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Unformatted text preview: WORMS, LIFE AND DEATH Nobel Lecture, December 8, 2002 by H. R OBERT HORVITZ Howard Hughes Medical Institute, McGovern Institute for Brain Research, Department of Biology, Massachusetts Institute of Technology, 77 Massachus- etts Ave., Cambridge, MA 02139, U.S.A. I never expected to spend most of my life studying worms. However, when it came time for me to choose an area for my postdoctoral research, I was in- trigued both with the problems of neurobiology and with the approaches of genetics. Having heard that a new genetic organism with a remarkably sim- ple nervous system was being explored by Sydney Brenner the microscopic soil nematode Caenorhabditis elegans I decided to join Sydney in his efforts. THE CELL LINEAGE After arriving at the Medical Research Council Laboratory of Molecular Biology (the LMB) in Cambridge, England, in November, 1974, I began my studies of C. elegans (Figure 1) as a collaboration with John Sulston. John, 320 Figure 1. Caenorhabditis elegans adults. Hermaphrodite above, male below. John Sulston took these photographs, and I drew the diagrams. Bar, 20 microns. From (2). trained as an organic chemist, had become a Staff Scientist in Sydneys group five years earlier. Johns aim was to use his chemistry background to analyze the neurochemistry of the nematode. By the time I arrived, John had turned his attention to the problem of cell lineage, the pattern of cell divisions and cell fates that occurs as a fertilized egg generates a complex multicellular or- ganism. John could place a newly hatched C. elegans larva on a glass micro- scope slide dabbed with a sample of the bacterium Escherichia coli (nematode food) and, using Nomarski differential interference contrast optics, observe individual cells within the living animal. In this way, he could follow cells as they migrated, divided and, in certain cases, died. That cells died as a normal aspect of animal development had been known by developmental biologists and neurobiologists for many years, and in 1964 Richard Lockshin and Carroll Williams had published a paper (1) in which they referred to such naturally-occurring cell death as programmed cell death. The study of this phenomenon was later to engage a substantial proportion of my scientific ef- forts. Johns initial analyses of the C. elegans cell lineage were focused on the de- veloping larval ventral nervous system. I found his discoveries about the rela- tionship between cell lineage and nerve cell fate very exciting: 12 neuronal precursor cells underwent the same pattern of cell division, and descendant cells with equivalent cell lineage histories in general differentiated into the same nerve cell type. For example, the anterior daughter of the posterior daughter of each of 12 neuroblasts became motor neurons of a class called AS by John White (Figure 2), who with Sydney was then defining the com- plete anatomy and connectivity of the C. elegans nervous system. I asked John Sulston if I could join him in the examination of other aspects of the...
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