Swiss Federal Institute of Technology, Zurich

A bioengineer discusses how mechanical forces in tissues may promote malignancy.

The connective-tissue protein collagen has been considered to be a structural barrier against tumour invasion in tissues. Enzymes that cleave collagen and other extracellular matrix (ECM) molecules were thus thought to promote tumour progression, but inhibitors of these enzymes have failed in clinical trials. And paradoxically, increased collagen expression is associated with a greater incidence of cancer spread.

Working with mice, Valerie Weaver of the University of California, San Francisco, and her team show that other ECM-remodelling parameters regulate malignancy (K. R. Levental et al. Cell 139, 891–906; 2009). They studied an enzyme that initiates collagen crosslinking and is often found in tissue around tumours. They reveal that the crosslinking increases the stiffness of collagen matrices, which upregulates growth-factor signalling and breast malignancy. This suggests that tumour progression depends on a tissue-remodelling process that is regulated by biochemical and mechanical factors.

Bioengineers developing implantable materials that promote tissue regeneration can also learn a lot from this paper. Dense collagen capsules typically form around implanted biomaterials, which has prompted a search for clues to how to engineer surfaces that promote blood-vessel formation and tissue regeneration rather than scarring.

Knowing which factors promote malignancy may also help us to engineer materials and tissues that tip the balance towards enhanced tissue regeneration. This paper might thus stimulate ideas on how to interfere with the interplay between ECM-crosslinking enzymes that enhance matrix stiffness and ECM-protein-cleaving enzymes. Doing so may affect mechanosensitive cell-signalling pathways, promoting regeneration.

Posted on February 3, 2010 07:19 PM | Permalink | Comments (0) | TrackBacks (0)

University of Washington, Seattle

A geneticist discusses a way to assess the effects of disease-causing gene mutations.

Although thousands of rare inherited disorders are clearly monogenic — caused by single-gene mutations — the overall picture is usually more complex. Genetic and environmental modifiers, as well as differences in the gene variants themselves, can affect how disease genes are expressed and how a disease manifests itself (the phenotype).

Marc Vidal of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his team reveal that disease-causing mutations may fit into two groups on the basis of the type of perturbation they cause. 'Edgetic' mutations affect specific interactions in a network of genes, whereas 'nodal' ones remove proteins from the network altogether (Q. Zhong et al. Mol. Sys. Biol. 5, 321; 2009). The researchers did computational analyses, using the tendency of disease-associated mutations to be in-frame — producing full-length mutated proteins — or truncating, producing truncated proteins, as a proxy for edgetic or nodal perturbations, respectively. They found that, for many genes underlying multiple diseases, different phenotypes were associated with different ratios of in-frame versus truncating mutations.

The authors then did experiments evaluating whether disease-associated mutations tend to disrupt known protein–protein interactions in a way that is consistent with edgetic versus nodal perturbation. They suggest that at least some of the phenotypic variability in monogenic diseases might correlate with specific patterns of network perturbation.

The experiments are limited, but the approach of cloning mutations and serially evaluating their impact is appealing. Various genome-sequencing projects will soon catalogue hundreds of thousands of coding variants of uncertain significance. Generalized, scalable methods to evaluate the functional relevance of these variants and to place them into a broader biological context will be crucial.

Posted on January 27, 2010 07:37 PM | Permalink | Comments (0) | TrackBacks (0)

Stanford University and Howard Hughes Medical Institute, California

A neuroscientist learns about algorithms for motor learning.

Under what conditions do people learn most effectively? This question is pertinent to several fields and to many neuropsychiatric disorders involving aberrant learning and memory. In motor neurobiology, understanding how people learn new movements may yield insight into the brain's motor-control algorithms and could help with physical training or rehabilitation.

A recent study by Maurice Smith at Harvard University in Cambridge, Massachusetts, and his colleagues suggests that the neural codes underlying motor control may help to dictate which movements are inherently more difficult to learn than others (G. C. Sing et al. Neuron 64, 575–589; 10.1016/j.neuron.2009.10.0012009).

They had volunteers grasp a robotic arm and make targeted, forward-reaching movements while the robot applied a perturbing force in a direction perpendicular to that of the reach. Volunteers learned to compensate for these perturbations most quickly when the magnitude of the disrupting force correlated positively with both arm position and velocity. Compensations involving only one of these factors took longer to learn and were learned less accurately. Even more challenging were disturbances in which the position and velocity contributions were negatively correlated to each other. Errors were systematically biased, as if the brain expected positive correlations.

The findings fit well with previous physiological recordings revealing that neural elements of motor control often encode information about limb position and velocity along positively correlated spatial directions. This aspect of the neural code for movement may impose constraints on how humans learn motor tasks and bias motor errors. More generally, many aspects of human behaviour might be shaped by underlying neural codes that affect the ease with which some behaviours are learned.

Posted on January 22, 2010 02:41 PM | Permalink | Comments (0) | TrackBacks (0)

University of Geneva Medical School, Switzerland

A cell biologist connects her research to bacterial brain invasion.

My main interest is in understanding how some cells organize their structure and components asymmetrically — a property called cell polarity. When I moved to my current job in a medical faculty I was asked to teach a course on infectious diseases. So I was very excited by the publication of a paper from Mathieu Coureuil at the University of Paris Descartes and his colleagues that brings together my passion and my teaching activity. The work shows that a bacterial pathogen can reach the brain by destroying cell polarity (Coureuil, M. et al. Science 325, 83–87; 2009).

Few bacteria are able to cross the blood–brain barrier, and it is not known whether those that can do so by moving through or between cells. The bacterium Neisseria meningitidis can cross this barrier. It adheres to cells lining the brain's blood vessels using type IV pili — hairlike appendages that connect the bacterium to the interior of these endothelial cells.

Using human brain endothelial cells and N. meningitidis in culture, Coureuil et al. show that a complex of polarity proteins — Cdc42, PAR6, PKC and PAR3, which form tight junctions between endothelial cells — are recruited to the site of bacterial adhesion. This results in depletion of these proteins at the junctions and thus the formation of gaps between infected cells.

Although this study was performed in cultured cells owing to a lack of suitable animal models, it strongly suggests that N. meningitidis enters the brain by disrupting the junctions between cells — allowing the bacteria to squeeze in between them — and not by penetrating the cells themselves.

This elegant paper unveils a route that may also be used by other pathogens that cross the blood–brain barrier. It also underscores an important function of cell polarity: protecting our brain from infectious diseases.

Posted on January 13, 2010 06:44 PM | Permalink | Comments (0) | TrackBacks (0)

The Salk Institute for Biological Studies, La Jolla, California

A cancer researcher ponders a fundamental connection between nutrients and gene expression.

Nutrient availability to single-celled organisms varies according to their environment, and proteins in the cell that sense nutrient levels alter gene expression to increase uptake and use of specific metabolites to fuel cellular processes. Conversely, most cells in multicellular organisms are exposed to constant nutrient levels by the bloodstream, and so far there are few examples of metabolism being directly coupled to the control of gene expression.

A recent paper by Craig Thompson and his colleagues at the University of Pennsylvania in Philadelphia uncovers a direct connection between a well-known metabolic enzyme — ATP citrate lyase (ACL) — and changes in gene expression (K. E. Wellen et al. Science 324, 1076–1080; 2009). Through a chain of reactions, ACL influences the functioning of the histones, proteins that package lengths of DNA — and unpackage them for 'reading'. This means that there is a basic — and surprising — relationship between cell glucose levels and gene expression.

We don't yet know how metabolic challenges — for example, fasting — in whole organisms affect ACL levels or activity. But we do know that some of the same proteins that increase tumour growth also modify ACL by attaching phosphorus.

It is likely that we are just at the tip of the iceberg in terms of our understanding of the molecular basis of how metabolic inputs dictate gene-expression changes in mammalian cells. Future studies using genetic models of ACL loss in distinct mouse tissues, as well as chemical inhibitors of the enzyme, will help to elucidate in which contexts it is critical for gene-expression changes in the whole organism. Moreover, our knowledge of this metabolic linchpin may provide a therapeutic window for the treatment of certain forms of cancer, almost all of which undergo metabolic adaptation.

Posted on December 16, 2009 08:26 PM | Permalink | Comments (1) | TrackBacks (0)

Pennsylvania State University

A biogeochemist ponders muddy molecules and past climates.

I am amazed by how humble fossil lipids in muddy sediments can yield insight into Earth's history. The structures and relative abundances of these marine biomarkers, which originate from cellular membranes, provide records of physiological and ecological responses to changing ocean chemistry and temperature. They help to quantify ancient climates, and may, for example, offer a peek at the future by providing clues to ocean temperatures when the poles were free of ice.

Shifting abundance ratios of membrane lipids from marine Archaea — a proxy called TEX86 — faithfully indicate modern sea-surface temperatures. Yet ancient temperatures signalled by TEX86 can be significantly higher than those indicated by other proxies, making TEX86 hard to interpret.

Julius Lipp and Kai-Uwe Hinrichs at the Center for Marine Environmental Sciences in Bremen, Germany, show that the constituent compounds in TEX86 may be a mixture derived from ancient microbes and those living in muddy sediments today (J. S. Lipp and K.-U. Hinrichs Geochim. Cosmochim. Acta 73, 6816–6833; 2009).

The authors identified the mud-dwellers' lipids from their polar functional groups; ancient lipids lack these groups because they are quickly lost after burial. The core hydrocarbons waving the polar flags probably account for the proxy's overestimation of temperature. By identifying contributions from organisms living in sediments, the researchers provide a powerful means to discern which environments preserve the primary TEX86 signature and thus under which conditions we can reliably use this important proxy.

Climate scholars should take note and take heart, because this work will ultimately strengthen our interpretations of these muddy molecules to help us better understand Earth's past and future climate.

Posted on December 11, 2009 11:42 PM | Permalink | Comments (0) | TrackBacks (0)

Howard Hughes Medical Institute, Stowers Institute for Medical Research, Kansas City, Missouri

A molecular biologist explores ways to revolutionize agriculture.

The complete absence of sex in a few species has long fascinated biologists, but their research is driven by more than just curiosity. Hybrid plants are the mainstay of agriculture, but require ongoing breeding and selection to maintain their desirable traits. Apomixis, or asexual reproduction by seeds, is rare among commercially important crops, but engineering plants capable of this could produce stable crops with valuable traits.

Three Herculean tasks are involved: alteration of meiosis (the cell division that normally reduces the number of chromosomes in the sex cells, or gametes) to maintain the full maternal genome; fertilization-independent development of the embryo; and formation of the endosperm tissue that nourishes the embryo.

Raphaël Mercier of the French National Institute for Agricultural Research in Versailles and his team have taken a step towards achieving this goal. Using a combination of three mutants, they engineered a mustard weed that produces gametes carrying the complete maternal genome (I. d'Erfurth et al. PLoS Biol. 7, e1000124; 2009). Their breakthrough came while characterizing a mutation in the aptly named omission of second division (osd1) gene, which causes the reproductive cells to skip the second meiotic division. By combining an osd1 mutant with mutations that modify two other steps in meiosis, the team made meiosis similar to mitosis — cell division that occurs in non-reproductive cells.

Conservation of the genes involved across crop species fosters hopes that the strategy can be applied to many of them. The problem of endosperm formation will have to be overcome, and unfertilized seeds will need to be coaxed into development. The available tool kit of mutants affecting these processes makes me optimistic that these challenges will be overcome. However, convincing consumers that heavily engineered plants can secure future food supplies may require more than scientific ingenuity.

Posted on December 2, 2009 06:57 PM | Permalink | Comments (0) | TrackBacks (0)

Laboratory of Climate and Environmental Sciences, Gif sur Yvette, France

A geoscientist is astounded by Earth's huge frozen carbon deposits.

I believe that the vulnerability of soil carbon to warming is one of the largest sources of uncertainty in the projection of future climate change. If, in a warmer world, bacteria decompose organic soil matter faster, releasing carbon dioxide, this will set up a positive feedback loop, speeding up global warming.

I was stunned to learn, from an article by Charles Tarnocai of Agriculture and Agri-Food Canada in Ottawa and his colleagues, that the global mass of soil carbon needs to be revised upwards by a frightening amount: from the 2,500 billion tonnes of carbon previously accounted for to more than 4,000 billion tonnes (C. Tarnocai et al. Glob. Biogeochem. Cycles doi:10.1029/2008GB003327; 2009). This is a result of the previously overlooked presence of vast amounts of peat, Siberian yedoma deposits (organic-rich permafrost) and other frozen carbon stores at high latitudes.

These massive stores deserve special attention because the boreal and arctic regions that house many of them are expected to warm more rapidly than average in the coming decades. Even a small leakage from these stores could cause an explosion in the growth rate of atmospheric CO2 as well as methane, a potent greenhouse gas emitted by flooded thawed soils.

So what do these findings mean for the role of high latitudes in the Earth system? We need more extensive field observations to monitor the stability of frozen carbon, and studies to measure the decomposition rates of such stores. And we should incorporate these processes into climate models such as those used by the United Nations Intergovernmental Panel on Climate Change. If I had to pick just one new PhD subject right now, exploring this terra incognita of frozen carbon and its impact on climate change would be the one.

Posted on November 30, 2009 10:43 PM | Permalink | Comments (3) | TrackBacks (0)