Like a magician employing sleight of hand, the protein mitoNEET -- a mysterious but important player in diabetes, cancer and aging -- draws the eye with a flurry of movement in one location while the subtle, more crucial action takes place somewhere else. Using a combination of laboratory experiments and computer modeling, scientists from Rice University and the University of California, San Diego (UCSD) have deciphered part of mitoNEET's movements to gain a better understanding of how it handles its potentially toxic payload of iron and sulfur. Their research was published online on January 23, 2012 in PNAS. "We scrutinize proteins with an unconventional approach," said Dr. José Onuchic, Rice's Harry C. and Olga K. Wiess Professor of Physics and Astronomy and co-director of the Center for Theoretical Biological Physics. "We use biophysics to probe biology rather than the other way around. Using computational theory, we find structures that are possible -- regardless of whether they've already been observed experimentally -- and we ask ourselves whether these structures might be biologically significant." Study co-leader Dr. Patricia Jennings, professor of chemistry and biochemistry at UCSD, who has collaborated with Dr. Onuchic for 15 years, said they save a great deal of time by using structural biophysics to guide their experiments on a wide variety of targets. For example, Dr. Jennings' laboratory determined less than five years ago that mitoNEET contained a novel folded structure. Since then, her lab has been using insights gained from static and dynamic snapshots of the protein to guide biological and biochemical studies. "I think people forget that proteins are machines with moving parts," said study lead author Elizabeth Baxter, a UCSD graduate student who works under the guidance of both Drs. Onuchic and Jennings.
A team of biologists at the University of York in the UK has made an important advance in our understanding of the way cholera attacks the body. The discovery could help scientists target treatments for the globally significant intestinal disease which kills more than 100,000 people every year. The disease is caused by the bacterium Vibrio cholerae, which is able to colonize the intestine usually after consumption of contaminated water or food. Once infection is established, the bacterium secretes a toxin that causes watery diarrhea and ultimately death if not treated rapidly. Colonization of the intestine is difficult for incoming bacteria as they have to be highly competitive to gain a foothold among the trillions of other bacteria already present in situ. Scientists at York, led by Dr Gavin Thomas in the University’s Department of Biology, have investigated one of the important routes that V. cholera takes to gain this foothold. To be able to grow in the intestine, the bacterium harvests and then eats a sugar, called sialic acid, that is present on the surface of our gut cells. Collaborators of the York group at the University of Delaware, USA, led by Professor Fidelma Boyd, had shown previously that eating sialic acid was important for the survival of V. cholerae in animal models, but the mechanism by which the bacteria recognize and take up the sialic was unknown. The York research demonstrates that the pathogen uses a particular kind of transporter called a TRAP transporter to recognize sialic acid and take it up into the bacterial cell. The transporter has particular properties that are suited to scavenging the small amount of available sialic acid. The research also provided some important basic information about how TRAP transporters work in general. Dr.
Scientists at Trinity College Dublin (TCD), Ireland, have developed a new vaccine to treat cancer at the pre-clinical level. The research team led by Professor Kingston Mills, Professor of Experimental Immunology at TCD discovered a new approach for treating the disease based on manipulating the immune response to malignant tumors. The discovery has been patented and there are plans to develop the vaccine for clinical use for cancer patients. The first cancer vaccine Sipuleucel-T (Provenge™) was licensed last year for use in prostate cancer patients unresponsive to hormone treatment. Unfortunately, this cell-based vaccine only improves patient survival by an average of 4.1 months. Vaccines for infectious diseases are highly effective at generating immune responses that prevent infection with bacteria or viruses. The immune system can also protect us against tumors and, in theory, a vaccine approach should be effective against cancer. In practice, this has proven very difficult because, unlike infectious diseases, tumors are derived from normal human cells, and are not made up of foreign substances or antigens capable of triggering an immune response. The tumors instead produce molecules that suppress the efficacy of the immune system. They generate regulatory cells that inhibit the immune response that could potentially clear the tumors. Professor Mills' group has developed a novel vaccine and immunotherapeutic approach that can overcome these obstacles and has the potential to significantly improve on existing technologies. The therapy is based on a combination of molecules that manipulates the immune response to curb the regulatory arm while enhancing the protective arm, allowing the induction of specialist white blood cells called killer T cells to target and eliminate the tumors.
In a study that holds major implications for breast cancer research as well as basic cell biology, scientists with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have discovered a rotational motion that plays a critical role in the ability of breast cells to form the spherical structures in the mammary gland known as acini. This rotation, which the researchers call “CAMo,” for coherent angular motion, is necessary for the cells to form spheres. Without CAMo, the cells do not form spheres, which can lead to random motion, loss of structure, and malignancy. “What is most exciting to me about this stunning discovery is that it may finally give us a handle by which to discover the physical laws of cellular motion as they apply to biology,” says Dr. Mina Bissell, a leading authority on breast cancer and Distinguished Scientist with Berkeley Lab’s Life Sciences Division. Dr. Bissell is a corresponding author of a paper describing this work in PNAS, along with Dr. Kandice Tanner, a post-doctoral physicist in Dr. Bissell’s research group. The PNAS paper was published online on January 25, 2012. Healthy human epithelial cells in breast and other glandular tissue form either sphere-shaped acini or tube-shaped ducts. The cell and tissue polarity (function-enabling spatial orientations of cellular and tissue structures) that comes with the formation of acini is essential for the health and well-being of the breast. Loss of this polarity as a result of cells not forming spheres is one of the earliest signs of malignancy. However, despite all that is known about cell morphogenesis, the fundamental question as to how epithelial cells are able to assemble into spheres that are similar in size and shape to organs in vivo has until now been a mystery.
A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of Illinois at Chicago (UIC) College of Medicine. The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online on January 8, 2012 in Nature Medicine. An estimated 4.1 million Americans are infected with hepatitis C virus (HCV), which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests. Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1 (Niemann-Pick C1–like 1) cholesterol absorption receptor, known to help maintain cholesterol balance, might also be transporting the virus into the cell. The receptor is common in the gut of many species -- but is found on liver cells only in humans and chimpanzees, says Dr. Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV. Dr. Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells. Dr. Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said that because the receptor is involved in cholesterol metabolism it was already well-studied.
A healthy human genome is characterized by 23 pairs of chromosomes, and even a small change in this structure — such as an extra copy of a single chromosome — can lead to severe physical impairment. So it's no surprise that when it comes to cancer, chromosomal structure is frequently a contributing factor, says Professor Ron Shamir of the Blavatnik School of Computer Science at Tel Aviv Universitu (TAU). Now Professor Shamir and his former doctoral students Dr. Michal Ozery-Flato and Dr. Chaim Linhart, along with fellow researchers Professor Shai Izraeli and Dr. Luba Trakhtenbrot from the Sheba Medical Center, have combined techniques from computer science and statistics to discover that many chromosomal pairs are lost or gained together across various cancer types. Moreover, the researchers discovered a new commonality of chromosomal aberrations among embryonic cancer types, such as kidney, skeleton, and liver cancers. These findings, published on June 29, 2011 in Genome Biology, could reveal more about the nature of cancer. As cancer develops, the genome becomes increasingly mutated — and identifying the pattern of mutation can help us to understand the nature and the progression of many different kinds of cancer, says Professor Shamir. As cancer progresses, the structure of chromosomes is rearranged, individual chromosomes are duplicated or lost, and the genome becomes abnormal. Some forms of cancer can even be diagnosed by identifying individual chromosomal aberrations, notes Professor Shamir, pointing to the example of a specific type of leukemia that is caused by small piece of chromosome 9 being moved to chromosome 22. When analyzing many different kinds of cancer, however, the researchers discovered that chromosomal aberrations among different cancers happen together in a noticeable and significant way.
Could preventing colon cancer be as simple as developing a taste for yerba mate tea? In a recent University of Illinois study, scientists showed that human colon cancer cells die when they are exposed to the approximate number of bioactive compounds present in one cup of this brew, which has long been consumed in South America for its medicinal properties. "The caffeine derivatives in mate tea not only induced death in human colon cancer cells, they also reduced important markers of inflammation," said Dr. Elvira de Mejia, a University of Illinois associate professor of food chemistry and food toxicology. That's important because inflammation can trigger the steps of cancer progression, she said. In the in vitro study, Dr. de Mejia and former graduate student Sirima Puangpraphant isolated, purified, and then treated human colon cancer cells with caffeoylquinic acid (CQA) derivatives from mate tea. As the scientists increased the CQA concentration, cancer cells died as a result of apoptosis. "Put simply, the cancer cell self-destructs because its DNA has been damaged," she said. The ability to induce apoptosis, or cell death, is a promising tactic for therapeutic interventions in all types of cancer, she said. Dr. de Mejia said they were able to identify the mechanism that led to cell death. Certain CQA derivatives dramatically decreased several markers of inflammation, including NF-kappa-B, which regulates many genes that affect the process through the production of important enzymes. Ultimately cancer cells died with the induction of two specific enzymes, caspase-3 and caspase-8, Dr. de Mejia said. "If we can reduce the activity of NF-kappa-B, the important marker that links inflammation and cancer, we'll be better able to control the transformation of normal cells to cancer cells," she added.
For the 26 million Americans with diabetes, drawing blood is the most prevalent way to check glucose levels. It is invasive and at least minimally painful. Researchers at Brown University are working on a new sensor that can check blood sugar levels by measuring glucose concentrations in saliva instead. The technique takes advantage of a convergence of nanotechnology and surface plasmonics, which explores the interaction of electrons and photons. The engineers at Brown etched thousands of plasmonic interferometers onto a fingernail-size biochip and measured the concentration of glucose molecules in water on the chip. Their results showed that the specially designed biochip could detect glucose levels similar to the levels found in human saliva. Glucose in human saliva is typically about 100 times less concentrated than in the blood. “This is proof of concept that plasmonic interferometers can be used to detect molecules in low concentrations, using a footprint that is ten times smaller than a human hair,” said Dr. Domenico Pacifici, assistant professor of engineering and lead author of the paper published online on December 26, 2011 in Nano Letters, a journal of the American Chemical Society. The technique can be used to detect other chemicals or substances, from anthrax to biological compounds, Dr. Pacifici said, “and to detect them all at once, in parallel, using the same chip.” To create the sensor, the researchers carved a slit about 100 nanometers wide and etched two 200 nanometer-wide grooves on either side of the slit. The slit captures incoming photons and confines them. The grooves, meanwhile, scatter the incoming photons, which interact with the free electrons bounding around on the sensor’s metal surface.
Analyzing all the genes of dozens of people suffering from a rare form of hypertension, Yale University researchers have discovered a new mechanism that regulates the blood pressure of all humans. The findings by an international research team headed by Yale scientists, published online on January 22, 2012 in the journal Nature, may help explain what goes wrong in the one billion people who suffer from high blood pressure. The study also demonstrates the power of new DNA sequencing methods to find previously unknown disease-causing genes. The team used a technique called whole exome sequencing — an analysis of the makeup of all the genes — to study a rare inherited form of hypertension characterized by excess levels of potassium in the blood. They found mutations in either of two genes that caused the disease in affected members of 41 families suffering from the condition. The two genes interact with one another in a complex that targets other proteins for degradation, and they orchestrate the balance between salt reabsorption and potassium secretion in the kidney. "These genes were not previously suspected to play a role in blood pressure regulation, but if they are lost, the kidney can't put the brakes on salt reabsorption, resulting in hypertension," said Dr. Richard Lifton, Sterling Professor and chair of the Department of Genetics at Yale and senior author of the paper. The mutations had previously been difficult to find because there were very few affected members in each family, so traditional methods to map the genes' locations had been ineffective. "The mutations in one gene were almost all new mutations found in affected patients but not their parents, while mutations in the other gene could be either dominant or recessive. The exome sequencing technology was ideally suited to cutting through these complexities," said Dr.
Over many generations, people living in the high-altitude regions of the Andes or on the Tibetan Plateau have adapted to life in low-oxygen conditions. Living with such a distinct and powerful selective pressure has made these populations a textbook example of evolution in action, but exactly how their genes convey a survival advantage remains an open question. Now, a University of Pennsylvania team has made new inroads to answering this question with the first genome-wide study of high-altitude adaptations within the third major population to possess them: the Amhara people of the Ethiopian Highlands. Surprisingly, all three groups’ adaptations appear to involve different genetic mutations, an example of convergent evolution. “These three groups took different genetic approaches to solving the same problem,” said senior author Dr. Sarah Tishkoff, a Penn Integrates Knowledge professor with appointments in the genetics department in Penn’s Perelman School of Medicine and the biology department in the School of Arts and Sciences. In addition to Dr. Tishkoff, the research was led by Dr. Laura B. Scheinfeldt, a research scientist in the genetics department at the Perelman School of Medicine. Other members of the genetics department who contributed to the research are Drs. Sameer Soi, Simon Thompson, Alessia Ranciaro, William Beggs, Charla Lambert, and Joseph P. Jarvis. The Penn team collaborated with Drs. Dawit Wolde Meskel, Dawit Abate, and Gurja Belay of the Department of Biology of Addis Ababa University. Their research was published on January 20, 2012 in the journal Genome Biology. One of the guiding principles behind evolution is natural selection; the more an organism is suited to its environment, the more likely it is to survive and pass on its genes.
