Recent developments at Burnham Institute for Medical Research, May 2009

Dr. Robert Liddington and colleagues, working with researchers at the Dana-Farber Cancer Institute and the Centers for Disease Control and Prevention, reported the identification of human monoclonal antibodies that neutralize an unprecedented range of influenza A viruses, including avian influenza A (H5N1) virus, previous pandemic influenza viruses and some seasonal influenza viruses. These antibodies have the potential for use in combination with other treatments to prevent or treat certain types of avian and seasonal flu. The study was published in Nature Structural and Molecular Biology.

Several inflammatory diseases have been linked to a group of genes that encode immune defense proteins, called NLRs. Post-doctoral fellow Benjamin Faustin, in Dr. John Reed's laboratory, in collaboration with Dr. Arnold Satterthwait and colleagues, studied how endogenous inhibitors of NLRs function in hopes of developing strategies for mimicking their actions. The intended result is ameliorating various autoimmune and inflammatory diseases where hyperactivity of NLRs has been implicated. In a paper published in Proceedings of the National Academy of Sciences USA, the Burnham investigators show that short pieces of anti-apoptotic Bcl-2 family proteins are sufficient to bind certain NLRs and suppress their activity. The findings have resulted in several new drug screening assays, which the team hopes to put to use to identify chemicals that mimic the endogenous inhibitors of NLRs and thus suppress inflammation.

The surfaces of cells are covered with sugar molecules called glycans, which are linked to proteins and lipids. The sugars of these glycoproteins and glycolipids can take many complex forms. In particular, the glycan makeup of normal and cancerous epithelial cells is very different. Several studies have suggested that glycan changes play a role in cancer metastasis, although the mechanisms by which they may do so have proved elusive. In a paper published in the Proceedings of the National Academy of Sciences USA, Dr. Michiko Fukuda, in collaboration with Dr. Minoru Fukuda, has now identified a receptor for cancer glycans in the blood vessels of the lung. Antibodies to this receptor prevented melanoma cells from entering into and growing in the lung. Since the glycan being studied is also expressed on the surface of colon, breast, lung and ovarian cancers, these findings have broad implications for the therapeutic targeting of tumor-associated glycans.

We know that the blood supply to a given body organ must be regulated in parallel with its growth. In disease states such as cancer, growth of blood vessels can feed the tumor, contributing to the disease process. The factors that control blood vessel growth are not completely understood. Dr. Masa Komatsu and colleagues at Burnham have recently discovered another piece of the puzzle for understanding how blood vessel growth is controlled. The Komatsu laboratory previously demonstrated that the R-ras regulator of cell signaling keeps blood vessel growth in check. When the R-ras gene is not active, blood vessel growth increases wildly. In a recent study published in the Journal of Biological Chemistry, the Komatsu group found that an important regulator called GABP increases the activity of the R-ras gene. This discovery identifies a potential target for new therapies aimed at reducing the blood supply to tumors.

Inflammation is a fundamental response to tissue injury. However, in many different diseases, including arthritis, asthma and psoriasis, inflammation causes harm. One of the key mediators of the inflammatory response is the T-cell. The T-cell is activated by a protein called Interleukin-2 inducible T-cell kinase (ITK). Recently, Dr. Gregory Roth and colleagues, in collaboration with a chemistry group at Boehringer-Ingelheim Pharmaceuticals, Inc., have made new inhibitors of ITK. The inhibitors were designed by looking at small molecule compounds that are known to exert ITK inhibition, albeit not very effectively. By customizing such compounds, Dr. Roth and colleagues were able to make new agents that are more effective at inhibiting ITK. This work was recently published in the Journal of Bioorganic and Medicinal Chemistry Letters.

In response to pathogenic challenge, B lymphocytes rapidly proliferate to generate antibody-secreting cells that can produce neutralizing antibodies in sufficient quantity to limit or eradicate infection. In collaboration with the laboratory of Dr. Mark Ginsberg in the department of pharmacology at UCSD, Dr. Robert Rickert and colleagues in the Infectious and Inflammatory Disease Center at Burnham reported an essential role for the beta integrin-associated molecule CD98 in B cell proliferation. B cells in mice lacking CD98 are unable to respond to any mitogenic stimuli, resulting in a failure to generate antibody-secreting cells. These findings, reported in the current issue of Nature Immunology, raise the possibility that disruption of CD98 function could be useful as a therapeutic means to block B cell proliferation in the context of leukemia or lymphoma as well as antibody-dependent autoimmune disease.

Cardiology researchers under the direction of Drs. Rolf Bodmer and Pilar Ruiz-Lozano in the Development and Aging Program have described automated techniques to quantify heart beat parameters that can be used for genetic screening in fruit flies and zebrafish to discover genes that control heart function. The research was published in BioTechniques. In addition, Drs. Vincent Chen, Jeff Price, Mark Mercola and colleagues have described new tools and methods for tracking the development of heart muscle cells in human embryonic stem cell cultures and for purifying large numbers of these cells for large-scale applications and pre-clinical trials. This research was published in PLoS ONE.

The laboratory of Dr. Huaxi Xu has reported in the Proceedings of the National Academy of Sciences USA that the commonly prescribed diabetes medication metformin increases the production and deposition of amyloid protein in the brain. The implication of this finding is that this drug may be potentially harmful when used as a monotherapy in elderly diabetic patients. However, the effect appears cancelled in the presence of insulin, suggesting that a combination therapy might be safe. Dr. Xu's laboratory also described how the amyloid precursor protein in diseased neurons influences the intracellular trafficking of other proteins involved in cell signaling and processing of the amyloid precursor protein itself in the Journal of Cell Biology. This study adds new insight into the mechanisms that control production of the amyloid protein, which is a hallmark of Alzheimer's disease.

A chemical reaction occurs in Alzheimer's disease involving free radical attack on a molecule called Drp1, which is important for the integrity of mitochondria, the energy powerhouses of the cell. The free radicals cause excessive activity of Drp1 that, in turn, cause the mitochondria to fragment. Once this happens, the energy of the nerve cell is compromised and connections to other nerve cells are lost and eventually the nerve cells die. The chemical reaction mediated by free radicals (in this case a form of nitric oxide or NO) is called S-nitrosylation. Dr. Stuart Lipton and Dr. Adam Godzik found that S-nitrosylation of Drp1 causes excessive mitochondrial fragmentation, energy compromise, and subsequent synaptic damage and neuronal death in Alzheimer's disease. The good news is that this provides a new disease target that could prevent synapse loss and nerve cell death in Alzheimer's disease, constituting a new strategy for counteracting the disease.

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