Jonathan and Bonnie Rothberg share not only a home and family but also a passion for probing the mysteries of the human genome. Together and separately, they attempt both to untangle genetic differences among individuals that can affect disease and to develop novel treatments that target disease at the genetic and molecular levels.

In 1993, when many scientists were trying to decipher the human genome, Jonathan Rothberg, Ph.D. ’91, had a vision: to mine the genome for drug targets. He founded CuraGen, a company that uses information systems, automation and robotics to develop drugs that target specific genes. In the company’s early years, Jonathan would bring home sets of newly generated differential gene expression (DGE) profiling data sets and ask his wife, Bonnie Gould Rothberg, M.D. ’94, M.P.H. ’05, to apply her medical background to make sense of the data. By January 1997, midway through her internal medicine residency at Yale-New Haven Hospital and with Jordana, the first of their three children, still an infant, she decided to place her clinical training on hold and assume a full-time position designing and analyzing DGE data. So she joined Jonathan at CuraGen, where she developed a pharmacogenomics program to understand the mechanisms that underlie differing responses to drugs. CuraGen developed five drugs (all in preclinical and clinical development) for treating cancer, the adverse effects of chemotherapy, kidney inflammation and type 2 diabetes.

As CuraGen grew, so did the Rothberg family. The birth of their second child, Noah, in 1999, led Jonathan to start another company. Noah turned blue the night he was born and the doctors had no idea what was wrong. “I wished I could just read off his genome,” said Jonathan. “I had a computer magazine with me and I thought that since the computer guys have been able to make things a million times faster and a million times cheaper by putting them on a chip, why not the genome?” Noah quickly turned a healthy pink, but nonetheless Jonathan created a new company, 454 Life Sciences, to pursue his vision of sequencing genomes.

454 Life Sciences is also attempting to reconstruct the genome of Neanderthals, an evolutionary predecessor and possibly a subspecies of modern Homo sapiens. “The wonderful thing about the Neanderthal project is that we may uncover the molecular basis for the mind,” Jonathan said. Since the genetic difference between modern humans and Neanderthals is only one-twentieth of 1 percent and the main distinction between the two species is largely cognitive, it’s possible that just a handful of genes are involved in human brain function.

But that’s not the Rothbergs’ only project. In 2002, Jonathan formed The Rothberg Institute for Childhood Diseases, a nonprofit organization dedicated to finding a cure for tuberous sclerosis, a genetic disorder that causes benign tumors to grow in the brain and other vital organs throughout the body, as well as cures for other orphan diseases of childhood. With three children under the age of five, Bonnie joined the institute as director of clinical development. Although her medical degree served her well, she felt that she needed formal training in clinical research design and analysis to conduct large-scale clinical research. While earning an M.P.H. at Yale, she rediscovered genomics as a subdiscipline of molecular epidemiology and is now pursuing a doctorate in chronic disease epidemiology. She is working with David L. Rimm, M.D., HS ’91, Ph.D., associate professor of pathology, using tissue microarrays to find proteins that could serve as prognostic markers for the speed of growth in melanoma tumors. Her work has also come full circle: at CuraGen she participated in the discovery of a drug for melanoma, a disease that she is now studying at Yale, where the drug is currently being tested.

With 25 U.S. patents, work featured on the covers of Cell, Science and Nature and election to the National Academy of Engineering in 2004, Jonathan has moved on to his next project, which he calls the culmination of his life observations. “If you walk into a lab, it’s very inefficient,” he said. “So I decided that instead of just miniaturizing gene sequencing, why not create a general-purpose machine very much like a computer but that would move chemicals or lab components around?” In 2004, he founded RainDance Technologies to develop a system for testing, profiling or sorting samples used in chemistry, molecular biology and biochemistry on disposable chips. The company expects to ship its first machine, which it calls the Personal Laboratory System, or PLS, in 2007.

Although Jonathan and Bonnie are both fascinated by science, it wasn’t their shared academic interests that brought them together. The two met at a party in 1993, but only began dating three months later when Bonnie found an opening in her on-call schedule. They were married in 1995. Jonathan acknowledges that hundreds of dedicated people have helped him turn his groundbreaking ideas into commercial successes. But he recognizes that his most important partnership, in life and in work, is with Bonnie.