1971: Vane Elucidates Aspirin's COX Inhibition Mechanism (1971)

Despite aspirin's 70-year clinical history by 1971, its molecular mechanism of action was entirely
unknown. The drug produced anti-inflammatory, antipyretic, and analgesic effects, but why remained
a mystery. John Vane, then at the Royal College of Surgeons in London, provided the answer through
a series of elegant experiments published in Nature New Biology in June 1971.

Vane demonstrated that aspirin and indomethacin—another NSAID—inhibited the enzymatic synthesis
of prostaglandins from arachidonic acid. He showed that guinea pig lung homogenates produced
prostaglandins when stimulated, that this production was blocked by aspirin, and that aspirin's
anti-inflammatory potency correlated with its ability to inhibit prostaglandin synthesis. He
proposed that prostaglandins are local hormones responsible for inflammation, pain, and fever,
and that NSAIDs work by inhibiting their biosynthesis.

The enzyme responsible was subsequently identified as cyclooxygenase (COX), which converts
arachidonic acid to the prostaglandin precursor PGH2 via a two-step reaction. Aspirin was found
to irreversibly inhibit COX by acetylating a serine residue at the active site (Ser530 of
COX-1), distinguishing it from other NSAIDs that inhibit reversibly.

The discovery of two COX isoforms—COX-1 (constitutive, protective in gastric mucosa and platelets)
and COX-2 (inducible, upregulated in inflammation) by Simmons and others in the early 1990s—
enabled the development of COX-2 selective inhibitors (coxibs). The tragic story of rofecoxib
(Vioxx), which selectively blocked COX-2 without inhibiting platelet COX-1, increasing
cardiovascular thrombotic risk, illustrated how the selectivity principle can produce unexpected
consequences when applied to enzymes with physiological homeostatic roles.

Vane shared the 1982 Nobel Prize in Physiology or Medicine with Sune Bergström and Bengt Samuelsson.