Oliver Smithies is one of the masters of giving motivational talks to young researchers. The talk he gave on Wednesday is only a slight variation of his Nobel lecture in 2007 (video and slides can be found here), or the presentation I heard in 2008 at the International Congress of Genetics. But as Eva Amsen said in a Twitter comment yesterday,
Once might be enough, but I do think every biochemistry student should see Smithies speak at some point.
The presentation used pictures from his lab notebook as the basic structure, starting with the first day working as a scientist (January 1, 1954), until the Saturday just before the Lindau meeting – in other words, spanning 56 years. In that ways he still sees himself as a student.
I’m still basically a student, not a complicated scientist.
Oliver Smithies started by telling us about his chance invention of molecular sieving electrophoresis (using starch instead of filter paper). His first project was on insulin precursors, but after finding six until then unknown protein bands in his electrophoresis of plasma, he seized the opportunity and switched the project he was working on.
I got a bit tired of taking my own blood…
This work obviously required a lot of human blood for his studies, and at some point Smithies had to ask his colleagues to help out. This work led to the discovery (in the haptoglobin gene) of the first genetic difference in humans not causing disease, in order words haplotypes. Some of the work was published in Nature in 1955.
Moving forward to the early 1980s (when Smithies was in his late 50s), he started to think about using homologous recombination to correct the single point mutation in the hemoglobin beta globin gene responsible for sickle cell anemia. When teaching a graduate course in molecular genetics at the University of Wisconsin in 1982, he came across a paper describing the isolation of a transformation gene in the human T24 bladder cancer cell line. This paper started a planning phase in his life as researcher, and he used the then standard calcium phosphate method to transfect the human beta globin gene. There were of course a lot of failed experiments along the way.
I did the experiment on my 58th birthday. It didn’t work. You don’t necessarily get compensation on your birthday.
Smithies in 1984 switches to electroporation for transfection. As this was then a new technology and the equipment was not yet commercially available, he built his own electroporation apparatus.
Never make equipment to save money. Make it when you can’t buy it.
In 1985 he published the results of this work in Nature. As he summarized it in the discussion, the frequency of success was modest (about 1 in 1000), but data show that planned modification of a human gene is possible in vivo. An important aspect of this and future work was the cooperation with other scientists. Oliver Smithies has almost always had a very positive experience with cooperations:
Never hesitate to ask for help from other scientists. Most of the time you will get it, so in 9 times out of 10 you will get joy.
Oliver Smithies ends his talk with a picture from his lab notebook from the previous weekend (June 26, 2010). And he concluded:
When you are still doing experiments on a Saturday when you are 85, you are enjoying life as scientist.
P.S. John Timmer from ars technica has also written a blog post about this lecture.