Clutter cutter: Computer modeling used to understand how messy cells contribute to cancer

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Life can be messy at all scales, requiring different organizational strategies — from cleaning the house, to removing damaged or expired cells from the body to avoid cancer progression.In a messy house, people use computers to manage paper and photo clutter; companies use computer systems to track their inventory. Now a team of researchers at Vanderbilt University in Nashville, Tenn., is taking a similar approach to cell-molecular inventory control for cancer. They have created computer models, using their programming framework (PySB), which enable them to explore the complex biochemical processes that drive cancer growth.”Our hypothesis is that understanding how the cell uses their protein inventory will lead to understanding why cells dysregulate and become carcinogenic. We expect model outputs will lead to novel, targeted cancer therapies — possibly by 2019,” explained researcher Carlos F. Lopez, who will present the work at the 58th annual Biophysical Society Meeting in San Francisco, Feb.15-19.Lopez is interested in understanding how cells in multicellular organisms engage programmed cell death — so-called “cell suicide” — for cellular removal. It is a natural part of many cells’ life cycle.When cancer cells avoid programmed cell death, uncontrolled growth fuels tumor progression. The Vanderbilt team expects their computer models to identify what goes wrong in these cases, at a speed and scale never before possible. Lopez noted: “We are bridging the nanoscale molecular-level biochemical interactions with the macroscale cancer tumor outcomes, which is a huge range in scales. Most people don’t realize this, but molecular chemical reactions at the nanometer and nanosecond level affect things that happen at the timescale level of years — nine orders of magnitude in space and time! For comparison, a nanosecond is to a second like a second is to one century.”Rather than listing the cellular biochemical reactions by hand, PySB enables the researchers to “write” the biochemical cellular processes as computer programs. …


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#Agriculture, #Alzheimer, #Body, #Carlos, #Cell, #Inventory, #Lopez, #Processes, #Protein, #Researchers, #Result, #University

New RNA interference technique finds seven genes for head and neck cancer

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In the hunt for genetic mutations that cause cancer, there is a lot of white noise. So although genetic sequencing has identified hundreds of genetic alterations linked to tumors, it’s still an enormous challenge to figure out which ones are actually responsible for the growth and metastasis of cancer. Scientists in Rockefeller’s Laboratory of Mammalian Cell Biology and Development have created a new technique that can weed out that noise — eliminating the random bystander genes and identifying the ones that are critical for cancer. Applying their technique to head and neck cancers, they’ve discovered seven new tumor-suppressor genes whose role in cancer was previously unknown.The new technique, which the lab recently applied to a screen for skin tumor genes, is particularly useful because it takes a fraction of the resources and much less time than the traditional method for determining gene function — breeding genetically modified animals to study the impact of missing genes.”Using knockout mice, which are model organisms bred to have a particular gene missing, is not feasible when there are 800 potential head and neck cancer genes to sort through,” says Daniel Schramek, a postdoctoral fellow in the lab, which is headed by Rebecca C. Lancefield Professor Elaine Fuchs. “It can take about two years per gene. Our method can assess about 300 genes in a single mouse, in as little as five weeks.”The researchers made use of RNA interference, a natural process whereby RNA molecules inhibit gene expression. They took short pieces of RNA which are able to turn off the function of specific genes, attached them to highly concentrated viruses, and then, using ultrasound to guide the needle without damaging surrounding tissue, they injected the viruses into the sacs of mouse embryos.”The virus is absorbed and integrated into the chromosomes of the single layer of surface cells that cover the tiny embryo,” explains Fuchs. “As the embryo develops, this layer of cells becomes the skin, mammary glands and oral tissue, enabling us to efficiently, selectively and quickly eliminate the expression of any desired gene in these tissues. The non-invasive method avoids triggering a wound or inflammatory response that is typically associated with conventional methods to knockdown a gene in cultured cells and then engraft the cells onto a mouse.”When the mice grew, the researchers determined which genes, when turned off, were promoting tumor growth, and what they found was surprising.”Among the seven novel tumor suppressor genes we found, our strongest hit was Myh9, which codes for the protein myosin IIa, a motor protein with well-known function in cell structure and cell migration,” says Schramek. …


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#Biology, #Health, #Mammalian, #Mutations, #Neck, #Noise, #Protein, #Rockefeller, #Schramek, #Single, #Tumors, #Virus

Superbright, fast X-rays image single layer of proteins

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In biology, a protein’s shape is key to understanding how it causes disease or toxicity. Researchers who use X-rays to take snapshots of proteins need a billion copies of the same protein stacked and packed into a neat crystal. Now, scientists using exceptionally bright and fast X-rays can take a picture that rivals conventional methods with a sheet of proteins just one protein molecule thick.Using a type of laser known as XFEL, the technique opens the door to learning the structural details of almost 25 percent of known proteins, many of which have been overlooked due to their inability to stack properly. The team of researchers led by the Department of Energy’s Pacific Northwest and Lawrence Livermore National Laboratories report their results with this unique form of X-ray diffraction in the March issue of the International Union of Crystallography Journal.”In this paper, we’re proving it’s possible to use an XFEL to study individual monolayers of protein,” said PNNL microscopist James Evans. “Just being able to see any diffraction is brand new.”Evans co-led the team of two dozen scientists with LLNL physicist Matthias Frank. The bright, fast X-rays were produced at the Linac Coherent Light Source at SLAC National Accelerator Laboratory in Menlo Park, Calif., the newest of DOE’s major X-ray light source facilities at the national laboratories. LCLS, currently the world’s most powerful X-ray laser, is an X-ray free-electron laser. It produces beams millions of times brighter than earlier X-ray light sources.Coming in at around 8 angstrom resolution (which can make out items a thousand times smaller than the width of a hair), the proteins appear slightly blurry but match the expected view based on previous research. Evans said this level of clarity would allow researchers, in some cases, to see how proteins change their shape as they interact with other proteins or molecules in their environment.To get a clearer view of protein monolayers using XFEL, the team will need to improve the resolution to 1 to 3 angstroms, as well as take images of the proteins at different angles, efforts that are currently underway.Not Your Family’s CrystalResearchers have been using X-ray crystallography for more than 60 years to determine the shape and form of proteins that form the widgets and gears of a living organism’s cells. The conventional method requires, however, that proteins stack into a large crystal, similar to how oranges stack in a crate. …


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