For the development of a powerful technology for manipulating the mouse genome with exquisite precision, which allows the creation of animal models of human disease.
This year’s Lasker Basic Medical Research Award honors three scientists who developed a powerful technology that allows scientists to create animal models of human disease. With this technology, researchers have engineered mice with conditions such as atherosclerosis, cancer, high blood pressure, and cystic fibrosis, allowing the study of many debilitating disorders. And the same technology is uncovering the secrets of normal biological processes as well, revealing, for example, how the nervous system develops or how immune cells collaborate to quash microbial invaders.
This progress depends on the ability of researchers to manipulate the genetic material of mice with exquisite precision. Scientists can disable — or knock out — a gene, and they can also change its properties in more subtle ways. These procedures generate animals that carry specific genetic alterations, and recreate the underlying cause of a human disorder or uncover the role of any gene of interest.
Inactivating a mouse gene takes two steps. In the first, scientists snip out its middle in a test tube using conventional tools of molecular biology. The challenge then is to replace the intact, functional gene in the mouse chromosome with the modified version created in the test tube. This genetic swap requires the introduced DNA to find the corresponding DNA in the chromosome. Less than two decades ago, conventional wisdom held that this task was impossible in mammalian cells, and that DNA could insert only at random sites.
At the time, knocking out a particular gene was about as successful as tossing a dart into a heap of spaghetti and hoping it hits a particular strand in a certain spot. Scientists could add DNA to mouse cells, but it landed in random places. They couldn’t yet target DNA to a particular site in the chromosome — in other words, to a specific gene. Today, hitting a bull’s-eye is a standard maneuver.
By building on several decades of fundamental studies in mouse embryology and molecular genetics, Mario Capecchi, Martin Evans, and Oliver Smithies brought this work to fruition and delivered the technology of gene targeting in living mice to labs around the world. Scientists can now create and breed mice with particular pathologies, study them systematically, evaluate the functions of genes in an intact mammal, and dissect even the most complex processes.
Award presentation by Ira Herskowitz
The release of the human genome sequence in draft form makes this a landmark year in the history of biology. Now we know that we have 30,000 or so genes (or is it 50,000?). We are now faced with several important questions, which include: First, what are the functions of these genes and the proteins that they code for? And, second, how can we use this information to improve human health?
Until the ability to knock out genes in the mouse was developed, determining the function of human genes seemed largely out of reach, tantalizingly so. For example, we might know of a human protein that is found only in certain cells of the brain and suspect what it might do, but how can we find out? Or, we might know of a gene in the fruit fly that is necessary for its development and see that humans have a very similar gene. Does it perform a similar function in humans? A powerful way to link a gene to function is to study the behavior of a mutant that lacks that gene and then see what the mutant can and cannot do. It’s somewhat like disabling an automobile by removing one part and then inferring the function of the part that was removed. But we can’t knock out genes in a human, so how can such mutants be produced?
The mighty mouse has come to the rescue. Its genes are typically 95 percent identical in sequence to ours, and we share the vast majority of our genes with the mouse.
An interview with Oliver Smithies by Raju Kucherlapati
Raju Kucherlapati, Scientific Director of the Harvard-Partners Center for Genetics and Genomics, interviews Oliver Smithies, whose work on homologous recombination led him to provide the groundwork to manipulate the mouse genome with exquisite precision.
Date of interview: September 20, 2001
Kucherlapati: I’m Raju Kucherlapati from the Harvard Medical School, and here with me today is Dr. Oliver Smithies. He’s the 2001 Albert Lasker Award winner for Basic Medical Research. Oliver, welcome.
Smithies: Thank you, Raju.
Kucherlapati: Oliver, first I want to congratulate you on this great accomplishment of being the Lasker Award winner this year.
Smithies: Thank you.
Kucherlapati: Oliver, it would be wonderful if you could tell everybody a little bit about your educational background.
Smithies: Yes, I would enjoy doing that because I have enjoyed my education. My primary education was of course in a little school in a country village near a big town. But then from that school I got to go to the local grammar school, as it was called in those days in England. A very distinguished school that was first opened in 1596, so it was a longstanding school and with a great scholastic tradition. And in that school when you got to the end of your time in it, you had the opportunity to be in the sixth form and to apply for scholarships.
So I applied for a scholarship under the guidance of my high school or grammar school teachers who were really marvelous people, and I got a scholarship to go to Oxford. Of all the colleges in Oxford — there are many colleges in Oxford, and you can apply for different colleges — I applied to go to Balliol, which is a college which was a very scholastic college. Now this was during World War II, so it was quite a small college then and you were taught by two levels. You were taught by the university professors and lecturers, and you were also taught by your tutor. He would be a very personal individual who you had personal contact with once a week.
They didn’t have very many students at that time, so the total college was only 90-odd students and my tutor probably had ten students. You would meet with him once a week and write an essay on a topic of his choice, not yours. This was a rather remarkable type of education because we were expected to read textbooks for one day of the week and then reviews for the second day, and then after that it had to be all original literature. So you got to enjoy learning from the original literature very early in your career and understanding the basic parts of science.
That was the undergraduate education. I took a degree in physiology, animal physiology, and I was actually a medical student. In actual fact, I dropped out of med-school and went to do chemistry, and then took a couple of years of chemistry and started to work with the same tutor now as my PhD advisor. And I did a PhD with him for two or three years, working on developing what we would now call a tool of biophysics. But that hadn’t been invented, there’s a name then and it was called “physical biochemistry” when I was doing it. So that was my primary education.
I should add that I lived in his house part of the time. We became very great friends; I felt part of the family. Because in World War II there weren’t enough places to live, so I stayed in their house and messed up their sink with my chemicals and got all of that by his wife, who was a marvelous person.
Anyway, then I went to the University of Wisconsin as a post-doc in physical chemistry and did a rather undistinguished couple of years of post-doc. Then, having been at a very susceptible age, I fell in love with an American woman — or girl I would have called her at that time — and we decided that it would be a good idea to get married. She didn’t want to go to England, so I went to Canada because of a visa problem.
I went to Canada and stayed in Canada for about seven years, and it was there where I did some work we might talk of later in relation to starch gel electrophoresis, and became a geneticist. I came back to University of Wisconsin at Madison again, but now as a geneticist on the faculty of genetics, and then became a professional geneticist. So that’s a rather long-winded account of what happened.