Insulin and growth hormone from bacteria

Insulin, made by the beta cells of the pancreas, lets body cells take up glucose. Without it, blood sugar stays high: diabetes mellitus. Insulin has two chains, A (21 amino acids) and B (30 amino acids), joined by disulphide bonds. Insulin from pigs and cows differs from human insulin by one and three amino acids respectively, and can cause allergies.

The body makes insulin in stages:

• First preproinsulin (110 amino acids).
• Removing its signal peptide gives proinsulin (86 amino acids: the A and B chains plus a C chain of 31 amino acids).
• Removing the C chain (and four linking amino acids) gives mature insulin (51 amino acids).

Bacteria cannot do this processing. So in the late 1970s, scientists cloned the genes for the A chain and the B chain separately in E. coli. Each was joined to the gene for β-galactosidase, under the lac promoter, so the bacteria made each chain as part of a larger fusion protein. The chains were cut free with cyanogen bromide, purified, and joined by disulphide bonds. The company Eli Lilly sold this human insulin as Humulin, in 1982: the first genetically engineered human medicine.

Human growth hormone (HGH, 191 amino acids), made by the pituitary, drives growth; a lack of it in childhood causes dwarfism. Before rDNA technology, one year's treatment needed the pituitary glands of more than 80 dead bodies, and risked passing on Creutzfeldt-Jakob disease, a deadly prion disease.

HGH, too, is first made with a signal peptide (26 amino acids), which bacteria cannot remove. The solution: the HGH cDNA was cut to remove the code for the signal peptide plus the first 24 codons of the hormone; those 24 codons were made chemically and joined back on. This gene, without the signal sequence, was expressed in E. coli, and sold as Humatrope and Protropin (1985).