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Family traits: After sequencing his genome, James Lupski discovered the mutations that led him and three of his siblings to develop a neurological disorder.

More than a dozen people who have had their genomes sequenced stand on stage in an R&D center near Boston. Billed as the last time all such people might fit in one room before the technology moves into the mainstream, the event doesn’t quite include the whole group: actress Glenn Close and South African archbishop Desmond Tutu, among others, didn’t make it. But those who did include James Watson, codiscoverer of the structure of DNA; Harvard historian Henry Louis Gates Jr.; entrepreneur Esther Dyson; and a smattering of leaders from gene-sequencing companies.

Leaning against a wall at one end of the stage is James Lupski, a pediatrician, clinical geneticist, and scientist at Baylor College of Medicine. Unlike many of the others, Lupski wasn’t interested in sequencing as a way to trace his ancestry or determine his future likelihood of developing some ailment. Instead, he had hoped to solve a medical mystery that affects him in the most personal way: the cause of a genetic disorder, called Charcot-Marie-Tooth disease, that struck him and several of his siblings as teenagers, severely weakening the muscles in their legs and feet. After a quarter-century searching for the gene responsible, the 53-year-old scientist finally found it by scouring his own genome, combing through the billions of DNA building blocks represented by the letters A, T, C, and G. It marks the very first time that whole-genome sequencing–determining the exact order of all the letters in an individual’s DNA–has identified the mutation to blame for a specific case of a genetic disease.

Since the human genome was first sequenced a decade ago, scientists have discovered thousands of genetic variations linked to different diseases. Until very recently, however, sequencing an individual genome cost millions of dollars, making it an impractical way to search for the cause of a particular person’s genetic disorder. Now the cost of sequencing has fallen so dramatically that it’s becoming realistic to do just that. A genetic test for inherited nerve diseases, which costs about $15,000, screens for only a limited number of genes. But now sequencing is available to consumers for $20,000 and provides the entirety of a person’s genetic information. Searching through it can reveal genes and pathways whose role in a disorder scientists may never have suspected. This could help illuminate the more than a thousand rare genetic disorders for which scientists have been unable to pinpoint a specific culprit. And it could contribute to a new way of thinking about the role heredity plays in many common ailments, such as diabetes and Alzheimer’s.

In Lupski’s view, the frontiers opened by whole-genome sequencing will be to traditional Mendelian genetics what ­Einstein’s discoveries were to Newtonian mechanics. “Newton wasn’t wrong,” he says. “We were just expanding our understanding to include relativity.” Mendel wasn’t wrong either: single genes and certain diseases do follow Mendelian patterns of inheritance. But, he says, “there are genetic modifiers and new mutations that ‘Mendelism’ perhaps did not anticipate.” Just as Newtonian physics is a special case of Einsteinian relativity, Mendelian inheritance is one piece of a more complete picture that will be revealed in the genome.

To bring that picture into better focus, Lupski is now sequencing the genomes of several patients with rare neurological disorders of unknown cause. The results are unlikely to have much immediate impact on their care: there are no effective treatments for their diseases right now. But the technology could offer new insight into those diseases and guide the way to future therapies.

The Hunt

At Baylor’s campus in Houston, the Human Genome Sequencing Center spans three floors of the building next to Lupski’s office. The center, one of three nationally funded labs in the United States, became a key player in the Human Genome Project in the late 1990s. In 2007, its director, Richard Gibbs, invited Lupski to help sequence the genome of James Watson. The high-profile project, completed later that year, was a technical accomplishment because it employed a new generation of cheap sequencing technologies. But it also highlighted the limitations of the approach: they’d identified mutations in genes whose function they knew little about. What’s more, Watson had no diseases that the researchers could try to trace to a gene. So Gibbs offered to sequence Lupski’s genome.

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Credits: Matthew Rainwaters

Tagged: Biomedicine

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