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At the Helm of the NINDS, Dr. Walter Koroshetz Speaks About New Initiatives

ARTICLE IN BRIEF

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DR. WALTER J. KOROSHETZ: “The good news is that neuroscience is attracting the best and brightest in science and medicine.”

Walter J. Koroshetz, MD, FAAN, talks about the influences that inspired his journey to neurology and the helm of the National Institute of Neurological Disorders and Stroke.

Had Walter J. Koroshetz, MD, FAAN, not joined a debate team in high school and realized that both sides of an argument provided equally cogent information and that there was no ground truth, he might have followed his heart into law. Dismayed at the power of manipulating words to sway an audience, he soon found himself at a local public library in Brooklyn, running his hands over an 888-page book, The Theory and Practice of Psychiatry. He read the first chapter on neurotransmitters and ion channels and was fascinated by the physical basis of neural activity. You can't argue with physics, he thought.

The following year, in 1971, Dr. Koroshetz arrived for freshman classes at Georgetown University and asked his biology professor about opportunities to do summer research in the area of ion channels and membrane biology. That landed him for two summers working in the laboratory of physiologist Jorge Fischbarg at Columbia University, who showed him how to measure the flow of ions across epithelial cells. Dr. Koroshetz was excited to be able to record electrophysiological signals and watch neurotransmission happening in real time. He continued to study ion channels and transporters throughout medical school at the University of Chicago Pritzker School of Medicine.

On June 11, Dr. Koroshetz, acting director of the National Institute of Neurological Disorders and Stroke (NINDS) since October 2014, was officially named its director.

Looking back on his long and distinguished career in neurology, Dr. Koroshetz laughed at the recollection of yet another paper that ignited an internal fire in the newly minted physician. In medical school in the late 1970s, Dr. Koroshetz became disillusioned with the reality that the field of neurology had very little to offer its patients. After medical school, he entered a residency in internal medicine and really enjoyed the therapeutic applications in the fields of intensive care, cardiac care, and general medicine.

During his second year of residency, while considering what medical subspecialty to pursue, he picked up a paper by C. Miller Fisher. Dr. Fisher, a Canadian-born neurologist, was the first to offer detailed descriptions of many neurological conditions, but was at his core a passionate student of the brain and behavior.

In the paper that captured the young Dr. Koroshetz's attention, Dr. Fisher wrote in exquisite detail about the neuro-ophthalmologic ocular changes that occur in dozens of different neurological syndromes. The precision, detail, and implications of this and his other works suggested that Dr. Fisher had an unusually prescient notion about how the brain worked. Fascinated by the neurology, Dr. Koroshetz applied for a second residency in neurology and moved to the Massachusetts General Hospital (MGH), where Dr. Fisher was still very active. “In Dr. Fisher's mind there was an underlying neurology to everything,” said Dr. Koroshetz. “He was the most amazing scientist I've ever known.”

In a telephone interview, Dr. Koroshetz talked to Neurology Today about life at the helm of NINDS and his plans for projects that will take advantage of the amazing advances in neuroscience and neurology that are leading to a richer understanding of diseases, and novel treatments for conditions that have never known cures.

HOW DID YOU GET TO THE NIH?

In 2007, I was being recruited to become a chair of neurology. I asked a good friend and former colleague, neurologist Dennis Landis, about his move from MGH to become a chair at Case Western. He suggested that there was a better job available and that I apply for the deputy director opening at NINDS. His wife, Story Landis, had been running the institute since 2003. It turned out to be a wonderful job as Dr. Landis was a great director and we worked together very well. Eight years later I am still on a steep learning curve, and am thrilled to lead NINDS forward during such an exciting time in neuroscience.

IS YOUR WORK GOING TO BE ANY DIFFERENT NOW THAT YOU'VE COME OUT ON TOP IN THE NATIONAL SEARCH FOR A NEW DIRECTOR?

Every director inherits challenges and must always have an eye towards the future. When I got here in 2007, it was clear that we needed a more efficient system to run clinical trials. Dr. John Marler started the Neurological Emergencies Treatment Trials (NETT) Network, which brings together a cohort of investigators at dozens of centers throughout the country to conduct clinical trials on acute injuries and illnesses that affect the brain, spinal cord, and peripheral nervous system. The NETT researchers have implemented protocols executed by paramedics working in the field or by doctors in the emergency department. It has proven very efficient in enrolling people in trials and moving the studies through to the conclusion.

With Dr. Petra Kaufmann, a neurologist recruited from Columbia University, we started the Office of Clinical Research and changed the way we were running clinical trials. We created milestones and inserted a futility analysis in our trial design. We also created the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), which brings the NIH together with researchers from academia, private foundations, and industry to test first-in-patient therapies. All around, it is more efficient and cost-effective. And it's an open network; scientists at any institution or industry can apply to conduct a study in the network. More recently, we launched the Stroke Network for phase 2 and phase 3 clinical trials in stroke.

Over the past few years, the growth in neuroscience research has been incredible. And the tools that are being developed are providing us with more information about the brain and specific diseases than we could ever have imagined. The BRAIN Initiative is especially exciting for the new tools it is developing to help us monitor and modulate neural circuit activity. We are developing strong collaborations, not only with neuroscientists but also with engineers, mathematicians, and physical scientists. Like the NASA space projects, the BRAIN Initiative requires great ideas from many fields of science.

WHAT ARE SOME OF THE CHALLENGES YOU FACE?

Limited resources to fuel science have always been a challenge and a big part of my job is talking to various stakeholders about the importance of research funding. I will direct NINDS during a remarkable time in history. We are continually brainstorming ways to fund great science. Advances won't come without new and creative resources to conduct research. We are a medium-sized institute; our budget is $1.6 billion a year. (The National Cancer Institute budget is $5 billion a year.)

The good news is that neuroscience is attracting the best and brightest in science and medicine. More and more PhDs are entering the field of neuroscience than any other scientific discipline. For the first time, the NIH neuroscience budget has exceeded the budget for cancer. This occurred despite a decade of flat NIH budgets and the fact that, given inflationary increases, we lost 23 to 25 percent of our purchasing power over that time.

We are always trying to figure out better ways to fund good science. We are now embarking on a new program where we will extend the number of years on a grant (from five to eight) for scientists with a strong track record and a compelling research program. We hope to make these new R35 awards available soon. We are also trying to grow the pool of physician-scientists by offering funding to residents to do research during residency and then for up to two years following the completion of their residency. This guarantees that they will have some funding for research when they come out of residency.

We are also recruiting the next generation of neuroscientists and neurologists to work in our intramural program and at the NINDS and the NIH Clinical Center. I spend a great deal of time meeting and writing to investigators, clinicians, politicians, and patient advocacy groups and going to meetings on all of the diseases we study and fund at the institute. It's important to know what scientists are doing in every field.

WHAT WERE THE FORMATIVE EVENTS IN YOUR NEUROLOGY CAREER?

I trained in internal medicine and then in neurology, and after residency I returned to the laboratory. I studied with Dr. David Corey, a superb neurobiologist who also had a passion for ion channels. Dr. Joseph Martin, the neurology chair at Massachusetts General Hospital [MGH], recruited me to become the neurologist for their Huntington Disease [HD] Center Without Walls. It was during those years that Dr. James Gusella and Marcy MacDonald identified the genetic location of the Huntington gene by linkage analysis. I was the neurologist working with the team of geneticists who carried out the first presymptomatic testing for HD. We collected DNA from patients on the east coast while others collected samples from around the world, and soon Drs. Gusella and MacDonald found the gene.

In the lab, I moved on to study the interplay between metabolism and the need for energy driven by excitatory neurotransmission. A mismatch between the two was a prevailing notion to explain the pattern of pathology in Huntington's disease. In thinking about how to test whether what seemed important in the culture dish actually occurred in patients, we developed the idea of checking for elevated lactate in the brains of HD patients, a sign of revved-up glycolysis. There was a group at MGH working on MR spectroscopy, and together we showed a consistent increase in lactate in the brain of our HD patients. The power of new MR techniques seemed clear.

My lab work was also relevant to neural injury in ischemic stroke, and I became a project PI on an NINDS Stroke Program Project Grant. The 1990s were an exciting time in stroke, as many of us were optimistic about anti-excitotoxic drugs for acute stroke. However, trials started failing and it was not clear why.

Around this time, the MGH MR research group unveiled their techniques for imaging acute ischemic brain injury (diffusion-weighted MRI) and abnormal brain blood flow (perfusion MRI). We applied these techniques to patients and could track the growth of stroke injury, a potent target for therapies. It also got me back in the clinical stroke effort.

I went on to start an acute stroke program to pursue intra-arterial clot lysis for patients with otherwise devastating strokes. The successful cases were nothing short of miraculous. Caring for these very unstable patients, I became active in neuro-intensive care again and eventually grew a staff of tremendously smart and skillful neurointensivists. In addition, I directed the MGH neurology residency program. The residents reported to me on almost every neurology case that came into the hospital, which was a tremendous experience for me, and great for our stroke research.

WHAT ARE YOUR EXPECTATIONS FOR THE FUTURE?

I am very impressed by the rapid clip at which advances are coming out of neuroscience laboratories and the new information about the neurobiology of disorders of the nervous system. The BRAIN Initiative is especially exciting because it is generating powerful new tools to monitor and modulate neural circuit activity and its dysfunctional neural circuits that cause our patients' symptoms. All in all, I believe that if NINDS can get the resources that our grantees need to maximize their contributions to science and neurology, then really good things are sure to happen.

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NEUROLOGY IN THE NEWS: Want to learn more about NINDS Director Walter J. Koroshetz, MD, FAAN? Tune in to the podcast interview to hear more about his journey to the helm of the NINDS and his plans and vision for the future of the agency: https://bit.ly/ninds-koroshetz

LINK UP FOR MORE INFORMATION:

•. Neurological Emergencies Treatment Trials Network: https://bit.ly/NINDS-NETT
    •. The Network for Excellence in Neuroscience Clinical Trials: https://www.neuronext.org
      •. The Brain Initiative: http://braininitiative.nih.gov