Gene Regulation
Special Online Collection

As in civil society, where there must necessarily be checks and balances on freedom of expression, cells have evolved a range of mechanisms to regulate the expression of their constituent genes. In the 28 March 2008 issue, Science and its online sister journal Science Signaling explored the myriad gene regulatory factors that control the expression of genomic information. As described in a series of Perspectives in Science, protein transcription factors and microRNAs are the largest families of gene regulatory molecules in multicellular organisms, but they are not the only players. Metabolite-binding riboswitches, pausing by the DNA-transcribing enzyme RNA polymerase II, and the spatial organization of chromosomes all contribute to the regulatory landscape. Also in Science, a News story explored how microRNAs are attracting the interest of biomedical researchers and biotechnology companies eager for new ways to diagnose and treat diseases. In Science Signaling, Perspectives discussed how oncogenic Ras directs the silencing of tumor suppressor genes, how intrachromosomal looping brings enhancers and promoters together to stimulate gene expression, and how the abundance of a transcriptional coactivator affects nuclear receptor-mediated transcription. Finally, a special video presentation on Science Online highlighted how our view of the genome is evolving from that of a simple information repository to that of a sophisticated and dynamic network in which DNA, RNA, and proteins interact to direct cell metabolism and function.


Engineered Signaling Circuit

The emerging field of "synthetic biology" seeks to move beyond the dissection of complex intracellular signaling pathways that control cellular responses, and to begin exploiting the acquired knowledge of these biological systems for new purposes such as creating custom-configured signal transduction circuits. In a Report in the 14 March 2008 Science, Bashor et al. report that they have accomplished just this. The team chose to modify a well-studied signaling pathway in yeast that mediates the organism’s response to mating pheromones. At the core of this pathway lies a "scaffold" protein called Ste5, which serves as an assembly platform for a series of sequentially acting enzymes that propagate signals through the pathway. The team started by creating a new protein interaction domain on Ste5. By then artificially recruiting positive and negative pathway modulators to the engineered scaffold protein, they were able to change the behavior of the pathway, for example, by accelerating or delaying pathway response times and modifying a gradual dose response into a switchlike all-or-none response. As noted in an accompanying Perspective by P. M. Pryciak, the results show that "signaling dynamics can be successfully reengineered by using rational approaches."


How DEET Works

Although people have been spraying and dabbing on the insect repellent DEET for more than 50 years, its mode of action has been poorly understood . . . until now. In a Report in the 28 March 2008 Science (published online in Science Express on 13 Mar 2008), Ditzen et al. used behavioral and electrophysiological experiments to investigate the effects of DEET in both fruit flies and the malaria-carrying mosquito, and to identify the compound’s molecular targets. Whereas fruit flies are drawn to the smell of food, mosquitoes are attracted to lactic acid, a component of human sweat, as well as carbon dioxide and 1-octen-3-ol alcohol emitted when we breathe. The team found that DEET acts on the olfactory system of both insects by inhibiting olfactory neurons that mediate responses to attractive odors. Thus, rather than "repelling" bugs, DEET blunts insects’ sensitivity to specific scents. An related News story by M. Leslie in the 14 Mar issue noted how understanding how DEET works is a first step toward developing more effective alternatives.


Staph Insights

Staphylococcus aureus is one of the most successful human pathogens and has been dubbed a "superbug" because of its ability to resist numerous antibiotics and evade host antimicrobial defenses. Two Reports in Science this month offered insights into how this bacterium is able to evade the onslaught of reactive oxygen species (ROS) released by the immune system, and described a possible therapeutic strategy for neutralizing Staph defenses.

The ability to grow and reproduce in the presence of radical nitric oxide (NO) -- a toxic compound released by host immune cells -- distinguishes S. aureus from many other bacterial pathogens. In the 21 Mar 2008 issue, Richardson et al. showed that in addition to free radical-scavenging mechanisms, S. aureus possesses an inducible L-lactate dehydrogenase enzyme through which it can divert glucose metabolism exclusively to lactate production when more sensitive enzymes are shut down by NO. Lactate production allows the microbe to maintain redox balance, retain virulence, grow, and replicate despite the host assault.

The pigment staphyloxanthin, besides giving S. aureus its golden color, also provides resistance to ROS. Interestingly, early steps in staphyloxanthin biosynthesis resemble those in cholesterol biosynthesis. In the 7 Mar 2008 issue (published online 14 Feb 2008), Liu et al. showed that a cholesterol biosynthesis inhibitor, which has been through initial human clinical trials as a cholesterol-lowering agent, blocks staphyloxanthin biosynthesis in vitro and results in colorless bacteria with increased susceptibility to killing by the innate immune system. The finding thus points to a new therapeutic approach to fighting S. aureus infection.


Survey of Antisocial Punishment

Recent research has shown that altruistic punishment -- the willingness of some individuals to incur personal costs to enforce societal norms -- helps to sustain cooperation in human societies. Now, in a Research Article in the 7 Mar 2008 Science, Herrmann et al. document the widespread existence of antisocial punishment, characterized by retaliation against those who seek to enforce cooperative behavior (listen to a related podcast segment). The team conducted public goods games -- in which players were given a set number of tokens and given the option to contribute to a group project -- with university students from 16 cities around the world. After each round of play, all players’ contributions were revealed, and players were given the option to punish each other for their choices by taking away tokens (an act that also cost the punishers a token). Players were willing to part with a token of their own in order to punish low investors for freeloaders, but the researchers found that whether freeloaders accepted their punishment or retaliated in kind varied widely across societies. Interestingly, the frequency and extent to which individuals who had been punished reacted by punishing the cooperators, correlates with previous survey data measuring the social norms of civic cooperation and rule of law in these same societies. Overall, antisocial punishment was rare in the most democratic societies and more common in societies with relatively weak norms of civic cooperation and the rule of law. An accompanying Perspective by H. Gintis highlighted the results.


Bipedal Beginnings

Bipedalism is a key human adaptation and a defining feature of the hominin clade (species more closely related to modern humans than any other living species). Fossil femur bones from the 6-million-year-old Orrorin tugenensis provide some of the earliest evidence of hominin bipedalism, but their functional and phylogenetic significance have been debated since their discovery in Kenya in 2000. In a Report in the 21 Mar 2008 Science, Richmond and Jungers presented a comparative morphometric (shape) analysis of these remains and femora from modern humans, living apes, and other fossil hominins. Their analysis confirms bipedal adaptations of the Orrorin femora, but also indicates that the fossils most closely resemble those of australopithecines -- which lived about 2 to 3 million years ago -- thus challenging the proposal that Orrorin was a direct ancestor of our genus, Homo. The morphology of the Orrorin femora also suggest that the australopithecine pattern of hip biomechanics evolved early in human evolution and persisted for almost 4 million years, until early Homo evolved a new hip and thigh configuration. An accompanying News story by A. Gibbons, as well as a podcast interview with Dr. Richmond, highlighted the findings.


Squid Beak Biomechanics

Living organisms are functional assemblages of different interconnected tissues. To avoid stress and damage to these tissues, nature often employs physical property gradients at interfaces between tissues with vastly different mechanical properties. At the interface between dentin and enamel in human teeth, for example, a several-fold change in hardness and other mechanical properties occurs smoothly across a width of about 10 micrometers. In a Report in the 28 Mar 2008 Science, Miserez et al. showed that the squid beak -- a sharp and rigid organic material embedded in soft supporting muscle tissue -- also employs a large stiffness gradient, spanning two orders of magnitude from tip to base. Whereas the cutting end of the beak is hard, the end that is held by muscle is soft and compliant. This gradient is correlated with a chemical gradient involving mixtures of chitin (a polysaccharide also found in insect exoskeletons), water, and histidine-rich proteins that contain dopa -- a compound present in a variety of structural tissues. As noted in an accompanying Perspective by P. B. Messersmith such studies of the structure and composition of complex tissues will enhance our ability to incorporate elements of biological inspiration into the design of synthetic materials. Lead author on the study, Dr. Ali Miserez discussed the findings in a related podcast interview.


Caribbean Reef Development

Coral reefs are among the most diverse and productive ecosystems in modern oceans. The recent decline of coral abundance due to human impacts has thus focused attention on the potential loss of biodiversity and the assumed importance of high coral diversity for reef resilience. In apparent contrast to this notion, modern rates of coral reef growth are broadly similar around the world, even though levels of species diversity vary widely from reef to reef. In a study reported in the 14 Mar 2008 Science, Johnson et al. investigated whether this disconnect has a long-term basis. Using a combination of new and published fossil and geologic data, the team compared changes in coral diversity and reef development within the tropical western Atlantic over the past 28 million years. They found that reef development was unrelated to coral diversity and that the largest reef tracts formed after extinction had reduced diversity by 50%. Their results suggest that high diversity is not essential for the growth and persistence of coral reefs and that the ecological characteristics of dominant coral species may be more important to reef building than the simple number of species.


Dating the Grand Canyon

The age and evolution of the Grand Canyon have been subjects of great interest and debate since geologists first set eyes on it. The canyon’s history has been uncertain in part because common dating methods that rely on the analysis of basalt flows and limestone deposits are uninformative for samples more than about 1 million years old. In a study reported in the 7 Mar 2008 Science, Polyak et al. overcome this limitation by taking advantage of recent technical advances in uranium-lead dating, a method that exploits the radioactive decay of uranium via other elements to lead. The team applied their dating methods to cave deposits marking former positions of the water table in the Grand Canyon’s walls, which thus serve as benchmarks of ancient levels of the river bed. The data suggest that the Colorado River has taken about 17 million years to cut its course downward through the 1-mile depth of the Grand Canyon and that the canyon has evolved via headward erosion from west to east. In addition, the eastern third of the Grand Canyon appears to have undergone much faster incision than the western part, and was likely completely cut through 5 to 6 million years ago. An accompanying Perspective by T Atkinson and M. Leeder highlighted the Report.


High-Precision Timekeepers

Atomic clocks based on a microwave transition in cesium atoms are the standard timekeepers of today, but clocks based on optical transitions of trapped atoms and ions offer the potential of better precision because they operate at much higher frequency. One requirement for any new timekeeping standard is the ability to compare the operation of one clock with another. Two studies reported in the 28 March 2008 Science have done just this. Each group compared two optical clocks and demonstrated a precision that significantly exceeds that of today’s best standards. Rosenband et al. (published online 6 Mar 2008) compared two single-ion optical clocks (that employ aluminum or mercury) and showed that the ratio of the frequencies of the two clocks can be measured with a fractional error out to the 17th decimal place. Ludlow et al. (published online 14 Feb 2008) found that two different optical clocks, one based on strontium and the other on calcium, set 4 kilometers apart are able to keep time with a fractional uncertainty out to the 16th decimal place. According to an accompanying Perspective by D. Kleppner the studies represent a milestone in timekeeping because both groups have achieved a level of precision that far surpasses that of the standard cesium clock.


Rings Around Rhea?

In November 2005, the Cassini spacecraft encountered Rhea, the second largest of Saturn’s moons. As anticipated, instruments found evidence of a tenuous dust cloud kicked up by the micrometeorites that constantly bombard Rhea’s surface. But as Jones et al. report in the 7 Mar 2008 Science, Cassini also recorded something unexpected: a dip in the amount of energetic electrons in the moon’s vicinity -- in regions extending about 6000 kilometers on each side of Rhea. Because the electron decrease is too substantial to be accounted for by electron-absorbing gas and dust, the researchers suspect the existence of unseen solid material that is doing the job. Combined observations from several instruments suggest that this material consists of grains and boulders up to a meter in diameter and forms a broad disk of debris in Rhea’s equatorial plain. Computer simulations imply that under the right conditions, these particles could remain in orbit forming rings that would be stable for millions of years. An accompanying News story by R.A. Kerr noted that the findings potentially mark two firsts: the first known natural satellites of a moon, which also form the first rings known to encircle a moon.


Second Hydroxyl Source

Hydroxyl radicals (OH) are often called the "detergent" of the atmosphere because they control the atmosphere’s capacity to cleanse itself of pollutants. Accurate modeling of the oxidizing (or cleansing) capacity of the atmosphere thus requires knowledge of all substantial sources of these radicals. It has been thought that the major route of hydroxyl radical production is the breakdown of ozone by sunlight in the presence of water vapor. Now, in a Report in the 21 Mar 2008 Science, Li et al. show that the bimolecular reaction of electronically excited nitrogen dioxide with water molecules is another important source of tropospheric OH radicals. Using measured rate data, along with available solar flux and atmospheric mixing ratios, the researchers showed that this reaction can supply as much as 50% of the OH under certain conditions. An accompanying Perspective by P.O. Wennberg and D. Dabdub discussed how this chemistry could have important implications for models of air quality, where the interactions of sunlight with emitted nitrogen oxide species, hydroxyl radicals, and reactive organic compounds are central in determining the rate of ozone formation.



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In Science Signaling

(Note: Science’s STKE changed its name to Science Signaling starting with the first issue in January 2008. For more information see the Science Signaling website.)

Matrix Stiffness and TGF-beta

Cells sense their surroundings not through sight or sound but through the "smell" or "taste" of various soluble factors and the "touch" or "feel" of insoluble mechanical cues. Elasticity of the extracellular matrix (ECM) -- a network of proteins and carbohydrates that surrounds cells -- is one of those mechanical cues, and has been shown to affect the phenotype of a wide range of cells including epithelial cells, neurons, and even stem cells. In a Perspective in the 11 March 2008 issue, R.G. Well and D.E. Discher discussed a recent report demonstrating that the stiffness of the extracellular matrix also influences the release of transforming growth factor-beta, a matrix-bound protein growth factor involved in embryogenesis, malignancy, and fibrosis. The new work shows that that a soft ECM deforms under the stresses applied by cells, leaving the protein complex that contains TGF-beta intact, and the growth factor sequestered in the matrix. A stiff matrix however, resists deformation and releases TGF-beta so it can bind cell-surface receptors and promote cellular differentiation and proliferation. The findings suggest that mechanics-driven mechanisms may regulate the equilibrium between storage and release of other matrix-bound growth factors as well.

Also in Science Signaling this month:
-- S.E. Henrickson et al. offered a slideshow presentation with accompanying notes on in vivo imaging of T cell priming (25 March 2008)
-- S.L. Jenkins et al. described how to use an online asynchronous discussion as a mechanism to introduce students to the peer-review process, and to assess student performance and understanding (4 March 2008)
-- B. Kemp-Harper and R. Feil reported on the 3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications, which took place in Dresden, Germany in June 2007 (4 March 2008)