On the day the Nobel Prize in Chemistry was announced in 2008, Dr. Martin Chalfie slept through the official phone call from the Nobel Prize Committee. He woke at ten after six and wondered to himself, “Okay, who’s the schnook that got the Prize this time?” When he opened his laptop and visited the Nobel Prize site, he discovered he was the schnook.
Dr. Chalfie, a lifelong classical guitar aficionado, shared the Nobel Prize in Chemistry with fellow biochemists Osamu Shimomura and Roger Y. Tsien in 2008 for the discovery and development of the green fluorescent protein (GFP) at Columbia University in New York, where he teaches. The discovery of GFP allows scientific and medical researchers to tag living cells and genes with the florescent protein and observe their active biological processes, a technique now used widely to investigate diseases like cancer, AIDS and Alzheimer’s.
For Dr. Chalfie, the guitar has always been a close companion. He recorded a podcast this year for the Nobel Prize Committee on how playing the guitar and composing leads to discovery. This summer, I dropped by his office to learn more.
“I was born in Chicago and lived there from the time I was 8 years old until I went to college—we lived in Skokie, on the North Side,” Chalfie says. “I was 12 years old when my father gave me a C-1 Classic Gibson guitar. I am the oldest of three sons and my father had been a professional guitarist during the 30s and 40s. He had grown up in Cincinnati.
“My father was a successful, professional musician during The Great Depression. Because radio stations at the time employed their own musicians to have on hand, he was able to work in various on-air popular orchestras,” Dr. Chalfie explains. “For this reason, my father was able to make enough money to get his family through the Depression. The family story is that his job allowed his younger brother to get through college and attend law school. It was interesting because his talent was enough to make that difference and it give him a steady income. Normally, you don’t think of musicians as having a steady income, but it was the opposite, in this case.
“My father decided, when he married my mother, that he no longer wanted to do all the traveling that was an inherent part of being a musician. So he dropped out of the profession entirely. He had other jobs for a while but soon joined my mother in the dress manufacturing company that her mother started in the 1930s.”
Dr. Chalfie’s father gave him a guitar when he was 13 years old, along with a wish that his son would learn to play classical.
“This was during 1959-1960s, he didn’t want me to learn popular guitar. At the time, there were really not many people playing classical guitar. Anybody outside of the guitar world would have heard of Segovia, but that was about it. This was really before we knew of Julian Bream, John Williams and others who studied with Segovia. My father had done a little bit of research and found a very good classical guitar teacher in Chicago, named Richard Pick. At the time, I think there were only two major guitarists within the U.S., at least as far as I know—one of them was Richard Pick and the other was Sophocles Pappas.
“Because we lived in Chicago, my father called Richard and asked if he would teach me. Pick’s response was, ‘I don’t teach young children.’ My father said, ‘I know you’ve published several books on your guitar teaching method. If I can work through the first book with my son in a year, would you take him as a student?’ Pick answered, ‘Well, yes, if he can get through the first book, I will take him as a student. That will be fine.’
“So for that first year, my father was my guitar teacher,” Dr. Chalfie says. “We mainly covered duets that are in the first volume of Richard Pick’s method book. My father called Pick again, a year later, and said, ‘My son has now gone through the first volume of your books. Will you accept him as your student?’ Pick said, ‘Yes, I will do that. By the way, how old is your son?’ My father said, ‘Thirteen. To which Pick responded, ‘When I said I didn’t take young children, I meant four and five year olds.’
“Now I look back and think, what a wonderful thing that was to have gone through that first year learning guitar directly from my father. He was a rather remarkable teacher in the sense that, he had been a professional musician, and I have no memory at all of him being frustrated or annoyed with me. He never said anything like, ‘No, no—look—this is how you play it.’ He was a very patient teacher and I have very fond memories of that time.”
With time, Dr. Chalfie became more interested in music theory and he has pursued his interest in the guitar and composing during his undergraduate years at Harvard through the present.
“There was much about music that Pick introduced me to, in addition to his own pieces. Just as I was finishing my biochemistry major at Harvard, I became fascinated by early lute music. Harvard has a very nice library with lots of Elizabethan and Renaissance music and I used to copy the lute music after looking it up on microfilm. I had a big collection that I played for the fun of it.
“Seven or eight years ago, I attended a New York Guitar Seminar at Mannes. At the time, my daughter was in the children’s program at Mannes because she is a very good singer–a talent that is unknown in either my own or my wife’s families. We have many musicians in both our families but singers are rare,” Dr. Chalfie says.
“One day, while picking her up, my wife spotted a brochure at Mannes for their guitar seminar and that summer it happened to be entirely focused on Brazilian guitar. My wife urged me to go and I had the time of my life. I decided that I needed a refresher. I needed to brush up on my technique and learn some new music because it had been decades.
“At that seminar, one of the performers was guest artist Arthur Kampela. In one of the pieces he plays, he takes a spoon and scrapes it across the bass strings. So the next day, which was the last day of the seminar, I walked up to Arthur and said, ‘You know, I went home last night after your performance and I tried to do the same thing you did with the spoon but it didn’t work. I think the spoon wasn’t in tune.’ He looked at me blankly and then realized I was joking. That was our introduction.”
Arthur Kampela’s Percussion Study II
“The most memorable of these preconceptions originated when I was in college, during the 60s. I would listen to Dave Brubeck . One of the songs they played was Unsquare Dance. In the album liner notes, it is written that this is a piece that is so difficult—it’s written in 7/4 meter and is basically impossible to play. Listen to Joe Morello, the drummer, at the very end of the piece and he lets loose with an exhalation of pure relief to have simply gotten through it.
These days, the repertoire Dr. Chalfie enjoys playing the most are the little pieces that he writes for himself.
“I compose at an exceptionally slow pace,” he says. “I must write about a note per week but I do try to come up with these little works, which I have recorded for myself. I am quite horrible at transcribing but I am in the process of putting these pieces into shape. I have an annoying habit of playing pieces that I like over and over again, to the point where my wife has quietly closed the study door, saying, ‘It’s nice but I just can’t stand hearing it for the thousandth time.’ That’s been a little hard but that is what I mainly do now—write these little two to three minute long pieces.
Dr. Chalfie plays a Jose Ramirez classical guitar, one that he purchased in Germany in 1972 when he went on his first sightseeing trip to Europe before he started graduate school.
“I had gone traveling with my father’s words in the back of my mind, ‘If you happen to be in Germany, Segovia played a Hauser guitar. Find out if you can get one of those,’ he says.
“I did go to Germany and visited various stores and got myself laughed out of them as the shopkeepers said, ‘You think we have a Hauser?!’ I didn’t know what I was doing. I hitchhiked all through Europe and was having a wonderful time when I found myself in the German city of Trier. This is an ancient Roman town and so I took photos of the ruins until I ran out of film. Because this was 1972, I had to go into town and get a new roll of film.
“I walked down a road to a photo shop and, interestingly, the road was bow-shaped with an island of houses that sat in between. I had walked down the right bow of the road to get to the camera shop and then decided I would return to the Roman ruins by taking the alternate left bow of the road and resume my picture-taking. I never did return to the ruins that day because, along the way, there was a guitar shop. And then there was this guitar. It seemed like a good guitar. But I had to call my parents and tell them I was going to need a little money for this one.
“I bought the Ramirez from this shop and I never did any more sightseeing because I spent my last one and a half days in Europe inside that guitar shop,” Dr. Chalfie says. “Several years afterward, my father said he wanted one. So he went to Madrid, Spain to buy his own Ramirez. I am not really sure where he got his guitar because he did have friends from the Gibson Guitar Company in kalamazoo who might have picked up the guitar for him. I still have my Ramirez and actually, I now have his, as he died in 1996. I have my father’s other guitars along with an old 1930s catalog full of Gibson guitars and the front cover features all the well-known guitarists of the time, including my father.
Dr. Chalfie’s father, Eli, performed with the Russ Morgan Orchestra, which Paramount Pictures filmed for a series of 2-reel music films called Music In The Morgan Manner. Eli Chalfie appeared in one of these 2-reel films during the early 1940s. Though his children had not ever seen the film, they were aware of it from various still photos around the house when they were growing up.
“In 1985, for my father’s 75th birthday, I decided to see if we could find a copy of this movie of him playing in this film. It was a lot of fun to pursue. Russ’ son, Jack, still runs the orchestra, I think, so it is one of the longest-running bands in the country,” Dr. Chalfie says.
“First, I called Paramount but they were not at all helpful. The film was in their vaults and they were not going to share it with me. Because I know everything has to be copyrighted, I figured the Library of Congress had a copy. I tried contacting them and learned I could not obtain a copy this way, either.
“I then looked in the phonebook and discovered there was such a thing in New York known as, ‘Film Music Libraries.’ I called them and the person who answered said, ‘We only have contemporary film music, but you should find yourself one of these nuts who just collects this stuff.’ When I asked if he had any idea where I could find one of these nuts, he said, ‘Yeah, my brother.’
“So this man gave me his brother’s phone number. I called him, and he said, with great excitement, ‘Oh yeah! The Russ Morgan Orchestra!’ But then he said, ‘I don’t have any of that stuff. I only have their films from the early 1930s so I don’t have the one you are looking for. But you should try—‘
“He then named two guys. ‘That’s all they do,’ he said. ‘They collect only Russ Morgan Orchestra stuff. One of these guys just gave his entire collection to the University of Kansas so that will be impossible to obtain, but there is this other guy who lives in upstate New York, who has only a P.O. Box and no telephone. There is no way of getting in touch with him other than writing him a letter.’
Dr. Chalfie sent a letter and the collector wrote back to say he did have the film and could make a copy.
“I sent him a FedEx label and had him post it to my brother in Chicago,” he says. “We received the film copy one day before my father’s birthday.
“We had bought him a video player and then we went into a little act: we had friends over to celebrate his birthday and then we told him we had a gift for him. We brought him over to the TV and showed him the video recorder. He thought we’d just gotten him the video recorder itself. We said, ‘You know what? I think there is something in here! There’s a movie—let’s watch it!’
“I have to back up to say one thing: this was 1985,” Dr. Chalfie explains. “From the 1960s onward, from the time my father taught me how to play guitar, he would always say how he was really fortunate there were not many guitarists around in the 1930s because he wouldn’t have ever made it, professionally. ‘There are too many good guitarists out there now!’ He felt that he wasn’t that good. This was his conviction.
“How are music movies made? Back in the 1940s, they had an orchestra and they had singers,” he says. “Just listening to singers might have been boring so the producers added some soloists and some orchestra bits. Usually there were dancers, too, and a comedian. But at one point, in this film, the musicians each took their solos and there was my father in this film, playing his solo.
“When we watched this part, my father turned to me and said, ‘You know, I wasn’t that bad!’ It was perfect, really quite wonderful,” Dr. Chalfie muses. “The whole effort of finding that film had been worth it.
“The other wonderful story about my father and the guitar is this: toward the end of his life, he started getting dementia, and this meant that he basically stayed at home. When I went to visit him, I had just picked up a new sheet music edition of Bach’s cello suites for guitar, which I brought along with me to play. When I played these pieces for him on his Ramirez, he liked it. I copied the music so he could enjoy playing them himself. Now, there is a joke about dementia that goes along the lines of, ‘The good thing about Alzheimer’s disease is, you get to hide your own Easter eggs.’
“That is what it was like for my father,” he says. “For the next year and a half, every day, he rediscovered Bach. He played the pieces over and over again and he had just as much love and enthusiasm for the music as he did the minute he first sat down with the music.
“I don’t think it gets much better than to rediscover Bach every day of your life. It’s an astonishing thing. So it worked out exceptionally well! It was very nice that he was able to play this music for a couple years and get such enjoyment from it.
When asked why he chose science as a career over becoming a musician, Dr. Chalfie says, “I don’t think I ever had the ability or motivation to become a professional musician. I think it takes a lot of dedication. I get nervous when I play. It gives me a great deal of pleasure to play and when I compose. Playing the guitar gives me a way and a means to calm down. It’s a long-term part of my personality. When I was on a three-week long trip recently to conduct various seminars, I took my guitar with me. It was a nice companion.”
He confesses how he initially had doubts about pursuing science as well and recounts the one summer that made him reconsider:
“I worked for a summer after my junior year in college in a laboratory to gain some experience but that was a complete disaster. I thought maybe I wasn’t cut out to be a scientist. I took on a series of odd jobs, doing various things. Then after about three years or so, I interviewed for a summer job to work at a laboratory and was hired on the spot for startling the guy with an idea that came to me, right in the middle of being interviewed. But then he was going to be away for the entire summer. He left me alone with other people who could show me how to do things but he was not there himself to oversee what I was doing.
“I was so enamored with my own idea that I did not do the experiment he wanted me to do. I did my own experiment. Fortunately, for me, the experiment worked. So when he returned and asked what happened with the experiment I was supposed to be doing, I told him I had no idea because I did this one instead—here are the results. This experiment wound up being my first scientific publication. It gave me the confidence to actually consider going to graduate school. And I’ve been stuck in it ever since!”
Little did Dr. Chalfie realize that, years later, an intriguing confluence of ideas, sparked by a jellyfish, would eventually lead to his winning the Nobel Prize for Chemistry in 2008 along with Osamu Shimomura and Roger Tsien.
“The story of what happened is this. There is much talk in science in terms of ‘accidental discoveries’—this was definitely the case here,” he says. “There is a departmental seminar at Columbia University that I usually attend, a series of lectures. This one particular lecture was on a subject I knew nothing about and, as the person started their talk, they described some work that had been done in 1962 by a biochemist named Osamu Shimomura and it was fascinating.
“Shimomura had been interested in discovering the proteins that create the fluorescence of a particular jellyfish, the Aequorea victoria, which lives in the waters along on the west coast of the United States. There are many different kinds of organisms that generate light, like fireflies, glow worms, jellyfish, single-cell organisms in the sea, angler fish, fungi and bacteria. They all generate light and they all do it in a different way. Shimomura’s experiments had been focused on why a jellyfish on the west coast of the United States generated light.
“Shimomura is a very good biochemist and he worked very hard to figure out all the different possibilities of how to isolate this protein but nothing seemed to work,” Dr. Chalfie says.
“And then, one night late in the summer, it became dark outside by the time he discovered his latest experiment did not work again. He tossed the prep into the sink. The sink also contained some of the seawater overflow in it from the tanks where they kept the jellyfish. He turned off the laboratory light to leave. As he did so, he just happened to glance back toward the sink.
“The sink, he discovered, was glowing brightly. It turns out that the seawater had something in it that he had never put into any of his experiments: calcium. The calcium in seawater is what reacts with the jellyfish protein to trigger its production of light. Now he could do all the separations to isolate the protein.
“He figured this out because he knew what was in the prep and he realized it was the water in the sink that activated its glow—so there had to be some element in the water itself that was causing the glow,” Dr. Chalfie says. “Shimomura was able to purify the protein. Given that the jellyfish is known as Aequorea victoria, he named the protein, aequorin.
“The problem, however, is the jellyfish produces green light in real life but aequorin plus calcium produced a blue light. Shimomura thought about this for a bit and realized there must be something else that converts blue light to green.
“So he took a handheld ultraviolet lamp and began looking at all the preparations he had. Part of the preparations that gave him the aequorin still produced blue light. But further down the line, he was able to find another portion that, when the UV lamp hit it, produced green light. So the idea is, a florescent molecule is a molecule takes light of one wavelength and converts it to another. He had discovered the first fluorescent protein.
“At the time I heard the seminar describing Shimomura’s work, I was working with a small round worm called C. elegans,” Dr. Chalfie says. “We know lots about this animal but there is one property about them that is very striking: it is transparent. In other experiments, we were cloning genes. One of the very first questions you want to know when you clone a gene is, what cell turns that gene on? So we were using the existing methods of finding what cells turned on the gene and then looking at what genes were active, as we were working with a transparent animal.
“Now, at the seminar I had just been told there is a protein, that if you shine blue light on it, you’ll be able to see precisely where that molecule is because it will shine green. It will label the cells if you insert the gene and you will be able to see it because all you are doing is shining a blue light on something within a living animal.
“So, for the rest of the seminar, I drifted into this fantasy, imagining all the experiments I could do if we could take this fluorescent protein from the jellyfish and shine blue light at it to see where it was green. That would be a terrific tool. I ignored the rest of the seminar because I was busy fantasizing,” Dr. Chalfie laughs.
“I got in touch the next day with someone who was working on isolating the DNA to code this protein we needed for the experiment and we collaborated from there. Initially, there were a few issues with the experiment but, three years later, we succeeded. The experiment worked beautifully. Because the protein is green and fluorescent, it is called the Green Fluorescent Protein or GFP.
“Now, many people are finding many other kinds of fluorescent proteins in all sorts of different organisms. People hunt scorpions in the Southwest by UV lamp because they emit a blue fluorescence, for example. There are corals and fish that have fluorescent proteins, too. It all started with Osamu Shimomura’s discovery, which he wrote up in a footnote in his paper in 1962. And that footnote, as far as I know, is the only footnote to have ever won its writer a Nobel Prize.
“I’ve often wondered why it was that no one else listening to that seminar had the same idea I did,” Dr. Chalfie ruminates. “As far as I can tell, the only difference is, I was working with an animal that was transparent. So it was very obvious to me that this protein would be a good thing to have. I was at the right place at the right time. It’s been estimated that, right now, in the 20 years since we published the paper, there are probably over 160,000 papers, which have been written about using fluorescent proteins in one way or another. It’s astonishing to see. But this is what I am now most known for.
Sitting on a ledge beside his office window is a silk-screened, enlarged image of one of Dr. Chalfie’s glowing round worms.
“The picture of the worm shows its nerve cells illuminated by GFP,” he explains. If you label a nerve cell, you can look for mutants that have fewer or more cells or where cells are growing inappropriately. All of these things allow you to study how normal genes function. We work on nerve cell development primarily in my lab.”
At the moment, Dr. Chalfie and his team are working on several different projects which start with a particular set of cells in the animal that respond to the sense of touch.
“That probably sounds arcane. And it is,” he says. “The reason we are studying these cells is that I find it interesting how we interact with the world around us and sense the world around us. Biologists, for the last 130 years or so, have known what the molecule is, in our eyes, which allows us to see, because it responds to light. It’s called rhodopsin.
“The reason we’ve known of this for such a long time is because it is a major protein in the eye,” he explains. “People have worked for years to figure out how it works but for the molecule that does the sensing. In the last 25-30 years, we’ve learned a lot about molecules, which allow us to detect signals from the outside world and most of these signals are chemical. So we now have a much better understanding of the molecules for the sense of smell, taste, or how we respond to hormones because there are receptors that bind the chemicals that lead to other things. That sensor is the receptor.
“We also have a lot of our senses that work mechanically, where cells or parts of cells are pushed around. Our sense of balance and acceleration are controlled by cells located in the ear, for example, and there are five different sets of cells in the skin that respond to touch of various types, whether it be harsh touch, light, texture, low and high frequency vibrations, etc.
“When you go to a doctor, for example, and he tests your reflexes by thumping your knee with a rubber-tipped hammer, what he is doing is testing a reflex, which starts from the tap to the tendon, which stretches the muscle,” Dr. Chalfie says. “The muscle has a sensor in it that detects the mechanical stretch. It then sends a signal to the spinal cord saying, the muscle is too long. That sends another signal to the muscle to shorten itself. The muscle contracts and you kick up your leg. So the doctor is actually looking at how long it takes for the kick reflex to happen to see if your nerves are working well. It is all triggered by the mechanical stretch.
“For all of these different sensors we know the cells that do the sensing, but we do not yet know what the molecules react to the mechanical signals. So this is what we are looking at.
“We are working in several different areas right now. One of these areas of focus is to understand the molecules that sense touch and fine-tuning its development. We did, in fact, find one of these sensors about nine years ago,” he says, “and we are figuring out how it can be altered.
“For example, our sense of touch can adapt very quickly and we can lose sense of wearing our clothes, eyeglasses, and jewelry after they are on us, until someone tells us to notice it. We’re not getting constantly stimulated by these things so we know that touch gets modified. We are aware of putting on our clothes but, after a while, you don’t feel them. There are other types of modulation that increase and decrease the sensitivity of touch. We are investigating these changes.
“A second project we are working on has to do with a special feature of these touch sensing cells, where, just as the animal becomes an adult, these individual nerve cells get ensheathed in the skin, which isolates them from other cells,” Dr. Chalfie says. “We think that is a protective mechanism. We don’t know exactly what they are being protected from. But many nerve cells in other organisms are ensheathed by surrounding tissue. We realized our system of using GFP gave us a terrific way to detect mutants that are defective in the ensheathment, which then lets us understand the molecular mechanisms whereby this developmental change takes place.
“So those are some of the things we are working on and it will change next week because, inevitably, something else always comes up and we’ll decide there is something else that is interesting.”
When asked if music plays any part in his research with the round worms, Dr. Chalfie says, “The C. elegans, are very small—they are only 1/25th of an inch long—and they eat bacteria. We have standard petri dishes where we can test them. Recently we’ve been trying to stimulate them to see if there is any sensitivity to frequency over a long period of time by gluing the plate onto a car speaker or car radio. Through a computer, we can put a tone through the speaker and stimulate the animal with this vibration.
“We were hoping to find cells that were going to be the ear but the animal responds only to the vibration, not any frequency of difference. That is too bad. So we’re not going to be playing Mozart to the worms to see if there are any changes in them.
“I have to tell you, though,” he smiles, “the person who has been doing the experiments with the car speaker sets up the computer and then walks away. As for the other people in the lab, the car speaker definitely has a negative effect on them, too. As a result, this experiment is now done in a room that is isolated. So we’re not been anything directly to do with our work and music other than to simply enjoy it when we are not doing our experiments.”
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Recommended reading for how music can spark great ideas: Music and the Mind, This Is Your Brain on Music: The Science of a Human Obsession, Musicophilia: Tales of Music and the Brain, Revised and Expanded Edition and Music, The Brain, And Ecstasy: How Music Captures Our Imagination.