Posted on October 11, 2007 - by MG

Yay Smithies et al, the Nobel prize is yours…!

And the prize goes to…the gene targeting guys!

There’ll be a few more scientists I used to know gnashing their teeth this week as more of their friends win the Nobel prize and they don’t.

(I once heard of one guy who would get wildly depressed with jealousy every year that one of his friends and not him joined the Nobel prize-winners club. I wrote a short story about it…which shall remain unpublished or because I named actual real scientists I know, to make it funnier… This story is handwritten in a drawer and I show it to me special science friends once in a while, for a giggle. The coda to this tale is that the guy in question finally did win. Obviously I can’t name any names…)

This year the Nobel Prize for Medicine went to the Sir Martin Evans, Mario Capecchi and Oliver Smithies, the guys who developed the technologies for creating a mouse with a gene ‘knocked out’. This means that you could look at the effect, in theory, of a single gene in a mouse, by creating a mouse that was normal in every way except that it lacked, say, the haemoglobin gene.
The early days of any new technique are always fraught with difficulties. I came into the gene targeting game in 1993, early-ish, but quite a few mouse knockouts had already been done. It still wasn’t easy though. Nowadays I bet rich labs just order a knockout mouse via the Web…

I was put on a project to knockout a gene called the FGFR3 – fibroblast growth factor receptor 3. It’s an interesting gene because a single mutation – one tiny change in the DNA code – results in the condition known as achondroplasia – aka dwarfism.

The first thing I had to do was to ‘restriction map’ the DNA in the chromosome – i.e. make a map of all the sites where ‘restriction’ enzymes could specifically cut into the DNA. Since DNA is too tiny to cut with scissors, molecular biologists use these naturally occuring enzymes to snip DNA into pieces. It’s just a matter of knowing which enzymes cut where and then picking your tools; the enzymes which will cut you out a nice chunk of precisely tailored DNA.

The mouse FGFR3 gene was spread over quite a large region of DNA so I used this delish and elegant new method that I’d read about. It worked like you wouldn’t believe, first time too!

I’d just mapped the FGFR3 gene and got partway into making the ‘knockout construct’ – the DNA molecule that you use to inject into mouse embryonic stem (ES) cells – a first stage towards the knockout mouse (the stage that Smithies contributed to the whole process).

And then a Big Hot Lab in the USA published the FGFR3 knockout mouse in a Damn Hot Journal.

Bah. So that was several months of my work down the drain! I went to see my boss. Did he know that Big Hot Lab had a couple of postdocs and a techie or two on the same project as little me?Hmmm, he said and peered hard at his computer screen, as if something rather canny had just occurred to him. “I may have heard a rumour or two…”

And that’s why I didn’t develop the FGFR3 knockout mouse and get a Cell paper and why I ultimately gave up science and had to do other things. Yes, but for that I might never have written a single novel.

Meanwhile, Oliver Smithies. I heard him talk once. What a character! He’s a Brit – a Yorkshireman I think (I may have remembered that wrong). but lives in North Carolina now. He flew in to talk at the Dunn School of Pathology, Oxford when I was a grad student. I mean that quite literally – Smithies has a pilot’s license and like John Travolta, flies himself to all his engagements.

This is rare for a scientist.

Smithies gave a fascinating talk, one of the best I ever saw in my whole time as a scientist. It featured lots of photos of his lab and his makeshift equipment. This guy is one of those rare, rare things – a scientist who is also a natural engineer.

Check out Smithies’ homemade electroporator – known by scientists as a ‘zapper’ for hitting cells with an electric current so that DNA goes in.

Years before Perkin-Elmer had patented the Polymerase Chain Reaction (PCR) and made a machine which allowed people to amplify DNA molecules by basically just sticking some DNA and Taq polymerase enzyme in a test tube and putting it into a Perkin-Elmer thermal cycler, Smithies was doing early ground-breaking PCR using bits of washing machine timers to do the thermal cycling. He showed us photos of stuff that you wouldn’t believe could be used to do proper science, equipment literally cobbled together from bits and bobs and stuck together with sticky tape. He was an elderly man even then but brimming with enthusiasm. I remember being quite inspired.

I’m chuffed he’s won. Best Nobel Prize news since Paul Nurse won for the yeast cell cycle genes.