09.26.2009, 2:16 PM

Oliver Sacks portrait by Doron Gild

Martin Chalfie is perhaps best known for his Nobel Prize-winning work on GFP, a jellyfish molecule that glows bright green when exposed to blue light. By injecting it into bacteria more than a decade ago to create the first tool for visualizing biological processes in living cells, Chalfie transformed the life sciences. “I realized this was going to be an extremely important tool,” Chalfie says. “What I didn’t know at the time was how far-reaching the impact of this molecule was going to be.” Now the pioneering scientist is busy illuminating mysteries beyond the glow of a curious jellyfish gene. Seed recently visited him at his office at Columbia University to root around his lab equipment, hear about how his life has changed since receiving the Nobel, and find out why he pokes worms with his eyebrow hairs.

Interview by Greg Boustead
Photographs by Nikki Schiwal

Time to Talk

This is a talking stick. Since winning the Nobel, I’ve been much more active on the lecture circuit. Earlier this year I gave a talk at the University of British Columbia as part of the annual Michael Smith Memorial Nobel Lecture Series, and they presented me with this stick as thanks. Elder members of the First Nations, who are the original Canadians, made it specifically for me. It’s beautiful. It’s carved with standard native symbols: There’s a worm, since I work on C. elegans. They wanted a jellyfish for GFP, but it’s not part of the standard symbols. So they added an orca, the killer whale, which is king of the sea—including jellyfish, I suppose. The idea is that no one but the person holding the stick can talk. You say your bit and then give it to the next person to talk—no interruptions! So this is really good for faculty meetings. I think staff meetings of all sorts would benefit from something like this.

Why the Worm?

For almost my entire career, I’ve focused on a roundworm known as C. elegans, a tiny animal 1/25th of an inch long. Why the worm? One of the geniuses of Sydney Brenner, who started the field of studying this organism in the early 1960s, is that one can answer that question in several different ways. One is that it is a very good system to do genetics. The animal goes from an egg to an egg-laying adult in only three days, so you get many generations quickly. And the majority of the worms are self-fertilizing hermaphrodites, which makes it possible to maintain the effects of severe mutants through a significant number of progeny. But one of the most profoundly important aspects of this animal is the fact that it’s essentially transparent. We can look under the microscope and see all the nuclei of all the cells in the animal.

The Art of GFP

This is a screen print done by Science and Technology Ventures, a licensing agency here at Columbia. It was based on a photograph taken in my lab using GFP to mark all of the nerve cells of C. elegans. The worm’s transparency is what led to the discovery of GFP as a biological marker. When I heard about GFP, I realized that we could see anything we want in a worm by labeling it with this molecule because the animal is transparent. The real advantage of GFP is it allows you to look in a living organism through time. You don’t have to kill the animal, fix it, and permeabilize it. It’s a very noninvasive way of getting a dynamic view of what’s happening in biological processes. You just shine blue light on the organism and you get green light out of it, and it’s so very, very nice.

Mind of a Worm

One of the wonderful accomplishments of research on C. elegans is that we know how all of the 302 nerve cells communicate. This is remarkable. The worm is still the only organism that we know how all of its nerve cells are connected to each other. Based on work started by John White and Sydney Brenner, we have reconstructed the entire nervous system of the animal. So one of my friends decided to take an image from that research and color-code the cells to make this picture of “the mind of the worm.”

A Glowing Model

A great thing about winning the Nobel is you get asked to quite a number of different affairs, graduate student fairs, assemblies, and so on. When I went to Stony Brook University a few months ago, one of the classes I spoke with used scientific information to make physical visualizations. They used coordinates from x-ray studies of a variant of the GFP molecule and built this three-dimensional model. It’s quite interesting and detailed.

The Tickle Test

A lot of our time is spent looking down a microscope at animals on Petri dishes and testing them to see if they are touch sensitive or not. GFP was a nice idea that came to us as an offshoot, but we spend much of our time identifying components that underlie mechanical sensors in cells. Biologists have a very good idea how we detect chemicals in the world around us. These chemical signals bind to proteins and that leads to a cascade of events that allows the cells to respond. But we have a lot of senses that work by physically manipulating cells, by pushing cells around in one way or another. And we don’t know as much about them. So we’re trying to attack this problem by finding touch-insensitive mutants of the worms that we study. We test touch in a very simple way: We take an eyebrow hair—usually my own—glue it to a toothpick, and tickle the worm under a microscope. Eyebrow hairs are nice because they are typically not cut, and therefore very thin and tapered. Eyelashes are too hard to get out. But an eyebrow is perfect.

Getting out of the Lab

These are solutions and reagents needed for the various experiments we run. Some of them contain chemicals that are light sensitive so we put aluminum foil on the outside to prevent the light from getting in. I have to admit, I haven’t done a lot of experiments recently. I spend most of my time in my office next door, working on papers or talking with post-docs about their studies. I enjoy that part of the job because I have a chance to think about what other people are doing. These interactions are quite wonderful. I have a very bad system for writing papers where I have post-docs write their paper way before we want to publish the work, simply because it allows us to codify what we’re thinking. I’m very opinionated about how I want things, and it causes a bit more work, but the process helps us better identify potential holes in the experiment and see what other work needs to be done than if we wrote up the first draft after the experiments were done.

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