Michael Dyer, a basic scientist at St. Jude Children's Research Hospital, was studying normal eye development and the genetic mutations that cause eye diseases when he was invited to meet a group of patients with retinoblastoma (a childhood cancer of the eye) and their families. The meeting was Dyer's first opportunity to interact with patients, and five years later, that experience still drives him to make discoveries in his laboratory that could translate into more effective treatments and, ultimately, a cure for this catastrophic disease.
When Dyer asked clinicians whether the 1986 discovery of the RB1 gene—the gene responsible for retinoblastoma and the first human tumor suppressor gene to be cloned—had made a difference in their approach to treating patients with retinoblastoma, he was surprised to learn that it had no impact whatsoever. That meeting, says Dyer, motivated him to build a new research program focused on developing treatments in the laboratory that can be efficiently moved into clinical trials.
He's been successful in that effort. For instance, his team genetically engineered a mouse model of retinoblastoma, a key tool for preclinical testing of potential new treatments. Using these mice, Dyer and his colleagues screened drugs approved for other childhood cancers to find a combination of medicines that would kill retinoblastoma cells more efficiently than existing regimens. Their efforts identified two drugs, topotecan and carboplatin, the combination of which appeared to work better than the current standard of care.
In 2006, Dyer teamed with clinicians at St. Jude to quickly move the topotecan/carboplatin combination into a clinical trial in children with retinoblastoma. That trial is now in its late stages, and the early results look promising. The total time from the development of the mouse model to the start of the clinical trial was just 18 months. "It's a great example of how efficiently a multidisciplinary team focused on patients and their families can move a finding from the lab to the clinic," says Dyer.
Since the clinical trial began, Dyer has identified a new genetic mutation that contributes to the disease by making retinoblastoma cells immortal; this malfunction provides a tempting drug target. Working with other St. Jude researchers, Dyer is now screening hundreds of thousands of chemicals to find one that suppresses the genetic error. "To our knowledge, this is the first high-throughput drug screening effort for any childhood cancer," says Dyer.
While investigating the causes of retinoblastoma, Dyer also made a serendipitous discovery that overturned a century of neuroscience dogma. The assumption had always been that once neurons matured and integrated into their surroundings, they could not divide. However, Dyer found that mature horizontal neurons—a type of retinal cell that integrates visual signals into electrical messages sent to the brain—can divide to produce identical daughter cells. Horizontal neurons proliferate out of control, due, in part, to malfunctions in Rb genes. When Dyer suppressed these genes in the retina, he found that horizontal neurons began dividing. Even more remarkable was the finding that while the cells divided, they maintained their elaborate three-dimensional structures, including their appropriate connections to other neurons. Watching this process through a microscope "has fundamentally changed my view of how neurons arise during development and are maintained for a lifetime," says Dyer.
This discovery has opened the door to new possibilities for treating not only retinoblastoma but also a broad range of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. "If existing neurons could be coaxed to divide and replace cells that have died, and we are able to harness this new understanding," says Dyer, "we may be able to improve the quality of life of patients who suffer from those diseases in ways that we hadn't thought possible before." If this line of inquiry comes to fruition, Dyer and his team will have once again bridged the gap between discoveries in the laboratory and application of that knowledge in the clinic.