One of the things I love about doing science, it's really puzzle solving.
Linda Buck was born in 1947 in Seattle, Washington. Her father was an electrical engineer by profession and an inventor by avocation, while her mother enjoyed solving puzzles of all kinds. Linda Buck believes her father’s inventiveness and her mother’s love of problem-solving contributed to her own later passion for science. Both parents taught her to think independently and assured her she had the ability to do anything she set out to do in life.
She stayed close to home as an undergraduate, attending the nearby University of Washington. Her initial academic interest lay in psychology, and she considered becoming a psychotherapist. Her direction changed when she took her first undergraduate course in immunology and decided to become a biologist. In 1975, she entered graduate school in the Microbiology Department at the University of Texas Medical Center in Dallas, a major center for the relatively new field of immunology. In Dallas, she earned a Ph.D. in immunology and gained her first insights into the molecular mechanisms underlying biological systems.
To learn the newest techniques of molecular biology, she pursued postdoctoral research at Columbia University, beginning in 1980. At Columbia, she gravitated towards the laboratory of Dr. Richard Axel, an investigator of the Howard Hughes Medical Institute, who first developed the transfer techniques that enable us to study genes in vitro.
Building on Axel’s studies of the neurons of the sea snail Aplysia, she undertook to develop a technique for identifying and cloning genes that may be expressed in one Aplysia neuron, but not in others. As her mastery of the techniques of molecular biology grew, Buck became increasingly fascinated with applying this science to the understanding of the brain, with its enormous diversity of cells and neural connections.
Near the end of her Aplysia project she read a paper that, by her own account, changed her life. There are few mysteries more profound and intriguing than how the stimuli received by our senses are encoded as impressions in the brain. The 1985 paper, by Solomon Snyder’s research group at Johns Hopkins University, discussed the potential mechanisms that might underlie odor detection. The human sense of smell can identify 10,000 or more different chemicals, and reacts completely differently to compounds that are nearly identical at the molecular level. Dr. Buck had never considered the process before and was fascinated.
In 1988, Linda Buck set out to map the olfactory process — the sense of smell — at the molecular level, tracing the progress of perceived odors through the cells of the nose to those of the brain. Working with the genes of a rat, she identified a family of genes that code for more than 100 odor receptors (ORs). She and her mentor, Richard Axel, published these findings in 1991.
Later that year, Dr. Buck left Columbia to become an assistant professor in the Neurobiology Department at Harvard Medical School, where she established a lab of her own. Following her initial discoveries of the means by which odors are detected by the nose, she set out to learn how these signals are perceived and organized. In 1993, she published her findings on how the inputs from different ORs are organized in the nose.
She pursued the olfactory system from the nose to the olfactory bulb, a set of neurons in 2,000 spherical structures called glomeruli. Findings concerning the glomeruli were published in 1994. It was a banner year for Dr. Buck. That same year, she became an investigator of the Howard Hughes Medical Institute, which has supported her work ever since, and she met Roger Brent, a fellow scientist who became her lifelong companion.
She would eventually identify genes responsible for 1,000 ORs in the mouse nose, and 350 in the human. Buck published her findings on the organization of olfactory impressions in the cortex of the brain in 2001, ending a decade of work at Harvard. In her years at Harvard, Buck’s group also investigated the chromosomal organization of OR genes, and began the investigation of the mechanism of taste.
In 2002, after ten years at Harvard, Dr. Buck returned to her native Seattle to join the Division of Basic Sciences at Fred Hutchinson Cancer Research Center, and to serve as Affiliate Professor of Physiology and Biophysics at the University of Washington. The return to the West Coast brought her closer to family and old friends, and to Roger Brent, who lives in Berkeley, California.
At Seattle, Dr. Buck continues to explore the mechanisms underlying odor perception, as well as the means by which pheromones elicit instinctive behaviors. Buck and her colleagues have determined how the mammalian brain translates as many as 10,000 different chemicals into distinct smells. She is now investigating the neural circuits that underlie innate behaviors and basic drives, such as fear, appetite and reproduction. Her laboratory has also developed chemical libraries to identify genes that control aging and lifespan.
As Dr. Buck published her findings, the reaction in the scientific community was unanimous; she was showered with every major honor in American science. In 2004, her pioneering work on the mechanism of smell was honored with the Nobel Prize in Medicine. Harvard University recognized her achievement with an honorary Doctor of Science degree in 2015. Today, laboratories all over the world apply her techniques and insights to the sensory systems of all species, from the simplest to the most complex.
Linda Buck was awarded the Nobel Prize in Medicine for unlocking a mystery that had baffled scientists for centuries. From infancy, we depend on our sense of smell to identify which foods are fit for consumption, and to warn us of impending danger, as in a fire. Although science had made great strides in understanding the mechanics of human vision and hearing, it was unable to answer the simple question: how do we smell the things we smell?
In 1988, Dr. Buck, a postdoctoral fellow at the Howard Hughes Medical Institute in New York City, set about applying the latest discoveries in genetics to this persistent puzzle. Dr. Buck conducted a series of experiments with the mouse genome, and discovered a family of genes specifically dedicated to creating the 1,000 olfactory receptors of the mouse nose. A similar family of genes create the 350 olfactory receptors in the human nose, possibly the largest family of genes in the entire human genome. With each cellular receptor responsive to a single, specific scent, each of the roughly 10,000 odors we can distinguish are perceived by different combinations of these receptors. These patterns are reproduced in the cells of the brain, enabling us to recognize odors years after we first encounter them.
When Dr. Buck published her findings, the reaction in the scientific community was unanimous; she was showered with every major honor in American science. In making the 2004 award, the Nobel Committee cited Buck for her “discoveries of odorant receptors and the organization of the olfactory system,” but these words only begin to convey the fundamental nature of this breakthrough. Dr. Buck’s subsequent research is uncovering the neural circuits that underlie our most basic instinctive responses, such as appetite, fear and aggression. Linda Buck has taken a revolutionary step forward in our understanding of the workings of the brain.
It’s something we almost take for granted, that we smell things, and react in different ways to different odors. When you were still a postdoctoral fellow at Columbia, you found in this commonplace experience not just a mystery to be solved, but something truly important to understand. Why is that?
Linda Buck: I was completely fascinated by this, and there was really nothing else I wanted to do more than to solve this problem.
Do you solve these problems by design? By trial and error?
Linda Buck: It’s puzzle solving, and that’s one of the things I love about doing science. It’s really puzzle solving, and the other part of it is that what you find is so beautiful. Nature’s designs are so elegant. I’m a very empirical scientist. I don’t theorize, because what usually happens is that the answer, the biological mechanisms that are used, are usually far more elegant than the theories that people come up with. Of course, you have to have a hypothesis, or some kinds of ideas to begin to explore. For example, the idea that there are proteins in the nose that recognize odorants was a quite reasonable one, and there was some indirect evidence for it. The question was how to find them. What I decided to do was to try to find genes encoding these molecules. I think Richard Axel also agreed that this was the logical thing to do, so I set out to do that. Instead of looking for a job and getting a faculty position, I stayed on there, with his blessing. I actually looked for a job, and of course, I just said — I didn’t say I was going to work on Aplysia — I said I’m going to do this, which of course, people would think was impossible, and I could never have gotten a grant to look for this, because who knows? Maybe I wouldn’t have found the receptors. So I set out to do it, and I worked very hard to do this.
That doesn’t sound like a nine-to-five job.
Linda Buck: Oh, no.
At one point, I switched over to working until five a.m. so that I would have all the lab equipment to myself. And I worked very long hours, but I loved it, you know. So what you do is basically try to come up with an idea. How are you going to find what you’re trying to find? And I tried several things before I hit on the right one. But it took taking a recently developed technique, and then changing that, modifying that, adding some layers onto that, and then pulling in some other way to analyze the data. So basically, I used PCR (polymerase chain reaction), which at that time was a relatively new technique, but I modified it, so that I developed a combinatorial PCR approach. I made the assumption that these proteins in the nose would be at least distantly related to other proteins that served as receptors or detectors on the surface of other cell types. There were some of these known, and there was some evidence that suggested that the proteins in the nose might transduce signals to the interior of the cell using similar mechanisms to some other receptors.
Nobody had ever done this before. What inspired you, or led you to believe that this was an important thing to do?
Linda Buck: It wasn’t as if I stood back and thought, “What’s the most important thing?” I remember when I started graduate school that I did survey what was around me and decide what was the most important thing — I thought — to do. I think that that was in the backdrop, that I wanted to do something important. But I don’t remember thinking, “This is an important thing! This is an important thing!” I might have done that, but I was always interested in taking on very challenging problems, and ones that I thought were important. I was never interested in taking small steps and adding bricks. I was always attracted to the bigger questions, and the challenges didn’t bother me. This was actually a very high-risk project, and in retrospect, it was potentially suicidal. I didn’t have to find the receptors. I mean potentially suicidal in terms of a career. But actually, that didn’t matter to me at that time.
Did you ever imagine that this long journey would take you to the Nobel Prize?
Linda Buck: No, I didn’t really think that.
Do you have to be willing to take risks as a scientist?
Linda Buck: Well no, you don’t have to. You don’t have to take risks at all. But I think to take big steps in science, you almost always have to take risks, and I think it’s very important to teach students that. It’s hard, because it can be scary to many people. They want to make sure that they’re going to get results. People have different personalities.
We know it was a long process. How did you feel when you knew you had really found something? What was it like?
Eventually I found the receptors, and it was really beautiful. I remember just being stunned looking at them, when I first had the first set of them. It was a Saturday night, I think, and I was in my kitchen, and I had colored pens, and I had written down the sequence, because at that time we didn’t have the software for analyzing DNA sequence information that we have now. So I had translated the sequences into proteins, and I was comparing the different ones, and I was coloring in places where they were the same, and I remember thinking that it was like patchwork quilts, where bits and pieces were exchanged between the different receptors to make proteins that would be able to detect different odorants. I had a friend in the other room who was watching TV or something, and I kept running back and forth saying, “Look at this! Can you believe this?” and it was just absolutely thrilling.
So then after that, we published the paper. I had been in Richard Axel’s lab forever, working very independently. He was quite unusual in that regard, that once people got there, so to speak, he would just let them go. But I was really very eager to have my own lab.
I moved to Harvard Medical School. I became an assistant professor there in neurobiology, and my next goal was to determine how the signals from these receptors in the nose were translated by the brain into perceptions. So there are actually about 350 different odorant receptors in humans, and about 1,000 different ones in mice. Mice we use as a model organism to understand how these systems work. So over the next ten years at Harvard, we used genes in coding the odorant receptors to try to understand how information is encoded in the system, and to give different perceptions. I was very fortunate to have a series of wonderful students and postdoctoral scientists that worked with me over that period, and it was a tremendous amount of fun just trying to figure out how it worked. We found out how information from the 1,000 different receptors is organized, first in the nose, and then in the two major relay centers in the brain: the olfactory bulb, which is in the front of the brain, and then the olfactory cortex.
Why is it important for us to understand this?
Linda Buck: Well, it’s how the brain works.
We don’t really know how the brain works, by and large. I mean it’s still a black box. I think the 1990s were the decade of the brain, but it still is not understood what a perception is, exactly. What happens in the brain when you perceive something? You see a friend walking down the street toward you, and maybe they say something to you. There’s activity and neurons in many parts of the brain. How do those come together to form a percept — a perception? It’s not known. We don’t even know what the neural circuits are that underlie appetite. We don’t know what happens when we feel an emotion like love, or we look at a beautiful piece of art. The brain is still a mystery to us, and it’s the most challenging area, to me, of biological science today. And I’d like to encourage the wonderful students that are here at this Academy of Achievement to consider a career in neuroscience, to try to figure out how the brain actually works. It’s a fascinating, challenging, very satisfying and rewarding thing to do, I think.
For someone who doesn’t understand what it’s like to be a scientist, what do you enjoy about it?
Linda Buck: I love doing science. I love thinking about it. I love trying to figure out how to solve a problem, and I love working with the people in my lab — the students and postdocs — and exchanging ideas, and trying to come up with strategies, and trying to figure out the data. So I don’t work at the bench anymore myself. They work at the bench, and then we discuss data, and we try to figure out what it means, and that’s a lot of fun. Like when you see results that you don’t expect. You thought it might have worked one way, and then you see something that doesn’t really match what you imagined, and then you try to figure out what could be going on. Intellectually, it’s like a game. It’s trying to figure out how to answer a question, and exploring different possibilities and then carrying out — if you’re actually working at the bench, which I don’t anymore — and then looking at the data, and it usually turns out that it doesn’t work the way you thought. Not exactly anyway. It’s really when you get the answers that you didn’t expect that you learn the most. So you see the results, and then you think, “How could that be? Why did we get these results?” And then you get ideas, and that stretches your imagination further, and I think that that’s where the greatest discoveries are made, when you find things that you never imagined. Then you have to work to try to understand them, and then you test those new ideas.
Along the way, before you realize success, such as you have, don’t you have to deal with setbacks and frustrations?
Linda Buck: You do have to be patient. Oftentimes things don’t work, you have to repeat them, you have to change them. In fact, I’ve often pointed out to students, this is why they call it “re-search.” Because you really have to do it over and over again. But it’s really the process that’s interesting, and that’s also where you learn. I was just saying to a wonderful student in my lab recently — brilliant student — pointing out how much she had learned by having to try different things. To think, to do research in the literature, to try to come up with how to solve the problem that she was trying to solve, and integrate things that she learned into the design of her experiments. She’s grown tremendously over the last year, and I’m so proud of her. You know, she’s learned things that I didn’t know, and that’s how you grow, and in doing that, you learn, and it’s satisfying. And then when you get a result, it’s fantastic. But it’s fun, the process is fun. It’s the day-to-day. You don’t — I don’t anyway — do science because of something that’s going to happen in the distant future, like, “I will get a paper,” or “I will get a prize.” It’s because I like actually doing it.
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