The Benefactor

How are scientific discoveries made? By geniuses, thinks the public. By great men, say historians of science. By giving us enough money, scientists tell their governments. Scientific discovery is evidently a dimly understood process. The new biography of Alexander Fleming by Gwyn Macfarlane sheds some unusual light on the fog. One reason for the prevailing lack of understanding is that the canons of writing in professional scientific journals – the ‘scientific literature’ – enforce a style of reporting that is profoundly anti-historical. They forbid reference to person, place or motive, and strongly discourage descriptions of chronological action. As a record of what a historian needs to know, the scientific literature is usually of little help. Because the deliberately impersonal voice of scientific communication conceals the real details of how an experiment was conceived, only by word of mouth within the scientific community does news flow as to who deserves the real credit. This grapevine, however, is not a great deal more accurate than any other system of organised gossip. Despite the importance to scientists of receiving due recognition for their discoveries, the prize distribution system is sometimes surprisingly crude and inaccurate. Credit tends to gravitate to the senior scientists because it is they who sit on the grant and prize committees and they tend to assume the lab chief deserves credit for what comes out of his laboratory. The Nobel Prize for the discovery of insulin went to John Macleod and Frederick Banting, whereas it was Banting and Charles Best who did the critical experiments, and James Collip who extracted the insulin; Macleod was the lab chief.

Since even scientists themselves have difficulty in accurately assigning credit for discoveries, how can historians hope to do better, let alone understand the phenomenon? Only if the historian is skilled and lucky enough to gain access to the raw laboratory data, or to interview the participants, are the real mechanics of discovery likely to come into focus. Only by supplementing the highly stylised account in the scientific literature can a historian hope to learn the true genesis of a discovery. Everyone knows, for example, that the discovery of insulin, one of the major advances of the century, was made when Banting and Best discovered how to keep diabetic dogs alive with extracts of pancreas. An excellent recent study by Michael Bliss,* a historian at the University of Toronto, establishes that a. the dogs were probably kept alive because Banting, in trying to make them diabetic, failed to remove their own pancreases entirely; b. Banting and Best did little that hadn’t already been tried twenty years before, which was why they weren’t awarded a patent; c. their published results do not tally with the raw data in their notebooks; d. Banting was guided in his experiments by a wholly erroneous theory he had developed; and e. what opened the gateway to their discovery was the luck of looking for insulin at a time and place where the right biochemical methods for extracting the hormone had at last become available. The interest of this analysis is its implicit demonstration that eureka-style insights by individuals are, at least in this case, a rather minor ingredient of discovery. The context of discovery is critical. Banting and Best happened to have in Collip the help of a very good biochemist. Though Macleod ended up with more of the credit than he deserved, he played an essential role in making Banting and Best repeat and improve their experiments. Had they failed, others would certainly have discovered insulin in time, probably within a few years. Granted a certain stage of development in knowledge of the body’s physiology and biochemistry, the discovery of insulin was inevitable.

What Bliss has done for insulin, Gwyn Macfarlane does for penicillin in this excellent new biography of Alexander Fleming. Macfarlane, an emeritus professor of clinical pathology at Oxford, brings exact professional knowledge and an easy writing style to his task. He starts with the popular account of the discovery of penicillin: that a strange mould colonised a plate of bacteria Fleming was culturing, and that, noticing the bacteria around the mould had died, Fleming divined the bacteria-killing properties of the penicillin it produced. All this is true, yet it is the smallest part of what really happened. Macfarlane’s analysis, like Bliss’s of insulin, focuses attention away from the individual scientist toward the rich texture of the discovery’s context.

Macfarlane became interested in Fleming through writing the biography of the man who in a truer sense discovered penicillin – Howard Florey. True, Fleming extracted a bacteria-killing substance from his mould. But he didn’t put it to clinical use because he concluded, erroneously, that it couldn’t possibly work in the human body. Moreover he was not the first to observe bacteria-inhibiting substances in moulds. He was merely one in a quite long line of researchers who stumbled across antibiotic action in nature and failed to turn it into a weapon against diseases. Indeed others even tried to use mould extracts to treat disease but failed because they used strains of mould that were feeble producers of antibiotic. Even Joseph Lister, the discoverer of antisepsis, tried treating patients with an extract of a penicillin-family mould in the 1870s.

Florey, a considerably more capable scientist than Fleming, undertook a systematic search for anti-bacterial agents. With the help of an excellent biochemist, Ernst Chain, he discovered that injection of penicillin directly into the bloodstream of animals had what then seemed a miraculous effect on bacteria. If Fleming had injected a thimbleful of his extract into a sick mouse in 1929, he would have seen the same result. Despite his interest in wounds, infection, and anti-bacterial agents, he failed to do the obvious experiment. History had to wait 11 years, until 1940, for Florey to arrive independently at the same point and then proceed to the next step. Surprisingly enough, that was far from being the final step necessary to make penicillin a household word. Despite the wartime urgency of finding better ways to treat sick soldiers, no pharmaceutical company in England or the United States was willing to invest in producing penicillin until Florey and Chain had proved its efficacy in a clinical trial – a test on humans, not animals. But without much larger quantities of penicillin than they had, the Oxford researchers could not conduct a clinical trial. Borrowing old book-racks from the Bodleian to hold his vats, Florey turned his laboratory into a semi-industrial-scale operation for producing penicillin. Clinical trials established its spectacular results, and American pharmaceutical houses started producing it in bulk.

Fleming discovered penicillin as a laboratory curiosity: Florey and Chain discovered penicillin as an antibiotic for curing human bacterial diseases. The discovery is similar to that of insulin, in that its first step – noting the effect of the substance – had been taken several times before the next step was managed: that of knowing enough chemistry to extract useful quantities of the agent. The critical factor in the discovery was the subtle, hardly visible feat of doing the experiment at the right time and place. Penicillin therapy would certainly have been discovered sooner or later. Through the diligence of Florey and Chain it emerged sooner than it might otherwise have done. But from a historical perspective the prime ingredients of the discovery probably lay not in individuals but in certain antecedent steps such as extraction techniques, and the invention of chemical systemic agents such as sulphonamide.

Another important aspect of scientific discovery which is often overlooked, perhaps because it is so hard to define, is that of tradition. Excellent scientists often breed excellence in their students. As has been noticed by Harriet Zuckerman in her study of Nobel Prizewinners, many successful physicists and biologists belong to master-apprentice lineages. Eleven of Ernest Rutherford’s students won Nobel Prizes. That’s partly because he vigorously pushed their candidacy for Nobel Prizes, and it’s also true that able students tend to seek out able teachers. Nonetheless, there is something in a research tradition that is imparted by the personal alchemy of a teacher, whether in the right choice of problems to tackle, or perhaps simply in the confidence that they can be tackled. Fleming certainly lacked the advantage of a great teacher. Sir Almroth Wright, Fleming’s mentor at St Mary’s Hospital, was Shaw’s model for Sir Colenso Rigeon in The Doctor’s Dilemma. He was less admired by his professional colleagues, among whom he was known as Sir Almost Right. Though he did useful work on vaccines, Wright’s conception of experimental method was seriously flawed and, to the extent that Fleming was influenced by it, may have contributed to Fleming’s erroneous inference about the limitations of penicillin. Florey, on the other hand, was trained by the distinguished physiologist Charles Sherrington. That difference alone goes a long way to explaining why the therapeutic effect of penicillin was discovered in Oxford, not in London.

Another important ingredient of the discovery is harder to explain, and that is Fleming’s mould. It was a very rare strain of Penicillium notatum. It also happened to be an excellent producer of penicillin. Fleming distributed it widely, and Florey, when he wanted to test it, found that a colleague down the hallway had it in stock. The mould was too rare to drift in through the window, as Fleming would sometimes suggest: probably it came from the collection of a researcher who worked on moulds in the room below Fleming’s. Fleming’s observation of the mould, however, is an event packed with so many improbabilities that, but for the contrary truth, it clearly could not have happened. The mould will only inhibit bacteria on a plate if it has grown there before them. The reason is that penicillin deranges growing bacterial cells, not adult ones. Building on the work of an earlier biographer, Ronald Hare, Macfarlane notes that a stray spore of the rare mould must have alighted on a plate which Fleming had seeded with bacteria but for some reason had chosen not to incubate before leaving on holiday. During his absence, the London weather was first rather cool, allowing the mould to grow, then very hot, providing enough heat for the unincubated bacteria to grow. On his return, Fleming glanced at the plate, saw nothing, and dunked it with others on his desk into a shallow tray of disinfectant. Wishing to show a few of the plates to a chance visitor, he reached for some at random, and picked a plate which happened to have avoided destruction in the disinfectant. Looking at it a second time, he saw the ring of dying bacteria around the mould. Antibiotics would have had to be discovered at some time, and once the first had been found, screening programmes would eventually have tested Fleming’s strain if Fleming had not. But that does not diminish the oddness of the circumstances that prompted his discovery, or the experience that enabled him to take advantage of it.

The Nobel selectors, getting a complex pattern of credit right for a change, awarded the 1945 medicine prize to Fleming, Florey and Chain. But for the rest of the world, its benefactor was Fleming. In every country Fleming travelled to, he was met by cheering crowds and people who would tearfully thank him for saving their lives or those of a relative. He was received by General de Gaulle, and five times by the Pope. The researchers at Oxford were chagrined at being left so completely out of the public limelight. Macfarlane harumphs about the power of the press, but his narrative makes crystal clear the reason for the disparity in treatment. Florey, imprisoned by the medical establishment’s attitude of unyielding aloofness, refused to talk to journalists: ‘My policy has been never to interview the press or allow them to get any information from us even by telephone.’ But St Mary’s Hospital, then dependent on public support, was only too eager to spread the good word about its researcher’s achievement. That Fleming reaped the lion’s share of the credit says little about the power of the press, a lot about the ease with which the press’s behaviour can be shaped. What did Florey expect? That the press would somehow get the true story from his colleagues? But how were even they to be sure of who had done what, when the scientific literature obfuscates the historical record on which allocation of credit should be based.

The press was not the only subject that elicited perverse reflexes from the British medical establishment. Patents also drove it to bizarre extremes of self-defeating behaviour. Chain, whose father was a German industrialist, urged that patents be taken out on the penicillin process, not least because if British firms failed to do so they would find themselves paying royalties to others. Edward Mellanby, the head of the Medical Research Council, told Chain that patenting was entirely unethical, and that if Chain persisted in ‘money-grubbing’ he would have no scientific future in Britain. Chain gave up, and everything happened exactly as he had predicted. When British pharmaceutical companies started large-scale production of penicillin after the Second World War, they had to pay royalties to the American firms and individuals who had locked up patents on the British invention. The Medical Research Council has an outstanding record as a patron of basic research, yet the lesson of the penicillin patent disaster was not really learned. The technique of making monoclonal antibodies, invented in its Cambridge laboratory in 1975, is about to revolutionise the diagnosis and possibly the treatment of many diseases, including cancer. But once again, no patents were applied for. The reasons for the omission were different, but the result was the same.

Both Fleming and the discovery of penicillin have been extensively mythologised. The strength of Macfarlane’s book is the way it holds Fleming resolutely in focus, neither denigrating him nor exaggerating his achievement. Such objectivity is hard to attain. Its value is that it shows the reader how discoveries are really made: not by lone-acting heroes but by a community of researchers who build on each other’s work and correct each other’s oversights; not necessarily by geniuses or giants, but by those who persevere and try the right experiment at the right time; not by flashes of insight but through the steady progress of an army of researchers who in time will pick a field clean of whatever it holds. Macfarlane’s book is a fine vignette both of Fleming and of the complex process by which secrets are prized out of the retentive substance of nature.