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Clyde A. Hutchison III - a brief career sketch

Hutchison graduated from Yale University in 1960, with a B.S. degree in Physics. While an undergraduate, he worked on bacterial spore germination with Carl Woese, then a postdoctoral fellow in the laboratory of Harold Morowitz. His graduate studies were in the laboratory of Robert L. Sinsheimer at Cal Tech. His Ph.D. thesis describes a collection of conditional lethal mutations that he developed to study the genes of bacteriophage phiX174, and their functions. While at Cal Tech he began a long-term collaboration with Marshall Edgell, a postdoctoral fellow in the Sinsheimer lab.

In 1968 Hutchison and Edgell moved to The University of North Carolina at Chapel Hill, where they joined the faculty of the Department of Bacteriology and Immunology. There they collaborated on the analysis of the DNA, and the virion proteins, of phiX174. They developed a marker-rescue assay for specific fragments of the viral genome, and used this assay to associate particular genes with specific restriction fragments of phiX DNA. During this period Hutchison and Edgell also applied restriction enzymes to the analysis of mammalian mitochondrial DNA, identifying restriction fragment length polymorphisms, and demonstrating maternal inheritance of mitochondrial DNA in mammals.

Hutchison met Fred Sanger at the first international conference on the application of restriction enzymes in Ghent, in 1974. As a result of this meeting he spent a sabbatical in Sanger’s lab at the LMB from June 1975 until August 1976. During this time he was a member of the group that sequenced the genome of phiX174. He was particularly involved with the analysis of the overlapping genes D and E, using mutants isolated during his thesis research to elucidate this problem.

While in Cambridge, Hutchison met Michael Smith, and they devised a plan to introduce specific mutations into phiX using synthetic oligonucleotides. Upon his return to Chapel Hill, Hutchison and Smith (at UBC in Vancouver) developed the method of site-directed mutagenesis (published in 1978). The Hutchison lab later developed methods for “complete mutagenesis”, in which each residue in a protein is individually altered. They applied this method to the HIV-1 protease in collaboration with the lab of Ron Swanstrom, and to regions of the HIV-1 reverse transcriptase.

Hutchison and Edgell continued their collaboration in Chapel Hill to apply the new sequencing and cloning technologies to the beta-globin gene cluster in the mouse, completing the sequence of the cluster over the next several years. While studying the globin genes their labs discovered and characterized the L1 retroposon, the most common long repetitive element in the mammalian genome.

In 1990 Hutchison began work with Mycoplasma genitalium, the organism with the smallest known genome for an independently replicating cell. A survey of the genome by shotgun sequencing in the Hutchison lab led to collaboration with TIGR, in an effort headed by Claire Fraser, to sequence the entire genome (published 1995). Hutchison spent a sabbatical year at TIGR 1996-1997 working to define the minimal set of genes required for cellular life. He has continued to work on mycolplasma in collaboration with TIGR, and as a part of the Berkeley Structural Genomics Center.

In 2003 Hutchison began to collaborate with Hamilton Smith and others at IBEA (Institute for Biological Energy Alternatives) to work on problems related to chemical synthesis of genomes. This collaboration soon resulted in assembly of the genome of bacteriophage phiX174 from a single pool of chemically synthesized oligonucleotides. The methods developed in this work are expected to enable the assembly of much larger genomes. A major goal is the assembly of a synthetic minimal cellular genome.

Hutchison is Professor Emeritus of Microbiology and Immunology at The University of North Carolina at Chapel Hill, where he continues to do research and train graduate students and postdocs. He is also Distinguished Investigator at the J. Craig Venter Institute in Rockville, Maryland. He is a member of the National Academy of Sciences and a fellow of the American Academy of Arts and Sciences.