GFP: Lighting up life.

I want to thank the Royal Swedish Academy of Sciences and the Nobel Foundation for this amazing and surprising honor. At first I wondered why I, a biologist and a person with less than enviable college grades in chemistry, had been selected. Then I realized that this prize had actually been given to the GFP molecule, and I am one of its assistants. Thank you for letting me be part of the celebration of a wonderful tool for visualizing life. Scientific inquiry starts with observation. The more one can see, the more one can investigate. Indeed, we often mark our progress in science by improvements in imaging. The first Nobel Prize, the physics prize of 1901, was an imaging prize, given to Wilhelm Röntgen for his discovery of X-rays and their astonishing ability to allow the noninvasive viewing of the human skeleton. A few years later the Nobel Prize in physiology or medicine was awarded for the development of silver nitrate staining to visualize nerve cells by Camillo Golgi and its improvement and use by Santiago Ramón y Cajal to demonstrate the cellular nature of the nervous system. This research laid the groundwork of modern neurobiology. Over the years several other imaging techniques and their developers have been honored by the Nobel Foundation for X-ray crystallography (William and Lawrence Bragg, physics, 1915; the ultramicroscope (Richard Zsigmondy, chemistry, 1925), NMR (Felix Bloch and Edward M. Purcell, physics, 1952), the phase-contrast microscope (Frits Zernike, physics, 1953), large-array radio telescopes (Martin Ryle, physics, 1974), the electron microscope (Ernst Ruska, physics, 1986), the scanning tunneling microscope (Gerd Binnig and Heinrich Rohrer, physics, 1986), computer-assisted tomography (Allan M. Cormack and Godfrey N. Hounsfield, physiology or medicine, 1979), and, most recently, magnetic resonance imaging (Paul C. Lauterbur and Sir Peter Mansfield, physiology or medicine, 2003). My road to imaging was not direct. I had been interested in science from when I was very young, but after a disastrous summer lab experience in which every experiment I tried failed, I decided on graduating from college that I was not cut out to be a scientist. Instead I did a series of somewhat random jobs including teaching high school chemistry. During the summer break from teaching, I tried laboratory research one more time, working with José Zadunaisky at Yale Medical School (New Haven, CT) (Fig. 1). The successful experiments of that summer and his support gave me confidence to apply to graduate school, and I entered the physiology department at Harvard (Cambridge, MA) in 1972 where I did my thesis with Bob Perlman. Bob and I had a wonderful relationship, which continues to this day. He is one of the warmest, kindest, and smartest people I know and a great person to talk over ideas with. My current studies, however, started when I was accepted as a postdoctoral fellow by Sydney Brenner at the Medical Research Council Laboratory of Molecular Biology (Cambridge, U.K.) and began working on the nematode Caenorhabditis elegans. In 2002 Sydney, Bob Horvitz, and John Sulston won the Nobel Prize in physiology or medicine for their work on C. elegans. All three shaped the direction of my research. Sydney gave me the opportunity to work with him and an amazingly gifted group of scientists, Bob, a friend since high school, gave me several crucial pieces of advice, collaborated on several projects, and served as an example of what one can achieve in science (I am still following in his footsteps), and John, with whom I collaborated the most and who taught me most about how to act honorably as a scientist, started me on the project that still occupies most of my time: the study of mechanosensation. My colleagues and I often call their Nobel Prize the first worm prize. The second went in 2006 to Andy Fire and Craig Mello for their discovery of RNA interference. I consider this year’s prize to be the third worm prize, because if I had not worked on C. elegans and constantly told people that one of its advantages was that it was transparent, I am convinced I would have ignored GFP when I first heard of it. These three prizes speak to the genius of Sydney Brenner in choosing and developing a new organism for biological research. The year before I learned about GFP, my lab had begun looking at gene expression in the C. elegans nervous system. We were studying the differentiation and function of nerve cells needed for mechanosensation. Mechanosensors respond to physical perturbation; they underlie many of our senses, including touch, hearing, and balance. These senses are poorly understood; in particular the transduction molecules, the molecules that detect the mechanical signal, are virtually unknown. The genetic studies that I had done with John Sulston were directed, in part, at discovering such transduction molecules. We thought that by obtaining mutants that were defective in touch, which was sensed by six cells in the animal, we could identify genes that were needed both for the production and differentiation of these particular cells and for transduction. In the late 1980s my lab began cloning several touch sensitivity genes and testing whether they were expressed in the animal’s touch receptor neurons. At that time three general methods were used to look at gene and protein expression. The first was the use of labeled antibodies, whose specificity created outstanding protein-specific markers. The second was the use of -galactosidase from the Escherichia coli lacZ gene, which could be expressed as transcriptional and translation fusions and visualized by the cleavage and subsequent oxidation of X-gal to an insol-