Cell Biology, Developmental Biology
St. Jude Children's Research Hospital
Dr. Dyer is also chair and member of the Department of Developmental Neurobiology at St. Jude Children's Research Hospital. Dr. Dyer was an HHMI early career scientist from 2009 to 2013.
Coordination of Proliferation and Differentiation During Neurogenesis
Michael Dyer calls basic research and its rewards "addictive."
The entire process intrigues him—formulating questions, designing and running experiments, interpreting results, and planning next steps.
"Once you've made a discovery, you're hooked," he says. Experiments that don't turn out the way you expected are the most interesting, he adds. "They force you to rethink your assumptions about the underlying biological principles." Dyer's love of the laboratory has paid off twice already, as he's revealed stunning exceptions to traditional views in neurobiology and cancer causation.
In graduate school Dyer became fascinated with the elegant process of embryonic development, which, he says, "works so beautifully most of the time." As a postdoctoral fellow in the Harvard Medical School lab of HHMI Investigator Connie Cepko, he studied how the growth and proliferation of nerve cells are controlled, using her lab's system for manipulating the development of retinal neurons in rodents and chicks.
In 2007 at St. Jude Children's Research Hospital, Dyer made a discovery that challenged the century-old dogma that mature, differentiated neurons can no longer divide. He showed that the Rb gene, a tumor suppressor, normally prevents horizontal retinal neurons from overproliferating. When Dyer blocked Rb family genes in the retina, he observed mature horizontal neurons dividing and forming new daughter cells that maintained their three-dimensional shape and connections with other neurons.
"That was a rare and unusual observation, to say the least," Dyer says. "What normally keeps them from doing that is the question I've been curious about ever since."
Following up on these discoveries has led Dyer, who became an HHMI early career scientist in 2009, to propose that every nerve cell has its own degree of pliancy. That property is established early in development and determines how susceptible the cell is to degeneration or cancer. Cells that resist degeneration may be more likely to become cancerous, and vice versa. Dyer has developed tools to measure cellular pliancy and intends to explore its molecular underpinnings and how it contributes to normal nerve development, cancer, and neurodegenerative diseases.
Showing that mature nerve cells can be made to divide has opened the door to new possibilities for treating a broad range of neurodegenerative diseases, including Parkinson's and Alzheimer's. "If existing neurons could be coaxed to divide and replace cells that have died," 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."
Dyer's studies of the Rb gene have also led to a possible explanation for how cancer—which usually develops over many years as a result of accumulated mutations—can occur so early in retinoblastoma, a rare malignant tumor that develops in infants and children. "How can retinoblastoma progress so quickly and acquire all the hallmarks of cancer?" he asks.
Researchers assumed that the Rb mutation led to massive chromosomal instability and many mutations. But Dyer found just the opposite: some retinoblastomas had few mutations or chromosome rearrangements. Instead, his research demonstrated that mutations in a single gene, RB1, alter the expression of numerous genes throughout the genome without altering the DNA structure itself—an epigenetic cancer trigger.
One of the genes epigenetically influenced is SYK (spleen tyrosine kinase), which is expressed at high levels in retinoblastoma. Dyer's findings, reported in 2012, showed that mutant Rb turns on SYK, while it turns down the expression levels of other genes. He demonstrated that blocking SYK activity with an experimental drug killed the cancer cells; his group is now modifying a SYK inhibitor to be directly delivered to the eye.
When he arrived at St. Jude, Dyer intended to focus on developmental neurobiology, not cancer. After he met retinoblastoma patients and their families, however, and learned that the cloning of the Rb gene in 1986 hadn't yet translated into improved care 17 years later, Dyer vowed to see what he could do to help the young patients. Using a mouse model he developed, he tested new drugs and found that a combination of two existing drugs—topotecan and carboplatin—more effectively killed retinoblastoma cells in mice than the standard treatment. Dyer says that the combination is showing promising early results in patient studies. He is now looking forward to incorporating some of the more selective targeted therapies, such as SYK inhibitors, into retinoblastoma therapy by delivering them directly to the affected eye.