Glioma development: where did it all go wrong?

Investigating the family tree of a tumor to identify its cellular origins is a daunting task. Liu et al. (2011) now use an elegant lineage tracing technique (MADM) to visualize glioma from its earliest stages. They show that mutations originally induced in neural stem cells lie dormant and only trigger malignant transformation following differentiation into oligodendrocyte precursor cells.     

Signalling to p53: where does it all start?

Alterations in the p53 gene product appear to be a major factor in human tumorigenesis and may influence the responses of many human tumors to therapy. Much effort has focused on understanding the signals which normally initiate p53 growth-suppressive functions. Though it has been known that DNA damage can induce p53, a recent publication reports data which suggest that p53 can be induced by depletion of ribonucleotide pools, even in the absence of detectable DNA damage⁽¹⁾. These observations provide new ideas about how cells utilize the p53 signal and open up new avenues of investigation for manipulating p53 function.     

The Origin of Life – How Long did it Take?

We do not understand the steps leading from the abiotic early earth to the RNA world. Consequently, we cannot estimate the time required for the origins of life. Attempts to circumvent this essential difficulty are based on misunderstandings of the nature of the problem.     

When did the human population size start increasing?

We analyze the frequency spectra of all available human nuclear sequence data sets by using a model of constant population size followed by exponential growth. Parameters of growth (more extreme than or) comparable to what has been suggested from mtDNA data can be rejected for 6 out of the 10 largest data sets. When the data are separated into African and non-African samples, a constant size no-growth model can be rejected for 4 out of 8 non-African samples. Long-term growth (i.e., starting 50-100 kya) can be rejected for 2 out of 8 African samples and 5 out of 8 non-African ones. Under more complex demographic models, including a bottleneck or population subdivision, more of the data are compatible with long-term growth. One problem with the data used here is that a subset of loci may reflect the action of natural selection as well as of demography. It remains possible that the correct demographic model is one of constant population size followed by long-term growth but that at several loci the demographic signature has been obscured by balancing or diversifying selection. However, it is not clear that the data at these loci are consistent with a simple model of balancing selection; more complicated selective alternatives cannot be tested unless they are made explicit. An alternative explanation is that population size growth is more recent (e.g., upper Paleolithic) and that some of the loci have experienced recent directional selection. Given the available data, the latter hypothesis seems more likely.     

How did parasitic worms evolve?

Nematodes are important parasites of humans and other animals. Nematode parasitism is thought to have evolved by free‐living, facultatively developing, arrested larvae becoming associated with animals, ultimately becoming parasites. The formation of free‐living arrested larvae of the nematode Caenorhabditis elegans is controlled by the environment, and involves dafachronic acid (DA) and transforming growth factor (TGF)‐β signalling. Recent data have shown that DA acid signalling plays a conserved role in controlling larval development in both free‐living and parasitic species. In contrast, TGF‐β signalling does not seem to be conserved; this difference perhaps points to how nematode parasitism did evolve.     

The fateful encounter of mitochondria with calcium: How did it happen?

A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca²⁺. In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca²⁺ concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca²⁺ occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na⁺/Ca²⁺ antiporter. A H⁺/Ca²⁺ release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca²⁺ from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca²⁺ across the inner membrane. In conditions of cytoplasmic Ca²⁺ overload mitochondria could store for a time large amounts of precipitated Ca²⁺-phosphate, thus permitting cells to survive situations of Ca²⁺ emergency. The uptake process was found to have very low affinity for Ca²⁺: since the bulk concentration of Ca²⁺ in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca²⁺. A number of findings had nevertheless shown that energy linked Ca²⁺ transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca²⁺ in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca²⁺ from vicinal stores in which the concentration of Ca²⁺ is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca²⁺ (not only of their own internal Ca²⁺). Their Ca²⁺ uptake systems was found to react very rapidly to cytoplasmic Ca²⁺ demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca²⁺ transport is its involvement in the disease process. Ca²⁺ signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca²⁺, dysfunctions of their Ca²⁺ controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes.     

The evolution of human adiposity and obesity: where did it all go wrong?

Because obesity is associated with diverse chronic diseases, little attention has been directed to the multiple beneficial functions of adipose tissue. Adipose tissue not only provides energy for growth, reproduction and immune function, but also secretes and receives diverse signaling molecules that coordinate energy allocation between these functions in response to ecological conditions. Importantly, many relevant ecological cues act on growth and physique, with adiposity responding as a counterbalancing risk management strategy. The large number of individual alleles associated with adipose tissue illustrates its integration with diverse metabolic pathways. However, phenotypic variation in age, sex, ethnicity and social status is further associated with different strategies for storing and using energy. Adiposity therefore represents a key means of phenotypic flexibility within and across generations, enabling a coherent life-history strategy in the face of ecological stochasticity. The sensitivity of numerous metabolic pathways to ecological cues makes our species vulnerable to manipulative globalized economic forces. The aim of this article is to understand how human adipose tissue biology interacts with modern environmental pressures to generate excess weight gain and obesity. The disease component of obesity might lie not in adipose tissue itself, but in its perturbation by our modern industrialized niche. Efforts to combat obesity could be more effective if they prioritized ‘external’ environmental change rather than attempting to manipulate ‘internal’ biology through pharmaceutical or behavioral means.     

How long did it take for life to begin and evolve to cyanobacteria?

There is convincing paleontological evidence showing that stromatolite-building phototactic prokaryotes were already in existence 3.5 × 10⁹ years ago. Late accretion impacts may have killed off life on our planet as late as 3.8 × 10⁹ years ago. This leaves only 300 million years to go from the prebiotic soup to the RNA world and to cyanobacteria. However, 300 million years should be more than sufficient time. All known prebiotic reactions take place in geologically rapid time scales, and very slow prebiotic reactions are not feasible because the intermediate compounds would have been destroyed due to the passage of the entire ocean through deep-sea vents every 10⁷ years or in even less time. Therefore, it is likely that self-replicating systems capable of undergoing Darwinian evolution emerged in a period shorter than the destruction rates of its components (<5 million years). The time for evolution from the first DNA/protein organisms to cyanobacteria is usually thought to be very long. However, the similarities of many enzymatic reactions, together with the analysis of the available sequence data, suggest that a significant number of the components involved in basic biological processes are the result of ancient gene duplication events. Assuming that the rate of gene duplication of ancient prokaryotes was comparable to today's present values, the development of a filamentous cyanobacterial-like genome would require approximately 7 × 10⁶ years—or perhaps much less. Thus, in spite of the many uncertainties involved in the estimates of time for life to arise and evolve to cyanobacteria, we see no compelling reason to assume that this process, from the beginning of the primitive soup to cyanobacteria, took more than 10 million years.Correspondence to: A. Lazcano     

How did East German genetics avoid Lysenkoism?

Lysenkoism gained favour in the Soviet Union during the 1930s and 1940s, replacing mendelian genetics. Opponents of Lysenko were dismissed from their jobs, imprisoned and, not infrequently, died. After World War II in some of the East European Soviet satellite states, Lysenkoism became the official genetics supported by the communist authorities, and thus, genetics and biology were set back many years. Yet the uptake of Lysenkoism was not uniform in the Eastern Bloc. The former East Germany (GDR) mostly escaped its influence, owing to the contribution of a few brave individuals and the fact that the country had an open border with the West (West Berlin).     

Subfunctionalization: How often does it occur? How long does it take?

The mechanisms responsible for the preservation of duplicate genes have been debated for more than 70 years. Recently, Lynch and Force have proposed a new explanation: subfunctionalization--after duplication the two gene copies specialize to perform complementary functions. We investigate the probability that subfunctionalization occurs, the amount of time after duplication that it takes for the outcome to be resolved, and the relationship of these quantities to the population size and mutation rates.     

Synaptonemal complex formation: where does it start?

The synaptonemal complex is a prominent, evolutionarily conserved feature of meiotic prophase. The assembly of this structure is closely linked to meiotic recombination. A recent study in budding yeast reveals an unexpected role in centromere pairing for a protein component of the synaptonemal complex, Zip1. These findings have implications for synaptonemal complex formation.