The Road Less Traveled

First, Aravinda Chakravarti drew a map of how scientists might unravel the genetics of complex disease. Then he blazed the trail.

By | November 1, 2012

Professor of Medicine, Pediatrics,
    and Molecular Biology and Genetics
Director, Center for Complex Disease Genomics
McKusick-Nathans Institute of Genetic Medicine
Johns Hopkins University School of Medicine
Things were not unfolding according to plan. Aravinda Chakravarti had done everything right to launch a successful career: he completed a bachelor’s degree at Calcutta’s
prestigious Indian Statistical Institute, published his first paper while still an undergraduate, and completed a PhD in human genetics at the University of Texas Health Science Center at Houston in 1979. But his postdoctoral fellowship at the University of Washington was not working out. “It wasn’t very positive,” says Chakravarti. “After 4 or 5 months, I knew it wasn’t going anywhere.”

When his eldest brother told him to bail out, Chakravarti was aghast. “That is anathema to a scientist,” he says. “We believe that if you cut the cord, your academic life is over.” But, screwing up his courage, Chakravarti took the risk and left the lab after 8 months.

“I went to work out in left field. I always liked working on things where there wasn’t a crowd. I’m still like that—I
don’t like crowds.”

He obtained a low-paying job at the University of Pittsburgh and spent the next 5 years teaching biostatistics and population genetics—no computer, no lab, and no research budget. But the time was not wasted, Chakravarti says in retrospect. “It helped me develop my teaching skills and to focus on theory. It allowed me to read and think.” He also caught up on rapidly advancing genetic technologies by becoming a part-time volunteer technician in a friend’s lab. Over time, Chakravarti bought his way out of teaching: he applied for and won an NIH Research Career Development Award so that he could open a lab of his own.

It was the first of many times that Chakravarti, now director of the Center for Complex Disease Genomics at Johns Hopkins University School of Medicine and a member of the elite Institute of Medicine, would forgo the traditional scientific career route. Instead of pursuing a personal research agenda, Chakravarti spent more than a decade constructing tools for colleagues’ projects. When he finally began his own research program, instead of identifying a trendy research area, he chose to study a little-known gut disorder called Hirschsprung disease.

From that road less traveled, Chakravarti has made unparalleled contributions to the genetics of complex human diseases. He pioneered now-ubiquitous genomics methodologies, made critical contributions to the Human Genome and International HapMap Projects, and elevated Hirschsprung to a shining model of complex human disease.

And he’s not done yet. Today, Chakravarti is undergoing another career renaissance, taking a step back from data gathering and tool building to focus on the theory and developmental mechanisms behind complex inheritance. Here, Chakravarti considers the genetics of hand clasping, the scientific value of family reunions, and how he avoided becoming a shoe salesman.


Chakravarti Takes a Chance

All thumbs. As an undergraduate in Calcutta, Chakravarti read an essay by J.B.S. Haldane, a renowned British-born geneticist turned Indian citizen, about ways an individual with little money can still do genetics research. “He said you could collect families and pedigrees to study inheritance, so that’s what I did,” says Chakravarti. His first-ever genetics project investigated how individuals clasp their hands—whether they cross their left thumb over right or right over left. “It’s largely a single-gene trait,” he says, “so I surveyed the kids in my high school and their parents and wrote the genetic model and a computer program to analyze the data.” Encouraged by a professor, he submitted the research to the first-ever meeting of the Indian Society of Human Genetics. “For whatever God-given reason, my paper was selected, so I got on a train and went to the meeting, presented the paper, and there was my career. By my final year in college, I knew I wanted to study genetic variation and how it shaped inheritance.”

Go-to guy. While teaching at the University of Pittsburgh, Chakravarti applied his extraordinary computational skills to others’ research problems. In 1981, he met Haig Kazazian, a pediatrician at Johns Hopkins University studying the genetics of hemoglobin disorders. “Haig was collecting all this [genetic] data, but didn’t know how to analyze it. By chance, we came across each other, and I said I had the right tools to begin to analyze it efficiently.” In 1984, they identified a recombination hotspot in the human β-globin gene, work published in the American Journal of Human Genetics. “I was finally intrinsically involved in the analysis of molecular genetic variation data in populations of patients. It was just what I wanted to do,” Chakravarti says. “It wasn’t my experiment or data, but by then I had convinced other people that I was a legitimate scientist. I started helping many other people with their positional cloning studies.”

CF success. One of those people was Lap-Chee Tsui at SickKids Research Institute in Toronto, who was trying to clone the gene for cystic fibrosis (CF). “I was collaborating with Lap-Chee on the idea that we could map the gene to a much smaller genetic interval by the same tricks that I had used and honed in studying the hemoglobin mutations. If we had enough markers, we could find the haplotype—the region common to all patients—providing selection had acted on a single allele. That turned out to be a crucial piece of evidence in the CF story. I developed a method by which we could narrow down the region and say, ‘Here is a 300-kilobase segment in which the CFTR gene must lie.’ All of the evidence came together in 1989, and led to the cloning of the gene for cystic fibrosis. This also provided the argument we use today for the mapping of common disease alleles in the general population by genome-wide association studies.”

Trailblazing. “In 1986, I had already begun going down an independent path. I had my own questions to answer, and was no longer satisfied providing tools to answer somebody else’s questions.” Chakravarti decided to focus on a complex disease—one in which many genes are involved—rather than a known single-gene disorder. He identified his first, and lifelong, project thanks to a student. “I was at a student’s master’s oral exam, and she was describing a genetic counseling project she had completed on this birth defect called Hirschsprung disease—and I knew nothing of Hirschsprung disease—and she described her data as arising from multifactorial inheritance whose genes could not be found. I knew it was a very different problem [than she presented] and decided that I was going to find its genes. I went to work out in left field. I always liked working on things where there wasn’t a crowd. I’m still like that—I don’t like crowds.”

Family reunion. To collect samples from families with a history of Hirschsprung disease—a birth defect in which nerve cells fail to correctly develop in parts of the bowel, resulting in an intestinal blockage that is treated by removing part of the colon—Chakravarti set out for rural Pennsylvania in 1990. “We’d been following a large kindred of Old Order Mennonites in Pennsylvania, so I organized a family reunion among them and collected DNA samples from 20 to 25 families. We also went and found families in Ohio, Indiana, and even Canada, related to these Mennonites. In a period of 3 years, we showed that two genes were absolutely necessary for the disease, and made mouse models that showed that even though [either of] the two individually didn’t create a phenotype in the mouse, if you combined them it would lead to a disease that resembled that in humans.” In 1994, his team published their mapping method, called identity-by-descent mapping, which is now a common genetics technique. “We’ve gone on to show many genetic mechanisms in this disease, and it has taught us every genetic lesson one can learn about complex diseases.”


Chalk it up to Chakravarti

Eeny meeny miny genome. Chakravarti spent 7 years working on the Human Genome Project and was chair of the National Human Genome Research Institute Advisory Council Subcommittee for the project from 1997 to 1998. “Early on in the human genome debate, a popular refrain was, ‘Whose genome are we going to sequence?’ This problem was argued to death. Many argued, including me, that the first human that we sequenced really didn’t matter. The whole idea was to do the first reference sequence well and improve the technology, and then sequence other genomes again and again and again.”

DNA for all. In 2000, Chakravarti was recruited from Case Western Reserve University in Ohio to Johns Hopkins to direct the Institute of Genetic Medicine. There, his team, with others, launched the International HapMap project, a freely available catalog of common genetic variants from 270 people with African, Asian, and European ancestry. “People forget that in 1998 to 2000, there were a number of companies trying to revisit the patenting of genetic variation. It was clearly our opinion that having this free and open database was much more useful to everybody.”

Midlife crisis. “In 2005, I had a break in my thinking. I decided tools were always going to change, and I didn’t want to spend my life making tools or being involved in large projects. Since that time, I’ve really tightened up my research agenda. Instead of a little bit of this and that, I said, ‘Enough,’ and refocused. Over time, my lab has studied fewer and fewer diseases.” Today, Chakravarti’s lab researches Hirschsprung disease, rare forms of autism, and sudden cardiac death. “We do not work so much on technology or community resources. We contributed to them, and perhaps it’s a little bit selfish, but now I want to use them.”

The big picture. “The genome project created this mentality that we need the parts list of everything. Scientists now want catalogs of all variants, but as we get into [gene] expression and transcription factor binding and other functional readouts, this is now an infinitely sized problem. Expression when? In what cell type? Under what conditions? The Human Genome Project was successful because it was a finite problem. But now we want to tackle each and every biological problem for all time. I think that is unlikely to happen. We need a few, well-chosen biological problems to solve so that we understand the underlying rules. I don’t have a lot of faith that if we simply build a larger and larger database with genomic, transcriptomic, proteomic, and metabolomic information, we will get to some profound understanding. I’m not saying the solution to some problems will not require a large experiment, but I don’t think the rampant creation of larger databases of everything will turn out to be very useful.”

Fleeting fame. Chakravarti learned a valuable lesson from his work investigating the CF gene. “Despite the major contributions by many to CF cloning, Lap-Chee Tsui did most of the heavy lifting. Nevertheless, many do not even know of his stellar role. That taught me you’d better be interested in what you’re doing, because fame is not going to sustain your interest in the science.”

Carpe diem. “Today, we’re trying to make careers cookie-cutter. You get a PhD, you go to some famous person’s lab, you get an R01—but life is not cookie-cutter. Most trainees have an unrealistic expectation that they’ll get a job and start with a $2 million dowry to begin their research career. And if they don’t get it, they think somehow their training wasn’t worth it, and they should look for a job outside academia. By those criteria, I should be selling shoes or something. But if you are interested in science, and you enjoy doing it, do it. It’s a great life, and having a great life shouldn’t be so connected to money.”


Chakravarti Contemplates

Rich poverty. “I was born in Calcutta, India, where I grew up quite poor but extremely happy in an intellectually rich home. Neither of [my parents] were scientists. My father came from the humanities: he wrote children’s books, he was a soccer player, he acted in the theater and sang on the radio. My mother was the more curious one. My parents gave us the need to read. I read everything and anything. I was one of three brothers and grew up in a very, very small apartment, but it never bothered me that we were deprived of things.”

Cooking with Chakravarti. “I wrote a cookbook as a graduate student, and it got me into a lot of trouble with my advisor because he thought I was wasting my time. I probably was. But it kept my sanity intact. Over the last 4 years, I’ve started cooking seriously again.”

Artful view. “I’ve gotten very interested in collecting Indian art, not that I have much time to do it. I just don’t think the life of a faculty member gives us enough money to cultivate a real interest in art, except for viewing it. Art is a very different kind of experiment—one person’s view of the world through their work.”

I’ll retire when . . . “I’ve really been extremely lucky with some of the trainees that I’ve had. Not only because they’ve done great things, but because they’ve opened doors so I learned things that I otherwise wouldn’t have. People wonder when to retire. I think the day you quit having really good students, you should retire.”  


Greatest Hits
• Pioneered linkage disequilibrium mapping to identify a recombination hotspot in hemoglobin disorders.
• Helped identify the famous deletion mutation that causes cystic fibrosis.
• Mapped the major genes and key noncoding mutations underlying Hirschsprung disease, an inherited birth defect of the gut.
• Chaired the third scientific planning subcommittee of the NIH National Advisory Council for the Human Genome Project and championed the study of common variation in human disease.
• Identified a common polymorphism significantly associated with autism susceptibility.

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Avatar of: nahal


Posts: 2

December 7, 2012

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