“Sometimes, as a scientist, you just have to keep asking questions. Ask big questions and look for an answer—what else are you supposed to be doing?”
That is the guiding principle of Fraser Glickman, PhD, a research associate professor and director of the Fisher Drug Discovery Resource Center at The Rockefeller University, where researchers investigate new molecules for the development of drugs and therapeutics.
Dr. Glickman’s career reflects a unique blend of curiosity and practical understanding of how to translate research into options for patients. In this conversation, he discusses his lifelong passion for science, how he became interested in drug discovery, the complementarity of academic and pharmaceutical research, as well as his vision for training the next generation of scientists.
THE THRILL OF RESEARCH
When did you decide to become a scientist?
The main thing in science is curiosity, and I’ve been curious about all sorts of things since I was a child. The first big topic I became interested in was evolution—the idea that human beings are related to primates. I remember seeing Stanley Kubrick’s movie 2001: A Space Odyssey when it came out, in 1969, and being really struck by the opening sequence with the apes, the way it combined the ideas of evolution and human progress.
From a young age I also loved helping my father, who was a veterinarian. I went to his office, tended to animals, watched him do surgery—always surrounded by skeletons and models. He was a talented artist and he drew wonderful pictures of anatomical diagrams, dissections, and so forth. I haven’t inherited his artistic ability, but I still have those drawings. They infused my earliest sense of science as a thing full of wonder, a vocation I wanted to pursue.
How did that vocation evolve into a career?
I went to Duke for college and I was considering a career in medicine, and through a work-study program I had the opportunity to work in a lab at the medical school. It was the lab of Dr. Darell Bigner, a neuropathologist who developed a type of monoclonal antibody called GFAP [anti-glial fibrillary acidic protein], which is still used today as a cell marker in the nervous system.
Monoclonal antibodies were a very new thing at the time, so I learned a lot of cool things. What I didn’t like was the animal work—handling mice for experiments. I could do it because my dad was a veterinarian, so I had seen it before. But I felt too sorry for them. I realized what I liked was working with the molecules and the chemistry.
Was that realization what lead you to drug discovery?
It all happened because of a chance encounter, to tell you the truth. I was working in the Research Triangle Park, in North Carolina, and one night at a bar I met a researcher named James Inglese, who was doing a postdoc in the laboratory of the biochemist Bob Lefkowitz. We became friends, and eventually we discovered that two proteins we were working on had a crucial thing in common.
These were both proteins that anchored to cell membranes, and we realized that they also shared a particular sequence of amino acids. We figured that might be what enabled them to attach to the membrane, and we ended up spending a whole summer trying to verify this experimentally. And it worked out beautifully! We published an article—which I’d never done before—and the research even proved useful for Lefkowitz and his work on G protein-coupled receptors, for which he won the Nobel Prize in 2012.
That was my first real taste of the thrill of research—of making predictions and seeing them work out. Based on that work, I was able to pursue a PhD in biochemistry, and a few years later I was hired by Novartis, where I spent over a decade working on dozens of drug discovery projects.
THE FISHER DRUG DISCOVERY RESOURCE CENTER
What brought you back to academic research after so many years in industry?
Drug discovery is an expensive activity. And what I learned from it, if I had to put it in a nutshell, is that it’s very, very risky. A lot of projects are going to fail before you find a way to succeed. So, when you are good at something, a private company will want you to keep at it, doing more and more of the same thing—the work can become repetitive, like manufacturing.
When The Rockefeller University approached me, I began to consider the possibility of doing drug discovery in a different way. Rather than aiming for a finished product, perhaps we could operate on a smaller scale, developing multiple ideas to the point where someone else might want to license them, or use them for further research. I thought it might be a way to get precious new ideas from Rockefeller’s outstanding faculty, and do what I was doing at Novartis with more creativity and flexibility.
That led to the creation of the High Throughput Screening Resource Center, which has now become the Fisher Center Drug Discovery Resource Center and is one of the foremost academic facilities for drug discovery in the United States. A place like this opens the door to all kinds of amazing opportunities, like finding a cure for Alzheimer’s disease. People have been trying to solve that problem for a very, very long time. And the Center enables researchers to explore new ideas and how they can be leveraged to provide better options for patients.
How exactly does the Center work?
We have two main functions. In the first place, the Center serves as a hub to help researchers in the execution of their ideas. Rockefeller’s faculty have great ideas about molecules that could be good targets for drugs, but they may not know everything about how to use the molecule they have identified to develop a new drug. That is where we come in—with our technical expertise, our instruments, and our chemical library of over 635,000 compounds—to see each project through to completion.
In addition, we are a resource center, meaning that we serve as a catalyst for innovation and collaboration. For instance, there is a biotech incubator upstairs [the Ford Center Incubator], and the companies that work there often come down to use our equipment, renting it from us instead of having to buy their own instruments, reagents, etc. This kind of exposure allows young scientists to consider many additional career paths connected with drug discovery, from joining a start-up to starting their own company as a spin-off of work done here at Rockefeller. There’s a lot more room for partnership and creativity.
What’s your vision for the future of the Center?
My primary goal is for us to become better educators, introducing students and postdocs to areas of research they might not otherwise get exposed to. Drug discovery has contributed to some of the biggest scientific breakthroughs, like the recent development of GLP-1 inhibitors—and it’s important for new generations of researchers to understand sometimes it takes decades, even generations, to develop drugs like these. So my hope is that young people here can get interested and educated in the fundamentals of drug discovery in a practical way.
I also think it’s essential for us to remain open to new technologies and their potential to transform our work. We’ve started using AI to write software for some of our projects, for instance, and it’s already replaced software we used to have to buy. Similarly, as a result of increased computing power, we may eventually reach a world where chemical libraries no longer need to exist—they could be replaced by libraries that are entirely virtual.
So the key is not to become rigid, or too set in one’s ways—which brings me back to the initial point about curiosity, I suppose. A lot of times, as a scientist, you have to remember to be like a beginner. Because becoming an expert kind of narrows your vision, but a beginner’s perspective is always open to things you didn’t quite realize before.
