Key to immunogenomics value: embed research in healthcare system

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

We recorded interviews with nationally recognized experts in this area 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 meeting presenter Robert Plenge, M.D., Ph.D., assistant professor of Medicine at Harvard Medical School – and Director of Genetics and Genomics within the Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital.

We discussed how immunogenomics has provided a flood of new clues about the genetic quirks contributing to many diseases, but the field must now, with the quirks as a guide, delve back into cells to learn the details of how such changes cause disease. To do so, they must collect human cells from patients known to have a given disease, and related efforts will accelerated the trend toward "embedded" genomics research.



Show notes for the interview:

1:01 Genomics is the study of DNA, RNA and the proteins that code for and how they contribute to health and disease. Immunology is the study of how several cell types fight infection, and why they attack our own tissues in some case to cause inflammation as part of inflammatory and autoimmune diseases. Immunogenomics then is the study of how these components work together, the genetic programming of the immune cell sets.

1:54 Plenge's work focuses on determining the genetic basis of predisposition for autoimmune diseases, and for rheumatoid arthritis in particular. Past genomic studies have determined some of the genes that contribute risk for rheumatoid arthritis, but immunogenomic studies are going further to determine the effect that genetic variations are having in cells, and at what that says about disease mechanisms.

3:19 The last few years have seen the rise of genome-wide association (GWAS) studies, where researchers use genomic technologies to examine every coding unit in the entire genomes of two sets of people (one with a disease, one without) to reveal every small genetic difference. They use tool called microarrays to look at large numbers of genetic sequences all at once, and to find small variations called single nucleotide polymorphisms (SNPs) associated with any given disease.

3:35 But GWAS studies only show that certain families have certain genetic variations that make them more susceptible to certain disease. They do not tell how or why the variations cause disease.  The next step then for Plenge and others will be to roll up their sleeves, go into the lab with this GWAS information and study the cells of people with disease-causing genetic variations to reveal disease mechanisms that can be countered with precision designed therapies.

4:29 Plenge's presentation talks about the importance of biomarkers, the physical measures that show a disease is underway or that a drug is countering it.. These are the tests that give meaning to clinical trial results. Researchers hope that new biomarkers will help them predict who will respond to a given treatment for rheumatoid arthritis based on their immunogenomic profile.

5:12 Plenge is working with the Pharmacogenomic Research Network (PGRN), organized by the National Heart Lung and Blood Institute, part of the Institutes of Health, to see if genomic patient profiles can be used to predict which patients are likely to respond, for instance, to an important category of treatments for rheumatoid arthritis called anti-TNF biologic drugs.

5: 47 It may be that most clinical trials will soon come to benefit from the addition of immunogenomic tools that predict any given patient's response to treatment, or their likelihood to experience a given complication of side effect.

6:22  It's easy to think of the immune system as involved in fighting infection, or even in autoimmune diseases like rheumatoid arthritis where the system mistakenly recognizes its own tissue as foreign and attacks it. Mounting evidence argues, however, show that "mistakes" by the immune system bring about inflammation at the root of cardiovascular disease, neurodegeneritive conditions, cancer, pulmonary disease, etc. A profound understanding of the interplay between genomics and immunology will offer tremendous opportunities to develop new therapies, says Plenge.

7:25 Immunogenomics may help to lessen the massive time and cost necessary today to conduct the average clinical trial. Plenge hopes that emerging techniques and advances will create efficiencies in medical research.  Treatments that address inflammation in rheumatoid arthritis may also prove to have utility in reducing inflammation contributing to say diseased arteries. The potential for this becomes greater the more profound the field's understanding of genomic/immune system interplay.

9:27 Many of the past studies in immunology and genomics were done in mice meant to serve as models of human disease.  But mice are different than humans. There are now many more opportunities to do what Plenge calls "embedded immunogenomics," where registries collect cells and data from human patients for study as part of routine clinical care.  The research is embedded in the healthcare system. If patients consent for a quick blood draw, researchers gain access to details of subsets of cells and genes linked to diseases, and can follow changes over time.

11:13  One emerging trend may be the uncoupling of such genetic registries from a doctor's office visit. People participating in the new registries may just stop by a lab (e.g. Quest Diagnostics) for testing whenever they don't feel well.

12:20 Plenge recommends that researchers interested in learning more about this area look into a database under development called Immunobase, which is working to catalog inherited genetic variations contributing to a wide variety of diseases. The work underway at Sage Bionetworks and  i2b2 (informatics for integrating biology and the bedside), an NIH-funded biocomputing initiative, represent other interesting initiatives. Patients interested in participating in research might look up 23andMe, and those with rheumatoid arthritis, the Arthritis Internet Registry.

Tune in next Friday to hear our talk with John O’Shea, M.D., chief of the Molecular Immunology and Inflammation Branch with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health.