The Scurvy Trials
Curing Scurvy with the First Controlled Clinical Trial
On May 20, 1747, as the fifty-gun fourth-rate warship HMS Salisbury cruised the English Channel off Plymouth during the War of the Austrian Succession, Scottish naval surgeon James Lind descended into the damp forward sickbay below the waterline. Eight weeks into her patrol, Salisbury had lost a tenth of her crew to severe scurvy. Twelve sailors lay immobilized in canvas hammocks sharing an identical progression: their gums were swollen into putrid black masses that loosened their teeth; purple petechial hemorrhages blotched their calves; their knees were locked rigid with coagulated blood; and old scars and healed bone fractures had softened and split open.
Throughout the seventeenth and eighteenth centuries, scurvy killed more British seamen than enemy broadsides, shipwrecks, and fevers combined. Just three years before Lind boarded Salisbury, Commodore George Anson had returned from a four-year circumnavigation having lost nearly 1,400 of his 1,900 sailors, over a thousand of them to scurvy.
Although merchant captains had occasionally observed that fresh citrus revived scorbutic crews, those reports were drowned out by the orthodoxy of the Royal College of Physicians in London. Led by Richard Mead and Herman Boerhaave, the medical establishment taught that scurvy was an "alkaline putrefaction" of the bodily humors caused by damp sea air, blocked perspiration, and salted beef. To counteract alkaline rot or purge corrupt humors, the Admiralty filled medicine chests with elixir of vitriol (diluted sulfuric acid), vinegar, seawater draughts, and wort of malt.
Lind had entered the Navy as a surgeon's mate after an Edinburgh apprenticeship. Faced with six incompatible remedies endorsed by competing authorities, he designed an experiment aboard Salisbury that eliminated every confounding variable of environment and diet. He moved all twelve scorbutic sailors into the same forward berth, verified equally severe symptoms, and placed them on an identical baseline diet of sweetened water-gruel, mutton broth, light puddings, and barley biscuit.
He then divided the twelve men into six pairs and administered a different fourteen-day protocol to each pair:
- - Pair 1: One quart of hard cider every day.
- - Pair 2: Twenty-five drops of elixir of vitriol three times a day upon an empty stomach, plus an acidified mouth gargle.
- - Pair 3: Two spoonfuls of vinegar three times a day upon an empty stomach, with vinegar-acidulated gruel.
- - Pair 4: Half a pint of seawater every morning as a mild purgative.
- - Pair 5: An electuary paste of garlic, mustard seed, dried radish root, balsam of Peru, and gum myrrh three times a day.
- - Pair 6: Two fresh oranges and one lemon every day, eaten on an empty stomach.
The ship's scant store of citrus fruit ran out after six days. Yet by that sixth day, one of the two sailors given oranges and a lemon had returned to active deck duty, while his companion was nearly free of symptoms and assigned to nurse the remaining ten men. Aside from slight improvement in the cider pair, the sailors given sulfuric acid, vinegar, seawater, and herbal paste showed zero recovery.
What Lind had isolated empirically was an acute failure of collagen synthesis. Because humans carry a mutated, non-functional GULO pseudogene, they cannot synthesize L-ascorbic acid (vitamin C) from glucose. In connective tissue, ascorbic acid acts as an obligate electron donor that keeps the iron atom ($\text{Fe}^{2+}$) in the active site of prolyl hydroxylase and lysyl hydroxylase in its reduced ferrous state. Without vitamin C, the iron oxidizes to inactive $\text{Fe}^{3+}$, halting the hydroxylation of proline and lysine residues along tropocollagen chains. Deprived of hydroxyproline, the polypeptide strands cannot form the hydrogen bonds required to fold into a stable collagen triple helix, causing capillaries to leak, tooth ligaments to dissolve, and old fractures to separate.
When Lind published A Treatise of the Scurvy in 1753, the Admiralty delayed forty-two years, partly because Lind recommended boiling lemon juice into a syrup (rob), unaware that heat destroyed ascorbic acid. Only in 1795, after physician Gilbert Blane persuaded the Admiralty to mandate a daily ration of three-quarters of an ounce of unboiled lemon juice after two weeks at sea, did scurvy vanish from the fleet, reducing admissions at Haslar Royal Naval Hospital from 1,457 cases in 1780 to two cases between 1806 and 1810.