Yale Bulletin and Calendar

January 21, 2000

Volume 28, Number 17

Paul Sigler

Paul Sigler, a pioneer in the field
of structural biology, dies

Paul Sigler, a Yale University scientist and one of the world's leading structural biologists, died of cardiac arrest Jan. 11 while walking to his laboratory. He was 65.

Sigler, who was Henry Ford II Professor of Molecular Biophysics and Biochemistry at Yale, was one of the pioneers and giants in structural biology, a field that has provided insights into the chemistry of life. Structural biologists study the three-dimensional atomic structure of proteins and nucleic acids in order to understand the mechanisms of fundamental biological processes.

He also was an investigator at the Howard Hughes Medical Institute and a member of the U.S. National Academy of Sciences.

Although Sigler was initially trained as a physician at Columbia following his undergraduate education at Princeton University, he turned full-time to a life of basic research after his internship and residency at Columbia-Presbyterian Medical Center.

In the early 1960s, Sigler joined a very small band of biophysicists who were attempting to unravel the secrets of enzyme function by determining the three-dimensional atomic structure of proteins using X-ray crystallography.

After a short time at the National Institutes of Health, Sigler went to what was then the mecca of molecular biology, the Medical Research Council Laboratory in Cambridge, England, and joined a group headed by Dr. David Blow. In 1967, the group succeeded in determining the atomic structure of the second enzyme ever to be solved.

Sigler then spent more than 20 years on the faculty of the University of Chicago. It was there that he established the structure of the RNA molecule involved in the initiation of protein synthesis. Sigler also began his early studies of proteins that regulate the expression of information encoded in genes.

He joined the Yale faculty and the Howard Hughes Medical Institute in 1989 to begin what turned out to be the most extraordinarily productive period of his career. At the time of his death, Sigler was leading a large and very active laboratory and was widely regarded as one of the preeminent leaders of his field.

The major scientific contributions of the Sigler laboratory concerned three areas. The most developed of these was the regulation of gene expression mediated by proteins that bind specifically to DNA. His studies showed how small molecules, such as steroid hormones, act on protein structure to alter the expression of the information in specific genes. These studies have implications for understanding cell differentiation and development, cancer and hormone regulation.

The second area of major scientific contribution by the Sigler lab involves the signal transduction pathway used in vision. The enzymatic chemical steps that are initiated by light falling on the retina and ending in a signal to the brain are being unraveled at a molecular level, including the mechanism whereby a central protein called a G-protein is regulated as a part of the signaling cascade. Related G-proteins form an important family of oncogenes.

Perhaps among his most stunning technical achievements was the structure determination of a large assembly of proteins whose function was to form a machine that assures the correct folding of other newly synthesized proteins into their correct three-dimensional structure. This macromolecular structure has provided mechanistic insights into a catalyzed process whose malfunction can lead to diseases such as Alzheimer's Disease.

Sigler's impact on the field of structural biology far exceeded his own contributions, as enormous as they are. Beyond his science, he was an exciting and enormous presence, an engaging teller of many stories and a person who befriended and communicated his enthusiasm for science to many all over the world.

Sigler is survived by his wife, Althea Jo Sigler of New Haven; one son, Jonathan Lewis Sigler of Jerusalem, Israel; four daughters, Jennifer Lea Sigler of Port Jefferson, N.Y., Michelle Ann Sigler of London, England, Deborah Ruth Sigler of Berkeley, Calif., and Rebecca Lynn Africano, of Norman, Ill.. a brother Miles, of Philadelphia, and eight grandchildren.

A memorial service was held January 13 at 4 p.m. in Battell Chapel.

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