December 14, 2007

Nobel lecture with the physiology or medicine laureates

Three of those guys up there are this year's Nobel laureates in physiology or medicine: Sir Martin Evans, Oliver Smithies and Mario Capecchi. It's a tradition now that the Nobel prize winners come to Uppsala to repeat the official lectures they give in Stockholm in association with the prize event. I was there early yesterday and managed to get a pretty sweet seat for the medicine lecture. Afterwards I went down to mingle, as I did last year. But there were a lot more people who got the same idea this time around. Last year we got to talk a bit at length with Andrew Fire and Craig Mello after the lecture but since all three laureates gave their lectures at the same occasion this year, there was barely time or space for a swift handshake and maybe a photo.

In case you didn't already know, the prize this year went to the development of the technique of gene targeting. By using gene targeting, it's possible to introduce a specific mutation in almost any gene you want and then develop a mouse that carries this change. The use of "knockout mice", mice where the function of a gene has been deactivated, is a development that's difficult to underestimate. Gene targeting can not only produce good models for a wide variety of human diseases, it also offers the possibility to study the function of specific genes in detail by either knocking them out completely or by modifying them in specific ways. Smithies and Capecchi independently developed the technique for replacing a normal gene with a modified version using the naturally occurring process of recombination and Evans developed the mice embryonic stem cells that made it possible to carry this modification through to an adult living organism.

The title of Evans' lecture was "Are ES cells a normal embryonic cell type or are they a tissue-culture artifact?" He started out by highlighting the importance of the ability to genetically modify a mammal such as the mouse, enabling us to make a model that is directly applicable to humans. He talked about how it's "fundamental science" -- finding out "how things work". Then he explained how he went "from culture to creature", how he developed the embryonic stem cells (ES cells) in culture and how the introduction of the modified ES cells into a mouse embryo produces a chimeric mouse: a mouse that has cells from both the modified ES cell-line and the normal embryonic cells. These chimeric mice can then be bred to produce offspring that only have cells derived from the modified ES cells. Most part of the lecture was a presentation of the evidence for the ES cells he developed being essentially the same as cells normally found in embryos and not cell culture artifacts. He concluded then that ES cells are part of the normal developmental path and not "stepped aside" due to the culture conditions. It was a brief and to the point lecture. Very nice.

Smithies continued with a very amusing lecture called "Turning Pages". It basically consisted of a slideshow of pages from his messy old lab notebooks -- "what it's been like to be a scientist working at the bench for over 60 years". The first page was dated January 1st (hahaha) 1954. He was very funny and engaging, even a bit inspiring, describing the more practical aspects of how he made his discoveries.

Capecchis lecture was called "Gene targeting in the 21st century: mouse models of human disease from cancer to psychiatric disorders". He didn't focus so much on the actual discoveries that earned him the prize but rather presented his current work investigating a form of cancer called synovial sarcoma by creating mouse models of the disease using gene targeting. It was a more regular research presentation of the kind you get at conferences, but it was still pretty nice.

The Q&A session afterwards was pretty regular, getting more into a couple of specifics. But one very important aspect came through with Martin Evans highlighting the multigenic problem. While it's immensely important to be able to study what individual genes do, with gene targeting for instance, we can only gain a complete understanding of "how things work" if we keep in mind that genes interact with each other in many different and vast networks to produce the functions we can observe. Smithies also made an important point by stressing that the gene targeting mouse models aren't only important in the knockout scenario, but that they can also be used to understand the "everyday differences", as he put it, that make one individual different from another. His thesis is that these "small" differences are due to quantitative differences in gene expression, or in other words that they're caused by differences in how much influence the gene has in different individuals rather than individual differences in the gene itself.

You can see videos of the official lectures given in Stockholm on the Nobel foundation website.

I'll post some more photos from the brief schmoozing with the Nobels as soon as I get them in my inbox. I didn't take that many myself.

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