Now 70 and president of the Salk Institute for Biological Sciences in the La Jolla neighborhood in San Diego, Gage is still trying to figure out how adults can continue to make new brain cells and keep their brains healthier and resistant to disease. As head of the institute, he also supports his colleagues’ broader work in novel approaches to treating cancer, how the properties in the food we eat shape our brains, the effect of isolation on brain functioning, and plant biology and climate change.
The Washington Post spoke with Gage on a video conference call recently to talk about growing up overseas, including in Frankfurt, Germany, and Rome; honing his interests in various labs; and giving mice a running wheel in their cages that sparked a key finding in understanding neuron growth in the brain
Q: How did you first become interested in neuroscience?
A: It was a chance encounter [on a bus in Florida] with someone I had known in Frankfurt. He was working in the laboratory of Robert Isaacson, a psychologist laying the physiological groundwork of a brain structure called the hippocampus. [The hippocampus is important in moving short-term memories into long-term storage.] Isaacson was studying epilepsy. My friend urged me to apply for a summer job. I was 18, and I stayed in the lab for 3½ years. . . . .
[After studying science in college] I then applied to a graduate program at Johns Hopkins University to study with Dave Olton, who did PhD work with Bob Isaacson. In their lab, we made lesions [or cuts] in rodents’ brains to study the anatomical basis of spatial memories. We’d make a cut in one area of the brain and see how it changed the animal’s behavior. Then, we would follow the recovery process. It was an amazing place to learn neuroscience.
After I finished my doctorate, I headed to Texas Christian University as an associate director of a new neuroscience program. We were interested in sprouting — how nerve fibers can regrow — in the hippocampus after injury and determining if this was responsible for the behavioral recovery. We found a high level of zinc in the hippocampus, and we began following a trail that led us to growth factors that are involved in brain development. [Growth factors do just what their name implies: they regulate a number of cellular events.]
I wanted to discover more about growth factors and joined the lab of Anders Bjorklund at Lund University in Sweden. He discovered that sprouting, the growth of neural branches, took place when the brain is injured. . . . I learned about neural transplantation and techniques to deliver cells into the brains of animals. We were interested in nerve growth factors and wondered if these factors were the source of this new growth that we were observing in the brains of the animals we studied.
Q: How did you start testing your ideas?
A: I moved to the University of California in San Diego in 1985. My lab began working on engineering viruses to insert nerve growth factor in cells to transplant into the brain and subsequently contributed to building the first safe viral packages to deliver genes to the brain. We also took skin fibroblasts, which are known to divide and grow, and overexpressed nerve growth factors and then inserted them into the hippocampus. We found that when we put cells expressing a certain growth factor in a dish with neural progenitor cells, they grew like crazy. This led to a long effort to learn how progenitor cells divide and survive in the brain.
In 1994, DNA co-discoverer Francis Crick was heading up the Salk Institute, down the road from UCSD, and he invited me to join the Salk. The job description was simple: he said I could do anything I wanted. . . . My new lab experimented with a synthetic molecule called BrdU, which gets into a cell’s DNA when it’s dividing. It is used to tag dividing brain cells. We designed experiments to see whether BrdU was getting inside of neurons undergoing cell division. We found that the molecule did get inside of the neuron in the adult rodent brain, and this was a great tool for us and others to identify the birth of new neurons in older brains.
Meanwhile, my colleagues and I were busy studying the birth of new neurons, which is called neurogenesis, in adult mice. We first discovered increased neurogenesis with exposure to enriched environments that contained running wheels and we were amazed, but then we wondered whether the running wheels alone or the enriched environment without running wheels could increase neurogenesis. We took away the running wheel and added small playthings to the cages. We were further amazed that both conditions increased neurogenesis in different ways. Our lab and others have replicated these experiments with a variety of items: tunnels and tubes, blocks, balls, wire mesh, poles, really anything they can climb around and in.
The mice that spent time running and playing showed evidence of neurogenesis in an area of the brain called the dentate gyrus of the hippocampus. [The dentate gyrus is important in taking our experiences and turning them into memories.]
Q: How did these findings lead to your work in humans?
A: Our goal was to see if neurogenesis was also going on in humans. We used BrdU attached to a fluorescent antibody to tag any dividing neurons, if they were there. A colleague from Europe had access to fresh autopsied tissue from cancer patients who had been injected with BrdU to track brain tumors before they died. In early 1997, we conducted studies on the autopsy tissue and we could see cells tagged with BrdU. This proved there were dividing young cells in the dentate gyrus of the hippocampus that had become mature neurons. We continued to do other studies to prove that the human hippocampus retains its ability to generate neurons throughout life.
Last year, two studies were published showing that there is still neurogenesis in the hippocampus in older people and those who died with Alzheimer’s disease.
Today, our findings and the work of many, many others have led pharmaceutical companies to develop drugs that target neurogenesis.
Q: You are also interested in the chemistry of food and behavior on life span?
A: Yes. We know that neurogenesis increases cognitive function and we wanted to find natural products in our diet that also increase the birth of new neurons in the adult brain. We have funding from the Mars Company’s research arm — the Mars Edge Cocoa Flavanol Science Hub — to study the chemistry of food and the effects of our life choices and our behavior on our brains, and to look at various flavonoids that can have an effect on neurogenesis. We are also studying the effects of diet on inflammation, which appears to block vascular health and neurogenesis. We want to determine if the food we eat influences inflammatory processes.
Q: Have you found anything yet?
A: Yes, we found that specific elements in certain plants we eat contain flavones, which are small molecules that plants use to protect their outer cell layers from excess light; they can have remarkable anti-inflammatory effects on mammals, including humans.
Since our work with plants and food, my wife and I have modified our diet. We generally eat less, and choose more vegetables and fish over red meat, processed foods and sugar. I have always been a runner, but our findings on neurogenesis and exercise have continued to inspire my runs. In addition to my daily running, we also take long walks and stay active.