The Nobel Prize in Physiology or Medicine 2007
Mario R. Capecchi, Sir Martin J. Evans, Oliver Smithies
Born: 23 June 1925, Halifax, United Kingdom
Affiliation at the time of the award: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Prize motivation: "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells"
My fraternal twin, Roger, and I were born prematurely on June 23rd, 1925, in Halifax, England, an industrial town in the West Riding of Yorkshire, although we lived outside Halifax at 2, Woodhall Crescent on Wakefield Road, a row house rented from the town. My father, William Smithies, was at that time working for his father, Fred Smithies, who paid him erratically. My mother, neé Doris Sykes, was a college graduate and taught English at the Halifax Technical College (where she met and fell in love with my father who was one of her students and younger than she). Not long after our birth, my father found a regularly paying job selling small life insurance policies to local farmers and their families. He was a kind and gentle man with a natural mechanical aptitude that he had inherited or learned from his father. A car was needed for a person selling insurance to scattered customers. So we were unusual in our neighborhood in the 1930s in having one. Not that the car was very special; it was a two cylinder Jowett and was in constant need of repair. I have vivid memories of "helping" my father, when I was about 8 or 9 years old, to select the least worn exhaust valves to use in keeping it running. (The stems of the valves wore badly.)
Our sister, Nancy, was 5 years younger than us, and a welcome addition to the family. She was a beautiful fair-skinned ginger-haired baby, and we 5 year old twins suggested naming her "Buttercup". All three of us were generally healthy and happy, although Nancy would not have survived infected tonsils without the then newly discovered miracle antibiotic drug "Prontosil" – the first of the sulfonamide drugs. I had a similar incident at age 7, but without the Prontosil, and was bedridden for 10 weeks after a bout with "rheumatic fever". This illness left me with what I now know was a trivial mitral valve murmur. However at that time the condition was considered serious, and I was not allowed to take part in sports for the next 7 years. But in the time that I might otherwise have spent in competitive sports I learned to enjoy reading and making things. And sometime before I was 11, I read a comic strip in which an inventor was the major character. This was what I wanted to be – an inventor! (I didn't know the word "scientist".)
Our mother introduced us joyfully to English literature by reading out loud to us, which she did beautifully, while we waited for my father to come home for the midday meal ("dinner"). Kenneth Grahame's "Wind in the Willows" and Lewis Carroll's "Through the Looking Glass" were favorites. And we heard and enjoyed Chaucer's "Canterbury Tales" spoken in middle English. We were often happy when our father was late. A dictionary was a part of our everyday life as children, and continues to this day to be a constant companion in our house.
The location of the house on Wakefield Road was ideal for children. Behind it was a long oak wood that covered several square miles. In the spring the wood was carpeted with blue bells, and in the fall with acorns. At other times it was a place for children, and lovers. It was also a source of the leaf mold that my maternal grandfather, Ben Sykes, and I collected for his garden. He was a highly intelligent but somewhat short tempered man who lost his job as a company manager because he couldn't get on with the son of his employer, who inherited the business when his father died. When I knew him, Grandfather Sykes was working as a paid gardener, which he enjoyed greatly. To keep his mind active, he began learning to speak French at age 70 plus. He enjoyed keeping bees too, and taught our father to love this activity. Later, when father was away in the army, we looked after his bees, and recovered their swarms. Roger kept bees for the rest of his life, and was still harvesting honey from hives that he had in his garden in a London suburb at age 81 shortly before he died.
Across Wakefield Road from our house was a large field from which we twins would help ourselves to rhubarb – illegally, of course. Beyond the rhubarb field was the Calder Valley canal and the Calder river, both heavily polluted when we lived there – but now recovering well. The Calder valley was even better for children than the long wood. It had caves in disused quarries; and our childhood girl friends, Margaret and Joan Smith, had a farm on the side of the valley. Above the valley was the village of Norland on the edge of a wild heather-covered moor. This moor was another of our playgrounds, and was where my father took his bees for them to collect the heather honey.
My father must have enjoyed mathematics, because I have a particularly vivid memory of him introducing me to decimals at an early age, writing with his finger on the condensate covering the wall above the bath that I was taking. I even remember the color of the wall as being blue. The same love of mathematics was deeply ingrained in Dr. G. E. ("Oddy") Brown who later taught me mathematics at Heath Grammar School. He conveyed enough of the logic and principles of mathematics that I didn't need to take any math courses at the University. Indeed, the examiners of my entrance examination to Oxford University commented that my mathematics was "very promising for a person so young." I suspect that they liked the comment I added to my answer to their question "How much does a Spitfire slow down when it fires its 8 machine guns?" Using their data on muzzle velocities, weight of a bullet, rate of firing, mass of aircraft, etc., etc., I calculated that the aircraft would slow down 150 miles per hour. I tried to calculate this again in several ways, but still got the same result. So I added the comment: "I don't believe this result. I think that the correct answer might be around 35 mph."
I have an equally but quite different vivid childhood memory of being shown, by my Smithies grandfather, how to straighten a bent nail. He, like me, couldn't resist picking up anything that he found lying around because "It might come in useful." This trait was well recognized by Jean Stanier, one of Sandy Ogston's graduate students at the same time as me. Odds and ends of discarded equipment and the like would be set aside and labeled NBGBOKFO – "No bloody good, but okay for Oliver." I still make new devices from what most people would call "junk."
My twin Roger and I went to the school in Copley, a village only a 15 minute walk from our Woodhall Crescent house. Our parents decided to let us go to this unpretentious village school rather than send us to a private school, even though the scholastic levels of the village school were less than desirable. It worked out well. Both of us passed the intelligence test used in 1936, as an entrance examination for acceptance of 11 year olds to a higher level of schooling.
Partly in preparation for this change, we moved to 33, Dudwell Lane, Halifax, a semi-detached house that was part of a collection of rather well designed but inexpensive new houses. This house was only a 15 minute walk from Heath Grammar School, the school which Roger and I now attended. Shortly after moving to 33, I met Harry Whiteley, the only son of the works manager of a local company that made precision time clocks for factories. Harry's and my interests matched perfectly, and we became and still are close friends. Harry's father had set up in the attic of their house ("the loft") a lathe, a good drill press and the hand tools needed for making many things. Harry knew how to use them, and the loft became our playground. I had somewhere read about a radio controlled boat, and we decided to make one. For the transmitter we used a spark coil from a T-model Ford. For the receiver we used a home made coherer, the same device as the one that Marconi had used in his first wireless telegraphy receiver. This was radio transmission at its basic minimum – and we never got it to work. But, encouraged by my grandfather's commercially made receiver, which used a crystal in place of the notoriously fickle coherer, we progressed to winding our own coils and made a much more up-to-date crystal set that worked well. This in turn led to a one-vacuum-tube radio, which I incorporated into my gas mask case instead of the gas mask that all British children were required to carry in the early days of World War II. Our best radio was a super-heterodyne of an advanced design and had four tubes. It worked as a "bread board", but disappointingly not when rebuilt as a more finished product.
When I was about 16, one of my father's friends gave me the engine from a motorcycle. Harry and I made it run, and became interested in owning a complete motorcycle. My first was a 1926 Rudge Whitworth which was notable for having rim brakes that did not work when it rained. Harry helped me exchange the front wheel for one with a safer internal expansion brake, and I used the Rudge regularly to travel to and from college. I also tried, but to no avail, to make it run on a gasoline-water mixture to eke out the very limited gasoline ration. Subsequently, by judicious trading, I managed to acquire motorcycles of increasing power, but always old, and they were an enjoyable and adventurous part of my life for several years. The cars that succeeded the motorcycles were equally old, and kept up my skills as a mechanic. Modern cars and laboratory equipment are unfortunately now only repairable by replacing subassemblies, so the current generation has lost this strong incentive to learn how to use simple tools.
Heath Grammar School was an Elizabethan free school founded in 1597. When we attended the school, it had a superb staff of dedicated and highly-educated teachers. History was taught by C. O. Mackley who tried, in vain, to persuade me to study history with him in the sixth form. Chemistry was the task of A.D. Phoenix – who kept order with the flick of the rubber hose from a Bunsen burner. H. Birchall, the games master, tried kindly to bring me up to speed in athletics, but it was a hopeless task with a boy beginning to play games at age 14. My first year in the sixth form, at age 16, was spent with a few other pupils in supervised study of physics, chemistry and mathematics at a more advanced level. The first term of my second year in the sixth was spent in unsupervised study in preparation for the Oxford University scholarship exams. I concentrated on physics (I was thinking of studying the subject at the university, although in the end I chose medical school), and was fortunate in being awarded a Brackenbury Scholarship at Balliol College. Consequently, the remaining two terms in the sixth form were a blast in more ways than one. I was allowed to do whatever I wanted to, which was messing around (alone) in the laboratory. I synthesized many substances that caught my fancy, including phenyl isothiocyanate, which my textbook said was one of the worst smelling substances known to mankind. I made nitrocellulose (a constituent of Nobel's smokeless powder), and mercury fulminate (the detonator for his dynamite). Perhaps from some innate cautiousness I did not try to make them explode. Quite the opposite was inadvertently true of the nitrogen tri-iodide that I prepared. I had spilled traces of it which exploded when Mr. Phoenix wiped the bench (he was heard to say in an exasperated and loud voice "Smithies!") My father had a similar reaction when some that I had put on the top shelf of our living room sideboard exploded with a puff of purple smoke as he walked by; it was extremely sensitive when dry.
I had three remedies for the homesickness that I felt on first going to Oxford. One was to look out of my college room window in the direction of my home in the north of England. Unfortunately I was actually looking south. I never did get the geography of Oxford right because of this error. The second remedy was to read all the Brontë novels again. The three sisters lived in Haworth, only a few miles from Halifax, and their novels were filled with descriptions of the Yorkshire moors that were such a part of my youth. The third remedy was to go down to the porter's lodge and look for a letter from home. Thereby hangs another tale. Balliol College at that time was heated only by open fireplaces in individual rooms. I lived in a room on the second floor reached by a spiral stone staircase. In the cold damp weather typical of autumn in Oxford, water would condense on the walls and trickle down the staircase. My room was narrow with ill-fitting windows at either end, and with stones covering half of its floor. It was heated (somewhat) with a small fireplace in which I could burn my weekly ration of coal – it was war time. On one occasion when I returned from my homesick visit to the porter's lodge, the corridor was full of smoke and my fire was gone. I followed the trail of smoke and found two second year medical students enjoying my fire in their grate. We immediately became friends. C. G. A. (Geoffrey) Thomas was one of them – which is how I remember the base-pairing rules of DNA – C with G and A with T.
A. G. "Sandy" Ogston, who had interviewed me during my scholarship exam, was the normal tutor for Balliol college's medical students, but his wartime duties prevented him from being my first tutor. David Whitteridge served in his place. Whitteridge was a brilliant scientist but a hard nosed tutor. I remember him saying to the Master of Balliol (A. D. Lindsay) during our end-of-term meeting that "Smithies can't spell". Lindsay's response "Oh, all interesting people can't spell," was encouraging. Whitteridge's comments "Diffuse, undisciplined, and at times inaccurate" written across my term paper were typically scathing, but deserved. His verbal comment to another student who had copied part of his weekly essay from a source that Whitteridge could recognize was equally to the point – "These scissors and paste jobs will do you no good." Oxford tutors could be ferocious, but that is what made their lessons unforgettable.
I studied anatomy and physiology with a little organic chemistry for two years as a medical student. I surprised the "real" anatomists and myself by winning the anatomy prize, I think because of my answer to one of the exam topics set by Professor Le Gros Clark, who was a pioneer in what we now call cell biology (he was also famous for uncovering the Piltdown-man fraud, and for helping Leakey with his pre-human fossils). I almost walked out of the room on reading the question: "Compare the regenerative powers of muscle, bone and nerve." But I suddenly thought of a principle that I thought made their similarities and differences understandable, and so I stayed. Perhaps Le Gros Clark enjoyed reading my answer as much as I enjoyed writing it.
My third year at Oxford was spent in studying for an honors degree in animal physiology (which included biochemistry). By then Sandy Ogston was back from his wartime duties and had resumed teaching and giving lectures on the application of physical chemistry to biological problems. He was best known for his three-point attachment explanation of how an optically active product can be generated from a symmetric precursor. My weekly tutorials with him were always stimulating and led to many memorable incidents. One occurred during the reading needed to prepare for a tutorial essay on carbohydrate metabolism. After learning something about metabolic pathways, I had been struggling to understand the biological "need" to carry out the complex series of reactions that the body uses to extract energy from carbohydrates. I found the answer in volume 1 of Advances in Enzymology in a long article written in 1941 by Fritz Lipmann. In this article Lipmann describes the difference between energy-rich and low-energy phosphate bonds, a difference that makes sense out of the complex series of reactions used to metabolize carbohydrate. I read his article in my Balliol college room with a level of excitement that I still remember. I even recollect the look of the glossy paper, the look of the pages, and the color of the cloth binding of the volume – a very similar feeling to that when I was introduced to decimals by my father.
This introduction to the importance of energy-rich phosphate was the cause of my later coming to Sandy's weekly tutorial with a way to generate an energy-rich phosphate bond from a low energy phosphoester bond by a cyclical oxidation and reduction scheme. Because my scheme could produce energy for nothing, I knew that it was wrong – like the Spitfire slowing down 150 mph – but I didn't know why. Together, Sandy and I – but mainly Sandy – realized that the standard free energy of a reaction (at that time used to classify the energy resulting from a reaction) was not a valid way of calculating how much energy the reaction would produce within a cell. One needed to know the actual concentrations of reactants and products in order to calculate this. My first scientific paper (Ogston & Smithies, 1948) was the outcome of this endeavor. Looking back at the paper, I can see Ogston's analytical mind at work – the paper hints at what is now known to be correct – the need to keep the reactants within a large molecular complex if realistic rates of reaction are to be achieved. This paper was the first of about half a dozen hypothesis papers that I have attempted over my scientific life.
My college "fire-stealing" friends were masters of how to study with the minimum of effort. We learned histology together by playing a show-and-tell game on Sundays that taught us to recognize the tissue on a microscope slide after only a second's glance – just as one recognizes a face. Once identified in this brief time, one could then carefully describe from memory what should be there. If the slide was of liver, for example, we would say "I can see the stellate cells of von Kupfer etc. etc." We never did see them, but this technique, passed on to subsequent generations, meant that Balliol students always came first in the histology examinations. Organic chemistry was equally conquerable if one used all one's senses, as illustrated by Geoffrey Thomas' finding that all the compounds which we were likely to be given could be identified by three tests: "taste, smell and appearance". I put his principle to good use in the final practical examination in Biochemistry. On being presented with a clear colorless, slightly viscous liquid that smelled of caramel and tasted acidic, I thought it might be lactic acid. A confirmatory test was positive, and I finished the exam in less than 10 minutes.
Sandy Ogston's fascination with the relevance of physical chemistry to biological systems was infectious, and I decided to drop out of medical school and do research in this field. The fourth and fifth years of my Oxford period were consequently spent in acquiring a sound background in chemistry. Since I already had a first class honours degree in physiology I did not have to worry about how well I would do in the exams. I could therefore pick and choose among the topics that I would study. I had a grand time. My organic chemistry was confined to biological compounds, my inorganic chemistry could emphasize the simple inorganic materials of biological relevance, Na+, K+, F-, Cl-, etc., rather than rare earths and the like. And I could emphasize those parts of physical chemistry that I enjoyed or were particularly relevant to biological systems. I remember well studying for and writing what I thought was an outstanding twelve-page essay on "The Pauli exclusion principle and the periodic table", which Ronnie Bell, my first tutor in chemistry, had assigned for one of my early tutorials. I only got half way down its first page when Ronnie spotted a weak link in my argument. The rest of the hour's tutorial was spent in teaching me that "You never, ever, write down anything that you do not understand, or cannot justify."
After completing the undergraduate part of the chemistry degree, and now in my sixth year at Oxford, I joined Sandy's lab in the department of biochemistry as a graduate student. It was a happy place. The oldest of us was Rupert Cecil (a veteran bomber pilot and a wing commander in the Royal Air Force). Rupert, in addition to his own research, managed the complex equipment of the laboratory with complete confidence. One of his responsibilities was a Svedberg ultracentrifuge – a large machine built on a concrete pillar and equipped with a powerful electric oil compressor in a pit below the floor. I never cared for the beast, and studiously avoided being sucked into its tentacles. Nevertheless, my thesis topic centered on an artifactual problem that the ultracentrifuge had generated – "the apparent conversion of the globulin fraction of plasma proteins into the albumin fraction." I was to look for some type of disassociation–reassociation reaction by studying the osmotic pressures of mixtures of proteins. I never did get to that part of my problem, but I had a thoroughly enjoyable two years trying. The outcome was a thesis, half of which was devoted to what are now (to me) un-understandable thermodynamic equations. On later re-writing this part of my thesis for publication I discovered a fatal flaw, so my equations never saw the light of day. The other half was devoted to my development of an extremely precise osmometer. The data it produced were so tight that the line through the experimental points had to be interrupted for them to show. This work was published (Smithies 1953), although the resulting paper has the dubious distinction of never being cited by me or by anyone else. Nevertheless, this thesis work re-enforced my natural inclination to pursue experiments to a conclusion with little regard for the time required to reach this end.
The osmometer required a home made water bath with its temperature controlled to within 0.001°C. This I achieved by using a submerged electric light bulb as a controlled heater. Sandy's next graduate student, Barry Blumberg (Nobel laureate in 1976), inherited my bench - and the water bath. He is said to have destroyed it in a fit of rage induced by the repetitious on-off cycle of its light bulb.
When the time came for me to think about post-doctoral work, Sandy urged me to think about going to the USA. I was not enthusiastic – but was persuaded to overcome my prejudices by Sandy and Robert L. ("Buzz") Baldwin. Buzz was a Rhodes scholar from Madison, Wisconsin, working towards his doctorate with Sandy, and he painted a fine picture of life in Wisconsin. So I applied for and was awarded a Commonwealth Fund fellowship to continue my education as a post-doctoral fellow under the guidance of J. W. (Jack) Williams, a learned physical chemist in the Department of Chemistry at the University of Wisconsin. There were other fine physical chemists in Jack's group, including Bob Alberty, Bob Bock, Dick Golderg and Lou Gosting. My stay with them increased my knowledge of physical chemistry greatly, but the work I did was not particularly rewarding; it culminated in another article that rightly received virtually no attention (Smithies, 1954). In contrast, the reward from the kindness and collegiality of these colleagues and of the other friends that I made in Wisconsin was enormous. They completely removed my foolish preconceptions about "Americans".
My regard for Americans was further increased by my meeting and becoming engaged to Lois Kitze, a graduate student working in virology. But she was reluctant to cross the Atlantic, as I had earlier been in the reverse direction. So, because my acceptance of a Commonwealth Fund fellowship precluded my staying in the United States, I looked for work in Canada. I was fortunate in finding David A. Scott, who in 1954, offered me a job in Toronto. "Scottie" was an older man when I met him, and was winding down a distinguished career in science. He was the first person to crystallize insulin as a poorly soluble zinc salt, which is widely used in the commercial preparation of insulin and still forms the basis for a slow release form of the hormone. He was a Fellow of the Royal Society of Canada, and of the Royal Society of England. When I met him, he was working by himself in a small room in the Connaught Medical Research Laboratories, a part of the University of Toronto, and spent his mornings looking for a protein in plasma which he thought might bind insulin. In the afternoons, he played golf. He offered me the opportunity to work on anything I wished "as long as it is related to insulin". After reading the available literature, I chose to look for a precursor to insulin. I never found it. But the difficulties I encountered in trying to find it, and a childhood memory that the starch which my mother used for my father's shirts turned to a jelly when it cooled, led to my invention of starch gel electrophoresis. The high concentration of starch needed to make a strong gel introduced a new variable into electrophoresis - molecular sieving. Finding the best variety of starch and how to process it for making the gels became necessary when my supplier's stock of processed starch was exhausted. Many hours were spent in testing all the raw starches that I could buy, and then in grocery stores finding potatoes from Holland Marsh, New Brunswick, Prince Edward Island and Idaho from which to make the raw starch. None gave as good gels as those made from my first batch. I eventually found out why: my original supplier had purchased starch processed by a second company that had used raw starch imported by a third company from Denmark because of an attack of potato blight in Canada!
The starch gel method proved very effective. With it I discovered previously unknown differences in the plasma proteins of normal healthy persons, which Norma Ford Walker and I showed were inherited (Smithies and Walker, 1955, 1956). Many new opportunities were opened up, and my friends suggested that I would be helped by having a technician. Somewhat reluctantly I agreed, and was joined part time by Otto Hiller, a young immigrant from Germany. He proved to be an excellent choice. We worked together well and soon became friends. Otto had an excellent mechanical sense, and began to make the starch gel equipment that I and other scientists needed for our work. He came along to Wisconsin when I moved there in 1960, but not as my technician. Instead he set up a business to manufacture the plastic equipment and assemble Heathkit® power supplies which were suitable for the gel electrophoresis. He also arranged for a manufacturer in Denmark to produce a starch suitable for making the gels, and then distributed the starch to scientists all over the world.
Otto and I spent many Saturday afternoons in his "shop" doing the same sorts of things that Harry and I had done in the loft. We assembled a Heathkit® digital alarm clock, and found out that it had a design flaw which caused it to lethally "electrocute" its own Intel CMOS integrated circuit. We worked out a remedy after several replacement chips, and had some enjoyable interactions with the Intel engineers who we found had drawn a Mickey Mouse on an unused part of the chip. This led us to try to make our own precision digital clock, and to attempt bread boarding a microcomputer using Intel chips. But our knowledge and bread boarding technique proved inadequate. So Otto bought a mail order kit for an Altair 8800 microcomputer, while my interest in making a computer was replaced by using a time sharing GE computer located in Milwaukee, 60 miles from Madison. Communication was by teletype, and the computer language was BASIC. The immediacy of a time-sharing computer suited me, and I subsequently enjoyed directing my student, Bob Goodfleish, while he wrote a group of programs to extract amino acid sequences from our Edman sequenator (Smithies et al., 1971). Nearly 10 years later I had the same enjoyment in directing John Devereux during the writing of a group of programs for analyzing nucleic acid sequences. The resulting paper (Devereux et al., 1984) is my most quoted, with > 6000 citations. More recently I have returned to devising new biological uses of computers, thanks to the existence of generic programs (such as Stella®) that a person can use for modeling complex biological systems without the help of a computer scientist (Smithies et al., 2000; Smithies, 2003). The greatest value of devising these computer models comes, I have found, from their forcing one to clarify which elements in a complex system are most critical, rather from their ability to replicate experimental data or make predictions.
The discovery of inherited differences in plasma proteins shifted my interests towards genetics. This shift, and my wife Lois' homesickness for the States, led me to return to Madison in 1960, to join the strong genetics group at the University of Wisconsin. But I continued to collaborate with my Toronto friends to decipher the molecular/genetic basis of the protein differences found in plasma. This work revealed how homologous recombination could affect protein structure (Smithies et al., 1962). It also led me to hypothesize that antibody variability might be achieved by recombination (Smithies, 1967). As a consequence, I had an enjoyable period devoted to protein sequencing with the automatic Edman sequenator.
This protein sequencing period ended with the advent of DNA cloning, which encouraged me to spend a sabbatical year with Fred Blattner on a floor below mine in the Laboratory of Genetics. During this time I learned to handle bacteria, bacteriophages and DNA (and took flying lessons at a small nearby airfield). Fred was deeply involved in developing safe procedures for cloning DNA, which at that time was thought might be environmentally hazardous. One of the safety tests required volunteers, of which Fred and I were two, to drink milk spiked with a large number of bacteria and then determine how many survived passage through the gut. The little packages of fecal material that we had to bring back to the lab were the sources of much merriment. During this period, I was invited to apply for various chairmanships in genetics, biochemistry and immunology. Somewhat selfishly, considering the great contributions that chairpersons can make to the scientific welfare of their faculty and students, I chose to continue my life as a bench scientist. But without this decision I might not have had the time to start the experiments, begun at age 57, which led to my best gene targeting paper, published after I was 60 (Smithies et al., 1985).
In 1978, Lois and I, by mutual and amicable consent, gave up on our less than ideal marriage. And several years later I followed my mother's example by falling for my post-doctoral student, Nobuyo Maeda. However, we were unable to find a way to continue working together in Wisconsin. So, after more than 25 years, I left Madison to accompany Nobuyo to Chapel Hill, North Carolina, where she had been offered an appointment in the Department of Pathology at the University of North Carolina. Nearly 20 years have passed since that move. We have been happy together, and our science has flourished. The academic environment in Chapel Hill is agreeable and collegiate. The weather changes more gently than in Wisconsin (except for occasional hurricanes), and the winters are less harsh than in the Midwest. As a full time research professor at UNC I have been able to spend even more time at the bench; and all my experiments using gene targeting to generate animal models of human genetic diseases have been carried out in the nurturing environment of the University of North Carolina.
Music has been a part of my non-scientific life, beginning quite early when, as children, Roger and I both sang in the choir at Copley church. We enjoyed the music and also the camaraderie of boys playing pencil games during the sermons. All three of us children were required by our parents to learn to play the piano from 7 until 11, at which time we could choose. Roger chose to learn to play the cello, and he continued playing it and the piano for the rest of his life. Nancy became a professional musician, and taught music in high schools. I stopped music lessons, but continued to sing in the church choir until my voice changed. Later at age 18 during my first year at Oxford I joined the Balliol college choir. In my second year, I auditioned for the Oxford Bach Choir with Sir Hugh Allen – a notoriously brusque conductor, famous for his sharp tongue. He began the audition with a comment and a question "You're from Balliol, I see. This is not your first year, is it?" I agreed. His next question was "Do you know how I know?" I replied "Yes sir, my tie [a Balliol tie] has been washed." The audition never flagged thereafter, even when he asked me to sing my lowest note, only to be interrupted by his secretary saying "Excuse me, Sir Hugh, but this gentleman is a tenor". To which he responded with "Oh, in that case sing your highest note!" followed shortly thereafter with "Stop! Stop!! You'll blow your head off!!!" I sang with his choir for the remainder of my time at Oxford. And I continued to sing tenor with great pleasure with the Symphony Chorus during both my times in Madison, and with the Mendelssohn Choir in Toronto. In Oxford, I learned to play the flute from an ex-army flute teacher. I was not good enough to play in an orchestra, but I happily played for many years with several small groups and with various accompanists.
My interest in flying also began at an early age, before I was 11. I had read all the "Biggles" books by W. E. Johns - fictional accounts of a World War I fighter pilot. I had also been entranced by the movie serial "Tail Spin Tommy" which played at the Saturday morning "Tuppeny Rush" cinema in Sowerby Bridge, a half hour walk from my home (the admission charge was two pennies). And I had read enough about sailplanes and their instruments to dream of flying them. But World War II broke out when I was 14, and gliding as a sport stopped. It was not until I was 38 that I had my first real encounter with flying. This occurred in 1963, during a visit to Toronto which I had made in order to learn from Gordon Dixon how to sequence proteins. The required experiments did not suit my temperament – so instead I went down to the Toronto Island Airport and spent the next 10 days taking flying lessons. Over the course of the next month, now back in the States, I took enough additional lessons at Morey Airport in Middleton, Wisconsin, to be able to solo (fly by oneself). But I did not continue. Not until the late 1970s, when I was 52, was I able to try again, thanks in part to the stimulus to learn new things that is part of taking a sabbatical year. This time, I took glider lessons from "Jake" Miller and power plane lessons from Field Morey. Field, the son of a Lindberg-era pilot, was and still is a world class flight instructor, and we have had many hours together as student pilot and instructor. And many more as friends, including the time in 1980, when I accompanied him as copilot on a record-winning flight for a single engine aircraft across the Atlantic from Goose Bay, Labrador, to Rekjavik, Iceland, and then on to Prestwick, Scotland. We knew it would be difficult because we did not have special fuel tanks. So at the end of the runway at Goose Bay and after being cleared for take off we shut down the engine and topped off the tanks until, after adding several gallons of gasoline, they literally overflowed. After flying for 8½ hours, we landed at Rekjavik with only 3 gallons of fuel left, enough to fly for about another 10 minutes! But we beat the previous record – by 17 minutes. Our record held for nearly 20 years.
I learned to fly by instruments with Field, and remember rejoicing with him when "Only one drop dripped" (of sweat from my face). One of my glider students - who, like me, would sweat profusely during instruction - came back from his first solo flight with a big grin on his face, with his hand on the back of his shirt, and with the comment "Look Oliver; it's dry!" Learning to fly is learning to overcome fear with knowledge. This same lesson applies to trying new things in science, and to life in general. I am forever grateful to Field for helping me to learn it, and for giving me the joy of flying airplanes, which still continues after more than 4000 hours of piloting – in all sorts of weather.
Approaches into airports on cloudy days are carried out with the help of two needles on a dial from which indirect evidence the pilot can infer the position of the aircraft; if the needles cross at right angles you can infer that you are on the beam. Our first assay for gene targeting was likewise indirect, being based on finding bacteriophages of a specific type; if we found the bacteriophages we could infer that targeting has occurred. The airplane instrument approach and the gene targeting experiment both have a moment of truth. When the aircraft comes out of the clouds, either the runway is there, or it is not. Likewise, when DNA from a cell colony identified by the indirect bacteriophage assay is tested directly (by a Southern blot), either the gene is altered or it is not. In 1985, at a Gordon Conference during which I first described our success in gene targeting, I told the audience how I was thinking of this airplane analogy while developing the critical Southern blot autoradiograph. On presenting the positive result to the audience I said "And there's the runway!" All the rest of the speakers at that meeting accompanied their critical data slide with the comment "And there's my runway!"
|Devereux, J., Haeberli, P., and Smithies, O. (1984). A comprehensive set of sequence analysis programs for the VAX. Nucleic acids research 12, 387-395.|
|Ogston, A.G. (1959). The spaces in a uniform random suspension of fibres. Trans. Faraday Soc. 54, 1754-1757.|
|Ogston, A. G. and Smithies, O. (1948). Some thermodynamic and kinetic aspects of metabolic phosphorylation. Physiol. Rev. 28, 283-303.|
|Smithies, O. (1953). A dynamic osmometer for accurate measurements on small quantities of material: osmotic pressures of isoelectric beta-lactoglobulin solutions. The Biochemical journal 55, 57-67.|
|Smithies, O. (1954). The application of four methods for assessing protein homogeneity to crystalline beta-lactoglobulin: an anomaly in phase rule solubility tests. The Biochemical journal 58, 31-38.|
|Smithies, O. (1967). Antibody variability. Somatic recombination between the elements of "antibody gene pairs" may explain antibody variability. Science 157, 267-273.|
|Smithies, O. (2003). Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function. Proceedings of the National Academy of Sciences of the United States of America 100, 4108-4113.|
|Smithies, O., and Walker, N. F. (1955). Genetic control of some serum proteins in normal humans. Nature 176, 1265-1266.|
|Smithies, O., and Walker, N. F. (1956). Notation for serum-protein groups and the genes controlling their inheritance. Nature 178, 694-695.|
|Smithies, O., Connell, G. E., and Dixon, G. H. (1962). Chromosomal rearrangements and the evolution of haptoglobin genes. Nature 196, 232-236.|
|Smithies, O., Gibson, D., Fanning, E. M., Goodfliesh, R. M., Gilman, J. G., and Ballantyne, D. L. (1971). Quantitative procedures for use with the Edman-Begg sequenator. Partial sequences of two unusual immunoglobulin light chains, Rzf and Sac. Biochemistry 10, 4912-4921.|
|Smithies, O., Gregg, R. G., Boggs, S. S., Koralewski, M. A., and Kucherlapati, R. S. (1985). Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature 317, 230-234.|
|Smithies, O., Kim, H. S., Takahashi, N., and Edgell, M. H. (2000). Importance of quantitative genetic variations in the etiology of hypertension. Kidney international 58, 2265-2280.|
From Les Prix Nobel. The Nobel Prizes 2007, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2008
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
Copyright © The Nobel Foundation 2007
MLA style: "Oliver Smithies - Autobiography". Nobelprize.org. 24 May 2013 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2007/smithies.html