Carl Cotman grew up in the suburbs of Cleveland, Ohio. His father was an electrical engineer who invented the sealed beam headlight. Dr. Cotman remembers having high quality biology and chemistry classes in high school. "I was pretty good at science and began to understand the biological basics of animals and people." In college he says he struggled with becoming either a Ph.D. scientist or going on to medical school. The bench won: He went to Indiana University for his doctorate, and got interested in the neurosciences.
"It was fascinating to think we could learn how the nervous system works and how it controls behaviors and dysfunctions and so on. I thought, if there was a chemical basis to mental dysfunction, now that was pretty exciting. I developed a passion for trying to understand the biological and biochemical basis of brain behaviors."
Dr. Cotman's career led him to the University of California at Irvine. He is a professor of neurology in the School of Medicine there and for many years directed the Institute for Brain Aging and Dementia, recently renamed the UCI Institute for Memory Impairments and Neurological Disorders, or UCI MIND.
While his own work shifted toward memory and cognition, and the basic mechanisms causing brain dysfunction in aging and the development of Alzheimer's, Dr. Cotman's early work on nervous system plasticity and nerve growth had a clear connection to spinal cord injury (SCI). His work attracted him to the American Paralysis Association in 1982, where several years later he organized its first Science Advisory Council (SAC) and became its first chair; he has remained active in the group and was instrumental in recruiting newly-injured Christopher Reeve to the APA mission, leading to what is now the Reeve Foundation. Dr. Cotman enjoys tennis, is an accomplished oil painter and is a grandfather times four. The following conversation took place between Dr. Cotman and Reeve Foundation staffer Sam Maddox.
Q. What are the qualities that make a good scientist – besides being curious?
A. You have to have a certain level of intelligence, of course, but the great scientists have a passion for what they do and they have a certain instinct. You can do a lot with logic but ultimately you have to feel it. You may get by being proficient but there must be a feeling for it. The same is true in art and painting, it's probably true for most professions – the most successful people have instinct and passion to take things to the next level. Beyond that, you have to be able to focus and concentrate on good research and good science and make sure it gets out to the public.
Q. You studied brain and behavior, what was the bridge from biochemistry to nervous system trauma?
A. I went from structural studies on the biochemistry of synapses [where nerves pass electrical or chemical signals to other cells] to studying axon [nerve fiber] growth. I was one of the first people to discover axon sprouting. For the first time it was shown that the circuitry of the brain is not really fixed but there is the possibility of rewiring. I also had some research and publications that correlated to recovery of function after nerve trauma; the link to SCI science was there.
Q. In the early days of what is now the Reeve Foundation, how were projects chosen for funding?
A. Funding projects in those early days, well, initially it was political, like a lobbying effort. Some of those initial projects the group funded with their heart in the right place but the studies were so lacking in rigor. Several of us working with APA believed it had an obligation to nurture the spinal cord field with good science or the field would never go anywhere. What was needed was an objective, fair way to choose projects to fund. So I was asked to form a science advisory council to conduct peer review of all grant applications. I tried to recruit the best people I could as a way of raising the bar for applicants and for the quality of science that would be reviewed and hopefully, funded. The makeup of a peer review panel speaks big time to the people applying; they want to know who's looking at their grants.
Q. The SAC today has the reputation as the model of nonprofit research funding…
A. This group is as good a peer review group as you're going to find. In all modesty, I have to say, I set the tone for the SAC and brought really good people forward, but I must also say, the Foundation gets a lot of credit for recognizing the need to keep the science first.
Q. Can you explain the process of how a science project gets funded?
A. From start to finish, it's complicated. First, you get an idea, which must be formulated precisely enough so that it's got some realistic endpoint. It used to be you could put out ideas with feasible endpoints and if you had a good reputation, seemed like you knew what you were doing, generally you would get funded. That's when funding levels were more generous. Now what you have to do is unbelievably complex, and borderline between rigor and artistry. It's like, you have to be able to say what the idea is in one line. If it takes more than one line, it's too complicated.
Q. Sounds like Hollywood high concept.
A. Unbelievable. You have to be able to make it exciting and worthwhile – and show that the proposal is really going to have potential impact.
At the Foundation, after a grant is submitted, a primary reviewer is assigned and is responsible for summarizing it with an initial evaluation. The proposal is then presented to the SAC and the full group discusses it. Sometimes someone will say, ‘oh, I agree' and everybody else agrees and it's done. In other cases there may be a lot of back and forth, some for it, some not, so sometimes we recalibrate. A downright disagreement turns on who can best make their case. I can recall a number of instances where the whole group finally shifted opinion to get behind something we came to agree was needed.
Q. Does the nonprofit model allow for taking more risks than say, the NIH?
A. In a private organization, you don't want business as usual, you want to push the edge, and the edge is always less clear than the middle ground.
Q. Tell us about your own science.
A. I used to do the kind of science the Foundation funds but moved more to the field of aging. I got interested in the question of how to keep the nervous system functional as we all get old. Some people do better than others – what's the secret of that? I came across the idea that physical activity was healthy for the nervous system. A collaboration I had with the MacArthur Foundation called Successful Aging showed that people who aged successfully had greater self-advocacy, higher education and increased physical activity. I thought, physical activity, now that's really interesting. I wonder why that is. I walked around in a daze, the absent-minded scientist thing ... what would it be that exercise could control in the brain, what's the one thing? I had an idea it was neurotrophic factors.
Our first study worked and it was unbelievable. I picked BDNF [brain-derived neurotrophic factor] because I figured it would do the most with the major projection neurons, the real workhorses, the big cells. The most amazing thing, I thought the physical activity thing would prevail in the sensory and motor systems. Son of a gun, it was in the brain, in the hippocampus. Turns out the BDNF molecule is the champion of maintenance, plasticity, learning, even depression. It's incredible how fundamental it is. Now in the learning field, people are showing that if a little BDNF is sprinkled in the brain, all of a sudden primates, and probably people, learn better. One of the things that keeps evolving is that physical activity is neuroprotective, too. It makes injury less severe. Those who are fit will absorb more injury than those who aren't.
Q. Does that lead to any advice for our golden years?
A. People have to stay active, if they can. Studies are coming out that people who are frail benefit too, not just fit people. For the spinal cord field, I would guess that some activity and training is always going to be part of the regimen for recovery.
Q. What can you tell people about spinal cord research now?
A. The spinal cord field is one of the more challenging ones. Look at the cord, it's this little thread that comes off this huge brain, it's smaller than your little finger. And all the nerves are running in a very organized fashion, so you nick part of it or compress it, there's not a lot of redundancy. There is the expectation for the instant fix, just as there is for Alzheimer's disease or Parkinson's disease, and it's true it could occur, but incremental progress is more the norm. And that's what's happened. We're taking incremental steps that keep getting closer and closer. Look at progress in this field; it used to be that a lot of effort was in understanding what goes wrong in injury and describing the molecular biology of it all. Now there's been a paradigm shift in the field what we are seeing is all about intervention-based studies.
There are so many things out there that look promising, including the stem cell field. There are clinical studies, some here at Irvine, that have a decent prospect of succeeding. SCI is heterogeneous so we're never going to fix everything with a single intervention. It's not just one thing, it's going to take multiple approaches.
I also think we're going to be able to mobilize the self-healing properties of the brain to a greater degree in the spinal cord. There's explosive potential, but it's hard science. Tough stuff to do. And the gap in time between discovery and a clinical trial is not short – 8 to 10 years.
People have to realize, we are making enormous progress. It is slower than anybody wants, but it is going forward. There are more clinical trials in higher animal models and people than ever before.
The Scientific Path
I've often wondered what it was in early regeneration and spinal cord research that led Carl to make his strong commitment to APA nearly 30 years ago; clearly he saw promise where most still saw only the old dogma of the spinal cord injured once and forever. I credit him with setting us on a scientific path that hasn't failed us yet, one marked by a brilliant and dedicated Science Advisory Council, a rigorous peer review process and a Board that appreciates the integrity of that process and listens to its scientific advisors.
– Susan Howley, Executive VP, Research