Oliver Smithies (1925–2017)

Oliver Smithies researched physical chemistry, biochemistry, and genetics in England, Canada, and the United States during the twentieth and early twenty-first centuries and contributed to the study of gene function. During the 1950s, Smithies developed a technique to improve separating proteins based on their physical properties. Later, in the 1980s, Smithies utilized homologous recombination, a process that involves two similar pieces of deoxyribonucleic acid, or DNA, that exchange information, to target and manipulate specific genes. Smithies’s research on homologous recombination helped lead to the creation of the knockout mouse, a model organism that has genetic alterations to a single gene, to help researchers understand the function of genes in development. In 2007, Smithies received the Nobel Prize in Physiology or Medicine along with Sir Martin Evans and Mario Capecchi for work on introducing specific gene modifications in mice. Smithies’s scientific contributions toward developing the knockout mouse provided a basis for subsequent research studying the impact of different genes on human health.

Oliver Smithies was born on 23 June 1925 in Halifax, England, to Doris Sykes and William Smithies. His mother taught English at the Halifax Technical College, now known as Calderdale College, in Halifax. Smithies’s father sold life insurance policies to local farmers and their families. Smithies’s parents met at Halifax Technical College, with Smithies’s mother having taught his father’s English course. Smithies had two siblings, a twin brother Roger Smithies, and a younger sister, Nancy Smithies.

When Smithies turned seven years old in 1932, his tonsils became infected, and he was left bedridden for ten weeks due to a rheumatic fever. Rheumatic fever is an inflammatory condition that affects the heart, joints, brain, and skin, with serious complications leading to long-term heart damage. Despite his recovery, the rheumatic fever gave Smithies a mitral valve murmur. A mitral valve murmur occurs when the mitral valve in the heart is not opening wide enough or does not seal properly when closed, causing abnormal blood flow through the left atrium to the left ventricle. In his biography, Smithies mentions that despite knowing later that his condition was trivial, doctors considered his illness serious at the time and prevented him from playing sports for the next seven years.

Instead of playing sports, Smithies spent time reading. Before dinner, Smithies’s mother read English literature to him and his siblings as they waited for their father to come home from work. According to his biography, some of Smithies’s favorite books included Kenneth Grahame’s Wind in the Willows, and Lewis Carroll’s Through the Looking Glass. Before Smithies turned eleven years old, he read a comic strip in which an inventor was the main character. According to his biography, Smithies wanted to become an inventor like the one in the comic strip, which was before he knew the word scientist.

In 1936, Smithies and his brother moved to 33 Dudwell Lane in Halifax and attended the Heath Grammar School in Halifax. While living there, Smithies became friends with Harry Whiteley. Smithies and Whiteley spent time in Whiteley’s attic using woodworking machines including a lathe, drill press, and hand tools Whiteley’s father had set up, to make things such as a radio. When Smithies was about sixteen years old, he received an engine from a motorcycle as a gift from one of his father’s friends, which he later repaired with Whiteley. Also at sixteen years old, Smithies participated in an advanced supervised study for physics, chemistry, and mathematics, at Heath Grammar School. Smithies attended Balliol College at the University of Oxford in Oxford, England, after receiving the Brackenbury Scholarship for academic excellence. When traveling to and from Oxford, Smithies rode a 1926 Rudge Whitworth motorcycle that he and Whiteley repaired. 

In 1943, Smithies began studying at Balliol College as a medical student. After his second year, Smithies had to choose between clinical work or an extra year taking classes. Smithies chose the latter option and began studying under Alexander George Ogston, also known as Sandy, an instructor in Balliol College’s biochemistry department, who researched the thermodynamic and kinetic understanding of metabolic sources of energy. According to his biography, Ogston’s fascination with physical chemistry in biological systems inspired Smithies to drop out of medical school to pursue research in that field.

In 1946, Smithies received his bachelor’s degree in physiology and stayed at Oxford to pursue a master’s and doctoral degree in biochemistry as one of Ogston’s graduate students. In 1948, Smithies achieved his first publication with Ogston, which critiques the standard approach to calculating how much energy a chemical reaction produces within a cell. Smithies and Ogston write that a person needs to know the actual concentration of reactants and products, not just the standard free energy of a reaction, to calculate the energy produced from a chemical reaction in a cell properly. A reaction’s standard free energy is the amount of energy it releases during the conversion of reactants to products at a temperature of twenty-five degrees Celsius and a pressure of one atmosphere.

Smithies continued his graduate school research by studying the conversion of the globulin fraction of blood plasma proteins into the albumin fraction of blood proteins. Globulins are a group of proteins in the blood that come from the liver and immune system. Albumin is a protein in blood that the liver produces that helps maintain blood pressure and fluid levels in the body. In 1951, Smithies completed his doctoral degree in biochemistry, with his thesis separated into two different parts. The first half of Smithies’s thesis focused on equations designed to describe the osmotic pressures of solutions and correct for interactions between protein solutions and surrounding electrolytes. The second half focused on his development of an osmometer. An osmometer is a device that measures the concentration of particles in a solution. Smithies published the second half of his thesis in 1953 while he was a post-doctoral fellow.

In 1951, Smithies began his post-doctoral work at the University of Wisconsin in Madison, Wisconsin, under the guidance of John Williams, also known as Jack, a physical chemist in the chemistry department. In 1954, Smithies published his work in Williams’s lab, which focused on the applications of four methods to assess how similar beta-lactoglobulin proteins were to one another. Beta-lactoglobulin is a protein found in cow milk. During Smithies post-doctoral work at the University of Wisconsin, he met Lois Kitze, a graduate student working in virology, who later became his first wife.

In 1954, Smithies received an offer for a post-doctoral position from David Scott, a researcher in the Connaught Medical Research Laboratories at the University of Toronto in Toronto, Ontario. Smithies’s research at the University of Toronto focused on finding a precursor to insulin. Insulin is a hormone that pancreatic cells make to help regulate blood sugar levels. While Smithies never found a precursor to insulin, the problems he encountered during his research led him to create a technique for electrophoresis.

One problem Smithies faced during his research on insulin was that insulin would stick to the filter paper he used during electrophoresis. Filter paper electrophoresis is a laboratory technique designed to separate proteins using the movement of charged particles passing through filter paper. During an interview with the Journal of Clinical Investigation, Smithies explained that he had a childhood memory of helping his mother clean his father’s shirts by using starch, which would cool and become a gel. He said that after hearing of other researchers utilizing starch grains in their electrophoresis, he decided to make a gel consisting of 15 percent starch and created what is known as starch-gel electrophoresis. Smithies stated while using the starch-gel insulin would move beautifully and would not get stuck. Using that technique he and Norma Walker, a researcher at the University of Toronto, identified unknown differences in plasma proteins. Following Smithies’s work on blood plasma proteins, he began studying genetics.

According to his biography, Smithies returned to the United States in 1960 because of Kitze’s homesickness and to become a professor of genetics at the University of Wisconsin. Smithies kept in touch with his friends in Toronto to continue researching the molecular and genetic basis for the protein differences found in blood plasma. In 1962, that research led to a publication in which he and his colleagues revealed how homologous recombination could affect protein structure. Homologous recombination occurs when genetic information is exchanged between two similar or identical pieces of DNA. In his biography, Smithies says that publication led him to propose a hypothesis in 1967 that genetic recombination could also cause variability in antibodies.

During the 1970s, Smithies’s lab transitioned from studying proteins to studying nucleic acids. Nucleic acids are molecules that involve the storage and expression of genetic information. Smithies’s transition to studying nucleic acids began by spending a sabbatical year researching with Frederick Blattner, a researcher at the Laboratory of Genetics at the University of Wisconsin, located one floor below Smithies’s research lab. During that time, Smithies learned more about bacteria, DNA, bacteriophages, and DNA cloning. Bacteriophages are viruses that infect bacteria. During Smithies’s sabbatical, he turned down invitations to apply for chairmanships in genetics, biochemistry, and immunology. In 1978, Smithies and Kitze divorced, and he later married Nobuyo Maeda, one of his post-doctoral students.

Throughout the early 1980s, Smithies conducted a series of experiments that utilized homologous recombination to insert a gene into a specific location of a mammal’s DNA. In 1980, Smithies and his colleagues successfully cloned two human fetal globin genes and presented data that suggested those duplicated genes exchanged genetic information. Fetal globin genes are genes that play a role in adapting to varying oxygen requirements during different stages of life. Smithies also contributed to the development of the Genetics Computer Group, or GCG, at the University of Wisconsin. The GCG was a service of the university’s Biotechnology Center from 1985 to 1989 and provided programs to analyze nucleic acids and protein sequences before becoming a subsidiary of US Pharmacopoeia, or USP, a non-profit organization that helps set the quality, purity, strength, and identity standards for medicines, food ingredients, and dietary supplements. The development of the GCG helps Smithies confirm his previous conclusions regarding the recombination that occurred between genes.

In 1985, Smithies and colleagues successfully inserted DNA sequences into a human beta-globin gene by using homologous recombination. Beta-globin is a component of a larger protein called hemoglobin, which is located within red blood cells and binds to oxygen. In their publication, Smithies and his colleagues establish that planned genetic modifications could be made within mammalian cells through homologous recombination. Smithies’s results utilizing homologous recombination for planned genetic modifications later helped in the development of the knockout mouse, which earned him the Nobel Prize in Physiology or Medicine in 2007. The award also went to Mario Capecchi, a professor at the University of Utah in Salt Lake City, Utah, and Sir Martin Evans, a professor at Cardiff University in Cardiff, Wales.

In 1988, Smithies became a full-time research professor at the University of North Carolina at Chapel Hill, or UNC, in Chapel Hill, North Carolina. According to his biography, Smithies left Madison to accompany Maeda at UNC, as she took a job as a professor in the pathology department. Smithies also states that he found the academic environment at UNC to be agreeable and collegiate and the weather in North Carolina to be gentler than in Wisconsin. As a full-time research professor, Smithies utilized gene targeting to create knockout mouse models to study human genetic diseases.

While at UNC, Smithies worked alongside Maeda to study cardiovascular diseases, such as hypertension and atherosclerosis. Hypertension occurs when the pressure in a person’s blood vessels is too high. Atherosclerosis occurs when plaque builds up inside a person’s arteries, which narrows the arteries and disrupts blood flow. In 1995, Smithies and Maeda published a twin study utilizing the knockout mouse model to determine how those diseases can come from defects in single genes. Smithies and Maeda showed that by causing a defect in the APOE gene in mice, the mice would develop atherosclerosis. The APOE gene is responsible for transporting fats to various cells and tissues in the body. They also showed that by increasing the number of AGT gene copies, mice would develop hypertension. The AGT gene helps regulate blood pressure and balances fluids and salts in the body. Smithies continued to conduct research on human-related diseases until his death in 2017.

Smithies received numerous awards throughout his scientific career for his work on starch-gel electrophoresis, homologous recombination, and the use of the knockout mouse model on human health. A few awards Smithies received specifically include the Gairdner Foundation International Award, the Albert Lasker Award, the Wolf Prize Laureate in Medicine, the March of Dimes Prize in Developmental Biology, and the Nobel Prize in Medicine or Physiology. Smithies twice received the Gairdner Foundation International Award, once in 1990 for his work on starch-gel electrophoresis and once in 1993 for his work on homologous recombination. Together with Capecchi, he won the Wolf Prize Laureates in Medicine in 2003 and received the March of Dimes Prize in Developmental Biology in 2005. Additionally, together with Capecchi and Evans, he received the Albert Lasker Award in 2001, and the Nobel Prize in Medicine or Physiology in 2007.

Over the span of Smithies’s scientific career, his work on gel electrophoresis and homologous recombination created laboratory techniques of separating proteins through starch gels and identifying gene function through the knockout mouse, respectively. The knockout mouse contributed to advancing medical research in areas such as cardiovascular diseases and cancers. As of 2025, researchers have identified over 16,000 genes in both humans and mice, with approximately 13,000 strains of knockout mice currently existing. Additionally, as of 2025, the GCG has provided over 130 software programs to analyze nucleic acid and protein sequences across over 650 academic institutions around the world.

In 2008, after winning the Nobel Prize, Smithies donated money to help the University of Wisconsin create the Oliver Smithies Symposium, to help young researchers learn about the excitement and disappointment that comes with discovery. From his time in graduate school to his death, Smithies made his lab notebooks accessible to the public through the UNC Dr. Oliver Smithies Research Archive. By the end of his career, Smithies shared over 150 laboratory research notebooks and published 361 papers.

Oliver Smithies died on 10 January 2017 in Chapel Hill at the age of ninety-one.

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22. Oliver Smithies. “Antibody Variability: Somatic Recombination Between the Elements of “Anti-Body Gene Pairs” May Explain Antibody Variability.” Science 157 (1967): 267–73.
23. Slightom, Jerry. Blechl, Ann. Smithies, Oliver. “Human Fetal G Gamma- and a Gamma-Globin Genes: Complete Nucleotide Sequences Suggest That DNA Can Be Exchanged Between These Duplicated Genes.” Cell 21 (1980): 627–38.
24. Smithies, Oliver, and Nobuyo Maeda. “Gene Targeting Approaches to Complex Genetic Diseases: Atherosclerosis and Essential Hypertension.” Proceedings of the National Academy of Sciences 92 (1995): 5266–72. https://www.pnas.org/doi/pdf/10.1073/pnas.92.12.5266 (Accessed May 27, 2025).
25. Smithies, Oliver, and Norma F. Walker. “Genetic Control of Some Serum Proteins in Normal Humans.” Nature 176 (1955): 1265–6.
26. Smithies, Oliver, George E. Connell, and Gordon H. Dixon. “Chromosomal Rearrangements and the Evolution of Haptoglobin Genes.” Nature 196 (1962): 232–6.
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