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Breaking Down Barriers in Science with Help from a Jellyfish: A Q&A with Martin Chalfie

The newly awarded Nobel laureate describes the fateful chain of events that put green fluorescent protein (GFP) in the spotlight, including its star turn in the Worm Breeder's Gazette
Chalfie,Shimomura,Tsien,GFP



Courtesy of Columbia University

On October 8, Martin Chalfie, chairman of Columbia University's Department of Biological Sciences, got the call that every scientist wants to receive—only he slept right through it. The Nobel Foundation was ringing him at about 6 A.M. (in New York City) to let him know they had just awarded him, along Osamu Shimomura and Roger Tsien, this year's Nobel Prize in Chemistry for their work on green fluorescent protein (GFP). A few minutes after the phone stopped ringing, Chalfie logged onto the Nobel Foundation's Web site to see who they had honored this year, only to find himself in the winner's circle for a tool he had helped develop to let scientists illuminate and study living cells in real time.

We sat down with Chalfie in his office on Columbia's campus to discuss the Nobel, GFP and his other research.

[An edited transcript of the interview follows.]

I know you've told the story of what happened the morning of the Nobel announcement many times already, but I wanted to hear it again. You weren't expecting the call?
No, I wasn't expecting it. I think people wonder whether they're going to be called. Because I'm the chair of a biology department, and it's something that's been used extensively in biology, there was some question of whether it would have been a chemistry prize. You don't anticipate it, but you do wonder. October comes around, you start to wonder about these things. Turned out that a couple of days before I had been reviewing some messages on our home phone, which is not in our bedroom but in the kitchen. I must have pressed a button [because] all of a sudden we had a different ring, and it was a much fainter ring than usual. I was thinking, "I really should change that back to the old ring." I know that when they announce these things, they call people at five o'clock in the morning. When I got up [on October 8], I looked at my watch and it was 10 after six. Like I said before, I wanted to see who the "schnook" was who won the prize. I opened up my laptop and checked online and I saw my name. I told my wife, "I think it's happened." I turned out to be the schnook.

Is there any indication ahead of time that you're being strongly considered for the prize?
No, it's completely secret and unknown; I can attest to that. I've had friends and colleagues who say, "Maybe this year," and if they say that enough you, you start to think it might be true. The day before [this year's announcement], I had actually gotten an e-mail from a [student in China] who was working on [Caenorhabditis elegans]  who wanted a copy of my paper [the 1994 paper on GFP that appeared on the cover of Science]. In his e-mail, he said, "Several of us have been discussing who will get the chemistry prize tomorrow, and we think it should go to Shimomura and Tsien." And that was it. I sent him a .pdf of the article and said thanks and told him maybe they should consider Douglas Prasher, too. So maybe he had some sort of inside line, or maybe he was just hopeful. [laughs] There's no inkling that these things are going to happen, it's a little like reading tea leaves.

You first heard about GFP during a neurobiology lecture given by Paul Brehm (a former Tufts University researcher now at S.U.N.Y. Stony Brook University) at Columbia University in 1989. Did you go to this lecture with the thinking that you would discover a tool that you could use for your C. elegans work?
Absolutely not. Paul had been invited from Tufts to talk to us. I went to the seminar not expecting to hear anything about this. Frankly, I don't remember anything else about his seminar because I was so excited about the possibility of doing this experiment. Because I had been thinking about transparent animals for about 12 years before this … I got very excited about the possibility that we could use this in C. elegans.


It's funny the role that fate played in the discovery and development of GFP. If anything along the way had been different, who knows what would have happened?
Absolutely, it's not directed. So we were able to show this is a reagent that could be used in many if not all organisms. All you need to do is shine light on the cell and you'll get light of a different color back. We now finally had a dynamic way of looking at gene expression, at protein localization. We could watch things in real time in living cells in organisms, and that's, I think, the real advantage of GFP.

Osamu Shimomura found the protein, without his work there would be nothing. Douglas Prasher cloned it, again without that work this work not have happened. [Chalfie and the researchers in his lab] were able to show that it could be used in a lot of different biological contexts as a marker, and that opened the flood gates for people to try to use it. And Roger greatly improved it … so that it was actually workable in many situations.

Have you met Dr. Shimomura and Dr. Tsien? How did your work build upon Dr. Shimomura's initial discovery of GFP [from the Aequorea victoria jellyfish]?
I've met both of them. We've never collaborated on anything because our [discoveries] came at different times and at different parts of the story. Osamu Shimomura was the person who discovered the green fluorescent protein in the very early 1960's. The next step along the evolution in terms of my involvement is that I heard about it and got together with Douglas Prasher [at the time working at the Woods Hole Oceanographic Institution in Massachusetts].

You first shed light on this in your February 1994 paper published in Science?
There is actually an earlier, non-official publication, a newsletter that went out to all the researchers in the field. This newsletter, the Worm Breeder's Gazette, was where you told people things that they might interested in before [the research was published]. So the October 1993 edition of the Worm Breeder's Gazette was the first general notification to people that we had this and we made several suggestions of how it could be used in worms.

You and your colleagues won the Nobel this year for a tool that you created over time, and it made me think of that old proverb, "Give a man a fish, he will eat for a day. Teach him how to fish and you will feed him for a lifetime." Is that what you've done with GFP?
I agree, it's very much like that. I've been wondering, as have several of my friends in e-mails to me, why the chair of a biology department suddenly gets an award in chemistry. I think this says a couple of things. First of all, this is actually a prize to a molecule; and it's rather fitting to give a chemistry prize to a molecule. It is a rather remarkable molecule that has quite a number of uses. Most of those uses have been in chemistry. I do think of this prize as the GFP prize, and I happen to fortunately be one of the people that goes along for the ride. There's also an aspect that these terms that we have of "chemistry" and "biology" or "physics" and "computer science" sometimes put up unnecessary boundaries or barriers to researchers who are actually working along the borders of these things. I'm taking [the award] as maybe a sign that these barriers need to come down a bit.

Getting back to your comment about GFP being a tool, the other thing I like about this prize is that it is an award for work that is basic, fundamental research. I view this as setting up lots of basic research to ask a lot of questions, some related to fundamental biological properties, some related to diseases but all now having a new tool with which to do this.

That's quite a legacy. Still, GFP is not the main direction of your research. What is the main focus of your work?
What I am primarily is a neurogeneticist, I use genetics to study problems in neurobiology. The one problem I study primarily … understanding of the sense of touch. We know what molecules are needed to sense light—what turns that signal that detects light into an electrical signal. We know how smells are detected. But we have a vast number of senses for which we know what the signal is, but we don't know what the receiver is. We don't know how cells convert that signal into an electrical signal that says, "Oh, this is happening."

I read about a grant that you're preparing. Does this have anything to do with your development or use of GFP?
No, this is a grant that looks at the development and function of sensing cells, and I'm going to find out if I can get an extension. [laughs]

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