Two researchers embark on a new collaboration in Woods Hole, using squid to study neurodegeneration.
Constanza Villalba
When University of Illinois cell biologist Scott Brady agreed to have Barnard College student Hannah Brown work in his lab during the summer of 2001, he had no idea who her father was.
Brady eventually learned that Hannah’s father was Robert Brown Jr. of Massachusetts General Hospital, whose lab discovered the first genetic mutations involved in amyotrophic lateral sclerosis (ALS). But Brady didn’t imagine that Hannah would eventually foment a collaboration between himself and her father, a collaboration that would make Brown one of the few ALS researchers who use squid to study the pathogenesis of the disease.
Brady spends his summers at the Marine Biological Laboratory in Woods Hole, MA, where the staff supplies him with long-finned squid, Loligo pealei. He uses the organism to study how neurons shuttle vesicles—tiny sacs that carry vital cell constituents—up and down the axon, the elongated part of a neuron. This movement of vesicles, called axonal transport, is particularly easy to study in the squid, because some of the animal’s axons are 1,000 times wider than the average human’s. Researchers can simply squeeze the contents of a giant axon onto a coverslip, much as you would squeeze toothpaste out of the tube, and then watch vesicles move in real time.
“We can obtain the axon’s contents in a highly ordered fashion—without dilution or disruption,” says Brady. “Then we can introduce whatever we want and look at the effects.”
Using squid preparations, Brady and others have shown in the last few years that abnormal proteins found in people with certain neurodegenerative diseases slow down axonal transport. He believes that this impaired transport could be at least partly responsible for the high rates of neuronal death characteristic of these diseases. Because of slow transport, parts of the neuron might not be getting the molecules it needs to function normally. Hannah learned about this first hand during her summer in the Brady lab.
Now Brady and his team suspect that transport inhibition might be a common feature in several neurodegenerative diseases, including Huntington’s, Alzheimer’s, Parkinson’s, and ALS.
Like other neurodegenerative diseases, ALS is marked by the presence of mutant proteins. In some forms of ALS, the affected protein is an enzyme called superoxide dismutase (SOD1), which Robert Brown has been studying for many years. He’s been struggling to understand just how the enzyme exerts its toxic effects.
After some time in Brady’s lab, Hannah began to wonder whether the mutant enzyme her father studied might inhibit axonal transport in the squid. Last year, after spending two more summers with Brady at Woods Hole and starting medical school at Harvard, she asked Brady if she could bring mutant SOD1 enzymes from her father’s lab to Woods Hole. Her first experiments with the enzymes took place last summer.
Joe DeGiorgis, an axonal transport specialist at the National Institute of Neurological Disorders and Stroke in Bethesda, MD, thinks their research sounds promising. He believes the squid is becoming an important model for human disease, so much so that he is mapping the squid genome. Knowing which genes are expressed in the squid could make the organism a more useful model for studying human disease.
The Brady-Brown collaboration is just starting out, and they have more experiments to do, so their findings have yet to be published. Hannah, now in her second year of medical school, will not be able to return to Woods Hole this summer, but she plans to keep close tabs on the research she started. Meanwhile, Brady, like the squid he studies, will return to the Cape when the weather warms up.
Constanza Villalba is a freelance writer in Waltham, MA.