Genentech and Axel Ulrich clone the human insulin gene

In January 1979, Axel Ullrich moved to a small company in San Francisco called Genentech. Many of the UCSF scientists moved to, or had an affiliation with Genentech.  Eli Lilly had research agreements with both UCSF and Genentech; they were interested in getting a clone of human insulin any way they could.

Once at Genentech, Ullrich continued his quest to clone human insulin.  The regulatory roadblock, NIH regulations requiring that recombinant DNA work be done in a P4 facility, was overcome by moving the research to France, which only required a P3 facility for such work.  Eli Lilly had a research facility in France and made it available to Genentech and Ullrich.  The second roadblock was getting enough insulin mRNA to effectively perform the cloning.

Ideally, Ullrich needed a large mass of human insulin producing cells, called beta cells, as his starting point.  The problem was that human insulin producing cells are located in a heterogeneous part of the pancreas, where they are sprinkled in amongst other cells.  If Ullrich took a patch of a normal pancreas as his starting point, the insulin producing cells would be a small fraction of his total cells, less than 1%. His cloning of insulin would probably not work, the messenger RNA would be too dilute.  He needed a large mass of beta cells.

Axel Ulrich was in Munich at the Diabetes Research Institute discussing his effort to clone human insulin with some physicians.  One of the surgeons mentioned that he had a patient, a woman who lived on a farm south of Munich on the edge of the Alps.  This woman had a rare type of tumor called an insulinoma that needed to be removed.

A tumor originates in a single cell.  Changes in the cell’s DNA allow that cell to overcome the regulatory systems that control the growth of the cell.  This woman’s tumor, an insulinoma, was a case where one particular beta cell in her pancreas had acquired some mutations that allowed it to quickly reproduce into a bundle of beta cells.  Left untreated, the tumor would continue to grow, dispensing insulin at higher and higher levels into her blood.  She would soon suffer from hypoglycemia and probably die. The tumor needed to be removed from her pancreas.

The surgeon in Munich removed the tumor and gave it to Ullrich.  Ullrich processed it and inserted it into a vector in E Coli.  He had cloned a human insulin gene, creating the first microorganism that could produce insulin.