January 10, 2008, University of North Carolina, Chapel Hill,
Brinkhous-Bullitt Research Building
Q. Were you surprised when you received the call from the Nobel Committee?
A. The answer is really yes and no. Because people have talked about it being possible for the last 10 years. By the time it’s gone that long, well then you figure that maybe they, for some reason or other, think it’s not a good idea. So the answer is mixed.
Q. So it finally happened?
A. Yes, it finally happened!
Q. As I understand the process somebody has to submit you. Is that correct?
A. Oh, it’s really quite complicated. I did not realize how complicated it was until I went to Stockholm and people told us. But apparently they receive 400-500 nominations a year, then they have the Karolinska Institute review the nominations, do the research and speak to people all over the world in medicine and physiology. They look to see if people have been nominated by several organizations or individuals. They reduce the number of nominations down to a handful of candidates. All the individuals who qualify within the Karolinska Institute, that’s called the Nobel Forum. They debate around the table until they arrive at the final decision. It’s a very thorough, and largely democratic, type of decision. They make a decision not too allow nationalities to come into it, where people are from.
Q. That’s got to be pretty hard to just narrow it down to the achievement that had the most impact.
A. And you see sometimes they go back… in our case they’ve gone back to work that was done 20 years ago. There is an enormous body of science eligible, you might say, if one can go back 20 years… that’s a huge span.
Q. I suppose there’s one good thing; they can see what the transformative effects of the innovation are.
A. Yes, I am sure that it was a big factor in the present case because it’s been obvious for quite a long time that the procedure that Mario Capecchi, Martin Evans and I devised has led to an enormous amount of work by other people that has helped them solve problems. It has general value that nobody really debates.
Q. So it is probably the case that more than one individual or organization submitted all of you for the prize
A. Oh I think that is obviously the case. It is probably the case for all who got proposed and then chosen.
Q. That had to make you feel good!
A. It did indeed.
Q. I watched the award program on the Internet. Were you nervous at the presentation?
A. Yes I was, but oddly enough, the thing I was nervous about was dropping it! You’re holding two things in your left hand and shaking hands with your right hand. The King [Karl Gustav XVI of Sweden] is very experienced at this, and you can tell because he holds it in such a way that it won’t slip off of the certificate (on the bottom). He gives you the clue that you better hold it in this way. Then you bow to the royal family, then the Nobel Committee, then the audience. There is a prescribed order that you sometimes smile about but understand that they want to make it a ceremony.
Q. So they give you a little training.
A. Oh yes.
Q. After your acceptance and the requisite speeches, did you get to spend some time in Europe? Did you go home to Yorkshire, England?
A. No, in fact I didn’t. Well that’s not true… it is sort of a tradition that the Nobel Laureates for Medicine or Physiology go to the University of Upsala, which is quite near to Stockholm, and give a shortened version of their Nobel lectures there. And often they are invited to another University and I chose the University of Lund that is in Malmo. I gave the whole series of lectures there. I had been there 50 years before, and I had a marvelous time. But none of the people who were there before were still there or alive (Dr. Smithies is 82 years old), but I could remember it because they had been very kind and gracious to me.
Q. I read an old interview last night between Bill Moyers and Maxine Singer, and she was talking about how she considered science one of humankind’s grand activities, continually seeking to understand how our world works. The person who inspired her was a high school chemistry teacher who really demanded a lot of her. This teacher ultimately set her on course for her career in science. Did you have one or more people in your life when you were growing up in Yorkshire, England inspire your science career?
A. I think I knew from early childhood that I wanted to be what I called an inventor. There was a comic strip I used to enjoy as a child and it had an inventor in it. I thought this was neat. I would like to be an inventor… I did not know the word scientist. But it obviously is the same thing. Especially the science I have done, a lot of it has been invention in an ordinary sense of the word.
I was very fortunate to have all sorts of inspiring teachers along the way. I remember I had a teacher from the age of 5 to 11, whose name was Nethergate -- he inspired me.
My father inspired me. I have a very distinct memory of him when I was a small boy. Having a bath, our houses tended to be cold, so there was condensation on the wall. He taught me decimals, writing them in the condensation. He made me understand what decimals were about probably before I was 11.
My high school was an Elizabethan schoolhouse and was founded in 1597! (There is a picture of the school in Smithies’ lab where we met.) It was a free school, but it was very rigorous and the teachers were of the high quality. I had a math teacher named Brown who had a Ph.D. from Michigan. I named him in my acceptance speech. He was the only faculty member who had a Ph.D. He was not a good disciplinarian and not many people liked him. But he was good mathematician and he just loved calculus, and he made me love calculus. Just to give you an idea, I never did any mathematics in college. All my mathematics training was just in high school, and that was the level of training Mr. Brown gave me.
In fact, my scholarship application (to Oxford) when they notified me I won, they made a comment “mathematics - very promising for a person so young.” I remember I couldn’t answer any of the questions and yet they said “very promising.” I think it was because I tried to answer them and I even remember one of the questions. This was in WWII and I was only 17 or 18. The Battle of Britain. (The air war) was going on. The question was “A Spitfire has eight guns and it fires so many bullets per seconds and the velocity of the bullets is X, how much does it slow down when it fires its guns?” So I tried it, and got several answers, I wrote down something like 150 mph. I told them I don’t believe it is wrong, I know it is wrong, it is probably about 30 mph. I think that’s what they meant about “promising” that you don’t necessarily believe what you see in a number. That you question it and use common sense.
Q. Undoubtedly they found some inventiveness in your approaches to solving the problem.
A. Maybe they did, I don’t know, but anyway I always enjoyed that one!
Q. That’s a great story. I read in one of the interviews with you, I think it was the News & Observer; I thought that it was intriguing that you learned to fly an airplane at the age of 50.
A. Yes that’s right. I had a very good teacher and he was another of the teachers that I acknowledged. When you learn to fly, it’s different from just learning to fly, what you really learn is how to overcome being frightened by knowing how to do it. Nearly all beginning pilots are frightened.
Q. The consequences of failure are drastic!
A. Yes that’s right, but by the time they are ready to fly by themselves that fear is gone because they’ve overcome it with knowledge. That was my message in my acceptance speech. That applies to science also, you see.
Q. Scientific experimentation is often… many times about failure before it’s a success.
A. People are frightened of failure so they’re frightened of doing something new, quite often. My message was that you could overcome the fear of something new with knowledge, so it means that you have to study a bit, maybe a lot.
Q. Maxine Singer also said that many times (during her experimentation) she did not even realize that she was asking the wrong question!
A. I know Maxine Singer and what she says is very much to the point.
Q. How did some of your past failures …how did they provide you more knowledge or guide you to then ask the right question?
A. Well, in fact, the experiment that I set out to do, that is now being acknowledged by the Nobel Prize, never worked. What I set out to do, I did not succeed. I succeeded in doing a part of it. Because what I set out to do was to try to correct a gene and eventually I wanted to work out a method of correcting a gene in the bone marrow of people who have genetic problems with hemoglobin. For example, sickle cell anemia or a type of anemia called Thalassemia is very common in the Mediterranean, India and China where there is malaria. We know what is wrong, we know which gene is wrong, and we have a good copy of the gene. I wanted to correct the gene. So that was the aim of my experiment. Now it turned out that I could alter a gene, which was what Mario Capecchi and I both independently showed, that we knew how to alter a gene. But the frequency of the success rate was so low that it was of no use at all for helping [those afflicted]. Not what I set out to do.
But it became clear that we could use it to alter genes in the mouse if we combined this technique with the work of Martin Evans. Evans was primarily responsible for discovering/developing the embryonic stem cells…he did this in mice over 20 years ago. So embryonic stem cells have been around for 25 years. Mario Capecchi and I both, almost within a couple of weeks of each other, contacted Martin Evans to ask him for his cells so that we could repeat our experiments in these cells because we could both see that it would lead to something more important than we had already achieved. Martin Evans was marvelous; he brought the cells to us personally, in his own pocket!
Q. I will segue back to that but how did your post-doctoral fellowship at Wisconsin come about? Were you excited about coming to America?
A. Circumstances of life as it was, my thesis advisor and my tutor at Oxford, his name was A.G. (‘Sandy”) Ogsden, he was very important in my academic life, and personal life for that matter. He suggested that it was a good idea that I do my post-doctoral fellowship in the United States. I wasn’t very keen, because I wasn’t sure that I liked America, and he said that’s all the more reason that you should go because of that stupid remark! He had a Rhodes scholar from the U.S. working in the lab, his name was Robert (“Buzz”) Baldwin from Wisconsin. He said you should go to the University of Wisconsin and do the work there. I was a physical chemist at the time, purely chemical type of work with biological substances. So I did my fellowship there… I did not achieve anything very significant at that time but I met an American girl there and got married. My first wife was American.
I went to Canada. Because of Visa problems I couldn’t stay in the States. I was there about seven years and did some important work there that was very well recognized. The work was devising, if you like inventing again, a method of separating proteins. It is called molecular sieving. It separated proteins partly because of the differences in their sizes. That turned out to be very useful. I had several awards with respect to that work.
Q. Please explain a little further the work of your Nobel co-recipients, Mario Capecchi and Martin Evans.
A. Yes, yes. Mario and I were really doing very similar work in parallel. We knew of each other’s work (specific gene alteration) but we didn’t actually do anything together. We would meet and we always had a good relationship, there was none of that fierce competition of the sort that is not healthy I don’t think. We did not feel we were having a race.
Q. Martin Evans was responsible for the embryonic cell portion of this research?
A. Yes. He moved this experimental work from doing it in the Petrie dish, culturing cells now became transferable to animals. Therefore you could change a gene in the test tube and ask what effect it had in an animal. Very powerful. That is where the power of the joint method, which we call gene targeting, that’s the power. It moves it from the test tube, to modify a gene to the unhealthy form, to the animal to see what the effect is. To obtain an animal model of the disease for example cystic fibrosis. It has been used by those researchers extensively… the work has also proved to be very valuable to the pharmaceutical industry. If they want to find a new drug that will modify, lower blood pressure, if you find a gene that when it’s knocked out causes blood pressure to be lower, then that gives them a clue. Maybe if we make a drug that will inactivate the product of that gene, then it can also reduce blood pressure. That’s the kind of chain of thought the companies use to identify a new target for a drug.
Q. I understand that your current work involves kidney disease. What are some the scientific, medical questions you are trying to answer?
A. Well there is a lot of… kidney disease can be very severe because if the kidney fails badly then the only hope is dialysis. That works, but the better solution is a kidney transplant. So learning what factors cause kidney failure, what genetic factors, what environmental factors -- are important. What I am interested in are the factors that cause the kidney to start to be unable to keep protein in the body. That’s called albuminuria. It’s the basic physiology of this process. I am not working on any particular disease I am just working on understanding how the kidney handles albumin. It is not work I was particularly trained to do so I have had to teach myself about it. I am still learning as I do the work and that is the fascinating part about science, as you do the work you learn more and more about the subject. You don’t necessarily know everything about the subject before you start. In fact it sometimes is an advantage to have basic idea but not all the details. Because then you are not overwhelmed with the failures of the past. You are naïve enough to think that you can succeed. At the same time you have to learn so it’s an interesting combination of naïveté and knowledge.
Q. Your wife is also a scientist at UNC?
A. She is a scientist here of her own right. In fact she received her appointment here at North Carolina before mine and I came because she received a good appointment in the Department of Pathology. I tagged along!
Q. Is she working on kidney disease also?
A. No she is working on factors that contribute to atherosclerosis. She’s done some very important work.
Q. Do you think the recent discovery of stem cells from skin is valuable and can resolve the ethics issues regarding embryonic stem cells?
A. The whole business is fascinating. Skin cells have scientific value. Anything derived from them solves the problem of rejections for transplantation. But keep in mind that much work is still ahead, it is expensive, and portions of the steps are dangerous. Remember that science progresses in small steps.
I think that the ethics issues of embryonic stem cells are looked at in the wrong way. I look at in the reverse way as presented… you are perpetuating the life of the embryo and helping many others. Unused embryos from in vitro fertilization are going to be destroyed. Why throw them away?
Q. So what is your secret to living such an active life at 82 years of age?
A. I have the good fortune of being born with “happy genes”. It is really important to do something that you love. Do something that retains your perpetual interest and curiosity.
Dr. Oliver Smithies Nobel Prize Acceptance Speech
Your Majesties, Your Royal Highnesses, Your Excellencies, Ladies and Gentlemen.
The three of us (Mario Cappecchi, Martin Evans and myself) thank the Nobel Assembly at Karolinska Institutet and the Nobel Foundation for honoring us today. And we thank our students and collaborators, whose help was indispensable in our research. But we also acknowledge an older debt --- to our teachers --- which I want to illustrate with three of mine.
The first, Dr. G.E. Brown, taught mathematics at Heath Grammar School in Halifax, England. “Oddy” Brown, as we called him, was a poor disciplinarian, and not much liked. But he loved mathematics, and the calculus, and he conveyed this to at least one student --- me!
The second, Field Morey, is a distinguished flight instructor. He taught me to fly 30 years ago, a difficult task because I was over 50 years of age! But he taught me something more important than flying --- namely, that it is possible to overcome fear with knowledge!
This same lesson applies to scientists – the fear of failing --- which many scientists have when trying something new --- can be overcome --- in the same way --- with knowledge.
The third of my teachers is Dr. A.G. (“Sandy”) Ogston. He was my tutor as an undergraduate at Balliol College, Oxford University, and later oversaw my change from medical school to graduate school in order to take up research. Sandy was an extraordinary scientist, and a dedicated teacher. And he conveyed to his students a view of science, which I quote in closing:
“For science is more than the search for truth, more than a challenging game, more than a profession. It is a life that a diversity of people lead together, in the closest proximity, a school for social living. We are members one of another.”
- A.G. Ogston
Australian Biochem. Soc. Annual Lecture
Search, Vol.1, No. 2, August, 1970
