Thursday, November 8, 2012

Immunogenomics: more powerful the more it's used

Here we present the fifth and final interview in our podcast series focused on immunogenomics, a field that is using new genomics tools to unravel the complexity of the human immune system and related diseases.

We recorded interviews with experts on the subject from UAB, Harvard, Stanford and the National Institutes of Health 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.

Our guest for this podcast is John O’Shea, M.D., scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and chief of the NIAMS Molecular Immunology and Inflammation Branch.

We talked about how immunogenomics will only achieve its potential when its tools become inexpensive and straight-forward enough that they can be folded into research efforts by non-genomics experts. O'Shea said early examples of that could be found in the symposium presentations, some of which provided insight into how the immune system drives disease while others predicted which patients should benefit most from new classes of drugs.

Show notes for the interview

1:01 Those who study the immune system have also closely studied genomics for years. What has changed in immunogenomics is the leaps made possible by new technologies. Immunologists now have the ability, given cheap, powerful tools, to conduct genomics studies as part of their research.

2:31 High-powered gene sequencing, bioinformatics and computing tools will only become truly powerful when immunologists, cardiologists and neurologists (non-genomics experts) start using them in their labs worldwide. Many presentations at the symposium represent examples of that starting to happen.

2:57 O'Shea's lab, which was a pure immunology lab five years ago, now includes several high-throughput sequencing machines, not to mention a dedicated computational biologist. Immunogenomics is changing the makeup of the average research lab.

3:34 Immunogenomics is important to O'Shea's research in particular because he works with immune cell signalling pathways that play a central role in autoimmune diseases like rheumatoid arthritis, where the immune system mistakenly targets and damages our own cells. It provides a whole new window on related mechanisms if you can understand which small variations in certain spots within our genetic code add risk for the disease.

4:03 Specifically, Dr. O'Shea is interested in immune signaling chemicals called cytokines that ramp up our immune response to infectious disease invaders, but that also trigger inappropriate immune reactions as part of autoimmune disease. Genomics tools helped the field determine that a certain cytokine signaling cascade called the JAK-STAT pathway was centrally involved in autoimmune disease. Now we know that small genetic changes, so-called polymorphisms, in STAT molecules confer risk for rheumotoid arthritis, lupus, Sjogren's syndrome, etc.

5:29 Interestingly, as the field tries to figure out what confers disease risk relative to the JAK-STAT pathway, a new class of drugs, the JAK inhibitors, are arriving on the scene. Some are under consideration for marketing approval at the U.S. Food and Drug Administration right now. With this arrival, new immunogenomics tools will help researchers understand which patients are more likely to respond to the new drugs, saving them time and misery.

6:08  O'Shea's presentation at the meeting was titled "Environmental Sensors and Master Regulators in the Emergence of Active Enhancer Landscapes." Put simply, all cells in a person have the same DNA, but all cells don't read the same sections of the instruction encoded in that DNA. To fulfill its specific functions, each cell reads certain parts of the same code, with mechanisms in place to open and close the right sections of the book. The mechanisms that control when genes are expressed are regulatory sequences, the subject of study in the science of epigenetics.

7:20 An increasingly popular theory is that the origin of many diseases, including autoimmune diseases, lies not with genes, but instead within the small pieces of epigenetic code, the enhancers and regulators, that control the process of when and where genes are turned on.

9:21 Genomics and epigenomics, the genetic cards we are dealt, have a great deal to do with our risk for disease, but our "environment" plays a big role as well. Environment in this context could mean sunlight, hormonal changes (estrogen versus testosterone), or how much inflammation a person has thanks to chronic disease. The excitement is around our new ability to measure the interplay between genetics and these other factors in disease risk using the new tools.

11:40 Over time, O'Shea and others have switched from using technologies that examine a single gene, to a few genes, and now, all human genes at once, the analysis of 3 billion coding units. As a result, many diseases are now known to be the result of changes in large networks of genes.

14;19 For more information on where immunogenomics meets epigenetics, O'Shea recommends the Nature website covering the ENCODE project, the NIH-funded effort to begin to map the regulatory portions of the human genetic code.

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