To hear Oliver Smithies tell it, there was a direct line from one of his first lab projects to the experiments that won him a Nobel Prize. Smithies showed that it was possible to target genes for disruption in mice, a technique that has revolutionized genetics and provided information relevant to human health.

You wouldn't have guessed it based on the first slide of his talk at the Lindau Nobel Laureates meeting taking place this week in Germany. The slide showed an early page from Smithies' lab notebook of a failed attempt to isolate insulin, an experiment that he had dragged himself into the lab to perform on New Year's Day.

By showing page after page of his notebook to the audience, Smithies gradually told the tale of how failing to purify insulin eventually led him to a successful scientific career.

The long and winding road

Smithies had tried to isolate insulin using a standard chemical technique called plate chromatography, but the protein didn't cooperate. So, thanks to another lab in his building, he tried a new approach, separating the protein on a gel made of starch. It worked so well that he started separating any mix of proteins he could get his hands on, just to see what showed up. One day, he ran a bit of blood serum and found double the number of proteins that most people thought were present.

Smithies dropped insulin like a rock and never looked back.

He began to hit up all his friends for blood samples and eventually found that different samples produced different patterns of proteins. There was a bit of confusion—the first sample that showed a different pattern happened to be Smithies' first female test subject, and that led to jokes about possible sex change operations. But, eventually, the region of the chromosome responsible for the differences was pinned down.

All the steps were illustrated by yet more pages from his notebooks, many with hand-drawn diagrams of his gels. His lab was so small—"it was just me!"—that Smithies couldn't afford a camera.

The reason for the difference in proteins eventually took Smithies in a new direction. Some people carried a region of chromosome where recombination had gone wrong, dropping an extra copy of some genes in between the normal ones. That got Smithies interested in the process of recombination, an interest that was furthered by the finding that some cancer-causing genes were the product of faulty recombination events.

If a bad copy of a gene could be generated by faulty recombination, Smithies reasoned, it should be possible to eliminate it through another recombination event. So, he began to generate the DNA needed to knock out the cancer-causing oncogene; more pages from the notebook appeared, including one that he pointed out was from his birthday.

"It didn't work," Smithies said. "You don't necessarily get special dispensation because it's your birthday."

Do it yourself

After enough failures, however, Smithies and his co-workers were eventually able to get the technique working and refine it, in part with a bit of homemade equipment. It wasn't the only bit of homemade equipment Smithies showed a slide of. After the PCR technique was published but before it was commercialized, he ended up making his own PCR machine.

"Make equipment if it will save time, but never make equipment to save money," he advised the audience, noting that a lot of custom hardware will end up wasting money in the long run.

Looking for ways to put his technique to use, Smithies crossed paths with Martin Evans, another one of the speakers. Evans had developed mouse cells that we now recognize as embryonic stem cells, and he developed a way of getting them incorporated into a developing embryo.

With Smithies' recombination and Evans' cells, "knockout mice" could be made with a researcher's gene of choice eliminated. Very quickly, key genes shared by mice and humans were knocked out by biologists at institutions around the world, which is why Smithies' award came in the medicine category.

At 85, Smithies remains an active scientist, and he finished his talk with a slide of another page in his notebook—one from last Saturday.