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Feature - Norman Who? - Eric Lax

The name we all associate with the discovery of penicillin is Alexander Fleming. Two others shared the Nobel Prize - but there is one name, Norman Heatley whose crucial involvement seems almost to be forgotten...

When asked to associate a name with penicillin, the first antibiotic, most people will mention Alexander Fleming, whose renown in the mid-twentieth was so great that he was famous on every continent of Earth and on the moon as well, where a crater was named for him. A few scientists and Nobel Prize buffs might also add Howard Florey, the Oxford University Professor of Pathology and head of the laboratory at the Sir William Dunn School, where the quirky antibiotic ingredient in the mould Penicillium notatum was first isolated and turned into a curative drug, and his colleague the biochemist Ernst Chain. But except to his Oxford colleagues, Norman Heatley, whose practical genius was essential to making the drug, is not simply forgotten, he was never known.

Fleming’s great contribution to penicillin is his chance observation in late1928 of the mould’s antibiotic power after a stray spore had grown in a dish of Staphylococcus he had cultured as part of the research he was doing for the chapter of a book on bacteriology. Unfortunately, every attempt he made over the next four years to isolate the active ingredient from the broth used to cultivate the mould was in vain; each time he tried to extract it, it vanished in the process. He was able to take the penicillin from the broth into ether, but could not get it beyond there without it disappearing. In 1929 he published a paper on this biological curiosity. What bit of interest shown by the few other researchers who looked at penicillin in the early 1930s met the same frustrating end and penicillin was essentially forgotten.

In 1936, Florey invited Heatley to join the interdisciplinary team he was assembling at the Dunn School. Heatley had taken a degree in natural sciences from St. John’s College, Cambridge, followed that with a Ph.D. in biochemistry, and was working in the lab of the great Frederick Gowland Hopkins. Heatley’s specialty was microchemical methods, used to estimate the amount of elements in organic substances. At Oxford he first he worked with Chain (also late of Hopkins’ lab), whose innovative approach to a biological problem was to reduce it to its chemical components. In 1938 Chain solved the biochemical riddle surrounding lysozyme, a substance produced by humans, animals, and plants that has a certain antibacterial power, and which coincidentally was also first discovered by Fleming, in 1921. This success led to interest by Chain and Florey in other naturally produced antibiotics and a thorough review of scientific literature by Chain uncovered Fleming’s paper on penicillin. As it happened, there was a sample of Penicillium notatum at the Dunn School and so as a matter of convenience they turned their attention to it.

In September 1939 Heatley took over the growing of the mould in its shallow liquid medium made from protein-rich bullock’s heart. He devised a more effective method for assaying the potency of what was produced and set out to find the best way to grow the most penicillin in the shortest time. He tinkered with the broth in which the mould grew as if making soup for a finicky child, recording in black ink in his lab book the precise details of every ingredient and jotting pertinent notes beside them in red. He added nitrate, sodium, and aluminum salts; he put in glucose (a sugar); he mixed sucrose (another sugar) and lactate (an acid) with a reduction of cow and horse muscle; he tried extracts of malt and various meats; he variously stirred in greater and lesser amounts of phosphate (a salt of phosphoric acid), glycerol (a soluble alcohol), peptone (a protein), oxygen, and carbon dioxide; he even slipped in some Marmite. He noted the effect of each on how the mould grew and behaved, and all he learned was that none of the recipes he concocted was helpful. The addition of yeast a couple of months later halved the growing time to ten days but did not increase the yield.

During a meeting in March 1940, Heatley, by nature modest and quiet, listened as Chain and Florey hotly debated why penicillin vanished. Then, half-apologetically, he put forward what he later called a ‘laughably simple’ idea, although heretofore it had crossed no one’s mind. If penicillin could be extracted from a neutral buffer of water into ether, why shouldn’t it be possible to transfer it out of the ether into water made alkaline by passing the mould broth back and forth between acid and alkaline to purify it, like extracting an egg yoke by slipping it between two broken shells?

Gwyn Macfarlane, an Oxford scientist and the author of biographies of Fleming and Florey, wrote of Heatley that ‘he was a most versatile, ingenious, and skilled laboratory engineer on any scale, large or minute. To his training in biology and biochemistry he could add technical skills of optics, glass- and metalworking, plumbing, carpentry and as much electrical work as was needed in those pre-electronic days. Above all, he could improvise – making use of the most unlikely bits of laboratory or household equipment to do a job with the least possible waste of time.’

From March of 1940 into early 1941, Heatley put all those skills to work as he devised and refined an automated extraction apparatus that W. Heath Robinson would have envied. His first design included a fifteen-foot-long pieced of spiraled glass he had flattened. The final model, whose frame he made after demolishing a discarded oak bookcase from the Bodleian Library, was about six feet high and three feet wide. It consisted of glass tubing mostly made by Heatley, assorted pumps, laboratory bottles, an old doorbell to signal when a bottle was about to become empty or full, coloured warning lights, nozzles, copper cooling coils that he fashioned, and more junctions between the various bottles and tubes than on the track of a complex electric train set. Altogether it might have cost five pounds. The machine was in use until November 1941, but unfortunately none of it has survived. One historian has likened it to Röntgen’s original X-ray tube. In the 1980s, the Science Museum asked Heatley to build a replica, which he found more expensive to assemble. ‘The rubbish dumps aren’t what they were in the 1940s,’ he later said.

Because no British pharmaceutical firm would take up the production of penicillin, in part because of war-related work and the damage wrought from heavy bombing and in part because despite an impressive start penicillin was still unproven, Florey and Heatley traveled to the United States in the summer of 1941 to try to interest a company there in the new drug. In 1943 researchers at Pfizer devised a method for growing penicillin in three dimensions, like brewing beer, which exponentially increased the yield that came from surface culture and led to mass production of the drug.

In 1945, Florey, Chain, and Fleming equally shared the Nobel Prize for Physiology or Medicine ‘for the discovery of penicillin and its curative effect in various infectious diseases’. Florey led the work, Chain’s contribution to discerning penicillin’s chemical make-up was critical, and Fleming gave them a starting point. But the man who figured out how to capture penicillin without it vanishing remained in the background.

Eventually there was a measure of acknowledgment. In 1990, on the fiftieth anniversary of the Dunn School group’s success, the University of Oxford bestowed on Heatley the first honorary Doctor of Medicine degree in its 800-year history. And in 1998 Professor Sir Henry Harris, who succeeded Florey as Professor of Pathology and was Regius Professor of Medicine, linked the four principal scientists responsible for penicillin: ‘Without Fleming, no Chain or Florey; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin.’

Norman Heatley died January 5, 2004, aged 92.

Read more about the discovery of penicillin in Eric Lax's The Mo[u]ld on Doctor Florey's Coat.

Eric Lax is a journalist whose books include the internationally bestseller Woody Allen, A Biography and the award-winning Life and Death on 10 West, an account of the patients, doctors, and nurses on the UCLA bone marrow transplantation ward; both were New York Times Notable Books. He has also written biographies of Paul Newman and Humphrey Bogart. His work has appeared in many magazines and newspapers, including The New York Times Magazine, Vanity Fair, The Atlantic, Life, and Esquire. He lives in Los Angeles with his wife and two sons.

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