Guess Who's Coming to Dinner? Innate Immunity!

Scientists from Stanford University have described an antibody that, in preclinical studies, was effective for treating a wide variety of solid tumors. The antibody targets a cell surface molecule, CD47, that serves, in the words of the authors, as a "don't eat me" signal to phagocytic cells of the innate immune system. In their studies, the authors found that tumor cells from cancer types including ovarian, breast, colon, bladder, glioblastoma, hepatocellular carcinoma and prostate cancers had, on the average, three times as much CD47 on their cell surfaces as normal cells. When they treated mice with xenotransplanted tumors with the antibody, they found that it inhibited cancer progression and prevented metastases, and was "potentially curative" if it was administered to earlier, smaller tumors. The antibody blocked the interaction of CD47 with another protein, SIRP-alpha, and the authors believe that small molecules that block this interaction would likely also be effective. The findings appeared in the March 26, 2012, issue of the Proceedings of the National Academy of Sciences.

Flu Fighter Gene Variant Identified

Some flu virus strains lead to worse disease than others. But the same flu virus strain will also cause worse disease in some people than in others. Now, scientists from the British Wellcome Trust Sanger Institute have found a gene variant that makes its carriers susceptible to much more severe disease when they are infected. Mice lacking the gene, IFITM3, were unable to prevent flu virus from spreading beyond their lungs after infection. As a result, a garden-variety, not usually particularly fatal influenza strain had effects on these animals that were comparable to the ravages of the 1918 Spanish flu. In humans, one form of IFITM3 leads to a splice variant that makes them less able to control influenza. Genetic testing of people hospitalized with the 2009 pandemic virus, showed that they were more likely than the general population to have the less-effective IFITM3 variant. In cell culture, IFITM3 also influenced the response to dengue virus and West Nile virus, leading the authors to conclude that "IFITM3 may also shape the clinical course of additional viral infections in [favor] of the host, and may have done so over human evolutionary history." Their paper was published in the March 25, 2012, advance online edition of Nature.

Transmembrane Pore is Pain Target

Researchers at the Canadian McGill University and University of Toronto identified a gene variant that affects pain sensitivity. The gene in question codes for the P2X7 receptor, which makes several different types of transmembrane channels. In mice with one coding variant, the receptor does not form one type of channel – a nonspecific pore – as efficiently as other variants. Mice that had lower levels of the pore had less pain after nerve injury. The authors also found that in two separate cohorts of pain patients, individuals with the same gene variant that was protective in mice also had less intense pain. The authors suggested that targeting pore formation might be a useful strategy for treating chronic pain. Their results appeared in the March 25, 2012, issue of Nature Medicine.

Neurotrophin Receptor and Insulin Resistance

Researchers from the Gladstone Institute identified an unexpected player in the development of insulin resistance: the neurotrophin p75 receptor, better known for its role in brain development. The authors looked at a role for the receptor in metabolism because it is found in fat and muscle tissues, in addition to the brain. They found that knockouts that lacked the receptor were more sensitive to insulin than their wild-type cousins, while overexpressing the receptor had the opposite effect. The authors concluded that targeting the interaction of the neurotrophin p75 receptor with its downstream targets "may represent a unique therapeutic target for insulin resistance and diabetes." That conclusion, and the experiments supporting it, was published in the March 26, 2012, advance online edition of the Proceedings of the National Academy of Sciences.

Breast Cancer Risk Gene, PARP Inhibitor Target

By using exome sequencing in patients with a family history of breast cancer, but no known risk genes, scientists from the Australian University of Melbourne have identified a new risk gene for the disease. Sequencing more than 1 ,000 patients with early onset breast cancer, they identified two separate mutations in the gene in question, XRCC2. The gene is in the same signaling pathway as BRCA1 and BRCA2, and so the authors hope that like with BRCA1 and BRCA2, mutations in the gene will make cells susceptible to the effects of PARP inhibitors. The authors said that in addition to the specific mutations it has uncovered, their study "demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases" more generally. Their work appeared in the March 29, 2012, edition of the American Journal of Human Genetics.

Old Guard More Important than Fresh Troops

Researchers from Oregon Health Sciences University (OHSU) have shown that in monkeys infected with the primate equivalent of HIV, the levels of memory T cells, which are already primed to remember a specific antigen, was largely independent of the level of naïve T cells, which have not yet developed the ability to respond to a specific antigen. The decline of helper T cells is a hallmark feature of HIV infection and its progression to outright AIDS. During this progression, the levels of naïve and memory T cells usually decline in parallel, and there have been some attempts to increase levels of naïve T cells to bring in new troops against the virus. The OHSU scientists suggested that based on their results, it would be more useful to target memory T cells, which are apparently capable of renewing themselves independently of levels of naïve T cells. The work appeared in the March 26, 2012, issue of the Journal of Experimental Medicine.

Heart Disease: More than High Insulin Levels

High insulin levels predict the development of heart disease. But researchers at the Joslin Diabetes Center have demonstrated that if mice are not insulin resistant, high levels of insulin in the bloodstream do not themselves cause heart disease. In human patients, high levels of insulin are a consequence of insulin resistance, and so the effects of both cannot be untangled. The Joslin team managed to separate the two by creating mice with low levels of insulin receptors. The levels were not low enough to cause outright insulin resistance, but did lead to high levels of blood insulin, because the insulin was not being cleared as rapidly. The authors found that such animals did not have more atherosclerosis at one year of age, suggesting that targeting insulin levels themselves is unlikely to affect heart disease risk. Their findings appeared in the March 15, 2012, issue of Arteriosclerosis, Thrombosis and Vascular Biology.

Sickle Cell, Beta-Thalassemia Gene Therapy

Researchers from Weill Cornell Medical College have used gene therapy to jump-start the production of functional hemoglobin in blood stem cells of patients with beta-thalassemia and sickle cell anemia. The authors increased the production of functional globin from the therapeutically inserted gene by coupling it to a so-called ankyrin insulator, which protected the therapeutic gene from epigenetic silencing once it was integrated. Mice treated with the approach had therapeutically useful concentrations of hemoglobin in their blood. The authors also developed a test that allowed them to identify patients that needed the fewest copies of the gene to achieve useful levels of hemoglobin. Such a test, they said, "would provide vital information to select the best candidates for these clinical trials" of the approach. Their results were published in the March 27, 2012, issue of PLoS ONE.

Putting the Wnt in Synapses' Sails

The brain's ability to change in response to experience is one of its critical features, and a team from the University of Utah has discovered one mechanism that the brain uses to adjust signaling strength. Neurons can recycle receptors, keeping them beneath the surface when a connection weakens and bringing them up to the cell membrane when it strengthens. Researchers discovered that neural activity activates the wnt pathway, a key developmental pathway, and that this activation sets off a cascade that ultimately resulted in more acetylcholine receptors on the cell membrane. In humans, acetylcholine receptors are involved in certain psychiatric disorders as well as the junction between nerves and muscles. The work, which could identify a mechanism for memory and, possibly, addiction, appeared in the March 30, 2012, issue of Cell.

Silent, But Not Ineffective

Proteins differ in the speed at which they are translated. And scientists from the University of California at San Francisco have provided some insight into how. The team used ribosome profiling to take a look at the factors that influence translation speed. Unexpectedly, they found that proteins, which necessitated rare forms of transfer RNAs, were not any slower to be translated, as long as the overall nutrient supply of the cell was good. Instead, what influenced translation speed was the presence of so-called Shine-Dalgarno sequences, which are ribosome-binding sequences that are upstream from the translated part of the messenger RNA. The work might enable the more rapid industrial production of therapeutic proteins. Because translation speed can affect processes like protein folding and targeting, it is also an example of how silent mutations, that is, mutations that do not change the amino acid sequence of a protein, can nevertheless have effects on its levels or functions in the cell. The paper was published in the March 29, 2012, edition of Nature.

– Anette Breindl, Science Editor