Dr. Schork is a Professor and the Director of Human Biology at the J. Craig Venter Institute and an Adjunct Professor of Psychiatry and Biostatistics at the University of California, San Diego. He is also the Head of Integrated Genomics at Human Longevity, Inc. located in San Diego.
Dr. Schork’s interests and expertise are in quantitative and integrated human genetics and genomics. He is especially interested in the design and implementation of methodologies to dissect the genetic basis of complex traits and diseases. In his recent seminar at the Buck Institute, Dr. Schork described some of the challenges in leveraging whole genome sequencing for genetic association studies. These challenges include accommodating global human genetic diversity, dealing with rare variant effects, assessing the ‘functionality’ of genetic variants, modeling polygenic effects, and being sensitive to the fact that humans are diploid and hence have two genomes (one inherited from each parent) whose composition is likely to be unique.
SAGE was able to ask Dr. Schork a few questions following his seminar and his interview is below.
Q: What is the main challenge of using genetic sequencing to understand idiopathic disease?
NS: There are a lot of challenges in this area. Keep in mind that the success ratio among all idiopathic diseases that have been sequenced is only about 30%. One of the challenges is to make sure that your sequencing method captures all of the variations that might be present in a pathogenic individual’s genome. It is hard to adequately characterize variations that are completely novel in a person’s genome when you suspect them as sequencing errors. It is challenging to tell the de novo variations from sequencing errors. Another challenge is that there is no guarantee that a single mutation would cause the disease. Sometimes you have to look for variations in multiple genes, which combined, cause the disease. Taking into consideration that all the potential combinations of variations might cause one disease is really hard. So the 70% of diseases that are yet to be diagnosed at the molecular level by sequencing could be a due to a combination of variations.
Q: What is the future direction of using human genomics to study longevity?
NS: There are a couple of different groups that are developing different approaches. For some groups, the idea is that if you collect enough individuals (one healthy long-lived group and one control group), you will be able to discover variations and/or patterns in the genome that can distinguish the two groups, which is more like a big data analysis. For other groups, the idea is to add biology into the analysis, which means you have to understand what the variations might do before you distinguish the variations. I think we can’t ignore biology. For example, if we want to look into genes that influence cognitive abilities later in life, then we are actually looking for genes that express in the brain. So why wouldn’t we want to leverage our knowledge of the genes expressed in the brain before jumping into the analysis. I think combining biology with big data statistical analyses is the way to go in the future. Also there is an issue of the cohort effect. For example, our current healthy centenarians were born in the 1910s. So you would like your control group to be individuals who were also born in the 1910s however, most of them have died, so this type of analysis is very hard.
Q: You joined Human Longevity, Inc. this year. What is the goal of the company?
NS: The Human Longevity, Inc. was founded by J. Craig Venter. It is a for-profit company. One of the goals of the company is to develop high throughput genome sequencing to understand genetic variations that might influence lifespan. We want to put together the largest gene – phenotype database ever, by sequencing the genomes of a large number of people as well as acquiring very detailed phenotypic information of these people in order to look for associations. The company started in the first quarter of this year, and right now we have more than 50 employees. We are recruiting more people now.
Q: Why did you leave the Scripps Research Institute and the join J. Craig Venter Institute?
NS: I am interested in human quantitative genomic and translational genomics. I want to make sense of genetic variations in ways that might impact clinical issues. But to do this, you need lot resources for clinical studies. Non-profit institutes like Scripps mainly focus on basic research; they don’t have a lot clinical resources. The J. Craig Venter Institute is located on UCSD campus. UCSD has a medical school and a hospital, so there is a natural connection between the J. Craig Venter Institute and their clinical resources. The other motivation for me is that Craig Venter wants to start a new program that I am very interested in at the Human Longevity, Inc., which is the largest gene – phenotype database. I am excited to move the science of human quantitative genetics forward.
Q: What is the bio-environment in San Diego?
NS: San Diego is a good place to pursue biomedical research. There are at least 5 distinguished institutes besides UCSD: the J. Craig Venter Institute, the Salk Institute, the Scripps Research Institute, the Sanford-Burnham Medical Research Institute, and the Genomics Institute of the Novartis Research Foundation. There are a lot of biotech companies surrounding these non-profit institutes, such as Illumina and Life Technologies. There are also some info-tech companies such as Qualcomm. It is a pretty vibrant environment for medical research.
Q: What would you like to suggest to our postdocs who want to pursue academic careers?
NS: I would like to encourage our postdocs to embrace multi-disciplinary approaches. For example, experimental researchers need to know computational work, and computational researchers need to know what has been generated in the lab. I think it is going to be harder and harder to survive if you only stay in one field. Understanding different technologies in terms of their limits as well as how they can be integrated together is very crucial. I would suggest that our postdocs know the limits of what they are doing and how these limits can be surpassed by other approaches. You don’t just want to be a person who just know about “X” and contribute “X” to the entire alphabet of a whole project.