|
ScienceWeek
SCIENCEWEEK
August 11, 2007
Vol. 11 - Number 31
--------------------------------
The way to do research is to attack the facts at the point of greatest astonishment.
-- Celia Green
--------------------------------
Contents (full text below):
1. Neuroscience: Shining Light on Depression
2. Evolution: An Embarrassment of Switches
3. Philosophy Of Science: The Cha-Cha-Cha Theory of Discovery
4. Books: Fame, Philosophy, and Physics
5. Systems Neuroscience: Timing is Everything
6. Chemical Biology: Ions Illuminated
7. Electrostatics: Color Discrimination
8. Plagiarism: Academic Accused of Living on Borrowed Lines
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
1.
Science 10 August 2007: Vol. 317. no. 5839, pp. 757 - 758 DOI: 10.1126/science.1147565
Neuroscience: Shining Light on Depression
Thomas R. Insel
Just as research during the Decade of the Brain (1990-2000) forged the bridge between the mind and the brain, research in the current decade is helping us to understand mental illnesses as brain disorders. As a result, the distinction between disorders of neurology (e.g., Parkinson's and Alzheimer's diseases) and disorders of psychiatry (e.g., schizophrenia and depression) may turn out to be increasingly subtle. That is, the former may result from focal lesions in the brain, whereas the latter arise from abnormal activity in specific brain circuits in the absence of a detectable lesion. As we become more adept at detecting lesions that lead to abnormal function, it is even possible that the distinction between neurological and psychiatric disorders will vanish, leading to a combined discipline of clinical neuroscience (1).
But before we can understand depression as a brain disorder, we need information on the specific neuronal circuits that contribute to the hopeless despair that forms the core of this illness. Neuroimaging studies of people with depression might be helpful for identifying brain regions of interest, but the temporal and spatial resolution of current functional magnetic resonance imaging and positron emission tomography may not capture the real-time dynamics of brain function that are most relevant to mood and cognition. In a new approach, Airan et al. report on page 819 of this issue the use of optical imaging to capture cellular activity at millisecond resolution in brain slices (2). Their study, which uses rodents with some of the behavioral features of depression, does not define the neurobiology of depression in humans, but it demonstrates how optical imaging--in this case, using voltage-sensitive dyes--can identify changes in brain activity, enabling correlations between real-time cellular activity and changing affective state.
The findings of Airan et al. are consistent with other results that implicate the hippocampus in rodent studies of depression. Chronic or intense stressors, such as social defeat, result in behaviors that resemble human depression, and these stressors have been reported to reduce hippocampal neurogenesis (3). They also down-regulate the hippocampal expression of brain-derived neurotrophic factor (4), a molecule that promotes neuron survival, proliferation, and differentiation. Clinically effective antidepressants increase hippocampal neurogenesis (5), and blocking neurogenesis during treatment prevents the antidepressant effect in rodents (6).
What about the hippocampus and human depression? Major depressive disorder is associated with cognitive deficits and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, part of the neuroendocrine system that controls the stress response. Because the hippocampus is involved in both forming new memories and regulating the HPA axis, one might expect a link between depression and the hippocampus. Indeed, some human neuroimaging studies have reported a subtle reduction in the size of the hippocampus in patients with depression (7), and postmortem studies have reported alterations in hippocampal gene expression (8). But the evidence thus far is unconvincing. Humans with hippocampal lesions have memory deficits but not mood disorders (9). And none of the imaging or postmortem findings have been shown to be specific to the hippocampus or to major depressive disorder. Although the absence of evidence is hardly evidence of absence, most recent clinical studies of the neurobiology of depression have been following a different lead.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
2.
Science 10 August 2007: Vol. 317. no. 5839, pp. 758 - 759 DOI: 10.1126/science.1146921
Evolution: An Embarrassment of Switches
Leonid Kruglyak and David L. Stern
What makes a human different from a chimpanzee or a mouse? Of course, we know the answer in broad outline. Mutations in the genome, sifted by natural selection, cause changes in appearance, physiology, and behavior--what geneticists call the phenotype. But we have only a vague picture of a more detailed answer. Precisely which mutations generate phenotypic evolution? It's not that we can't find the mutations. Today's DNA sequencing technology readily identifies all differences between two genomes. There are simply too many differences--tens of millions between human and chimp, for example (1). An unknown fraction of these mutations alter the phenotype. Nonetheless, the molecular effects of mutations provide a rough guide to their phenotypic effects. Some mutations change the amino acid sequence of proteins, thereby altering their functions, and some change so-called cis-regulatory regions, altering when and where proteins are produced. We know a lot about the first class, but much less about the second. Several recent papers, including one by Borneman et al. on page 815 of this issue (2), demonstrate a surprising abundance of cis-regulatory changes between closely related species.
It is easy to identify mutations that alter proteins, because of the simplicity of the genetic code. Linear strings of DNA nucleotide triplets encode proteins, and each triplet always specifies a particular amino acid. Thus, mutations that alter a protein can be immediately read off from the DNA sequence. By contrast, we are only beginning to understand how the cis-regulatory code works (3). Cis-regulatory regions contain short strings of nucleotides, from 6 to 20 nucleotides in length, scattered irregularly in the vicinity of the protein-coding DNA. Proteins called transcription factors bind to these short DNA strings--transcription factor binding sites--to regulate the production of messenger RNA and thus the synthesis of proteins. In 1975, King and Wilson found that only about 1% of amino acids differed between a set of human and chimpanzee proteins (4). They thus proposed that changes in cis-regulatory regions--evolutionary switching of transcription factor binding sites--might cause the majority of phenotypic differences between species. This hypothesis has gained support from studies over the past decade (5).
Recent computational studies across species illustrate that many transcription factor binding sites have evolved quickly. That is, binding sites present in one species are often absent in another (6-8). New findings provide experimental evidence for this conclusion. These studies use a technique called chromatin immunoprecipitation to capture from cells a particular transcription factor along with its bound short DNA strings. These DNA strings are then identified by hybridization to DNA microarrays (9, 10).
Using this approach, Borneman et al. examined binding of two transcription factors in three yeast species. In only about 20% of cases did a transcription factor bind to the same site (meaning, approximately the same position with respect to the target gene) in all three species. In some cases, the absence of binding corresponded to a loss of the appropriate binding site. Surprisingly, in other cases, the absence of binding in one species occurred despite conservation of the DNA sequence. In a similar study that compared transcription factor binding between human and mouse genomes, Odom et al. (11) found that 41 to 89% of cis-regulatory regions bound in one species were not bound in the other. Even when the same gene region was bound by a particular transcription factor in both species, the precise position of the bound site with respect to the target gene often differed between species.
Do all of these evolutionary switches in transcription factor binding sites cause phenotypic differences? For two reasons, it seems likely that many do not. First, change of a single site may not alter gene expression. Transcription factors often bind to multiple sites within the same cis-regulatory region and act synergistically to regulate gene expression (3) (see the figure). Thus, individual binding sites may be gained and lost during evolution while the phenotype remains the same (12, 13). Second, the phenotype is robust to some changes in gene expression (14). For example, changes in enzyme concentration often have little effect on the output of a metabolic pathway (15).
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
3.
Science 10 August 2007: Vol. 317. no. 5839, pp. 761 - 762 DOI: 10.1126/science.1147166
Philosophy Of Science: The Cha-Cha-Cha Theory of Scientific Discovery
Daniel E. Koshland Jr.
Scientific discoveries are the steps--some small, some big--on the staircase called progress, which has led to a better life for the citizens of the world. Each scientific discovery is made possible by the arrangement of neurons in the brain of one individual and as such is idiosyncratic. In looking back on centuries of scientific discoveries, however, a pattern emerges which suggests that they fall into three categories--Charge, Challenge, and Chance--that combine into a "Cha-Cha-Cha" Theory of Scientific Discovery. (Nonscientific discoveries can be categorized similarly.)
"Charge" discoveries solve problems that are quite obvious--cure heart disease, understand the movement of stars in the sky--but in which the way to solve the problem is not so clear. In these, the scientist is called on, as Nobel laureate Albert Szent-Györgyi put it, "to see what everyone else has seen and think what no one else has thought before." Thus, the movement of stars in the sky and the fall of an apple from a tree were apparent to everyone, but Isaac Newton came up with the concept of gravity to explain it all in one great theory.
"Challenge" discoveries are a response to an accumulation of facts or concepts that are unexplained by or incongruous with scientific theories of the time. The discoverer perceives that a new concept or a new theory is required to pull all the phenomena into one coherent whole. Sometimes the discoverer sees the anomalies and also provides the solution. Sometimes many people perceive the anomalies, but they wait for the discoverer to provide a new concept. Those individuals, whom we might call "uncoverers," contribute greatly to science, but it is the individual who proposes the idea explaining all of the anomalies who deserves to be called a discoverer.
"Chance" discoveries are those that are often called serendipitous and which Louis Pasteur felt favored "the prepared mind." In this category are the instances of a chance event that the ready mind recognizes as important and then explains to other scientists. This category not only would include Pasteur's discovery of optical activity (D and L isomers), but also W. C. Roentgen's x-rays and Roy Plunkett's Teflon. These scientists saw what no one else had seen or reported and were able to realize its importance.
There are well-known examples in each one of the Cha-Cha-Cha categories (see the figure). Two conclusions are immediately apparent. The first is that the original contribution of the discoverer can be applied at different points in the solution of a problem. In the Charge category, originality lies in the devising of a solution, not in the perception of the problem. In the Challenge category, the originality is in perceiving the anomalies and their importance and devising a new concept that explains them. In the Chance category, the original contribution is the perception of the importance of the accident and articulating the phenomenon on which it throws light.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
4.
Science 10 August 2007: Vol. 317. no. 5839, pp. 752 - 753 DOI: 10.1126/science.1145110
Books: Fame, Philosophy, and Physics
Jeroen van Dongen (Reviewer)
Einstein: A Biography
by Jürgen Neffe
Translated from the German (1) by Shelley Frisch. Farrar, Straus and Giroux, New York, 2007. 487 pp. $30.
Einstein: His Life and Universe
by Walter Isaacson
Simon and Schuster, New York, 2007. 718 pp., illus. $32.
In 1921 when the earliest Einstein biography, by the Berlin publicist Alexander Moszkowski (2), was about to appear, Einstein tried to halt its publication, because seeking the limelight was frowned upon in the German academic milieu of his day. His name had been widely publicized following the 1919 British eclipse expedition that had confirmed central predictions of the theory of relativity. In its aftermath, a group of rightist physicists and agitators had started to publicly protest the clamor about relativity and its Jewish, liberal, and pacifist creator.
Despite Einstein's initial resistance, his fame has far from diminished. This year, a great many biographies later, two new books try to capture again his science, politics, and private life: Walter Isaacson's Einstein: His Life and Universe and Jürgen Neffe's Einstein: A Biography. Isaacson and Neffe, both successful journalists, shared a privilege that their predecessors lacked: access to Einstein's most private correspondence that had remained closed in the Einstein Archives at the Hebrew University in Jerusalem until the summer of 2006. New perspectives on Einstein's personal life might therefore be expected from their books.
Indeed, Neffe discusses at length Einstein's divorce from his first wife, Mileva Mari , and the troubled relationship with his two sons. Einstein could at times be harsh and selfish toward his family, as when he presented Mari (who desperately wanted to remain married) with chilling terms under which he might agree to endure living together with her; she would practically have been reduced to his maid. Although bad endings to bad marriages happen to good people, others too have observed a lack of empathy on Einstein's part [e.g., Thomas Levenson (3)]. Neffe, however, seems to be short of sympathy for his subject and consistently portrays Einstein in the darkest light imaginable. He even mentions an unnamed diary that is supposed to state that Einstein was beating Mileva. Neffe does not shy away from sensationalism or simplistic explanations: He offers as a matter of course the presumption that Einstein's talent had to be accompanied by some form of autism. And when Einstein's second wife (and cousin), Elsa, passed away after close to 20 years of marriage, Neffe claims that her "ensnared husband" exhibited barely any emotion and simply started to work harder. Isaacson's account is better informed: Einstein wept when Elsa died. He did delve into his work, but "ashen with grief," as his collaborator Banesh Hoffmann recalled.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
5.
Nature 448, 652-654 (9 August 2007) | doi:10.1038/448652a; Published online 8 August 2007
Systems Neuroscience: Timing is Everything
Phillip Larimer & Ben W. Strowbridge
Interactions among neurons in brain circuits underlie sensory perception and information storage. Work in locusts shows how the timing of different neuronal signals is synchronized to ensure effective communication.
Most biological systems can adapt to different conditions and environments. The nervous system has elaborated on this ability and developed mechanisms that use prior experience to predict future events. Many of these mechanisms could potentially support behavioural prediction. However, little is known about which specific mechanisms are used during common tasks, such as learning how to hit a baseball or remembering to avoid poison ivy. In a seminal study, Cassenaer and Laurent1 (page 709 of this issue) demonstrate a specific predictive mechanism that operates during olfactory learning in locusts.
In both mammals and insects, olfactory stimuli trigger diffuse, but reproducible, patterns of neural activity in many interconnected brain regions2. At the initial processing stage, odorants in the environment evoke all-or-none electrical discharges, which are recorded in neurons as spikes (action potentials). As the cells involved in the odorant-to-spiking conversion have only broad selectivity3, the activity of any one neuron is a poor predictor of odorant identity. Instead, odorant identity seems to be encoded by populations of neurons whose activity becomes transiently synchronized in response to sensory stimulation. Individual neurons often respond to several odorants and probably participate in many transient 'cell assemblies'2. The insect brain affords excellent accessibility for electrical recordings from several neurons, making it useful for determining how odorant-evoked activity patterns develop.
Network oscillations also have an important role in the processing of olfactory information by linking together the neurons that collectively represent a specific odorant. The presence or absence of a single spike on a specific oscillation cycle defines cell assemblies that are activated by an odorant. In honeybees4 the disruption of network oscillations impairs olfactory discrimination, highlighting the oscillations' relevance to information processing.
Olfactory information is processed sequentially by different brain regions that are linked by network oscillations. In insects, simple olfactory stimuli activate large subsets of projection neurons in the antennal lobe — a region analogous to the olfactory bulb in mammals. The neural representation of sensory information becomes significantly sparser in the second5-and third1-order stages of olfactory processing (Fig. 1a). Sparse coding is advantageous because it facilitates the recall of memories from partial cues and allows for denser, more reliable storage of biological information6
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
6.
Nature 448, 654-655 (9 August 2007) | doi:10.1038/448654a; Published online 8 August 2007
Chemical Biology: Ions Illuminated
Christopher J. Chang
Calcium ions act as signals between cells, but their exact locations — at the nanometre scale — have been difficult to pinpoint. The latest biosensor promises to reveal these details in dynamic living systems.
Cell signalling is all about location. This concept is best illustrated with calcium signals — cells funnel bursts of calcium ions to specific locations, where the ions selectively activate a wide variety of physiological functions. Calcium signals ebb and flow to cellular hotspots that are confined to regions ranging in size from micrometres down to tens of nanometres. But despite the importance of localization for controlling the effects of calcium signals on cells, it has been a daunting task to study calcium and other transient cellular signals at the nanometre scale.
Reporting in Nature Chemical Biology, Tour et al.1 describe a promising approach to this long-standing problem. They have developed a calcium sensor that allows rapid, selective and sensitive tracking of localized calcium signals with high temporal and spatial resolution.
Fluorescence microscopy is a powerful technique for imaging, in real time, many aspects of communication within and between cells. The difficulty with this method for determining the movement of dynamic cell signals such as calcium is detecting the non-uniform variation in signal concentrations within highly localized regions. Being able to detect these signal fluctuations is essential, as they may lead to drastically different biological outcomes. Synthetic, small-molecule (that is, non-protein) fluorescent indicators — such as those in the Fura, Fluo and Calcium Green families of compounds — show very rapid and selective responses to calcium. But these indicators are distributed diffusely in cells and so are unable to provide resolutions using conventional light microscopy. Alternatively, protein-based biosensors can be introduced at specific subcellular locations using genetic engineering. This approach provides an easy way to place calcium probes into cells, but such sensors are limited by their slow responses, and their large sizes can perturb the system of interest.
The strategy now presented by Tour et al.1 combines the tunability and small size of synthetic chemical indicators with the spatial resolution and control of genetically targeted proteins. They have developed a prototype small-molecule sensor, known as Calcium Green FlAsH (CaGF; Fig. 1a). This molecule comprises a receptor that binds selectively to calcium, a fluorescent reporter that responds to calcium binding, and two arsenic groups that label proteins only at specially incorporated peptide sequences that consist of four cysteine amino acids. This study builds upon previous work from the same group2 that showed that small arsenic-containing dyes target tetracysteine peptide motifs. The addition of a calcium-reporting group to the dyes introduces an extra dimension that allows calcium's function in cellular systems to be studied using molecular imaging.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
7.
Nature 448, 656 (9 August 2007) | doi:10.1038/448656a; Published online 8 August 2007
Electrostatics: Colour Discrimination
Richard Webb
Like charges repel, unlike charges attract. The simplest way to show this is to charge up different pieces of insulating plastic by rubbing them on your shirt and watching what they do when brought up close to one another. Amit Mehrotra and colleagues use a similar idea to separate a mixture of red and blue sand grains falling into a hollow acrylic cylinder, purely through the different amount of charge each is carrying (A. Mehrotra et al. Phys. Rev. Lett. 99, 058001; 2007).
The red and blue grains were all of the same size and positively charged, with the charge density of the blue grains being about six times that of the red. The authors also made the cylinder positively charged by rubbing it lightly with nitrile gloves. The grains were mixed up on a vibratory feeder, and then discharged into the cylinder from a metal chute.
On entering the cylinder, the charged grains separated spontaneously into red and blue components (pictured). Oddly, however, it was the more positively charged blue grains that moved towards the positively charged cylinder walls — rather than being more strongly repelled, as basic electrostatics would seem to demand.
The authors show through simulations that the sand particles are not, in fact, going against the grain. The effect is caused by negative charges induced on the underside of the metal chute, whose concentrated attraction causes a 'beard' of falling sand grains to grow on the lip of the chute. This beard is sufficiently repulsive that the more highly charged blue grains levitate more strongly off the end of the chute, resulting in two falling streams separated according to colour.
Pretty as it is, the experiment also has a practical aspect. The ability to separate grains by how much charge they carry, rather than by charge sign, could have applications in technologies that exploit electrostatic charging — aerosol drug delivery, xerography and filtration, for example.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
8.
Nature 448, 632-633 (9 August 2007) | doi:10.1038/448632b; Published online 8 August 2007; Corrected 8 August 2007
Plagiarism: Academic Accused of Living on Borrowed Lines
Allegations prompt fears over prevalence of plagiarism.
A shockwave could be about to hit the normally tranquil waters of social science. A German economist, specializing in environmental science and technology, has allegedly committed serial plagiarism and invented academic affiliations going back decades. The case should act as a warning sign to editors about how widespread plagiarism and deception may be, experts say.
Events may only now be catching up with Hans Werner Gottinger, 63, who is drifting into retirement in the town of Ingolstadt, Germany. This week the journal Research Policy is set to retract a 1993 paper by Gottinger, which analysed demand for spin-off technologies from Ronald Reagan's Strategic Defense Initiative. An accompanying editorial explains that two referees concluded that the article substantially plagiarized a paper published in 1980 in the Journal of Business by Frank Bass, then an economist at Purdue University in West Lafayette, Indiana. The editorial also profiles other cases of plagiarism.
Gottinger claims that he has "only scant recollection" of events so long in the past, but insists that he did not intend to plagiarize. He adds that he has "sincerely apologized" for any misunderstandings.
Problems with his paper came to the journal editors' attention in June, when a student noted that whole paragraphs and strings of complex mathematical equations in the Bass paper — which analysed demand for consumer-durable technologies — had been repeated almost exactly in Gottinger's paper. Gottinger did not acknowledge the Bass paper in his work.
Further investigations by one of the journal editors, Ben Martin, an expert in science policy at the University of Sussex in Brighton, UK, revealed that this was not the first such case. In 1999, the editors of the economics journal Kyklos had withdrawn a 1996 paper by Gottinger after finding that it had plagiarized a 1992 paper in the journal Economics of Innovation and New Technology. And by googling various strings of text from half a dozen other Gottinger papers, Martin identified yet another case — a 2002 paper by Gottinger about an economic model of global warming in the International Journal of Global Energy Issues, in which whole sections were remarkably similar to a 1997 article in the Journal of Environmental Economics and Management, by economist Zhiqi Chen of Carleton University in Ottawa, Canada.
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
|