Elion, Hitchings and rational drug design

Drugs had mostly come from natural products, chemically modified, or from trial and error. George Hitchings tried a different route. In 1942 he joined the Wellcome Research Laboratories in Tuckahoe, New York, run by the British firm Burroughs Wellcome, as head and sole member of its biochemistry department. His idea was that cancer cells, bacteria, protozoa and viruses might build nucleic acids differently from normal human cells, and that a false building block could stop them while sparing the patient.

Gertrude Elion joined him in 1944. Her grandfather's death from cancer, when she was 15, had steered her into chemistry at Hunter College, which charged no tuition. Laboratory jobs for women were scarce, and she had taught school and done quality control for a food company. She never finished a doctorate; when Brooklyn Polytechnic Institute told her she would have to give up her job to study full time, she kept the job. The group tested compounds on Lactobacillus casei, a bacterium that needs folic acid or purines and pyrimidines to grow.

In 1948 they found diaminopurine, which blocked the bacterium and experimental leukemia but proved too toxic in patients. Thioguanine followed in 1950 and 6-mercaptopurine in 1951. Tried with the Sloan-Kettering Institute in leukemia patients resistant to methotrexate, 6-mercaptopurine produced complete remission in about a third (1953). Hitchings's group also made pyrimethamine for malaria (1950) and trimethoprim for bacterial infections (1956); trimethoprim binds the bacterial enzyme dihydrofolate reductase 100,000 times more strongly than the human one. Both worked better with sulfonamides.

A sulfur-substituted relative of 6-mercaptopurine, azathioprine (1957), suppressed the immune response and was for a long time the only drug to prevent rejection of transplanted organs. Allopurinol (1963) blocks uric acid formation and treats gout. Acyclovir, described by Elion and coworkers in 1977, is switched on by an enzyme that herpes virus makes in infected cells, and was the first effective drug against herpes infections. Elion's colleagues later developed the AIDS drug AZT on the same principle.

Elion and Hitchings shared the 1988 Nobel Prize in Physiology or Medicine with James Black. Hitchings died in 1998 and Elion in 1999.