Alternatives to purifying insulin from animal glands.

Animal insulin is not exactly the same as human insulin.  The amino acid sequence for human, pork, and beef insulin had been worked out.  Pork insulin differed from human insulin by one amino acid, one letter in the sequence of 51. While beef insulin differed at three of the 51 locations.  A small portion, about 5%, of people taking insulin, have allergic reactions to these animal insulins. These people would particularly benefit from human insulin.

One alternative was the straight synthesis of insulin.  Insulin, like every protein, is made up of atoms. Insulin consists of 777 atoms: 257 are carbon, 383 hydrogen, 77 oxygen, 65 nitrogen and 6 sulfur atoms.  If one could arrange these 777 atoms in the proper order, with each atom bound to specific other atoms, then one would have insulin.  This straight chemical synthesis was actually done by several groups, first by a team in Shanghai, China as part of Mao’s Great Leap Forward.  The Chinese project took a team of people seven years, they began in 1958 and successfully finished in 1965.  Unfortunately, the yield was low and the Eli Lilly team saw that it would be too expensive to make insulin this way on an industrial scale.

A second alternative appeared in the 1970’s.  Insulin is a protein.  Inside a laboratory, cells make proteins within a test tube all the time.  If the scientists at Lilly could just convince a cell to make this particular protein, they could grow insulin in vats and have an unlimited supply.   The understanding of molecular biology was progressing to the point where it was clear the capability to have a bacteria produce a human protein would soon arrive.

A gene is a piece of DNA that codes for a protein. A protein, like insulin,  can be represented by a linear sequence of letters from an alphabet of twenty letters.  DNA can be represented by a linear sequence from an alphabet of just four letters.  Marshall Nirenberg had worked out the way to translate from the DNA code to the protein code.  Three letters in the DNA language, say ACA, could be uniquely translated into the protein language, T.

The trick was to put the DNA representing insulin into a cell that could easily be grown in the laboratory. This trick was called recombinant DNA technology.  The term “recombinant” refers to the process of taking DNA from one organism (a human) and “recombining” it with DNA from another organism, a bacterium.

Irving Johnson knew about the trick in principle, but he didn’t know how exactly to do it.  At first, he tried to hire people who could do it, but the training was specialized and only a few people in the country knew how to do it.  He eventually came to the conclusion that Eli Lilly needed to partner with the people who had the expertise in this area.