OBSERVATIONS Rusty Gage shares his inspiration

Observations

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Complacency has never been part of Fred (Rusty) Gage’s genetic make-up, neither as he has ascended to the ranks of the world’s most renowned neuroscientists nor as he’s taken the helm as President of the Salk Institute.

With a quiet intensity and knack for explaining even the most complex biological principles in simple terms, Gage often speaks in analogies akin to scientific processes. Having called the Salk home for nearly 25 years, he has made critical discoveries in what has been considered one of the “last frontiers” of biology: the human brain. Among his most seminal breakthroughs, Gage found that neurogenesis occurs in adults—that humans are capable of growing new neurons throughout their lifespan—launching entirely new fields of research.

Maintaining a large and robust lab today, Gage continues to make discoveries around how the brain can change over time, an area called neuroplasticity. His lab explores myriad topics in neuroscience, developing cutting-edge tools and methods to reveal what happens to brain cells as we age or suffer from diseases such as Alzheimer’s and schizophrenia. He also explores how mobile genetic units dubbed jumping genes generate individual diversity between neurons, and how those activities contribute to making us who we are.

After receiving his BS from the University of Florida and PhD from Johns Hopkins University, Gage—who speaks Italian, German and Swedish—did research at Lund University in Sweden and at the University of California San Diego before arriving at the Salk Institute. During his scientific explorations, he has garnered numerous accolades and broad recognition, including from the National Academy of Sciences, National Academy of Medicine, American Academy of Arts & Sciences, and American Philosophical Society, as well as having served as president of the International Society for Stem Cell Research and the Society for Neuroscience. In addition to being a member of more than a dozen prestigious scientific organizations, he holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease at the Institute.

Inside Salk sat down with Gage to discuss what he is most excited about in the realm of scientific discovery and what he looks forward to at Salk.

Tell us about your path to Salk

In 1995, I was a professor in the Department of Neuroscience at UC San Diego, and I was considering a new position heading a new center. The Salk Institute offered me a position in a new laboratory of genetics, so with little hesitation, I left UC San Diego, where I had been for the previous 10 years. My years there were a great experience, but at the time I felt that I was at a place in my own research that I wanted to go in new directions. I needed to be in a new environment and found it appealing that there were no “walls” at Salk: you are free to pursue your research however you see fit. That’s a rare environment.

From the moment I got here, I knew I had made the right decision. Francis Crick, who was President of Salk at the time, in negotiating with me about the position, said something to the effect of, “we’re not hiring you for what you’re doing, we’re hiring you for what you are—just continue doing great and creative work!” That’s what happens at Salk. Fields of research can change over time, but having an ethos of exploration, of going where the science may lead you, even if it’s unexpected, that’s the important thing.

From Crick and others at Salk, I learned to think of science in a broad perspective and ask: “Is this really the most important question?” Another thing Crick advised was to consider how you are going to prove your theory wrong. Think about the critical experiment that can destroy your hypothesis and use that to make your science stronger. We have a tendency to hang onto our own hypotheses much longer than we should, which can prevent us from looking at the larger picture and asking what are the big ideas we should be investigating.

As the Institute’s President, what is your vision for Salk?

At Salk, we have a history of focusing on innovative ideas and we continue that legacy today as we embark on several major pushes to tackle the biggest issues facing our time. I am looking ahead to identify what we should do next. Of all the questions that intrigue me, that’s the most exciting: what is the next game-changing idea?

Together with Salk’s supportive board and leadership team, we’re aiming to build upon the dedication and commitment to science of my predecessors to address the next set of “big ideas” in biology. In particular, I am expanding upon the groundwork that Nobel laureate and former Salk President Elizabeth Blackburn laid out for what we’re calling “Salk Next 50,” in which we’re looking at where we want to be in 50 years in terms of science and as an Institute. Part of this entails evaluating ways to continue to enhance the Salk experience and ways in which we can continue to support our faculty and recruit new talent to the Institute.

What are some of the big ideas happening at Salk right now?

We are already pursuing several ambitious projects: tackling five of the world’s deadliest cancers; optimizing plants in order to mitigate the effects of climate change; and developing strategies to make big strides in neuroscience, healthy aging and metabolism. Some of these efforts are what we call “high-risk, high-reward” projects—the ideas may not be conventional enough for traditional types of funding and support and the payoff may not be immediate, but we believe they have potential. These thoughtful forays into new areas of research are what make the Institute fertile grounds for truly groundbreaking and interdisciplinary ideas.

In regards to my area of neuroscience, I am excited about some of our upcoming efforts to investigate the most intractable neurological mysteries and diseases of the brain. Specifically, we are setting our sights on Alzheimer’s disease.

Can you tell us more about the challenges of understanding Alzheimer’s?

Alzheimer’s is an aging-related neurodegenerative disorder that results in severe memory loss and cognitive decline; nearly 50 million people worldwide currently suffer from this disease and related dementias. The human and global costs of this devastating disease are immense, yet numerous clinical trials targeting Alzheimer’s have failed to stem this public health crisis. It is imperative to explore alternative mechanistic drivers for Alzheimer’s and to understand the disease within the broader context of aging.

The biggest risk factor of Alzheimer’s is age. More than 90 percent of Alzheimer’s cases are sporadic, meaning the presence of the disease is rarely linked to genetics. There is no single mutation driving it. Rather, it appears that age is setting you up for some other event that triggers the disease. And, as people worldwide live longer, the need to find novel treatments and therapies for diseases of aging becomes more urgent.

So we need to understand how to slow down aging and, even more fundamentally, define what aging is from various perspectives in the cell: mitochondria, proteins, nuclear pores, and energy production to name a few. All of these are seemingly separate areas of study, but they are all linked together; if we perturb one area in the cell, the other areas are impacted. We need to explore and understand this network and connection.

Do you think new treatments for Alzheimer’s are within reach?

There are so many exciting developments in neuroscience that it really feels like a golden age for the field. I’m optimistic that we will make significant progress in our lifetimes.

For example, with a recent gift from South Korea’s NANOS company to establish an Alzheimer’s bank of human cells, we will gain an invaluable experimental resource for both researchers at Salk and the Alzheimer’s disease research community at large. The funds will establish a dedicated laboratory space called the NANOS Alzheimer’s Disease Stem Cell Suite, which will serve as a cell bank focused on Alzheimer’s. This cell bank will house both stem cells and somatic [body] cells from human donors, which are critical for analysis and testing of therapeutic drugs.

With the body of knowledge we have accumulated at Salk and the committed support from companies such as NANOS, we believe novel therapies for Alzheimer’s may be feasible.

In addition to your own research, you’ve had a profound influence on a number of scientists who have come through your lab over the years and with whom you regularly reunite at your alumni events. What is your mentoring approach?

When I first started mentoring, some of the trainees were not much younger than I was. I was learning how to mentor while mentoring. It felt a bit like building an airplane while it’s in flight. In general, I like people to figure out what they really enjoy doing within science. But it can be especially helpful to ask students, “What’s fun for you? What do you enjoy doing?” It’s not just about the conceptual stuff, but technical interests too. What you understand matters, but what you’re good at and what you like matter, too. For postdocs, I try to help them build a line of discovery, not just a single set of experiments; once you’ve solved a problem, how will you build on it?

Once I think I have a clear view of a where a student or trainee wants to go, I ask them: “Do I have this right?” Mentoring is an intuitive process where you check in periodically to see that trainees are moving along the trajectory they want to be on.

You cannot minimize the responsibility that a mentor has when taking somebody on as a trainee. Over time, I’ve learned to be more proactive in reflecting to my trainees how they appear to me. Honest discussions with trainees are difficult for mentors but they are incredibly important. Some way through my career I realized that if you just let people go along a direction that you believe to be incorrect, without intervening, you’re not being an effective mentor.

You still enjoy working in the lab when time allows—what brings you back to the bench?

I think it’s incredibly important for laboratory heads to stay connected to the research and keep up to date on techniques. Being at the bench, even once in a while, reignites a passion for experimentation, which is what drew many of us to science to begin with. Maintaining involvement with the generation of the lab’s data helps keep me connected to the fundamental science. Plus, it’s fun.

Given the enormous demands of running both an institute and a laboratory, from where do you draw inspiration? What keeps you motivated, excited, inspired?

Aside from exercise and a moderated diet, over the last few months I’ve gotten into the habit of writing down inspirational quotes from historic figures—world leaders, philosophers, poets—people who, in the turn of a phrase, have gifted us with words that afford us perspective, lift us up or motivate us into action. Inspirational thinking emerges from functional crises.

What I’ve been reminded of, however, is that I don’t need to look far at all for inspiration; it’s right here, every time I set foot on our campus. It’s here because, at this Institute, we literally and figuratively set our sights on the horizon. At Salk, we are bold enough to say we are fearless in the face
of any challenge and are not afraid to look at who we are as an Institute—and who we are as an institutional family. Jonas Salk had a notion that there are people who are evolvers, and there are people who are maintainers of the status quo. He wanted this Institute to be populated with evolvers who consistently ask the big, hard questions.

I find that everyone at Salk—from administrators to laboratory heads and staff to our donors—want to be part
of a place founded by a big thinker so that more big thinking can be done to improve the lives of people around us, and around the world. Our charge is to be truly fearless in the face of any challenge and to look beyond ourselves and continually seek to enrich the lives of others, for those at Salk now and the generations who will follow us in coming here to set their own sights on the horizon.

All of us, at Salk and beyond, are united through a mission to better humanity. We embrace that mission on a scientific level every day. The best version of humanity demands that we, as humans, are the best versions of ourselves. To me, nothing is more inspiring than that.

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