The phrase “you have Huntington’s disease” has long been one of the most dreaded a doctor can utter. But today, thanks in part to work at MIT, the first glimmers of hope for progress against Huntington’s may be starting to appear.
The dread, which keeps many at risk for the inherited brain disorder from even undergoing genetic testing, is understandable. The disease leaves victims subject to uncontrollable body movements, severe depression and an Alzheimer’s-like loss of memory. Moreover, it’s almost always fatal.
Treatments exist that ease some symptoms but there’s no cure, says MIT’s Troy Littleton, who got to know several Huntington’s patients while in medical training in Texas. Depending on how bad your genetic defect is, he says, “you may die in your late teens, or you may live into your 40s.” But you won’t survive into old age.
Littleton, who has appointments in both biology and brain and cognitive sciences, and who is a member of the Picower Center for Learning and Memory, wants to change that grim outlook. His methods involve deploying the tools of molecular biology to explore exactly what Huntington’s does to the brain. One shorter-term goal is to identify another gene defect that blocks the action of the mutant Huntington’s gene. Longer term, he hopes his work will aid the struggle against not only Huntington’s but other neurological disorders, including Alzheimer’s and Parkinson’s.
The Catfish Effect
Taking part in a quest for a Huntington’s cure isn’t something Littleton dreamt about as a boy. Growing up in a small city in rural Louisiana, he says, “I didn’t know what a scientist was.”
Littleton did have a flair for science, though, which led him to set his sights on becoming a doctor. But his first job as a Louisiana State University undergraduate helped change his mind.
“When I was a senior in high school, the university sent me a list of the part-time jobs available,” says Littleton. “There were things like working on the grounds, and this being Louisiana, that didn’t seem very appealing.” Another entry, though, was “research assistant.” “I thought, ‘Work in an air-conditioned lab? That sounds like a really good idea.'”
While at the lab, whose focus was catfish sensory systems, the young Louisianan found himself drawn by the allure of research. He did go on to get an M. D. degree, at Baylor College of Medicine in Houston, and has no regrets –– his encounters with patients, he says, “were an experience I wouldn’t trade for anything” –– but he also earned a Ph.D. in neurobiology.
In probing Huntington’s –– whose victims include the late writer and folksinger Woodie Guthrie –– Littleton relies on studies of the fruit fly. And if that seems like an odd choice, in fact it makes a lot of sense.
Many of the fruit fly’s genes are known to be similar to ours. And while that trait alone doesn’t set it apart from thousands of other species, others do.
Scientists have studied the insect for years, so its genes and practically everything else about it are pretty well understood. Generations of flies can be bred very rapidly –– a big plus when you’re probing a hereditary ailment. And, it’s easy to study the biological equivalent of the electrical-wiring junctions that are part of the flies’ tiny but still complex brains.
These brain cell-to-brain cell links are called synapses. “We’re really interested in the synapse,” says Littleton, “and Huntington’s seems to have fundamental effects at these junctures.”
What kinds of effects? One theory is that the protein linked with the abnormal Huntington’s gene forms clumps in brain cells. These so-called aggregates then travel down the cells’ feathery appendages and block the cell-to-cell signaling we all need to function normally.
Using flies with human Huntington’s genes engineered into their genetic machinery, Littleton has turned up evidence for this idea. “We’ve shown that the aggregates do travel toward the synapse,” he says.
Search For New Defects
But while the flies involved show Huntington’s-like symptoms, the results don’t prove the causation theory. Impeded signaling probably does play a role in the disease, says Littleton, “but we just don’t know whether that’s the main cause.”
While seeking to solve such mysteries, his lab is also looking for gene changes that protect flies against their Huntington’s-like ailment. Even with a fast-breeding species it’s a grueling task: you create “random” mutations in flies with bad Huntington’s genes, and if particular insects escape the disease you launch a high-tech quest for the gene change that produced the protective effect. But since no good alternatives for patients exist, efforts like his lab’s are essential.
“Someday, gene therapy may protect individuals who have the Huntington’s gene,” says Littleton. “But the one million-plus individuals who will be afflicted by Huntington’s in the next 25 years or so are probably going to need some kind of drug treatment.”
Needed, says the scientist, is an agent that helps individuals at risk for Huntington’s without causing severe side effects. “We need to disrupt the toxic effects of the disease-causing mutant Huntington’s protein without interfering with the protein’s normal functions in the body,” he explains. “And that’s what we’re trying to do.”