Human genetics and finding function: an interview with Aravinda Chakravarti

Human Genome Organisation (HUGO) Council member Aravinda Chakravarti, Ph.D., has a listing at Johns Hopkins University that reflects his far-reaching contributions to research and medicine. It reads: “Professor; McKusick-Nathans Institute of Genetic Medicine; Departments of Medicine, Pediatrics, and Molecular Biology and Genetics at the Johns Hopkins University School of Medicine; Department of Biostatistics at the Bloomberg School of Public Health.” 

A leader in human genetics research for decades, Chakravarti is now delving beyond gene discovery into understanding the molecular pathways associated with complex human disease. During a recent visit to The Jackson Laboratory, where he is a co-director and faculty member at the annual Short Course in Medical and Experimental Mammalian Genetics, Chakravarti spoke about his current efforts and the directions in which he thinks human genetics research needs to go.

Q: You said recently that you were streamlining your research efforts. How so?

A: When you are a geneticist who studies humans, all phenotypes are of interest. As such, my research has spanned genetic studies of numerous human diseases and medical traits. Over the past two decades, we geneticists have become very proficient at disease gene discovery, and, like others, my laboratory has ended up mapping and discovering genes associated with many different diseases. 

But while finding and localizing genes isn’t a big challenge any more, it is still very difficult to figure out what they actually do and how their malfunctions lead to disease. Clearly, one aim is to understand their normal function and another to figure out how changes in that normal genetic program leads to disease. For chronic diseases of humankind—cancer, heart disease, neurological diseases, anything—we still are largely ignorant of how genetic abnormalities lead to disease. That is still mostly a black box. That’s the part that many labs, including my own, are focusing on more closely and looking to solve. Unfortunately, this may require a disease-by-disease solution.

Q: Why is it so hard to figure out the function of a gene when you have localized it and already know the sequence?

A: Figuring out a molecular function of a single gene is straightforward, but typically a single gene has many alternative functional forms with many different functions. Understanding these functions across development and aging remains challenging since the universe of possibilities is so large. Moreover, few genes function by themselves and many functions are only evident by one gene interacting with another . . . figuring out this aspect is still in its infancy since the universe of these possibilities is even larger. One has then also to consider that the gene may have different functions in different cell types and tissues. That's why it’s hard.

A good example of that is genetic research on sudden cardiac death that we’ve been doing for the past eight years. The prominence of sudden cardiac death is increasing as the common sources of cardiovascular disease owing to lifestyle factors are better controlled. It has remained medically elusive, with various possibilities of the pathology arising from structural (mechanical) or functional (electrical conductivity) problems in the heart. When we started studying this in 2005, we needed ways to distinguish between these hypotheses. This is where genetics and genomics can be surprisingly beneficial. My group was at the vanguard of developing and using SNP array technology for genomic studies and we performed one of the first genome-wide association studies of the QT interval from human EKGs to suggest NOS1AP variation as an intrinsic cause of sudden cardiac death. We published our finding in 2006, but moving from that genetic signal to figuring out precisely how cardiac physiology is affected has been a long road and taken over 7 years. We have a much better idea of the underlying NOS1AP function but there is much more to understand before we can intervene in humans to prevent disease.

Q: Even with the technology improvements? Why?

A: Even when we’ve localized the gene we need to create a cellular system where we can study the functions of this gene, by knocking its function out for example. For sudden cardiac death, we also need a cellular system that can simulate part of the cardiac physiology . . . that is, we should be able to demonstrate both molecular and electrophysiological disruptions by disrupting NOS1AP function. All of this takes time since the components are not “off-the-shelf.” Other problems are the development of new paradigms since it’s increasingly clear that, for complex diseases, many disease mutations are non-coding and we have to understand not the effects of a mutant protein but abnormal levels of a normal protein. We are at the beginning of understanding gene regulation from this viewpoint. What happens when there’s too much or too little of a protein? Why and how does this matter? What is the protein doing—or not doing—that affects cardiac physiology on such a rapid timescale? And we still have to figure out where the protein localizes in the cell and how varying its levels affects its functions. 

Q: So finding the gene and knowing its sequence is just the start . . . 

A: Yes, the sequence is necessary and reveals much, but it’s not sufficient. Finding a gene leads to many questions that still need to be answered. Where is it expressed? At what level? When during development? Where does the protein localize, in what tissue and where in the cell? All give clues to function. Geneticists and genomicists have been a bit slow in trying to incorporate biochemical and cell biological assays and technologies to solve problems in these areas. There need to be close collaborations with cell biologists and biochemists to understand gene function. And, of course, understanding some aspects of function in another species can be greatly helpful to its study in humans. Success in genetics shouldn’t be seen as an isolated success but rather as integrated with all other important aspects of biology.

Q: With all of those questions left to answer, how can genetics and genomics help disease research and medicine?

A: Human diseases are affected by many different genes, as well as currently unknown aspects of lifestyle and environment. There will be various stages of understanding as we unravel these factors one by one, but we can impact therapy without understanding it all. Primarily, genetics and genomics can accelerate our understanding of the molecular basis of human disease and thereby point to therapy avenues that are currently nothing more than guesses. This is where professional organizations like HUGO can help, through international data sharing across populations, diets, environments, behaviors and cultures so that we can make faster progress from diverse viewpoints. It’s important to bring together different people and make it a truly global effort. HUGO can also play an important role by focusing attention on rate limiting factors and working with funding agencies to maximize what we can accomplish. 

Q: What are some of the most important issues facing human genetics research?

A: The major issues are sharing of samples, sharing of data, and access to technologies. Then there’s the challenge of computation. A biologist used to be able to collaborate with a quantitative expert and be able to answer their question, but that’s not good enough any more. Since current data sets are very large, we need to query these data sets to even pose the questions. Thus, we need to be computationally trained to ask the right questions in our research and be able to address the issues of handling huge data sets and analyzing them. In a way biologists need to be multi-lingual and be able to understand the language of computing as well as biology.

On a related topic, we also need to address education and make sure quantitative and computational training are significant parts of the whole educational process. We need to get away from the “soft” science thinking—biologists aren’t naturalists running around with butterfly nets any more—and train all students in the “hard” quantitative techniques.

Q: It sounds like it will take a while to change the field.

A: Moving forward, we in the field who are interested in human disease will have to master three areas: biology, computation and clinical science. Although so much of current education is geared to training specialists, it is the educated generalist who can traverse all three of these areas that will be successful. It can be done—we just need to act on it.