Thursday, 25 November 2010

Cancer’s conversions

A developmental transition may be a useful model for tumor progression.

Until recently, the universally accepted dogma in cancer research stated that replicating cells accumulate several rounds of mutations before becoming cancerous. According to that dogma, the mutations that result in metastatic spread throughout the body occur late in tumor progression. This idea has recently been challenged by the identification of cancer stem cells (CSCs), which provide a new explanation for both the initiation and propagation of tumorigenesis. Rather than following a linear process that starts with unchecked replication and ends with the loss of adhesion molecules that drives metastasis, CSCs can self-renew, proliferate, differentiate, and even revert back to a stem cell state, producing metastatic cells at unexpected stages of the disease.

With a new understanding that cancer progression does not necessarily follow a particular order, researchers have been looking for models to help explain how and when cancers become aggressive. While the idea of CSCs helps explain some observations that do not fit within the accepted dogma, researchers have proposed another idea based on a normal process in embryonic development called the epithelial-to-mesenchymal transition (EMT). Embryonic development requires epithelial cells to change gene expression patterns, lose their adhesion molecules, and become motile, mesenchymal-like cells that invade the extracellular matrix and later differentiate to form the interior tissues of the body such as skeletal muscles and the heart. A similar process, which includes the loss of adhesion molecules and the activation of common genes by Wnt/β-catenin and other signaling pathways, is also a prerequisite for malignant tumor development, particularly the metastatic process. Studying the basic biology of EMT, therefore, could shed light on the processes that cancer cells undergo as they develop.

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Saturday, 20 November 2010

Induced global mutations

Imagine that some organisms find themselves in an environment in which they can no longer survive or reproduce. Their only hope of salvation is that a lucky mutation will crop up and enable them to deal with their adverse circumstances. If mutation rates are low, which they usually are, the chances that any will survive are slim. But if they have mechanisms that kick in in stressful conditions and increase the rate of mutation throughout the genome, things might be better.Many individuals will perish quickly (they get mutations that make matters worst), but the chances that one or two will have a liberating mutation are enhanced.


The mutation rates in bacteria are enhanced when they encounter an environment that is so hostile that they completely stop growing and reproducing. In such conditions, a spate of new mutations is generated throughout the genome. Every little single mutation is random, in the sense that it is not function-specific, but the general genomic response - the increased mutation rate - may be adaptive.


Not everyone accepts that stress-induced mutation is an evolved adaptation, however. Some people argue that the spate of mutations that occur in adverse conditions is simply a by-product of stress-induced failure. When cells are stressed, especially when starved, one of the things that may happen is that they are no longer able to produce the proteins needed for DNA maintenance and repair. It may even be that starved cells are obliged to turn off their DNA-caretaker genes to save energy. If so, faults will occur and remain uncorrected. In other words, there will be a lot of mutations. In this case, the generation of mutations is just a pathological symptom of the problems cells are experiencing, not an evolved adaptive response to adverse conditions.

From: Eva Jablonka & Marion Lamb - Evolution in four dimensions

Wednesday, 17 November 2010

Molecular animations

Suggested by Glen Oomen (Medical Illustrator) & Serena Jennings (my colleague):

Sunday, 14 November 2010

Population thinking

Generalizations in biology are almost invariably of a probabilistic nature. As one wit has formulated it, there is only one universal law in biology: "All biological laws have exceptions". This probabilistic conceptualization contrasts strikingly with the view during the early period of the scientific revolution that causation in nature is regulated by laws that can be stated in mathematical terms. Actually, this idea occurred apparently first to Pythagoras. It has remained a dominant idea, particularly in the physical sciences, up to the present day. (...) With Plato, it gave rise to the essentialism. For him, the variable world of phenomena was nothing but the reflection of a limited number of fixed and unchanging forms, the essences. These essences are what is real and important in this world. Constancy and discontinuity are the points of special emphasis for the essentialists. Variation is attributed to the imperfect manifestation of the underlying essences.


Darwin, one of the first thinkers to reject the essentialism (at least in part), was not at all understood by the contemporary philosophers (all of whom were essentialists), and his concept of evolution through natural selection was therefore found unacceptable. Genuine change, according to essentialism, is possible only through the saltatation origin of new essences. Because evolution as explained by Darwin, is by necessity gradual, it is quite incompatible with essentialism.

Western thinking for more than two thousand years after Plato was dominated by essentialism. It was not until the nineteenth century that a new and different way of thinking about nature began to spread, so-called population thinking. What is population thinking and how does it differ from essentialism? Population thinkers stress the uniqueness of everything in the organic world. What is important for them is the individual, not the type. They emphasize that every individual in sexually reproducing species is uniquely different from all others, with much individuality even existing in uniparentally reproducing ones. There is no "typical" individual, and mean values are abstractions. Much of what in the past has been designated in biology as "classes" are populations consisting of unique individuals.

From Ernst Mayr - The Growth of Biological Thought

Tuesday, 2 November 2010

Strong immunity = low fertility

A study in wild sheep may help explain why natural selection has not eradicated weak or self-destructive immune systems

A fluctuating trade-off between reproduction and survival in a feral population of Soay sheep may resolve the age-old question of why natural selection has failed to eradicate genes for both infection-prone and self-assailing immune systems.

The potential answer, published in Science this week (29th October), comes from the nascent field of ecoimmunology, which examines how different levels of antibodies in the blood of wild animals can influence their ability to survive and produce young.

Specifically, the authors found that, among a population of isolated, wild sheep, individuals with higher levels of antibodies associated with autoimmunity in other species were more likely to survive harsh weather conditions, but also reproduced less. Consequently, the benefits of high immunity, such as quick and efficient riddance of infection, may come with a cost -- less energy for reproduction.

"This paper reveals that more [antibodies] might not always be better, and that to understand the evolution of immune systems, it will be critical to study them in free-living, outbred organisms," Lynn Martin, an ecoimmunologist at the University of South Florida, who was not affiliated with the study, said in an email to The Scientist.

Researchers have found that feral rodents can hold comparatively high concentrations of antibodies in their blood, but, mysteriously, autoimmunity diseases such as type 1 diabetes and lupus are only seen in humans and lab, domestic, and captive mammals, said Andrea Graham, an evolutionary biologist at Princeton University and first author on the study.

There was "this nagging question of whether autoimmunity was some weird freak of captivity," added Andrew Read, evolutionary biologist at Pennsylvania State University, who did not contribute to the study.

Using blood samples collected every August for 11 years from the Soay sheep population on Hirta, an island in the St. Kilda archipelago of Scotland, Graham and colleagues from the University of Edinburgh in Scotland measured the concentration of antinuclear antibodies (ANAs), or autoimmune antibodies that attack the contents of the cell's nucleus as if it were foreign material. They then compared these levels to other variables of fitness such as survival and reproduction.

Researchers found that adult females with higher levels of ANAs lived longer by surviving more bitterly cold, parasite-infested winters. However, these same females were less likely to have babies the following spring. The correlation was only present during particularly harsh winters, however, when sometimes nearly 50 percent of the population died, suggesting heterogeneity in immune response is produced by natural selection acting on an ever-changing environment.

Ewes with high levels of ANAs also produced young with higher chances of survival through the next winter than young born to mothers with weak immune systems, suggesting a genetic basis for the varied immune responses in the sheep population.

"Immune response is only one part of the fitness component," said Peter Hudson, a disease ecologist at Pennsylvania State University, who was not affiliated with the study. "When [an individual] is not being exposed to pathogens, then high immune response could be too costly."

According to the results, when parasite prevalence is low and food is abundant, individuals with low immune responses will have the highest fitness because they will have the energy to produce the most young in the shortest period of time. But when the threat of infection is high and the winters are brutally frigid, individuals with high immune responses will survive and live on to have more children, while others die off. Thus, these trade-offs exhibited by the Soay sheep can account for their heterogeneity in immune response.

Read and Martin agreed that the next step is to experimentally manipulate antibody response in large populations to discover whether a causal, rather than correlational, relationship is present in this survival-reproduction trade-off.

The field of ecoimmunology "has been a controversial field because it's really hard to decide what to measure without a history [of the population]," noted Read.

This study demonstrates its potential benefits, however, Graham argued. "I firmly believe that we wouldn't have been able to find out such cool things about the immune system without this long study on the Soay sheep," she said. "Now that we understand all the nuts and bolts of the immune system [from traditional immunology], we can go on to try to understand it in the real world, because that's what really matters."

A. Graham et al., "Fitness Correlates of Heritable Variation in Antibody Responsiveness in a Wild Mammal," Science, 330:662-65, 2010.

Source: The Scientist

Top 7 genetics papers

A snapshot of the highest-ranked articles in genetics and related areas in the past 30 days

1. Mapping transcriptomes
While mapping every transcriptional start site and operon of Helicobacter pylori at single-nucleotide resolution, the authors identify novel small RNAs, reveal the widespread nature of antisense transcription, and unveil a new technique to investigate the genomic complexities of other important pathogens, such as Salmonella and Mycobacterium tuberculosis.

2. Epigenetics in mind
The body's tendency to silence the expression of one parental allele in favor of the other -- a phenomenon known as genomic imprinting -- is much more widespread in the brain than scientists have believed, according to a new genome-wide study in mice. Surprisingly, more than 1300 genes expressed in the mouse brain appear to exhibit "parent-of-origin" epigenetic effects.

3. Translation goes local
Protein synthesis is a complicated game, but for the first time researchers have shown direct interaction between a transmembrane receptor, called DCC, and the translational machinery in rodent neurons, a step that likely facilitates localized protein production.

4. No RNA "dark matter"?
Most of the DNA that's transcribed into RNA in fact codes for proteins, a finding that disputes previous studies that suggested that the majority of mammalian transcripts are non-coding "dark matter."

5. Super E. Coli
The mother cell of E. coli maintains a constant growth rate throughout its replicative life (hundreds of cell divisions), despite accumulating damage and an increased probability of death, suggesting that growth and aging are decoupled, unlike all other studied aging models.

6. How autophagosomes form
Under conditions of starvation, autophagosomes form to resupply the cell by bringing nutrients from the cytosol or other organelles to the lysosomes, ensuring the cell's survival. New findings reveal an essential ingredient to this mysterious process: the outer membrane of mitochondria.

7. New tumor targets?
A scan of 1800 megabases of DNA from 441 tumors reveals more than 2500 somatic mutations, providing the mutation "spectra" for cancers, including protein kinases and G-protein-coupled receptors, some of which may serve as druggable targets.

Source: The scientist

What is systems biology?

For the fun of it, here are a few examples of definitions:

To understand complex biological systems requires the integration of experimental and computational research -- in other words a systems biology approach. (Kitano, 2002)

Systems biology studies biological systems by systematically perturbing them (biologically, genetically, or chemically); monitoring the gene, protein, and informational pathway responses; integrating these data; and ultimately, formulating mathematical models that describe the structure of the system and its response to individual perturbations. (Ideker et al, 2001)

[...]the objective of systems biology [can be] defined as the understanding of network behavior, and in particular their dynamic aspects, which requires the utilization of methematical modeling tightly linked to experiment. (Cassman, 2005)

By discovering how function arises in dynamic interactions, systems biology addresses the missing links between molecules and physiology. Top-down systems biology identifies molecular interaction networks on the basis of correlated molecular behavior observed in genome-wide "omics" studies. Bottom-up systems biology examines the mechanisms through which functional properties arise in the interactions of known components. (Bruggeman and Westerhoff, 2007)

Why is it so difficult to come up with a concise definition of systems biology? One of the reasons might be that every definition has to respect a delicate balance between "the yin and the yang" of the discipline: the integration of experimental and computational approaches; the balance between genome-wide systematical approaches and smaller-scale quantitative studies; top-down versus bottom-up strategies to solve systems architecture and functional properties. But despite the diversity in opinions and views, there might be two main aspects that are conserved across these definitions: a) a system-level approach attempts to consider all the components of a system; b) the properties and interactions of the components are linked with functions performed by the intact system via a computational model. This may in fact reveal another source of difficulty when trying to define systems biology, which is to find a general and objective definition of "biological function" (or Lander's "goal of the system", see our brief post Teleology and Systems Biology). Feel free to comment and suggest on this...

Posted originally by Thomas on July 23, 2007