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Developmental neurobiologist J. Paul Taylor, MD, PhD, thrives in an environment that promotes stellar science. And it never hurts to throw in a healthy dose of serendipity.
In pinpointing rare genetic mutations involved in motor neuron diseases, he and his colleagues at St. Jude Children’s Research Hospital made a stupendous realization; their findings also uncovered clues essential to understanding a molecular mystery that has eluded cancer experts for more than a decade.
“Five or 10 years ago, nobody would have imagined that the gene families involved in motor neuron diseases were similar to genes involved in childhood sarcomas,” Taylor says.
This finding is the latest in a series of discoveries suggesting that degenerative diseases and cancer may have common origins.
Finding new, rare genetic changes involved in motor neuron diseases was a Herculean task, made possible only by the powerful technology available at St. Jude.
“Years ago we found disease genes the ‘old-fashioned’ way,” Taylor says. Progress was limited because researchers needed to study large families to make a connection between a disease and a specific genetic change.
Then along came a game-changer: a new type of technology called high-throughput genome sequencing, available as part of the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.
“The technology brought to St. Jude by this project enabled us to start finding these genes,” Taylor says. “This discovery would not have been possible without the Pediatric Cancer Genome Project.”
It was only in the nuts and bolts of the discovery that the connection to cancer became clear. To find the culprit mutations, Taylor’s team scrutinized the genomes of several families with motor neuron diseases and found two rare mutations not previously linked to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The genetic changes altered a region or domain found in specific types of proteins that help deliver genetic instructions within cells.
Abnormalities in this type of protein domain have also been found to be responsible for most cases of Ewing sarcoma, a bone cancer that occurs in children and adolescents. However, it was a mystery what the protein domain normally does inside cells, an essential piece of information for understanding its role in disease.
“The normal function of the domain was critical for us to determine, because it is the key to understanding ALS, and it is the key to understanding sarcomas,” Taylor says.
What his team found was surprisingly simple. The domain, now known as a prion-like domain, normally allows proteins to clump together to perform their duties in cells and then disperse when the job is complete. But in cells with the disease-causing mutations, the proteins continue to accumulate instead of being disassembled.
In ALS, the mutation appears to cause a blockade of the chemical and electrical signals that control muscles in the limbs and torso, and muscles that control speech and breathing. The disease causes paralysis and is usually fatal within five years of diagnosis.
The discovery makes St. Jude the first to reveal the function of the prion-like domain in proteins associated with many diseases.
Armed with the new insights, St. Jude researchers are now investigating exactly how the mutations in this domain drive cancer.
“This is an exciting time. It is conceivable that if we find a drug that disentangles these prion-like domains, not only would that be beneficial for blocking ALS, but the same drug would be used to treat children with Ewing sarcoma,” Taylor says.
He is collaborating with St. Jude colleagues to connect the dots.
“We want to take full advantage of molecular-targeted therapies for pediatric solid tumors,” says Howard Hughes Medical Investigator Michael Dyer, PhD, of St. Jude Developmental Neurobiology. “Integrating laboratory-based research with clinical research is essential to raising the survival rates for children with these cancers.”
Discoveries that cross the boundaries between childhood and adult diseases can occur seamlessly at a place like St. Jude, where scientists and clinicians collaborate to understand the foundations of disease processes.
Basic research like Taylor’s is necessary to underpin future progress.
“This exemplifies the importance of fundamental research,” he says. “A narrow research focus may only offer limited opportunities for insight into what’s causing disease. If you broaden your scope and define your research on the basis of fundamental questions about the biology of disease, it can yield some unanticipated connections.”
Abridged from Promise, Summer 2013