Oliver Smithies

Oliver Smithies
Born	23 6, 1925
Birthplace	Halifax, West Yorkshire, England
Died	Template:Death date and age Chapel Hill, North Carolina, United States
Nationality	British, American
Occupation	Geneticist, physical biochemist
Known for	Starch gel electrophoresis, gene targeting, knockout mice
Education	University of Oxford (BA, DPhil)
Spouse(s)	Nobuyo Maeda
Awards	Nobel Prize in Physiology or Medicine (2007), Albert Lasker Award for Basic Medical Research (2001), March of Dimes Prize in Developmental Biology (2000)

Oliver Smithies (23 June 1925 – 10 January 2017) was a British-American geneticist and physical biochemist whose inventive approach to laboratory science yielded two contributions that fundamentally reshaped the biological sciences. In 1955, he introduced starch as a medium for gel electrophoresis, a technique that became indispensable for separating and analyzing proteins. Decades later, he co-discovered the method of using homologous recombination to alter animal genomes with precision, enabling the creation of gene-targeted ("knockout") mice — organisms in which specific genes are deliberately inactivated to study their function. For this latter achievement, Smithies shared the 2007 Nobel Prize in Physiology or Medicine with Mario Capecchi and Martin Evans. A self-described tinkerer who built and modified his own laboratory instruments throughout his career, Smithies spent his final decades at the University of North Carolina at Chapel Hill, where he continued conducting experiments well into his late eighties. His work has had lasting implications for medical genetics, drug development, and the understanding of human disease.

Early Life

Oliver Smithies was born on 23 June 1925 in Halifax, a mill town in West Yorkshire, England. He grew up in modest circumstances during the interwar period. From an early age, Smithies exhibited the mechanical curiosity and hands-on problem-solving instinct that would come to define his scientific career. He was known throughout his life as an inveterate tinkerer, someone who preferred to build or modify instruments himself rather than rely on commercially available equipment.

Smithies's early interest in science was nurtured during his schooling in Yorkshire. He attended Heaton Grammar School in Bradford, where his aptitude for the sciences became apparent. His childhood and adolescence coincided with the Second World War, a period that shaped a generation of British scientists. Despite the disruptions of wartime, Smithies pursued his academic interests with determination and secured a place at the University of Oxford, where he would begin his formal scientific training.

His early experiences with practical problem-solving — taking things apart, building devices, and finding unconventional solutions — became a hallmark of his approach to science. Colleagues and students would later remark that Smithies brought an engineer's mentality to biological research, constantly asking not only what experiments to do but how to do them better with purpose-built tools and techniques.

Education

Smithies attended the University of Oxford, where he earned his Bachelor of Arts degree. He continued at Oxford for his doctoral studies, completing his Doctor of Philosophy (DPhil) degree in 1951 under the supervision of Alexander G. Ogston. His doctoral thesis, titled "Physico-chemical properties of solutions of proteins," reflected his early focus on the physical and chemical behavior of biological molecules — an interest that would prove foundational for his later innovations in protein separation technology.

His training at Oxford provided Smithies with a rigorous grounding in physical biochemistry, equipping him with the quantitative and experimental skills he would deploy throughout his subsequent career. The postwar period at Oxford was one of considerable intellectual ferment in the biological sciences, and Smithies was exposed to leading figures and emerging ideas that would influence his research trajectory for decades.

Career

Starch Gel Electrophoresis

After completing his doctorate at Oxford, Smithies initially worked in the United Kingdom before moving to North America. He held positions at the University of Toronto in Canada and subsequently at the University of Wisconsin–Madison in the United States.

In 1955, while working at the University of Toronto, Smithies introduced a technique that would become one of the most widely used tools in biochemistry and molecular biology: starch gel electrophoresis. Prior methods for separating proteins by electrophoresis used media such as paper or liquid buffers, which offered limited resolution. Smithies discovered that partially hydrolyzed starch could be formed into a gel that served as a superior separation medium, enabling researchers to distinguish between proteins that had previously been indistinguishable. The starch gel acted as a molecular sieve, separating proteins not only by their electrical charge but also by their molecular size and shape.

The impact of this innovation was immediate and far-reaching. Starch gel electrophoresis allowed scientists to detect genetic variation in human blood proteins for the first time, revealing the existence of protein polymorphisms — natural variations in the structure of proteins between individuals. This discovery had profound implications for population genetics, forensic science, and the study of inherited diseases. Smithies himself used the technique to study the genetics of haptoglobins, a family of blood serum proteins, and his work in this area produced some of the earliest demonstrations that protein variation could be used as a genetic marker in humans.

The technique was eventually superseded by polyacrylamide gel electrophoresis and other methods, but starch gel electrophoresis remained in use for decades and established the principle of gel-based protein separation that underpins modern proteomics. It is often cited as one of the foundational techniques of molecular biology.

University of Wisconsin–Madison

Smithies joined the faculty at the University of Wisconsin–Madison, where he spent a significant portion of his career. During this period, he continued his work on protein biochemistry and began to turn his attention to the newly emerging field of molecular genetics. His laboratory at Wisconsin became known for its innovative and often unconventional approach to experimental problems, with Smithies frequently designing and constructing custom apparatus for his experiments.

It was during the 1980s that Smithies began the work for which he would ultimately receive the Nobel Prize. He became interested in the possibility of using homologous recombination — a natural process by which cells exchange segments of DNA between similar sequences — to introduce specific genetic changes into mammalian cells. The goal was to develop a method for precisely altering genes in living organisms, rather than relying on the random integration of foreign DNA that characterized earlier transgenic techniques.

In a series of landmark experiments, Smithies demonstrated that it was possible to target specific genes in mammalian cells using homologous recombination. His approach involved introducing DNA sequences into cells that were designed to match and replace a specific segment of the genome. When the introduced DNA recombined with its homologous sequence in the cell's chromosomes, the targeted gene was altered or inactivated. This technique came to be known as gene targeting.

Working independently but in parallel, Mario Capecchi at the University of Utah achieved similar results, while Martin Evans at the University of Cambridge (and later Cardiff University) developed the embryonic stem cell lines in mice that made it possible to propagate gene-targeted cells into whole organisms. Together, their contributions created the technology of knockout mice — genetically modified mice in which a specific gene has been deliberately disabled.

Knockout mice rapidly became one of the most important tools in biomedical research. By observing the effects of inactivating a particular gene, scientists could determine the gene's normal function, model human diseases, and test potential therapies. The technique has been applied to thousands of genes and has contributed to advances in fields ranging from cancer biology to immunology to cardiovascular medicine.

Smithies's own laboratory used gene targeting to study genes involved in blood pressure regulation, blood clotting, and cystic fibrosis. He was particularly interested in the genetics of hypertension and developed mouse models to investigate the roles of specific genes in regulating cardiovascular function.

University of North Carolina at Chapel Hill

In 1988, Smithies moved to the University of North Carolina at Chapel Hill, where he joined the Department of Pathology and Laboratory Medicine as the Excellence Professor of Pathology and Laboratory Medicine. He would remain at UNC for the rest of his career, continuing active research for nearly three decades.

At UNC, Smithies continued to refine and apply gene-targeting technology. His research focused increasingly on using knockout mice to study the genetics of common human diseases, particularly hypertension and atherosclerosis. He developed mouse models that allowed researchers to examine the contributions of individual genes to complex cardiovascular phenotypes, work that had significant implications for understanding human heart disease.

Smithies was known for his remarkable dedication to hands-on laboratory work. Even after receiving the Nobel Prize at the age of 82, he continued to perform experiments himself, arriving at his laboratory bench regularly. He maintained detailed laboratory notebooks throughout his career — a practice he regarded as essential to scientific rigor. His notebooks, which span decades of research, have been digitized and preserved by the University of North Carolina as a resource for historians of science and students. His "γ notebook," in particular, has been cited as containing early formulations of the ideas that led to gene targeting.

Smithies was also recognized as a devoted mentor who trained numerous graduate students and postdoctoral researchers during his time at UNC and his earlier appointments. Colleagues described him as generous with his time and ideas, and as someone who took genuine pleasure in the day-to-day work of science.

His work at UNC also extended to studying the molecular basis of cystic fibrosis, using gene-targeted mouse models to investigate the function of the CFTR gene and its role in the disease. He additionally explored topics in oxidative stress and its role in cardiovascular disease in his later years.

Smithies held the title of Excellence Professor of Pathology and Laboratory Medicine at UNC until his death in 2017. He became the first Nobel laureate affiliated with the University of North Carolina.

Personal Life

Smithies married Nobuyo Maeda, a fellow scientist and professor of pathology and laboratory medicine at the University of North Carolina at Chapel Hill. Maeda, a researcher in her own right, collaborated with Smithies on aspects of his gene-targeting work and continued her scientific career at UNC.

Smithies was known for his love of flying. He was a licensed pilot and owned a small airplane, which he flew regularly. His interest in aviation paralleled his love of tinkering and mechanical problem-solving; he approached flying with the same methodical, hands-on enthusiasm he brought to his laboratory work.

He became a naturalized citizen of the United States while maintaining connections to his British roots. Smithies was described by colleagues as modest, approachable, and deeply committed to the practice of science for its own sake rather than for personal recognition.

Oliver Smithies died on 10 January 2017 in Chapel Hill, North Carolina, at the age of 91.

Recognition

Smithies received numerous honors and awards over the course of his career, reflecting the significance of his contributions to biochemistry and genetics.

In 2000, he was awarded the March of Dimes Prize in Developmental Biology, shared with Mario Capecchi, for their pioneering work in gene targeting.

In 2001, Smithies received the Albert Lasker Award for Basic Medical Research, one of the most prestigious awards in biomedical science, again shared with Capecchi, for contributions to gene targeting.

In 2007, Smithies was awarded the Nobel Prize in Physiology or Medicine, shared with Mario Capecchi and Martin Evans, "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells." The Nobel Committee recognized that their work had created an essential tool for understanding gene function and for modeling human diseases in laboratory animals.

Smithies was elected a Foreign Member of the Royal Society (ForMemRS). He was also a recipient of the North Carolina Award, the state's highest civilian honor.

In 2009, Smithies received the Gold Medal of the American Institute of Chemists, recognizing his outstanding contributions to the chemical sciences.

In 2011, the University of Oxford honored Smithies with a degree ceremony in recognition of his achievements.

Legacy

Oliver Smithies's contributions to science have had a lasting and transformative impact on biomedical research. His two major innovations — starch gel electrophoresis and gene targeting — each represented fundamental advances in the tools available to biologists, and both continue to influence scientific practice.

Gene targeting, the work for which Smithies is most widely known, has been used to create thousands of distinct knockout mouse strains, each designed to investigate the function of a specific gene. These animal models have become indispensable in virtually every area of biomedical research, from cancer and immunology to neuroscience and metabolic disease. The principles of gene targeting also laid the intellectual and technical groundwork for subsequent advances in genome editing, including the development of CRISPR-Cas9 technology, which has further expanded the precision and accessibility of genetic modification.

Several institutions have established lectures and visiting positions in Smithies's name. The University of Toronto hosts the annual Oliver Smithies Lecture, which has featured Nobel laureate speakers including Jennifer Doudna in 2025. Balliol College, Oxford, established the Oliver Smithies Visiting Research Lectureship, which brings scholars to Oxford to pursue research across disciplines.

His laboratory notebooks, preserved and digitized by the University of North Carolina, serve as both a historical record and a teaching resource, offering insight into the experimental reasoning and iterative problem-solving that characterized his approach to science. The University of North Carolina has recognized Smithies as a central figure in its institutional history, noting his status as the university's first Nobel laureate.

Smithies is remembered by colleagues not only for his scientific achievements but also for his personal qualities: his modesty, his commitment to working at the bench, and his belief that scientific progress arises from curiosity, patience, and the willingness to build the tools needed to answer new questions.