Hopkins Medical News: Big Man in Genes

Big Man in Genes

By Gillian McCallion | Portrait by Rich Riggins

The head of the prestigious McKusick-Nathans Institute of Genetic Medicine talks about why even school children must begin to understand some of the basics of his field.

Aravinda Chakravarti and I have been downstairs to grab a cup of rum and butter coffee. He has removed his tie, undone his top button, checked his e-mail and we are ready to talk. He slides across his perfectly ordered office to fiddle with an expensive-looking stereo, explaining that he once read an article on the virtues of playing music in one's office. Apparently it makes awkward silences less awkward. In general, he chooses classical music. No one can be offended by that. "I'd better turn this off," he says now.

Chakravarti is the new Henry J. Knott Professor and director of the McKusick-Nathans Institute of Genetic Medicine. At 47, some might suggest, he is young to hold such a position. His track record suggests age has never been an issue.

Chakravarti arrived in the United States from his hometown of Calcutta, India, in 1974 on the day Nixon resigned. He'd finished an undergraduate degree in statistics and mathematics and was headed for the University of Texas in Houston to do a doctorate in human genetics. Three years later, he was cited among the "who's who of students at American colleges and universities." By 1989 he'd become an integral part of the team that identified the gene responsible for cystic fibrosis.

Chakravarti is perhaps best known for his analyses of the genetic predisposition and molecular mechanisms involved in such common and complex human diseases as diabetes, heart disease and mental illness. He is somewhat less well-known for an Indian cookbook he authored during his graduate student years, "Not Everything We Eat Is Curry." One year ago, he arrived in Baltimore from Cleveland's Case Western Reserve University, handpicked by a blue-ribbon committee as the first head of the McKusick-Nathans Institute of Genetic Medicine. With him were his wife Shukti, an assistant professor of medicine, and their two daughters Priya, 13, and Indira, 8.

As the world propels into an era in which genetic knowledge will become crucial to the practice of medicine, Chakravarti talked about how he views his role at the helm of the prestigious institute.

There was a lot of speculation about who'd be chosen to head up this Institute of Genetic Medicine. Any thoughts on why you got the job?
One reason may be that I come from both a computational and an experimental genetics background. Also, genetics has changed. It's gone from the study of the importance of genes in single gene disorders, which, although very important, affect relatively small numbers of patients, to the study of genes that affect common disorders which are subject to the influence of multiple genes. We're all interested in these common disorders but not very many geneticists know and understand them in molecular terms. I believe my previous work is important to this understanding.

These multiple gene disorders are the so-called complex diseases?
Yes, traits like hypertension, heart disease or mental illness. These are common chronic disorders. The importance of genes in these disorders is not in doubt but the way in which these genes play out their roles is very much in doubt.

What's been your big contribution in this area?
I was one of the first few scientists to vocalize the importance of genomics in the study of complex traits which was largely descriptive before that. I also recognized the details of some of these common complex traits and the methods by which they could be identified and understood including the use and importance of studying genetic variation in SNPs (single nucleotide-polymorphisms). But neither of these is my greatest contribution. That is yet to come, I hope.

It sounds like you have a professional Holy Grail?
I have no single Holy Grail, but it would be great to know, even in a single disorder, why we need mutations at more than one gene to elicit a disease effect. I think we need that conceptual understanding even in one system. We have the beginnings of this in some cancers but not for most disorders.

Are we close?
Yes, I think we are near. Perhaps in a year or two we'll have some understanding of what the meaning of a complex disorder is. We call these diseases complex because we're ignorant about the biochemical nature of their genes and mutations and the nature of the interactions that lead to such intricate biochemical behavior. We need genomics technology, but to crack the genetic basis of complex diseases we'll also need to understand the basis for complex inheritance. Once we do that, I suspect we'll start understanding the general rules of the nature of these disorders.

Changing to a new university can't be easy. What persuaded you to come to Hopkins?
That's actually fairly simple. I wanted to make some changes in human genetics. If you want to do that, the institution really matters. This sounds odd but despite all the hoopla there aren't a lot of institutions that really appreciate what genetics is and what it can do. My colleagues at Hopkins do. Secondly, Hopkins is close to many other fantastic institutions along the east coast, and to the NIH. Thirdly, it's possible to attract an excellent caliber of trainee here.

Thinking about the core group you want to put together must be taking up a lot of your time-not only the trainees you want to bring in, but also your genetics faculty. Do you have some underlying principles for choosing your faculty?

The most important is to gather together individuals who believe in the same kinds of changes I do and who are outstanding scientists. Genetics is a very young field, at least in its modern incarnation, so my bias is to bring in many more junior faculty than senior. Junior scientists are more adaptable to change and they're also the repositories of all this new information.

The three areas we plan to concentrate on are complex disorders, epigenetics—which is the study of why two entities that have the same sets of genes and the same form still can have different behaviors—and developmental genetics. We need faculty members who are very well versed and comfortable with all the new technologies. In general, biologists aren't. Ideally, we need faculty who can bring in expertise in genomics, in computational biology and in manipulating the actions of multiple genes simultaneously.

You've said you want to help the public think about genetics in a new way. What exactly do you mean?
My goal is simply to change the way we do human genetics, to make human genetics much more real in the clinical realm and to make genetics of the human a much more intrinsic part of both basic research and education.

Do you think scientists in general have a good track record when it comes to educating the public about their work?
I think they're much better today than they used to be, but I'll go out on a limb and say in general scientists have not been very interested in educating other people about what they do and why they are doing it. It just hasn't been high on their list of priorities.

Is there any reason why it's necessary for the average person to have an idea of what goes on in scientific research?
At one point, people believed that science was completely serendipitous. Newton didn't have to spend much money to have an apple drop on his head. Einstein was so brilliant that great ideas just occurred to him, but that's not how we practice science now. Science happens because of a very persistent and thoughtful and highly structured way of doing experiments, a very thorough way of sifting through nature. And because we do it this way it requires great amounts of public support. There is no longer the perfect trust that once existed between the public and scientists. As scientists, we need to be much more transparent. Individual scientists need to speak to and write for the public at large explaining what they do, even when they have no exciting discovery to report.

You've even talked about wanting the institute to form relationships with elementary schools. Isn't the science education that our children are receiving satisfactory?
My children are taught many more aspects of science than I ever was, although clearly a few decades have passed since then. In terms of biology there seems to be an emphasis on ecology and population biology. The brain is not really covered in depth. Children know about genes but not really in any meaningful way. It's probably a question of time but it is an area of concern to me. The only way of having a scientifically aware society is by giving people the relevant information. Getting anything into the school curriculum is a fairly difficult process. But there are many organizations working in this area and one has to keep at it.

How about teaching the medical world about advances in genetics?
Yes, I am quite concerned about educating our colleagues. The word genetics is too broad and we have to emphasize much more specificity. We have to teach physicians, for example, why all these modern advances make sense and why they are important to the lives of their patients.

Would you say that this general lack of understanding about genetics is your biggest frustration?
I tend not to focus on frustrations; I wouldn't be doing this job if I didn't believe that one could make a difference. But I do think the aspect that I probably find most frustrating and really the biggest challenge is that knowledge of genetics is really very non-randomly distributed among the constituency that needs to understand it.

And that constituency is?
Scientists and physicians first of all. Various scientists understand genetics to varying degrees. Some clearly believe that genetics is no more than a set of tools. Genetics is much more than that. It is an intellectual construct, it's a way of viewing the world through the lens of variation. What makes genetics unique isn't that it's defined by a set of codes-all biological systems are. In the case of genetics, though, this code and changes to it are inherited. And it is this feature that affects variations in gene functions that form the basis for most human diseases.

But if genetic medicine is going to become a reality, politicians also have to understand it. There are major questions concerning privacy, confidentiality and insurability that need to be dealt with. There are clearly a few members of the government who understand it very well but the vast majority don't believe it's important enough to warrant their attention. So the most frustrating aspect is that scientific fixes may come before societal fixes.

The current administration in Washington certainly appears to have some ideas that could affect genetic research.

The previous administration was more knowledgeable about these issues but it was not knowledgeable on day one. I think that whatever the administration, the outcome really depends on whether or not it has some articulate people who understand the issues and can get the president's and Congress' attention.

Right after they finished mapping the genome, scientists and the press made a lot of claims about the impact that was going to have on medicine and research. What's the reality?
In science we like things to be pre or post something-in this case pre or post genome. I actually don't think we are post-genome. I think that this is the beginning of the genome age, merely after we have the sequence. We have yet to show how best to interpret it and use it. The most obvious implication is that we have to change the way we do the science. In the past we haven't considered how a genome's worth of biological information impacts, for instance, the metabolism of glucose or the way in which tumors metastasize. How do we do this? It's one thing to conceptualize it but to be able to do it practically and to make the thinking and the technology widely available… that's a challenge.

Let's end with a personal question. What do you do when you're not working?
These days, I spend as much time as I can with my family. I didn't do enough of that in the past. But this job is really tough and if I'm not careful, I could burn myself out.