Steve Warren's search for the fragile X gene
Outfitted in a too-long white coat, Steve Warren played the part of Alexander Fleming, the discoverer of penicillin, in a school play in his East Detroit hometown. The experience convinced the third grader that he wanted to do research, although he assumed (maybe because of the white coat) that he would first have to become a physician. So, like Fleming, he set off on that path, until, like Fleming, the excitement, reality, and urgency of actually doing research changed his direction.
As a freshman at Michigan State University (MSU), in the first of several fortuitous turns, Warren got a part-time job running diagnostic tests for genetic disorders. He had found his field. During summers, he worked with the genetics group at Henry Ford Hospital. His mentors were so impressed that they asked the undergraduate to set up Detroit's first Tay Sachs screening program. Warren used his own blood serum as the control, returning to Detroit every year to donate more liters.
Considering whether to go to medical school, Warren decided to go straight for the PhD. Medical school and residency, which his fiancée Karen was preparing to do, seemed exciting but would take him away from research too long. He was in a hurry. As an MSU undergraduate, he already had taken all the courses required for his doctorate. As a graduate student, he worked in pediatrics genetics, with his own set of patients. He also did research -- publishing 12 papers -- on Bloom syndrome, an extremely rare genetic disease causing increased susceptibility to cancer. He discovered why: cells from patients mutate at higher rates.
Warren first met "marker X syndrome" (the condition later renamed fragile X) as a postdoctoral student at the University of Illinois at Chicago. In another stroke of fortune, a former lab bench mate told him about his own postdoctoral work at the University of Hawaii, then the mecca for marker X studies. Warren was intrigued. Like Bloom disease, marker X had chromosome fragility, but unlike Bloom, in which breaks occur randomly, marker X breakage occurs in one place.
After his postdoc, job offers abounded but Emory University made an offer he could not refuse. Instead of running a diagnostic lab, he could devote all his time to research. He knew his plan to find the marker X gene was ambitious. He told himself if he didn't make tenure, he could always run a diagnostic lab elsewhere.
As the tenure clock ticked, however, the search proved elusive. Emory gambled that he would succeed, based on recommendations from leading scientists and Warren's selection by the Howard Hughes Medical Institute, which had the uncanny ability to recognize and fund researchers just before their first big success.
As described in more detail in the Research section, Warren placed the human X chromosome in a rodent cell line and then looked for a rearrangement of human and rodent genes suggesting a translocation following chromosome breakage. It didn't work because the bacteria in which the fragile human DNA was placed were unstable. Then, serendipitously, he heard Baylor postdoc David Nelson describe how he and mentor Tom Caskey cloned human X chromosome DNA using yeast, not bacteria. The three became collaborators, a team that went international when Holland scientist Ben Oostra provided genetic material from numerous marker X families.
Nobel Laureate James Watson, co-discoverer of the structure of DNA, heralded the Warren team's discovery of the newly named fragile X gene as the "first major human triumph of the Human Genome Project." After the hurrahs died down, Warren assumed that he would start a new search for the genetic basis of some other disease. But there were so many unanswered questions about fragile X. Why was the inheritance pattern so unusual? Why did it have such a wide variability in effect? By then, Warren knew many families with affected children. He could not abandon fragile X.
This decision paid off again and again.
As the Research section describes in detail, Warren's team next characterized the protein produced by the fragile X gene: the result of a mutation in which the chemical information in the gene is repeated multiple times, causing it to stop producing protein. Never before seen, this kind of mutation has since been found in other genetic disorders, although no other psychiatric disorder is understood at the level of fragile X. Understanding the protein enabled Warren to develop the first biological diagnostic test for fragile X and better explain why it could have such a wide range of effects, depending on how much protein was still produced by a damaged gene.
What next? Warren again had the good luck of sitting next to the right person: Brown University's Mark Bear, the scientist who had discovered that the way neurons learn is dependent on protein synthesis. Warren knew that the fragile X protein regulated protein synthesis in neurons so the loss of this protein might weaken synapses between neurons, inhibiting the learning process. This would explain how the faulty gene causes its damage.
And now what? Genetic wisdom then held that insults like fragile X, occurring during development, could not be undone. As an electrophysiologist, Bear shrugged this off. He was used to applying substances to bioneurological systems to see how they reacted. The two scientists wrote a pivotal paper on the possibility of using compounds directed to a specific receptor to compensate for the effects of the faulty fragile X protein.
Labs across the country began looking at such drugs in fragile X mice and fruit flies. Warren and Peng Jin, then a postdoc, now faculty at Emory, went another route, screening some 2000 drugs already approved by the FDA for other uses. (Always in a hurry, Warren knew that prior approval meant there would be no delay in translating to humans.) The class of drug that screened positive made sense with what they knew about how fragile X functioned. And sure enough, when exposed to these GABA agonists, the biochemistry and brain wiring of drosophila with fragile X began to become more normal and their fragile X-type confusion and behaviors began to change. Clinical trials in humans are now under way.