Profiles in Cancer Research
Dr. Raju Kucherlapati
Paul C. Cabot Professor of Genetics and Professor of Medicine, Harvard Medical School Director Emeritus, Harvard Medical School-Partners HealthCare Center for Personalized Genetic Medicine
Principal Investigator, Genome Characterization Center, The Cancer Genome Atlas
Like the thousands of scientists from around the world who worked on the Human Genome Project (HGP), Dr. Raju Kucherlapati knew it would take unprecedented teamwork and determination to tackle one of history’s great scientific challenges. Fifteen years later, they had successfully mapped the genome, but their success was only a first step toward a new kind of medicine.
“Our goal now is to help physicians to better understand human disease and develop medical tools that can help match treatments to individual genetic variations,” said Dr. Kucherlapati. He was a key contributor to many of the scientific milestones that led to the Human Genome Project, a collaborating researcher while it was under way, and among the authors of the published results.
During the subsequent decade at Harvard, he has been instrumental in key initiatives as the era of personalized medicine has begun to take shape. “If you want to translate scientific knowledge into clinical practice, you’ve got to be closely affiliated with patients and a good hospital,” he explained.
He also serves as a principal investigator for The Cancer Genome Atlas (TCGA), an effort funded by NCI and the National Human Genome Research Institute that builds on the Human Genome Project to systematically characterize the genomic changes that occur in cancer. He and researchers at Harvard Medical School and Brigham and Women’s Hospital, one of TCGA’s Genome Characterization Centers, are working to characterize the genetic and genomic changes found in cancer samples. Their goal is to understand how cancer develops and to identify meaningful subtypes of cancer to help determine which drugs are most likely to work and in which patients. This research could also lead to novel therapeutic approaches.
Early Days and Compelling Colleagues
Born in India during World War II, Dr. Kucherlapati came to the United States in 1967 to attend graduate school at the University of Illinois. Very soon he became interested in the work of Dr. Frank Ruddle, a professor at Yale whose genetics laboratory was at the forefront of human gene mapping.
In exploring the possibility of a post-doctoral position in the lab, Dr. Kucherlapati decided to simply contact Dr. Ruddle directly. “I didn’t quite realize how presumptuous it might seem to just fire off a letter to Yale,” he said, but he was delighted to receive an invitation in response. “When he said, ‘Come on over!’ I packed up my Volkswagen Beetle and headed to New Haven the day after my thesis defense, before he could change his mind.”
For decades, most work on the behavior of genes was done not in mammals but in fungi and bacteria. At that time, the Ruddle lab was helping to pioneer methods to sequence human genes.
The Ruddle lab attracted interest from a number of researchers, including a geneticist from the University of Wisconsin, Dr. Oliver Smithies, a future Nobel Laureate with whom Dr. Kucherlapati began mapping the beta-2 microglobulin gene. Their relationship continued after Dr. Kucherlapati became an assistant professor of genetics at Princeton, and it eventually led to an effective way to target genes that would become a staple of genetic research, the “knockout mouse.”
Dr. Kucherlapati later played a key role in helping NCI develop the Mouse Models of Human Cancers Consortium in the 1990s. He helped newly appointed NCI Director Dr. Richard Klausner decide that significant new progress could be made if there were better model systems for studying genetics, and he would eventually be one of the authors on the 2002 paper that reported the sequencing of the mouse genome.
Decoding the Human Genome
By 1990, Dr. Kucherlapati was on the Genome Research Review Committee, providing peer review for grants to support the Human Genome Project, and would later serve on the National Advisory Council for Human Genome Research.
He was also active in the lab. The vast undertaking of the Human Genome Project was organized around the 23 pairs of human chromosomes, where the DNA base pairs are strung in long sequences, some of them composing genes. Dr. Kucherlapati received funding to work on chromosome 12 and collaborated on the project with several other prominent researchers, including Dr. Richard Gibbs, currently director of the Human Genome Sequencing Center at Baylor College of Medicine.
“The goal was always to try to bring together different people who were already doing the work,” Dr. Kucherlapati explained. “Frank [Ruddle], Sherman Weissman, and David Ward from Yale joined in, and altogether we constituted a national ‘team’ for [chromosome] 12,” he said, “first mapping and later for sequencing.” The scientists talked on the phone often in this pre-Internet era, and convened for meetings a couple of times each year. “Raju brought amazing leadership and organization to the chromosome 12 group,” said Dr. Gibbs. “He’s a valuable colleague and much appreciated collaborator.”
“We shared everything about what we were seeing and doing. It was really the first time at the NIH that we agreed to deposit all of the data generated in our separate labs in the public database within 48 hours,” recalled Dr. Kucherlapati. “It was highly controversial. There were those who just hated it; who thought that big science is not real science or that all good science has to be done in small, individual labs. But I’ve always felt that working with other people is exciting.”
Team Science Can Be Personal
And he was very good at it, said Dr. Smithies, who cherishes their long and rewarding friendship. “Successful collaborations often make for the best of friends. We’ve worked together on a number of projects,” Dr. Smithies recalled, thinking fondly of many long weekends spent discussing science and other topics with his friend and colleague.
As their collegial relationship matured, said Dr. Smithies, it exemplified the key to successful collaboration. “You really have to think about what can benefit the other person,” he said. If everyone takes that tack, he has found that one’s own interests will automatically benefit.
The beta 2-microglobulin project took about 3 years, and Dr. Smithies said that it was their previous collaborations that made it work so effeciently. “Without some of the things I learned in our earlier work together, I wouldn’t have been able to design the experiments” that ultimately led to the 2007 Nobel Prize in Physiology or Medicine. In fact, on one of the key papers referenced in that citation, published in Nature in 1985, Dr. Kucherlapati was listed as senior author.
“When he won the Nobel, Oliver asked me to come to Stockholm,” said Dr. Kucherlapati. “It was tremendously exciting to be a part of that.”
“The collaboration with Raju,” said Dr. Smithies, “and the friendship that grew out of it, I regard as a very precious part of my scientific life.”
The list of scientists Dr. Kucherlapati has worked with is long and illustrious, and the era of human genetics his career has spanned has been historic. Far from looking back, however, he is energetically advocating for the transformation of medicine that is now becoming possible.