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Archive - Feb 3, 2013

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Recreating Natural Complex Gene Regulation

By reproducing in the laboratory the complex interactions that cause human genes to turn on inside cells, Duke University bioengineers have created a system they believe can benefit gene therapy research and the burgeoning field of synthetic biology. This new approach should help basic scientists as they tease out the effects of "turning on" or "turning off" many different genes, as well as clinicians seeking to develop new gene-based therapies for human disease. "We know that human genes are not just turned on or off, but can be activated to any level over a wide range. Current engineered systems use one protein to control the levels of gene activation," said Dr. Charles Gersbach, assistant professor of biomedical engineering at Duke's Pratt School of Engineering and member of Duke's Institute for Genome Sciences and Policy. "However, we know that natural human genes are regulated by interactions between dozens of proteins that lead to diverse outcomes within a living system. In contrast to typical genetics studies that dissect natural gene networks in a top-down fashion, we developed a bottom-up approach, which allows us to artificially simulate these natural complex interactions between many proteins that regulate a single gene," Dr. Gersbach said. "Additionally, this approach allowed us to turn on genes inside cells to levels that were not previously possible." The results of the Duke experiments, which were conducted by Dr. Pablo Perez-Pinera, a senior research scientist in Gersbach's laboratory, were published online on February 3, 2013 in the journal Nature Methods. Human cells have about 20,000 genes that produce a multitude of proteins, many of which affect the actions of other genes. Being able to understand these interactions would greatly improve the ability of scientists in all areas of biomedical research.

Scientists Capture Key Moments in Cell Death

Scientists at the Walter and Eliza Hall Institute have for the first time visualized the molecular changes in a critical cell death protein that force cells to die. The finding provides important insights into how cell death occurs, and could lead to new classes of medicines that control whether diseased cells live or die. Controlled cell death, called apoptosis, is important for controlling the number of cells in the body. Defects in cell death have been linked to the development of diseases such as cancer and neurodegenerative conditions. Insufficient cell death can cause cancer by allowing cells to become immortal while excessive cell death of neurons may be a cause of neurodegenerative conditions. Dr. Peter Czabotar, Professor Peter Colman, and colleagues in the institute's Structural Biology division, together with Dr. Dana Westphal from the institute's Molecular Genetics of Cancer division, made the discovery which is published in the January 31, 2013 edition of the journal Cell. Dr. Czabotar said activation of the protein Bax had long been known to be an important event leading to apoptosis, but until now it was not known how this activation occurred. "One of the key steps in cell death is that holes are punched into a membrane in the cell, the mitochondrial membrane," Dr Czabotar said. "Once this happens the cell is going to go on and die. Bax is responsible for punching the holes in the mitochondrial membrane and visualizing its activation brings us a step closer to understanding the mechanics of cell death." Using the Australian Synchrotron, Dr. Czabotar and colleagues were able to obtain detailed three-dimensional images of Bax changing shape as it moved from its inactive to active form. The active form ruptures mitochondrial membranes, removing the cell's energy supply and causing cell death.