Clyde A. Hutchison III

Clyde A. Hutchison III (November 26, 1938 – September 27, 2025) was an American biochemist and microbiologist notable for his research on site-directed mutagenesis and synthetic biology. He was professor emeritus of Microbiology and Immunology at the University of North Carolina at Chapel Hill, distinguished professor at the J Craig Venter Institute, a member of the National Academy of Sciences, and a fellow of the American Academy of Arts and Sciences.

Early research Born at New York City in 1938, Hutchison graduated from Yale University in 1960, with a B.S. degree in physics. He studied for his PhD at Caltech, working on the bacteriophage ΦX174. While at Caltech he began a long-term collaboration with Marshall Edgell.

Site-directed mutagenesis In 1971, Clyde Hutchison and Marshall Edgell showed that it is possible to produce mutants with small fragments of bacteriophage ΦX174 and restriction nucleases. Hutchison later collaborated with Michael Smith and developed a more general method of site-directed mutagenesis using a mutant oligonucleotide primer and DNA polymerase. Smith and Hutchison used a 12-nucleotide oligomer with a centrally positioned single mismatched nucleotide as primer, a circular single-stranded ΦX174 DNA as template, and E. coli DNA polymerase I in which the 5'-exonuclease had been inactivated by subtilisin. The polymerization with the primer annealed to the template generated a double-stranded DNA product that contained a mutation and could be converted to a closed circular duplex by enzymatic ligation. Transfection of E. coli with this molecule produced a mixed population of wild-type and mutated phage DNA. For his part in the development of this process, Michael Smith later shared the Nobel Prize in Chemistry in 1993 with Kary B. Mullis, who invented polymerase chain reaction.

Hutchison later developed methods for "complete mutagenesis" in which each residue in a protein can be individually altered.

Synthetic biology In 1990 Hutchison began work on Mycoplasma genitalium, which has the smallest known genome that can constitute a cell. It led to a collaboration with The Institute for Genomic Research (TIGR) to sequence the entire genome of the organism in 1995. In 1996 Hutchison spent a sabbatical year at TIGR; there he discussed with Hamilton Smith and Craig Venter the idea of a minimum cell - cell with the minimal set of genes required for survival. M. genitalium however is slow-growing and attempts at transplanting its genome to another species became protracted and proved unsuccessful. The synthetic-cell team however showed that it is possible to transplant the natural genome of Mycoplasma mycoides, whose genome is twice the size of M. genitalium, into a related species Mycoplasma capricolum. The team therefore decided to switch to the faster-growing M. mycoides as the donor species. In March 2010, a synthesized M. mycoides genome was successfully transplanted into M. capricolum. The resulting organism was called "Synthia" by the popular press.

Hutchison worked on creating the minimal cell. New versions of the synthetic genome with genes removed were transplanted into recipient cells, and the resultant cells' growth rates and their colony size were monitored. Other more complex bacteria such as cyanobacteria were also being assessed for the feasibility of genome transplantation.