CONTACT US | STAFF | OTHER LINKS
 

SMITHIES, OLIVER


INTERVIEW
OCTOBER 27-28, 2005

BIOGRAPHICAL SKETCH

TOPICAL OUTLINE

MAJOR PAPERS

INTERVIEW HISTORY AND RELATED MATERIALS

FLYING

CHILDHOOD AND EDUCATION

POSTDOCTORAL FELLOWSHIP AT WISCONSIN

STARCH GEL ELECTROPHORESIS

THE DEPARTMENT OF MEDICAL GENETICS

TEACHING AND STUDENTS AT WISCONSIN

HAPTOGLOBINS; HOMOLOGOUS AND NON-HOMOLOGOUS RECOMBINATION

PCR; ETHICS OF GENETIC INFORMATION

HOMOLOGOUS RECOMBINATION AND GENE TARGETING

UNIVERSITY OF NORTH CAROLINA; COMPLEX DISEASE

TOOLMAKING, PATENTING, INVENTION, AND DISCOVERY

RELIGIOUS UPBRINGING; MUSIC

PROFESSIONAL ISSUES; GENETICS AND RACE

CLOSING COMMENTS






BACK TO MAIN LIST

Oliver Smithies shared the 2007 Nobel Prize in Physiology or Medicine for his work in developing the methods of gene targeting.  Smithies refers to himself as a “tool-maker,” and this idea is discussed at length in the interview.  He describes himself as a craftsman, an inventor, more than a theoretician.

Biographical Sketch

Oliver Smithies was born on June 23, 1925, in Halifax, Yorkshire, England.  Like most of his generation, he was strongly influenced by the Depression: he claims still today to pick up bits of string or wire he finds along his path.  Smithies refers to himself as a “tool-maker,” an idea discussed at length in the interview.  He has built with his own hands much of the equipment used in the laboratory over the years, including a very early prototype of a polymerase chain reaction (PCR) machine.  In October, 2007, Smithies was awarded a Nobel Prize in Physiology or Medicine, which he shared with Mario Capecchi and Richard Evans.  The prize acknowledged Smithies’ role in developing knockout mice, a fundamental tool for molecular geneticists. He discusses this innovation and the work leading to it in some detail in this interview.

Smithies attended college during the Second World War.  He graduated with first class honors in Physiology from Balliol College, Oxford, in 1946 and then took a master’s and a D. Phil. in biochemistry at Oxford in 1952.  His doctoral thesis concerned the measurement of osmotic pressures.

In 1951, Smithies came to America to pursue postdoctoral work in physical chemistry at the University of Wisconsin, in Madison, under John Warren "Jack" Williams.  His project, to look for a precursor to insulin, required him to analyze the components of blood serum, but existing methods of separation were too crude.  The need for an improved method of separating out protein components led him to invent starch gel electrophoresis, one of the most important tools of 1960s human genetics.

Electrophoresis, the use of electric fields to separate the components of a mixture of different proteins, was then in a period of rapid evolution.  The technique dates to 1937, when Arne Tiselius developed the first electrophoresis method at Uppsala, using a huge and expensive apparatus.  A wide range of new methods and materials were being tried to improve the speed, lower the cost and effort, and improve the yield of electrophoresis. Smithies’ application of cooked potato starch as a matrix was cheaper, easier, and produced higher yield than other methods; but it also turned out to have unexpected properties, most notably its precision, which stems, Smithies says, from the fact that the pore size within the gel approximates the molecular size of many proteins.  He first published his invention in the journal Nature on Feb. 12, 1955.  Starch gel electrophoresis proved to be a watershed in biochemical genetics.

In 1960, James F. Crow hired Smithies to the University of Wisconsin’s Department of Medical Genetics.  He was promoted very rapidly, with appointments as Associate Professor in 1961 and full Professor in 1962.  He remained at Wisconsin until 1988, when he moved to the department of Pathology and Laboratory Medicine at University of North Carolina, his home at the time of the interview.

Smithies’s early experiments with starch gel electrophoresis led to his characterization of haptoglobins, proteins that bind free hemoglobin in the blood, and subsequent description of non-homologous recombination, which he suggested was a mechanism of gene evolution that might be important in the etiology of some blood diseases and in antibody production.  His work on gene evolution led him to the technique of homologous recombination, which exploits sequence identity as a means of gene splicing.  A 1980 article in Cell, coauthored with J. L. Slightom, showed how DNA could be exchanged between chromosomes through homologous unequal crossing over.  Smithies combined recombinant DNA with homologous crossing over and developed the concept of “gene targeting,” which would make possible gene therapy through the substitution of functional genes for nonfunctional ones.  A classic 1985 paper in Nature demonstrated proof of concept.  Mario Capecchi in the U.S. and Richard Evans in Wales inverted the idea, using it to disable a gene rather than to activate a damaged or missing one, and developed technique of “knocking out” a gene in an experimental animal.

In addition to the Nobel, Smithies has been recognized with a Lasker Foundation Award (2001), the William Allan award of the American Society for Human Genetics (1964), an endowed chair at Wisconsin and election to the National Academy of Sciences (1971) and to the American Association of Arts and Sciences (1978); he served as president of the Genetics Society of America in 1975.

Timeline

June 23, 1925

Born in Halifax, England

1943

Received Brackenbury Scholarship, Balliol College, Oxford

1946

First class honors, Physiology

1951

Post-doctoral fellowship, phyisical chemistry, University of Wisconsin, Madison
(Tiselius and Kunkel develop paper on boundary electrophoresis)

1952

M.A., D.Phil. awarded by Oxford (for work completed prior to 1951)

1954

Visiting researcher at Hospitcal for Sick Hildren, Toronto
Invents starch gel electrophoresis (pub. 1955)

1960

Appointed Asst. Prof. of Medical Genetics, University of Wisconsin
(Promoted to Assoc. Prof., 1962; Prof. 1963)

1962

With George Connell and Gordon Dixon, paper on haptoglobin genes

1975

President, Genetics Society of America

1978

Fellow, American Academy of Arts and Sciences

1985

Paper on homologous recombination (basis of gene targeting, knockout mice)

1986

Fellow, American Association for the Advancement of Science

1988

Moves to University of North Carolina, Chapel Hill

2001

Lasker Award, shared with Mario Capecchi and Martin Evans

2007

Nobel Prize in Physiology or Medicine, shared with Mario Capecchi and Martin Evans

© 2010 OHHGP. All Rights Reserved. Designed by PENDARI.COM