St. Stephens's School Rome
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FG: My family lived in Frankfurt, Germany. My father was a stockbroker with Merrill Lynch and one of his customers was Reverend Bain, who was one of the founding members of St. Stephens and he recommended that I go. The school was very new, I believe only in its third year or so. We had some experiences of living in Italy before. We lived in Naples in ‘61 and ‘62 and we visited Italy often, so my parents felt it would be a good experience.
We were in Parioli in an old villa, which I think now is the Bulgarian Embassy. It was this beautiful building. We had all our classes in the villa, including my German class in a room with a bathtub! At the time there were one hundred and fifty students including ninth grade through post-graduate. We had about five or six kids who had already graduated high school and came for a type of finishing year, which is something people did in those days.
It was great. The School was very international, with probably a bigger American influence then than there is now. Many of us were from families who lived overseas with a large number from North Africa and Saudi Arabia, because of the oil companies, and from Northern Europe. A large proportion of the students were boarders like me. We stayed in hotels actually. Do you know the Byron Hotel?
The owner of it and the Lord Byron made a deal with the school. The girls stayed in one hotel and the boys in another. We were across the street from the Roxy Bar. It was sort of idyllic, my memory of it anyway. It was the mid-late ‘60s. I met my future wife, a fellow student, there, and we’re still married.
My sister was a scientist. She was the one who continued to press me to have an interest in science. In school, I was more about living in Rome and taking advantage of art history and the humanities. I was probably angling in those directions, but my sister kept sending me articles and books saying, pay attention to this, to keep me interested in science.
I went to the University of Florida, Gainesville. My sister and my father went there. Honestly, I wasn’t interested in returning to the States but my parents made it very clear that I was to go back to the States for college. The first summer after my freshman year, I needed to work so I could go back to Europe. I got a job working in a research laboratory at the medical school. I just got hooked, honestly. I worked with a great group and my mentor was fabulous, as were all the students. It was a very large lab. They were studying epilepsy and there was a lot of experimentation. Also, the lab was an early adapter of computers. I was quite excited about the computer programming, which was at the early stages, combined with the experimentation work in genetic forms of epilepsy. I knew right away this is what I wanted to do. It was a very supportive environment and I worked in the same laboratory from my freshman year until I graduated.
In particular, I’m interested in the brain and what we call plasticity--its ability to be shaped by our experiences. It’s amazing to me that certainly as we develop, but even as mature adults, the experiences we are having are not only influencing us but they’re actually changing structurally how the brain works. So your experiences today, for example our conversation, will have an impact on you, not only in an emotional but also on a physical level. These connections may be transient but it’s amazing how dynamic they are. Computers are hardware, and the brain has been used as an analogy for the computer. However, it isn’t. The brain is biological tissue and, while it processes information, it’s really structurally plastic and changes based on experiences in the environment. I think it’s these physical and chemical changes that occur in the brain and how they accumulate over time that fundamentally attracted me from the beginning.
It’s a dirty little secret in brain science that we don’t understand memory. We don’t understand how memories are formed on a physical level. We can talk about it in psychological terms. At a tissue level or a molecular level, we don’t really know. There are a couple of major theories that people are pursuing and I’m particularly interested in them. I think that, with some of the new technologies that are coming on board in brain science and science in general, this challenge is something we might crack. It isn’t just tools that are needed though; it’s also theory. We have to develop good theory in parallel with the technology.
I was at the University of Lund in Sweden and I was a junior faculty member there. We lived there for four years, my wife and I, and both of our daughters were born in Sweden. We were at a juncture to decide if we going to continue to live there permanently or move. We both spoke Swedish, had many Swedish friends, and had adapted to the culture. Before we made a commitment, we wanted to take a look at opportunities available in the US.
I was offered a few interesting jobs, but at the University of California San Diego I was offered a tenured position as associate professor, which was a pretty good job in the California system. The University of California San Diego and this whole research area is a mecca for brain science. There are many different institutes here and even at that time, 1985, it was packed with great people. I decided to take the job and I stayed at the University of California San Diego for ten years. I was a professor with a big lab; I would say it was pretty successful. I was collaborating with a variety of people and some of my friends were across the street at an independent research institute called the Salk Institute for Biological Studies. It was a small organization with very little administration and no teaching requirements, which freed up the scientists who worked there. After ten years at UCSD I was being asked to consider different positions running various institutes, but instead of taking an administrative position as a head of an institute, I realized that my real joy was doing research full time. I moved to the Salk Institute in 1995. It wasn’t a very big move physically - just across the street – but it changed the structure of my life a great deal. I moved here and I’ve been here for twenty-three years. I’ve been in San Diego for thirty-three years. As a side note, my mother is from San Diego and I lived here briefly when I was five years old.
Traditionally people have been taught that when we’re born we’re endowed with the brain we’re going to have. There may be an increase in connections in the brain and they may grow during a period of time, but the number of brain cells we have remains constant. Certainly, as an adult, the idea that there could be a substantial number of new neurons being formed was not considered; in fact, we would lose them as we aged. There are lots of ways you can lose neurons. However, through a series of experiments in our lab, we in fact found that some new cell division appeared to occur in a particular area of the brain, and we wondered what those cells were.
It turned out that in one structure called the hippocampus, which is the structure where memories are formed, there were dividing cells called stem cells and they turned out to be neural stem cells, which means they could divide and give rise to new neurons throughout life. The finding that adult humans could have new neurons was a big surprise. In 1998, we published a prominent article in which we showed that this happens. What we do as individuals throughout life can influence how many new neurons are being created. So, for example, what we call environmental enrichment, i.e., exposure to complex diverse experiences, increases the survival of the total number of these cells in our brain. In addition, physical exercise, movement, increases the number of cells that are dividing. We now know something about what this process - what we call adult neurogenesis - is good for and why we have it.
It’s not a life-or-death phenomenon; it is actually useful in being able to discriminate between events, places, individuals, or emotions that are closely related to each other. This ability is called pattern separation. For example, I were walking down the street and I saw somebody who looked familiar to me but I couldn’t really make out who they were, depending on how well my adult neurogenesis is working, I would be able to draw up an image of that person from the past and place them into a context. What this type of memory does and what these cells do is they help us retrieve past memories to compare with what we’re seeing right now, so that we can determine whether or not it’s the same or different. Not only is just facial recognition involved; it’s also emotions. We have an experience and it brings up an emotion that we had previously in that space. Even tasting food can draw up memories of past experiences. We can assign value to it, whether or not it was a good experience or a bad experience, or we can add more of the details of what happened. This process helps link past memories with current events.
It is true that with age there is a decline in adult neurogenesis. However, that decline can be mitigated through the kind of things we’ve shown. Having a variety of experiences coming into our brain, seeing new things, learning new things, and learning new languages, that’s one. Another is physical exercise, which clearly has an impact on new neuron growth. Stress is another feature; what we call high, non-adaptive stress or pathological stress, which means too much stress, can suppress neurogenesis. Good stress, which is motivated movement with learning new activities, that’s being positively stressed. If you overdo it, you’re increasing certain negative hormones in your body that can suppress neurogenesis. You have to reach that nice balance. Diet is another contributor; we know that there are a variety of foods that are good and bad for the brain and this is a big area of study now. We know so little about the biochemical nature of the foods that we eat, so our understanding is currently at a primitive level.
In the process of studying adult neurogenesis, we examined what we called neural stem cells. We have developed techniques that allow us to study them in great detail. In particular, we were looking at what mechanisms allow these primitive cells to become the right kind of neurons. How do we foster these cells? In the process of looking at this, we found a genetic event that occurs just as the cell is making the choice to become a neuron. It was a surprise. Just as a side note, five trillion cells make up your body. Your brain has one hundred billion and every one of those cells has its own DNA. And you as a person, with all of your trillions of cells, emerged from a single cell that was the conjunction of your mother’s egg and your dad’s sperm. They came together; that was a zygote, one cell. That cell divided into more complex cells until it made five trillion cells. That’s pretty amazing.
So every cell is like its own little factory and it has its nucleolus, its own complemented DNA. It was thought that your DNA was all the same, as it emerged from the same cell. Well, it turns out there can be changes that occur in individual cells over the course of development, and little bits of DNA can mobilize and jump from one location to another location in the DNA. These are called mobile elements.
People believed this process occurred only in plants. Then it was discovered in mammals, but only found to occur in the testes. What we discovered was that, even in the adult brain, every time a neuron divides there is an activation of these mobile elements. This finding was not easily accepted when we published our research in 2005. It is another form of plasticity that I like to study. Neurogenesis is a cellular form of plasticity, with new cells being born. Mobile elements represent a genetic form of plasticity, where new genes can be introduced in individual cells. We call it somatic mosaicism because it occurs in each individual cell, not in the germ line. It’s not just in your dad’s sperm or your mom’s egg. This makes each cell slightly different from another.
If you take a brain from a person who has died and examine it, going into individual neurons and mapping the entire genome for these neurons in this area of the brain, you would assume that two cells right next to each other should have the exact same genetic material, but they don’t. They’re different. This is a little bit freaky for some people. This whole area of investigation is now opening up two fields. One asks, why does this occur? The simple answer would be that most of the neurons in our brain remain the same throughout life except for in the area in the brain that we discovered, yet we change over time and we have new experiences. How do we provide a greater diversity of potential to respond to experiences over the course of our lifetime? One way is to add some random variation, with some cells that expand their potential for us to respond to things in our environment. That’s a theory, but it’s consistent with this idea of diversity. The other field being explored studies the regulation of how these elements move around; this regulation is tightly controlled, because, if it’s not tightly controlled, you can have too much mobilization or too little. There’s an enormous effort to try to find out more about how it’s regulated and its impact on diseases, in particular, diseases that seem to be affected by misregulation. We call them the affected range: bipolar disease, schizophrenia, depression, and various forms of psychosis. This is an area of investigation that is quite exciting.
To every cell! In every person.
There is sort of a parallel story going on in a different, mechanistic way. How do we understand the mechanism by which this happens, what are the controlling events? How does this interplay with aging and diseases?
Alzheimer’s is not only one of the most prevalent diseases in the world, its impact is increasing dramatically. It looks like there may be a tripling of the number of people who will be affected in the next thirty years. I must say that, while we think of is as a Western disease, Alzheimer’s is affecting the entire world, and we know that it is a genetic disease. The single biggest risk for Alzheimer’s disease is getting old; it is an age-related disease.
Interestingly, ten years ago scientists would say they knew more about Alzheimer’s disease than the same scientists would admit to now. In other words, we were more optimistic then than we are now. There were some core hypotheses that a lot of people were following with tremendous enthusiasm and many of these hypotheses have been clinically tested now. They are not turning out to be as correct as we thought. So people are going back to the bench, back to the basics to try to understand why.
Part of the problem of studying Alzheimer’s and any other brain-related diseases is that we don’t understand the brain. If you don’t really understand how the brain is truly functioning, then it’s going to be more difficult, obviously, to understand how to treat it. When you think of heart disease and you think of cancer and the progress that has been made regarding these two diseases, it’s quite impressive. We know a lot more about cancer; we can grow these cells in a dish and study new properties of expanding cells that we can track. Heart disease occurs in the heart, which is basically a pump. We can figure it out. The brain is really much more complicated, with many more cells. The point I’m try to make is that, while it is true that we’re not making as much progress therapeutically right now, we are at a critical point because we have new tools that will allow us to reexamine the function of the brain in ways that we have never done before. While we accept that we don’t understand as much as we thought we did, there is renewed enthusiasm due to new tools that are so much more detailed and refined that we’ re getting a better map of how the brain works.
We’ll look back on this as the Golden Age of neuroscience or brain science because of the amount of fundamental knowledge we are developing of how the brain works. It’s only through understanding these basic mechanisms that we will come up with realistic therapeutic interventions.
Achievement is one thing; as for the awards, I feel quite honored to have been recognized by these various organizations and, of course, they’re important to me. However, these are accolades that come from doing what I feel is the right thing to do. So, is it really pride because this is a consequence of doing what I want to do? I’ll tell you what I am proud of, what gives me great joy at this point: looking at the trainees who have come through my laboratory and are now populating the world with their laboratories as professors and directors of institutes. My successes reflect theirs to a large extent, due to the work they did while they were in my lab. It’s interesting; every two years we have a two-day Gage Lab retreat/symposium where all the members of my past labs from the last thirty-five years come together. Everyone gives a short talk with updates of what they’re working on. We even have students of students.
About two hundred from all over the world. It's great fun and a great group of people. It’s not just a social group. They also collaborate with each other.
I am still very active in the laboratory. My focus is on what I’m working on now and making sure that we do it right and that it’s correct. I always worry, are we doing as well as we possibly can and not going too far out on a limb? But, on the other hand, that is where the rich fruit is! Way out there. I haven’t started thinking in the past and about what I’ve done; I enjoy the challenge of what we’re doing now. I keep learning all the time. I’m humbled by how much I don’t know and how much there is to learn. I have to keep learning new techniques and new bits of knowledge in order to answer the questions that I’m interested in right now. It motivates me every day to learn more. I learn from my students and my fellows who I bring in from other labs. They have studied different disciplines and they help the lab expand and get into new areas.
There was enormous skepticism when we first started talking about plasticity. We had battles. There were articles in The Atlantic and the about the battles that were going on between scientists in these different camps. Some of my colleagues were telling me that I had to be careful and hope that I was right.
The same thing occurred with the findings about mobile elements and somatic mos aicism; even today people are skeptical. I don’t see a straight path of success after success. I’ve been very fortunate to be associated with very good research institutions and people of very high caliber. My colleagues always set high standards for me. My career has been influenced dramatically by my senior colleagues, who encouraged me and cautioned me; they helped me grow. Now it’s my turn to do the same with the junior colleagues around me. Everyone knows doing research is a struggle. We have to get our papers published, we have to get grants; they’re the lifeline of keeping our labs going. The universities don’t pay for this. We have to apply for federal grants and raise money from private foundations. We spend a lot of time raising money and recruiting the very best lab members. They are the lifeblood that keeps the level of scientific achievement going up.
Regarding the lab members, there are two groups. The members who are here until they get their PhDs. That’s about five years, five and a half years. Then there are the people who already have their PhDs. They’re doing their post-doctorate fellowship. That’s three to five years. This is the last training they’ll receive before they try to get their own positions. It’s a long interview process.
I think we have the tools and better knowledge now to focus on the human brain. This may sound a little funny but we’re going to use the diseases that are unique to the human brain to better understand how the brain works. How things go wrong will give us insight on how it functions correctly. We’re doing more disease-related work in both neurogenic diseases and psychiatric diseases and we’re particularly interested in the overlap between the two: how common underlying pathways can go slightly wrong in one direction and give us one disease, then veer off in another direction for what appears to be a completely different disease.
What still gives me joy is discovering something that no one knew before. It’s an amazing feeling to actually discover something. The more unexpected it is, the more exciting it is. What’s interesting about science is that if the fact you’ve discovered is actually true, then many other things have be true because there are constraints on science. It’s not free-floating. If A is B then that means for sure that D is going to be related to A in this way. If you do that experiment it’s got to work or else the first part isn’t correct. Once you have a fact you can build on it. That’s what makes discovering a real truth so exciting - because you know that you’ve just uncovered a whole new net of things that also have to be true.
I am very fortunate to have an absolutely fabulous family. My wife, Mary Lynn, has been a companion and, I must say, a colleague. She’s my editor and edits everything that goes through my lab. Every manuscript, every grant. Nobody would want to publish anything from our lab unless Mary Lynn has gone through it. She has taught more people than you can imagine how to write. We have two lovely daughters, so amazingly supportive. They’re in their mid-30s. We still return to Italy often with them; we spent ten days in Rome and rented a place on the Tiber in December 2016 with the whole family. We all like to cook and we have big cook fests where everyone tests out new recipes and we send photos to one another. We try to stay healthy. I run every day. I believe in my own research (laughter), so exercise and enrichment are important, trying to keep my brain active.
It’s amazing how many of the people that I knew from St. Stephen’s, from 1966-1968, are still friends today. We just had dinner in La Jolla recently with Rick Routhier and Richard Winkler, both of whom have served as trustees and were underclassmen, two years younger than me. We have other close alumni friends, too, and the memories are wonderful. Of course, I’m married to an alum. I’ve been on the board of trustees of the school for a long time; I think I got on in ’78 or ’79, and I’ve just gone emeritus this year. I will still stay active. In the early days of my tenure, there were some rocky times. I felt part of my commitment was to try and help the school through those times. The school has done very well. It’s fun to watch as the school changes over time and it really has changed. It’s not the point to say whether it’s for the better or for the worse. The point is the school is staying up-to-date, maturing, evolving, and staying current.
It may sound like the same old story you have heard from other people, but I would recommend that you explore all your educational opportunities. Try a lot of things, but try to figure out what you’re really passionate about, what you really enjoying doing, and try to interface that with something that you’re good at. There are some things that we may enjoy but we’re not particularly good at. Combine your skill set with what you enjoy doing and then don’t listen to anybody else. Go for it. Go as deeply as you can. Don’t approach things on the surface. Dig deep to find out what’s really going on and try to make some kind of significant difference in that process or vocation that you love. Make it better.
