Cracking Cases With a Genetics Gumshoe

Brendan Lee, Researcher

Photography by Charles Ford By Jerry Ianelli May 31, 2015 Published in the June 2015 issue of Houstonia Magazine

Image: Charles Ford

Brendan Lee was 23 years old the first time he discovered a new gene. The year was 1989, and Lee, now the chair of the Baylor College of Medicine’s Department of Human and Molecular Genetics, was a graduate student at the State University of New York Downstate Medical Center, one of the nation’s top medical schools. He’d been tasked with treating more than eight members of a family who were all living with the exact same type of skeletal dysplasia, a group of disorders that cause dwarfism. This was long before anyone had mapped out the human genome, however, so Lee was armed with little more than his wits and a backlog of medical literature. “It was like a detective story,” he remembered. “We didn’t have all the technology we have now. All we knew was that the son was short, the father was short, and that they all had terrible osteoarthritis.” 

He began by making a detailed list of the family members’ symptoms: all were of short stature, suffered from back problems and had growth plate abnormalities and eroded cartilage in their joints, the last of which had caused the arthritis. Oddly, all suffered from eye issues as well. “They were all very nearsighted,” he said. Aware that there were only a handful of genes that impact such a disparate set of body parts, Lee correctly isolated one—COL2A1—which regulates the production of collagen in bone cartilage. “It was like landing on the moon,” he said. The discovery, which he and four colleagues subsequently wrote about in Science magazine, helped him land a residency at Baylor, where he’s remained ever since, hunting down rare diseases for the better part of two decades.

Last July, the National Institutes of Health announced it was creating a countrywide network devoted to studying what it termed the “most difficult to solve” medical cases in America. The labs of just six hospitals were chosen to participate, hospitals like UCLA, Harvard, Duke—and Baylor. The partnership, called the Undiagnosed Disease Network, will essentially crowd-source patient data among the member hospitals, in the hope that someone suffering from a mystery condition in, say, California could have Lee sequence his or her genes in Texas without having to fly all the way here. In this way, Baylor’s lab hopes to treat 150 patients over the next four years. “The goal is not for any of the single sites to work alone,” Lee said, “but to collectively leverage the national brainpower.” After nearly a year of planning, the network is scheduled to go live soon, whereupon patients will be able to upload their medical data to a web portal and request help without a doctor’s referral. 

There are some 5,000 to 8,000 disorders considered rare by modern medicine—that is, afflicting less than 6 percent of the population. These include things like Marfan syndrome, cystic fibrosis and a host of lesser-known maladies. “When I started my career, rare diseases were thought to be ‘zebras,’ or unusual happenstances of nature” without genetic bases, Lee said, words flying from his mouth at a mile-a-minute pace, as if any second lost to frivolity is one he could have spent saving a life. At 49, his face is young-looking (his round cheeks squeeze into dimples when he smiles), although a hedge of thick, wolf-like gray hair envelops his head, giving him the overall air of a college student wearing a wig. 

Lee, who was born in Hong Kong, moved with his family to New York as a young child, promptly embarking on a series of academic successes so outrageous they border on comedy: He skipped a year of middle school, got into Stuyvesant High School (New York’s famed magnet school for the hyper-intelligent), completed his bachelor’s degree in three years, and skipped yet another year on the way to earning his PhD. At Downstate, he nearly studied chemistry until, fortuitously, a professor roped him into joining a new molecular biology institute that had just formed at the university. “At the time, all I knew about DNA was that it was a big molecule and there was a lot of it,” Lee recalled. Still, the potential for sleuthing excited him. “It’s a view onto nature that no one has ever seen, on some level.” 

He decided to focus on treating children, mostly because rare disorders usually manifest themselves early in life. Many such illnesses are left undiagnosed or misdiagnosed each year, especially when a patient shows symptoms that a doctor has never seen before. “Time to treatment can vary dramatically,” Lee said. “Part of the reason is because, if it’s something that has no context at all, it can be many years before we understand the mechanism” at work. 

He typically begins by extracting DNA from blood samples he takes from his patients, then inserting it into genetic sequencing machines, which resemble whirring inkjet printers with flat-screen monitors attached. But while the machines reveal the sequence, the interpretation of that sequence is entirely up to Lee and his team. “That’s one of the most important steps, the interpretation,” he said, adding that one disorder could be caused by hundreds of different genes. “That’s the real holy grail of the process.” 

Consider the case of East Texas native Jonathan Oliphint. In 2010, Oliphint, then 15, was suffering from a rare genetic condition that caused ammonia to build up in his body, making his blood pressure swing up and down wildly. That year, his blood pressure shot up dangerously high and wouldn’t stabilize, no matter what medications his doctors prescribed. Lee had previously treated Oliphant, so when the boy’s parents contacted him about his present condition, Lee went to work, eventually locating the culprit in a malfunctioning gene, one which regulated the amount of nitric oxide in Oliphant’s body. After treating him with organic nitrates (the same sort of medicine often given to angina patients), the boy’s condition stabilized. Once again, Lee had used DNA evidence to solve a case.

“It’s like genetic CSI,” Lee reflected. 

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