultimately modified organism behavior. With the exception of one type of neuron, all of the glia-deprived sensory neurons lost sensitivity for their stimuli. These results indicate that glia are required for multiple aspects of sensory organ function. An accompanying Perspective by A. Reichenbach and T. Pannicke discussed how the new data help to clarify the role of glial cells in multicellular animals with different degrees of complexity.


Innovation and Migration

The expansion of modern human populations in Africa 80,000 to 60,000 years ago and their initial exodus out of Africa have been tentatively linked to two tool-building traditions -- called the Still Bay and Howieson’s Poort industries -- during the Middle Stone Age in southern Africa. However, establishing the correct sequence of events during this stage of modern human history has been hampered by inadequate chronologies. Now, in a Report in the 31 Oct 2008 Science, Jacobs et al. present the ages -- using single-grain optical dating combined with statistical modeling -- for nine archaeological sites from varied climatic and ecological zones across southern Africa. Their results indicate that both industries were short-lived (less than 5000 years), separated by about 7000 years, and coeval with genetic estimates of population expansion and exit times. Comparison with climatic records shows that these bursts of innovative behavior cannot be explained by environmental factors alone. The researchers note that compilation of similar chronological data sets from East and North Africa may help determine whether the emergence of innovative technology in southern Africa was a precursor to the latter human exodus, or whether population expansions were the stimulus for the Still Bay and Howieson’s Poort industries.


Mimicking Gecko Feet

The ability of gecko lizards to scurry up walls and cling to ceilings by their toes has fascinated scientists for decades. The creatures owe this remarkable ability to microscopic branched elastic hairs on their feet that are able to induce atomic-scale attractive forces to strongly grip surfaces. In a Report in the 10 Oct 2008 Science, Qu et al. reported on the latest attempt to mimic this impressive adhesive effect. The team showed that a disordered array of vertically aligned carbon nanotubes -- consisting of a straight body segment with curly entangled tops -- can achieve macroscopic adhesive forces almost 10 times that of a gecko foot. A strong shear adhesive force, forged when the tangled portions of the nanotubes become aligned when pressed onto a surface, allows for a strong grip of vertical surfaces without slipping, while a much lower normal adhesive force enable easy removal and reattachment. In addition to the ability to stick objects to walls, the material could have many technological applications, including connecting electronic devices and substituting for conventional adhesives in the dry vacuum of space.


Stellar Insights

Two Reports in the 24 Oct 2008 Science presented satellite observations that reveal new insights into the shape of the sun and the sun-like pulsing of distant stars.

-- Michel et al. used data gathered by the space satellite CoRoT (Convection Rotation and Planetary Transits) to probe the structure of three distant stars in the same class as the Sun. They found that these stars are hotter and have much finer granulation than our Sun and that the amplitudes of their pulsations are about 1.5-fold greater. An accompanying Perspective by M. H. Montgomery explained how helioseismology -- the study of a star’s interior through its pulsation modes -- may represent a promising approach to learning about the structure and evolution of more distant suns, as well as our own.

-- Fivian et al. (published online 2 Oct) investigated the shape of the Sun, which is an important indicator of its internal processes, magnetism, and rotation. Using data from a suite of sensitive aspect sensors onboard the spacecraft RHESSI (Reuven Ramaty High-Energy Solar Spectroscopic Imager), the team determined that the Sun is more oblate (flattened at the poles) than expected and that this flattening is due to enhanced magnetic activity. A Perspective by G. A. Chapman highlighted the Report.


Volcano Seismicity Simulations

Active volcanoes produce a variety of characteristic earthquakes before and during eruptions. Understanding how each type of earthquake is associated with different physical processes can therefore be helpful for eruption forecasting, especially when combined with geochemical data and ground-deformation monitoring. In a Report in the 10 Oct 2008 Science, Benson et al. simulated volcanic seismicity in the laboratory using basalt samples from Mount Etna volcano in Italy. In a series of experiments in which the rock was deformed and fractured, followed by rapid decompression of stored fluids, the team recorded small-scale seismic signals (also known as acoustic emissions) similar in type and location to those observed at many active volcanoes. Moreover, using a simple scaling relationship, the researchers demonstrated that their laboratory data could be scaled up and related to a natural volcanic event, with fractures of 50 millimeters in the lab samples corresponding to faults of about 200 meters in nature. Taken together, the results suggest that some natural quakes may also originate from the rapid release of pressure in fluids (such as heated water, steam, or magma) flowing through fractures. An accompanying Perspective by L. Burlini and G. Di Toro highlighted the study.


Measuring Spin Currents

Electrical currents transport charge, but certain experimental setups allow them to transport spin as well. Applications that can take advantage of these spin currents include magnetic memory systems, sensors, and efficient electronic switches, but the development of these so-called spintronic devices has been hindered by the difficulties associated with measuring the flow of spin currents. In a Report in the 17 Oct 2008 Science, Vlaminck and Bailleul described a new and reliable method for measuring spin currents that makes use of the Doppler effect -- the change in frequency and wavelength of a wave that results from a source moving with respect to a medium or a moving medium. A common example is the change in pitch of a car horn that an observer hears as a car passes by. Focusing on spin density waves, which are excitations of polarized electrons that propagate through magnetic systems, the researchers showed that an electrical current injected into a spin wave system produces a frequency shift in the propagating spin waves. This change in frequency can then be used to determine the effective flow of spin in the magnetic material. An accompanying Perspective by R. D. McMichael and M. D. Stiles highlighted the Report.


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In Science Signaling

MAPK Signaling Dynamics

Signaling cascades involving mitogen-activated protein kinases (MAPKs) regulate cell growth and differentiation and are conserved across all eukaryotic species. MAP kinases also play an important role in the mating cycle of the budding yeast Saccharomyces cerevisiae, during which haploid cells secrete pheromones that promote cell-cell fusion. Two Perspectives in the 21 Oct 2008 issue of Science Signaling highlighted recent insights into the dynamics of pathways involving MAPK signaling in yeast. H. G. Dohlman discussed new work showing that a graded pheromone stimulus will confer a response that is either graded or switch-like, depending on whether the kinase scaffold protein is located to the plasma membrane or in the cytosol. T. C. Elston, meanwhile, discussed how microfluidic devices and application of linear time-invariant (LTI) system theory, in which a pathway is defined as having an output that is directly proportional to the input, have revealed the rate-limiting steps in the MAPK cascade that regulates the high-osmolarity glycerol (HOG) pathway (involved in maintaining osmotic balance). In addition, analysis of pathway bandwidth -- a measure of how quickly a pathway can respond to an oscillating signal -- has led to the identification of feedback loops that control the dynamic range of the pathway.

-- M. B. Yaffe discussed how biologists are turning to mathematical models and computational approaches to understand the complexity of cellular signaling (28 Oct 2008).
-- Lund et al. reported on how brain-derived neurotrophic factor (BDNF) regulates a GABA receptor subunit through the repressor ICER (14 Oct 2008)
-- N. R Gough and J. F. Foley, in a podcast, talked about how the bacteria that cause periodontitis evade destruction by promoting crosstalk between two receptors that regulate the immune response (7 Oct 2008)