Friday, October 19, 2012

Human immuno-genome interview series: UAB's Casey Weaver

Most of the time The Mix covers general research topics, but for the next several Fridays we will feature a podcast series focused on the emerging field of immunogenomics.

We recorded the interviews live at a recent immunogenomics symposium organized jointly by the HudsonAlpha Institute for Biotechnology and leading medical journal Nature Immunology. The symposium was sponsored in part by UAB and its Center for Clinical and Translational Science.

Immunogenomics as a field is using new genomics tools to unravel the complexity of the human immune system and related diseases, which are now known to include heart disease, neurological disease and cancer because of their interplay with inflammation. The work promises to improve diagnostic tools and offer new treatment approaches.

Among the most important of genomics tools are microarrays, which enable researchers to measure the expression levels of many genes at once, and bioinformatic programs, which identify patterns in the massive data sets generated during genomic analysis of individuals and populations.

Our guest for this podcast is meeting presenter Casey Weaver, M.D. professor in the Department of Pathology within the UAB School of Medicine. We discussed how immunogenomic tools have helped researchers to finally grapple with and begin to dissect the complex workings of the immune system, and specifically, of T cells.

Show notes from the podcast:

:57 Our view off the immune system has been zooming in for years, from early studies that looked at the system at the cellular level, to studies that examined the relevant molecules inside cells, and now, to studies looking at the genes that control it.

2:00 Weaver's team has been trying to understand how T cells, one of the workhorse cell types of the precise, thorough and massive adaptive immune response, are controlled by genes that code for cytokines, signaling proteins that ramp the immune response up and down as needed. The team is also interested in the process by which more stem-cell-like T cells "decide" to become one of several more specialized cells, depending on the kind of bodily invader encountered.

2:24 CD4+ T cells are the "master regulators" of the immune response, and Weaver studies how these cells decide to mature into different types of immune cells depending on the kind of immune response needed. His work in recent years has been aimed at mapping the genes expressed in each scenario.

2:45 Weaver's team is working to genetically engineer mice in which researchers can see a readout of which genes are expressed in which immune cells and when. It has became clear how limited the current understanding is of how immune genes are controlled in T cells.

4:13 Every kind of microbial challenge (virus, bacterium, fungus) requires a different kind of immune response to eliminate it. CD4+ T cells differentiation adapts to each threat, matching up with so that it can oversee the right response.

5:11 Along with genes controlling T cell responses, there are often small pieces of genetic material that regulate when and where genes turn and of.  Weaver's team has spent time identifying several of the regulatory genetic elements that control T cell cytokine genes. Several of these elements are cis (lie alonside) the genes they control.  

5:51 Rapid advances in genomic data and technology have enabled researchers to establish correlations between small changes in genes, and in the regulatory elements that govern them, and susceptibility for many diseases.

6:19 How susceptible a given person is to an immune-mediated diseases may depend on small changes in certain genes, so-called single nucleotide polymorphisms or SNPs, but the field is not sure of their data.  Does a certain SNP cause disease, or is it just in the same region as something else that does?

6:59 One way to answer that question is to test the impact of a SNP in a live organism where the immune system is at work. Part of the strategy in Weaver's lab then has been to put part of a human cytokine gene with a SNP associated with a disease into a mouse model, and to see if it has the predicted impact.

8:15 Part of the difficulty of analyzing gene expression traditionally has been that transgenic techniques (putting human genes in a mouse) may end up putting that gene into the mouse genome in several places and randomly.  That makes it hard to pick up the subtle readouts you need to tell whether or not a SNP is contributing to a disease. Weaver's solution, one used by other labs as well, is to insert entire genes into the genome that include the SNP under study, in effect creating a level genetic playing field on which to judge the contribution of each SNP to disease.

11:06 Weaver recommends those interested in more information on the field see the National Center for Biotechnology Information and the UCSC Genome Browser.

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