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Interview with Breakthrough Prize-Winning Neurologist and AAAS Fellow Mahlon DeLong

Emory University neurologist and AAAS Fellow Mahlon DeLong was one of six scientists awarded a $3 million Life Sciences Breakthrough Prize in December. DeLong received the award for his work studying the brain circuits involved in Parkinson's disease.

A group of billionaires including tech giants Mark Zuckerberg and Sergey Brin began awarding the prizes in 2012 with the goal of "advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career." The awards ceremony—which the founders hope will help bring celebrity to the winning scientists—was hosted by actor Kevin Spacey and aired on the Science Channel on Jan. 27.

DeLong and the other winners will help select next year's Breakthrough Prize recipients. AAAS MemberCentral interviewed DeLong about his research, his reaction to winning the prize, and his advice for young scientists.

AAAS MemberCentral: Please briefly describe your research.
Mahlon DeLong, Emory neurologist and AAAS Fellow: Our research has been focused on the role of a group of interconnected brain structures—the basal ganglia—which lie deep in the cerebral hemispheres. At the time I began my research, the function of these structures was uncertain, although it was well recognized that diseases affecting the basal ganglia were associated with major disturbances of movement, including difficulty initiating and executing movement, as seen in patients with Parkinson's disease. I focused initially on the role of these nuclei in the initiation and control of voluntary movement. We found that only a portion of the basal ganglia were involved with movement. After numerous studies we concluded that the basal ganglia were organized differently from what had been believed. We concluded that, just as in the cerebral cortex, separate regions of the basal ganglia were involved with movement, cognition and emotional/reward functions. We viewed the basal ganglia as components of large segregated cortical-subcortical networks. This schema of a family of parallel pathways helped us to understand how disorders of the basal ganglia, such as Parkinson's and other neurologic diseases, result in disturbances not only of movement, but also of cognition, complex behavior, emotion and reward. It also led to our finding of an important role of the motor circuit in the symptoms of Parkinson's disease.

It had been found in the 1960s that the basal ganglia contained large amounts of the neurotransmitter dopamine and that the loss of this transmitter was responsible for the development of Parkinson's disease, a neurologic disorder characterized by tremor, slowness of movement and muscular rigidity. Although it had been dramatically demonstrated that replacement of dopamine was initially highly effective in treating this disorder, the later development of drug-induced side effects in many patients limited its usefulness. Novel therapeutic approaches were greatly needed.

Although dopamine loss was clearly responsible for the development of the motor features of Parkinson's disease, the actual changes in the basal ganglia were unclear. Our studies demonstrated excessive and abnormal discharge of cells in two components of the basal ganglia, the internal pallidum and the subthalamic nucleus (STN). In a series of studies we showed that inactivation (lesioning) of cells in the motor portions of the STN as well as in the internal pallidum, resulted in an immediate cessation of tremor and rigidity and restoration of more normal movement. These findings provided strong evidence that abnormal activity of brain cells in portions of the basal ganglia was responsible for the symptoms of Parkinson's. They provided, as well, a clear rationale and novel target for surgical approaches in patients with advanced disease. Importantly, these studies contributed significantly to the revival of surgical treatments for Parkinson's—in particular, direct lesioning of the internal pallidum (pallidotomy), a procedure that had been largely abandoned following the introduction of levodopa [a Parkinson's medication].

The subsequent introduction of the less invasive technique of high-frequency electrical deep brain stimulation (DBS) by Alim Benabid, when applied to the STN, provided the same clinical benefit as lesioning. The use of DBS, which acts like a cardiac pacemaker for the brain, produces clinical effects similar to lesioning, but has a major advantage in that it does not cause irreversible damage and is adjustable and reversible. Deep brain stimulation of the STN is now the treatment of choice for patients with advanced Parkinson's who are intolerant of levodopa and related drugs as well as other movement disorders.

AAAS MemberCentral: Share a story from your past that led to you choosing your field of work.
DeLong: I had always planned to be a physicist and had taken only "hard science" courses in high school and early undergraduate years. I actually left physics in order to study history and spent a year abroad as an exchange student and got my undergraduate degree in history. It was only in my last year of undergraduate work that I had a rather sudden awakening about brain research, where there were fascinating questions about behavior to be answered. I turned to neurophysiology, which seemed to me to be the most direct way of studying the brain at that time. I attended medical school and spent years afterwards doing basic research, but eventually became a neurologist, working closely with neurosurgeons.
AAAS MemberCentral: What was your reaction when you won the Breakthrough Prize?
DeLong: My initial reaction was a combination of shock and disbelief.  Like most who receive such recognition, I felt how difficult it was to take sole credit for work that involved major effort and input from students, fellows and colleagues. I also realized how fortunate I was to have had so many opportunities and good luck. My years of pure research were fundamental in preparing me for the later clinical phase, since I gained tremendous experience and familiarity with the basal ganglia.
AAAS MemberCentral: What has surprised you the most about your career?
DeLong: I would say how many different directions I took, from hard sciences, to history and finally basic neuroscience and clinical application in neurology and neurosurgery. At all points, I realize I was just following my interests and responding to opportunities at hand.  
AAAS MemberCentral: What advice do you have for young scientists?
DeLong: When it comes to picking a career, do what you really enjoy, so that "work" doesn't become work. To me, research was like being on a voyage of discovery to places where no one had ever been. The excitement of this is at times addictive, although most of the days were routine and hard work. Be ready for the opportunities that come your way, especially the unexpected ones. Have a plan and do the things you like, but be willing to take chances and advantage of unexpected opportunities. Work with the best people you can, in the best places you can—and when it is your time to shape initiatives and programs, find the very best people you can, especially if you think they are even better than you.


Summer Allen

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