Announcer: Welcome to the Salk Institute’s Where Cures Begin podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.

Allie Akmal: Welcome to Where Cures Begin, Dr. Rusty Gage.

Rusty Gage: Thanks. Good to be here.

Allie Akmal: You are a neuroscientist, and for many years it seemed that scientists thought that the brain does not generate new neurons, that you are born with all the neurons you will always have. And then in the 1990s, you had some pretty revolutionary work that came out on this topic. Can you talk a little bit about that?

Rusty Gage: Yeah. Actually, it was back in the 1960s in fact that an investigator from MIT made the observation that there may be new neurons being born in the rat brain after birth. It was quite controversial and the methodologies that were being used at the time made it so that you couldn’t determine whether or not … The actual type of cell that was dividing was a bit controversial. We added to this some new methodologies that allow you to definitively show that new neurons could be born in an adult individual and what kind of neurons they were.

Allie Akmal: Gage published his groundbreaking paper with Swedish collaborators in the prestigious journal Nature Medicine in 1998. They documented the birth of new neurons in the adult human brain region called the dentate gyrus, part of the hippocampus, which is important for learning and memory.

Rusty Gage: And then we went on to show that they weren’t just being born in the adult, but they were influenced by your environment.

Allie Akmal: Wow.

Rusty Gage: So for example, you could increase the number of new neurons being born in your brain through exercise, physical movement, and went on to show that it was by blood circulation of certain proteins in the blood that stimulated the vessels near these cells that caused them to proliferate and grow and develop. Since then, people have found that the environment that we live in and work in and play in is affecting the rate at which these cells integrate in quite a detailed manner.

Rusty Gage: Finally, we were beginning to understand a little bit more about how they function and what they do in our environment, which are closely associated with each other. In 2006, there was a remarkable discovery by a group in Japan where they showed that you can take a somatic cell from your body, like a bunch of skin cells, grow them in a dish and you could engineer them to become embryonic stem cells, and embryonic stem cells are the most primitive cells that can give rise to every different cell type in the body.

Rusty Gage: We had already started working with embryonic cells before, but when we had this, we could do person-specific cells and drive them into making brain cells. So I could take your cells, reprogram them and then make them into your brain cells and measure and quantify your brain cell function in a dish.

Allie Akmal: That is astonishing.

Rusty Gage: And that’s emerged as a way to model human behavior, human functioning, brain functioning in ways that we’d never thought of it before. Now in the last four or five years, there’s been an emergence of this idea or this observation that if you cluster the cells in a particular way, they will form spontaneously into structures that are very similar to the three-dimensional structures inside our brains.

Allie Akmal: Wow.

Rusty Gage: So now we’re having this opportunity of not just having a monolayer of cells that do interesting things and look at them autonomously, but now we can get three dimensional structures, and this is very exciting.

Allie Akmal: Here, Gage is referring to structures called brain organoids, which much more closely resemble the three-dimensional nature of the brain with a variety of cell types than a flat layer of cells in a dish does. These organoids are revolutionizing the way neuroscientists can model brain development in diseases and even test potential therapies.

Allie Akmal: So does all this new understanding plus the new tools that are coming online make you optimistic about our ability to tackle health challenges like Alzheimer’s or other kinds of neurological disorders?

Rusty Gage: Yeah. One of the things that has emerged as a result of developing these tools, and specifically, continuing to speak about this for neurogenesis, there are three studies that came out this year showing that in Alzheimer’s disease, there’s a decrease in this process of neurogenesis, and it fits nicely with some of the early cognitive deficits that you see in Alzheimer’s disease. For example, this ability to recall things in the past or to make good discriminations between one person and another. It’s very like what we are beginning to see these new neurons in the hippocampus involved in.

Allie Akmal: Fascinating.

Rusty Gage: Plus, we also know that the hippocampus is one of the structures that’s the first area to be affected in Alzheimer’s disease. So that’s driving the development of new technology, not just for the pure knowledge of how this functions and the remarkable fact that there’s new neurons being born, but the relationship to disease.

Rusty Gage: And in one case, the Alzheimer’s disease relationship is there. But concomitantly, it’s also true for diseases such as depression and PTSD where individuals have a hard time generalizing beyond a particular stimulus so that something happens to them, an emotional event happens to them, they do what we call perseverate or they give the same response to the same stimulus over time and don’t generalize to other more neutral stimuli.

Rusty Gage: This is particularly true in PTSD. You can think of the instance where in a war setting, there’s a bomb explosion happens and a person is traumatized, but people that PTSD often can’t see the difference between what happened in the past and what’s happening now. So even small events or small sounds can set them off because they haven’t generalized and they haven’t been able to adapt to the new surroundings. So these disease situations are also drivers for basic knowledge. We need this information to understand these diseases and obviously come up with some ways of treating them.

Allie Akmal: When did you first become interested in the brain or in becoming a scientist? Did one happen first? Were you more interested in science generally and then got interested in neuroscience or did it start with neuroscience?

Rusty Gage: My sister was a scientist and so when I was in high school, I had inclinations towards other things other than science, but my sister would keep sending me science books all the time and I was interested in philosophy and humanities, history of art. I was a boarding student in Rome, Italy, and so I was surrounded by all this culture and I thought that was the direction I was going. My sister would always send me books at all times of the year.

Rusty Gage: When I went to college my freshman year, I got a job in a lab to get some money and mostly what I was doing was coding. And this is in the days where we used these cards where you type in the card and feed it into the computer that was used to run our experiments or analyze our experiments in electrophysiology. But the lab I was working in, though I was hired to do the computer part of it, it was a neuroscience lab and it was actually a lab that worked in the same area that I work in now in the hippocampus and they were in some learning memory. So to some extent I’m doing the same thing now that I did quite a few years ago, and I’ve been doing the same thing ever since. I stayed on in that same lab throughout my undergraduate years and then did my PhD in the lab of the student of the guy that I worked at as an undergrad. So it’s sort of this big family.

Allie Akmal: Uh-huh (affirmative). So there was something about the work that just fascinated you? Is that how it happened?

Rusty Gage: Yeah, I think that’s part of it, but I also enjoyed the community of scholars, just the idea that people were interested in studying and learning. I was fortunate early on in my career to be in a pretty big and active laboratory where there were people my age, but there were graduate students and postdocs, big collaborators. Science really became more than just … It wasn’t a job. It was like a way of life. I feel the same way now.

Allie Akmal: You have a reputation for being a dedicated mentor and you host lab reunions with your alumni from around the world every few years. Could you tell us a bit about your thoughts on the importance of mentorship and maintaining those connections?

Rusty Gage: I had the advantage, I admit, to having had outstanding mentors and so I took the best, what I thought were the best parts from all of them. And one of the things I feel is very important is to spend time with the trainee, with your trainee, to really get to know them and what their motivations are, where their strengths are, where their weaknesses are—and be very honest about this. There has to be a real sense of rapport and honesty, and then help craft the question. But it has to be their question. It has to be their idea and then let them run with it. Let them make some mistakes. My style is more guiding and helping frame things rather than writing out the details of what experiments to do. They have to learn to do this and the way you learn things best is by doing them.

Rusty Gage: The other feature is that I try to get people to work together in the lab, and I have a relatively large lab so people have different expertise and by collaborating together, they can ask a harder problem because they’re bringing different things to it.

Allie Akmal: Some listeners may not know that you have two jobs. You manage an active lab and you have also been president of the Salk Institute for the last several years. And as president, how do you see the future of scientific research at Salk?

Rusty Gage: Next year is the 60th anniversary of the Salk Institute.

Allie Akmal: Wow.

Rusty Gage: We have actually been planning and thinking about this over the last couple of years now, thinking about who we want to be for the next 60 years and are there any areas that we want to cover that we haven’t covered before. Do we want to emphasize one thing over another going forward? And we actually formulated some new ideas, areas that we’re going to emphasize that we haven’t in the past.

Rusty Gage: But a couple of things I can tell you. One is that we are working together more than we ever have before as collaborators on big projects. So for example, the individuals in the plant area have teamed up together to address issues related to climate change and, as I think Joanne has talked about previously in these podcasts, they’ve been able to, by working together, attack a problem in a way that you really couldn’t do it as a single lab. And by doing so, they’ve also gotten a lot of good support for that externally.

Rusty Gage: Another area that is growing interest in science everywhere is in what we’re calling bioinformatics or information theory, and it evolves out of this idea that we’ve developed some new techniques that have allowed us to generate more and more data. And this is true for every field where you can generate lots of data. That’s not the bottleneck anymore. The bottleneck is how to analyze that data, how to reduce the data into smaller packets that are manageable and then to build theories around our understanding of these areas so we can extract more meaning out of this massive amount of data that we’re having.

Rusty Gage: Well, this is going to be a major area for the institute. We are going to even be hiring some new people with skill sets in the areas of computer sciences, mathematics, and other areas of statistical knowledge. We made an effort about four or five years ago to begin hiring in this area and we call it right now integrative biology. So we’ve got a good group and it’s growing. It’s becoming more important to the institute, but we’re going to emphasize it more going forward.

Rusty Gage: Jonas Salk really helped us to appreciate what was a flat structure. So we have 53 or so faculty members, and yet there’s no departments. There’s no chairman of this or chairman of that. Everybody sort of pulls their own weight and helps the junior people as they’re moving along. And another thing is that Jonas really felt that the institute was one, and it wasn’t only about the faculty. It was the staff and I remember him walking around and knowing the names of the gardeners and staff and really realized that we were all together in this and that no one group is more important than others in getting to the end.

Allie Akmal: What advice would you give aspiring scientists or institutions or labs looking to attract the type of top talent that you’ve been able to attract over the years?

Rusty Gage: Well, let’s just take it as an institution trying to attract new faculty, for example, to draw them in. And the best way that that can happen is of course to have a reputation at the institution for not just doing outstanding research, but for providing support for the junior people’s activities. And you have to have successful individuals at all stages of the career from starting to mid-career where they’re taking off, even to the point where they’re not as productive and longer in perhaps day-to-day lab activities, but they’re contributing in a deeper, theoretical way. We talk about this as the arc of a scientist’s career where they’re working very hard at the beginning but not necessarily very productive. And then they learn how to do it better and they become really productive during this phase.

Rusty Gage: And then toward the end of the career, they may not be as materially productive, but heir contribution is changing now. They’re there helping and mentoring and helping younger people to get on. We at the Salk have a really great opportunity there because we have a lot of these senior investigators to very late in the career. We want our best and brightest to stay with us throughout the arc of their career and part of a great institution. We’ll be able to do that and make it clear to people that there are lots of ways in which they can contribute.

Allie Akmal: Your lab has many women in it, from senior scientists levels to post-doctoral researchers and graduate students all the way to lab technicians. I think you’ve talked before about how supporting women in science is another area in which your sister really influenced you.

Rusty Gage: She was a developmental biologists and then got into human resources, actually.

Allie Akmal: Oh.

Rusty Gage: Yeah. But was particularly interested in how women could be encouraged to stay in sciences. So she was actually in the engineering department at the University of Washington, Seattle, where she had a large program trying to increase the percentage of women graduate students. And she realized that it wasn’t all about just getting the students in. She was one of the founders of this society for women in science, but she said, “You have to have role models.”

Rusty Gage: So she got the school taught. It wasn’t just hiring a grad student. You have to hire women on the faculty so the students have models for role models, and so they increased the percentage of faculty. We’re trying to do that here at the institute too. We’ve made some, I think, some excellent hires, and I think part of that is that if you hire well and you have it more balanced, then more women will want to come because they see that they’re encouraged. Three recent hires, Kay Tye, Dannie Engle and Sue Kaech are sort of models of what you would like to have as faculty members in the institute at these different levels.

Allie Akmal: In January, 2019, neuroscientist Kay Tye joined Salk as a full professor and cancer biologist, Dannielle Engle, joined as an assistant professor. Susan Kaech is an immunobiologist who was recruited as a full professor in 2017 and also serves as director of the NOMIS Center at Salk.

Allie Akmal: Switching gears now, what are some of the joys and challenges of being both president of Salk and the head of a busy lab?

Rusty Gage: One thing it has done for me though has reinforced my love of science and my enjoyment at discovery and discussing science and learning science. By virtue of me having a lab and being president, I’m aware of the complexities and problems on a day-to-day basis of trying to run a lab, so that as president, I can address those areas and issues in ways that if I were only president, I might not really appreciate. So for example, I know how important it is to have a very effective grants department. I think at a personal level it’s a struggle to manage time and as a result I’ve had to decrease my travel, but I have a really talented lab who have really supported my presidency in a very honest way, so you don’t sort of hide the fact that you’re president. We know that’s true. How can we work around it? So we have meetings on weekends and on Saturday and Sundays where we put time aside to do some of the business work that we need to do in the laboratory.

Allie Akmal: A lot of times when people are so busy professionally, the first thing that goes is all that extra personal stuff. Have you been able to maintain a balance?

Rusty Gage: Yeah. I actually am and have always been very aware of the importance of physical exercise, and so I work out every day.

Allie Akmal: Oh, that’s great.

Rusty Gage: I run every day.

Allie Akmal: Wow.

Rusty Gage: And I used to play squash every day or multiple times a day, a week with Tony Hunter. We did for a very long time, and others. One of the joys of working at the Salk Institute is that it does feel like an integrated group of individuals and the faculty appreciate and understand the role that all staff play in making this a remarkable place. And you can feel the respect that goes both ways. So you have staff and administrators who like being here and like helping the mission of the Institute and the faculty understanding they couldn’t do what they’re doing if there wasn’t this amazing infrastructure and we want to foster that.

Rusty Gage: One of Jonas’s favorite, or our favorite sayings that he gave us years ago was, “We want to make sure that we are good ancestors.” That means that you want how you behave now, you want the people that are coming later on to have thanked us for doing the things that we did to ensure that the Institute is the best it can be.

Allie Akmal: Thank you so much for joining us on Where Cures Begin.

Rusty Gage: It’s been a pleasure.

Announcer: Join us next time for more cutting edge Salk science. At Salk, world-renowned scientists work together to explore big, bold ideas, from cancer to Alzheimer’s, aging to climate change. Where Cures Begin is a production of the Salk Institute’s Office of Communications.