Tuesday, March 18, 2014

How diabetes drugs may work against cancer

Summary: A major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments has been pinpointed by researchers. By identifying cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumors will be sensitive to these anti-diabetic drugs known to inhibit this pathway.
For several years, a class of anti-diabetic drugs known as biguanides, has been associated with anti-cancer properties. A number of retrospective studies have shown that the widely used diabetes drug metformin can benefit some cancer patients. Despite this intriguing correlation, it has been unclear how metformin might exert its anti-cancer effects and, perhaps more importantly, in which patients.
 Now, Whitehead Institute scientists are beginning to unravel this mystery, identifying a major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments. By finding cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumor will be sensitive to the anti-diabetic drugs known to inhibit the pathway in question. Their work is described online this week in the journal Nature.
To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, Kıvanç Birsoy and Richard Possemato, postdoctoral researchers in Whitehead Member David Sabatini’s lab, developed a system that circulates low-nutrient media continuously around cells. Of the 30 cancer cell lines tested within this system, most appeared unaffected by a lack of glucose. However, a few of the lines thrived and reproduced rapidly, while others struggled. The varied responses to a glucose shortage were puzzling.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” says Possemato, who coauthored the Nature paper with Birsoy. “The cancer-relevance of the alterations that we found as underlying this response to low glucose will still need to be investigated.”
Birsoy and Possemato wondered whether certain cancer cells’ susceptibility to a low glucose environment could be exploited to attack tumors. They screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation, a metabolic pathway in mitochondria. The powerhouses of a cell, mitochondria are membrane-bound organelles with their own DNA, including genes that control oxidative phosphorylation.

Birsoy and Possemato hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer. If true, the hypothesis would suggest that further impairing mitochondrial function, with biguanides—which are known oxidative phosphorylation inhibitors—could push the mitochondria beyond their limits, to the detriment of the cancer cells.
They first tested their hypothesis in vitro on 13 cell lines with glucose utilization defects and mitochondrial DNA mutations. Compared to control cells, those sensitive to low glucose were five to 20 times more susceptible to phenformin, a more potent biguanide than metformin. Birsoy and Possemato then tested phenformin’s effectiveness in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the tumors’ growth.

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” says Birsoy. “And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.” To confirm the accuracy of their proposed biomarkers, Birsoy and Possemato want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Posted by:
Gauri Shah
Faculty (BII)

Monday, February 3, 2014

New forensic technique for identifying cloth fibers

AVS: Science & Technology of Materials, Interfaces, and Processing
Crime-scene investigators may soon have a new tool to help them catch evildoers. Researchers have demonstrated the proof-of-principle for a new forensic technique to identify individual fibers of cloth, which often all look alike.

"White cotton fibers are so common and have so few visual distinguishing features that they are largely ignored by forensic scientists at crime scenes," says Brian Strohmeier, a scientist at Thermo Fisher Scientific, a laboratory-instrument company based in Massachusetts. But most of today's fabrics have gone through various manufacturing and treatment processes -- for example, to make them stain resistant, waterproof, or iron-free -- leaving unique organic chemicals on the surface of the fibers. So by analyzing the chemical signature on the surface of individual fibers, forensic scientists can, for instance, identify the origin of scraps of fabric evidence found in crime scenes.

Strohmeier will describe this work at the AVS 60th International Symposium and Exhibition in Long Beach, Calif., held Oct. 27 -- Nov. 1, 2013. In the new method, he and his colleagues used a well-known technique called X-ray photoelectron spectroscopy (XPS) -- but with a twist. In XPS, the test sample is zapped with a focused X-ray beam, which then knocks out electrons from the surface of the sample. A detector then counts the electrons and measures their kinetic energies. The resulting spectrum reveals the chemical signature of the surface.

XPS has been used before to characterize the surfaces of textile fibers that don't have chemical coatings,
Strohmeier says. But to study the surface chemistry of treated fibers, the researchers need to go deeper and analyze the layers just beneath the surface. To do so, the researchers fired a beam of argon-ion clusters onto the sample fiber. The beam drilled away a shallow hole on the surface of the fiber, revealing the layer underneath. Each cluster contains thousands of atoms, and because the clusters break up on impact, they don't cause as much damage to the chemicals that are being measured -- whereas a beam of single ions would.

With the layer underneath now exposed, the researchers used XPS to study its chemical contents. By blasting the sample with the beam longer, the researchers can scrape away deeper layers for analysis.
With this technique, the researchers were able to identify textile materials based on the surface chemistry that's the result of different manufacturing processes. They were also able to distinguish materials that had undergone different chemical treatments but were otherwise identical.
Previously, XPS hadn't been used much in forensic science, Strohmeier says. There was no accepted standard for XPS methods in forensics, it often took hours to analyze each sample, the technique required relatively large samples with areas of several square millimeters, and XPS instruments were a lot more expensive than other forensic tools. But, he says, XPS instruments have improved to the point that analysis now takes minutes and you only need tens to hundreds of square microns of sample area. And, only in the last couple years have argon-ion cluster beam technology been able to do the kind of depth-profile analysis demonstrated that the researchers demonstrated.
While these new results don't yet establish a bona fide technique for forensics, Strohmeier says, it does show great potential for analyzing fibers and the surfaces of other kinds of evidence collected at crime scenes.

Posted by:
Gauri Shah(faculty)

Tuesday, January 21, 2014


A savannah monitor lizard.
By THE NEW YORK TIMESPublished: December 16, 2013
Biologists have found that savannah monitor lizards extract oxygen from the air when inhaling and when exhaling — a characteristic, known as unidirectional breathing, that is most associated with birds. The discovery of this trait in lizards, reported in the journal Nature, raises questions about when and why it evolved. Either it developed in the 270-million-year-old common ancestor of lizards, birds and alligators (which were also recently found to practice unilateral breathing) — much longer ago than originally thought — or it developed independently in each evolutionary branch. As for why it evolved, the long-held theory that it aided flight in birds appears to need updating.
Posted by :Gauri Shah
Faculty Biotechnology


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