Miracle Cure
Page 10
So: another open window. Another accidental contamination. Another brilliant discovery illustrating the power of serendipity.
Or, perhaps not. For decades, historians and scientists have puzzled over the inconsistencies in Fleming’s account. For one thing, the famous window in Fleming’s lab (today preserved as a museum) appears to have rarely, if ever, been opened in order to avoid exactly what Fleming later claimed: the accidental introduction of a contaminant. For another, the timing seems as fuzzy as the fungus itself: The original account has the Petri dishes left alone for more than five weeks, but in 1944 Fleming himself said that the effect was observed after only two. Though Fleming’s chronology puts the discovery of the world-historic Petri dish on September 3, the first day in which he noted it in his lab notebooks is October 30.
Most tellingly of all: If the Penicillium mold had appeared after the staph colonies were well established, they would have killed it long before it could produce penicillin in the first place. Fleming could not, of course, have known this, but the way penicillin kills or degrades staphylococci is by disrupting the mechanism the bacterium uses to build new walls during the process of cell division—which means that it works only when the bacteria are dividing.* Unless the mold is present before the staph, no ring of bacterial death.
This doesn’t mean that Fleming was fraudulent, or even forgetful, either in his account of the discovery of lysozyme or of penicillin. The most appealing explanation for the discrepancies between either account and, well, logic, is something else: playfulness.
Fleming grew up in a family that was notoriously fond of cards, table tennis, and quizzes. As an adult, he was an avid player of croquet and snooker, and a skilled rifle shot (he was originally recruited to St. Mary’s as a shooter for the hospital’s famously competitive sports teams). As a golfer, he far preferred what might be called creative versions of the game, up to and including using his putter as a pool cue. He painted, too; not well, but certainly inventively: When he was a young researcher at St. Mary’s, Fleming regularly created images—Madonna and Child; the logo of St. Mary’s; the Union Jack—on Petri dishes, using agar as the canvas and microorganisms that turned different colors as they grew as pigments. (It’s worth noting that this kind of “painting” demanded an almost terrifying level of both bacteriological knowledge—which ones turn red, which green, and when—and hand-eye coordination.) One of his biographers observed: “Fleming’s natural level was indeed play. . . . ‘I play with microbes’—his often repeated description of his work—was literally true. Most of his research was a game to him and indeed most of his enjoyment came from games of all kinds.”
But while Fleming loved to play with microbes, he was almost completely at sea when it came to human interaction: a terrible conversationalist and a worse lecturer. He was painfully shy, and had no interest in discussing either his methods or results, which is why it’s at least plausible that Fleming’s penchant for games, combined with his natural reticence, persuaded him to cast the lysozyme discovery as if it had been the equivalent of drawing a winning hand at bridge.
Understanding why he would trot out such a similar story for the far more important discovery of penicillin requires some additional context. The first, and most important, fact about the discovery is that hardly anything about it was documented at the time. Six months would pass before Fleming published his results in 1929, and penicillin would remain at best a novelty, at worst a dead end, for another decade. By the time the magnitude of the discovery came to light, it’s certainly possible that the details had faded in Fleming’s memory, or that he recalled a sequence of events reminiscent of his earlier discovery without any intention to deceive. The debate about his reasoning (if any) and motives (ditto) continues, with no resolution in sight.
This wouldn’t be very important except for the significant matter of credit, which, as we shall see, would become a very thorny issue indeed. Insofar as any one person is associated with the discovery of penicillin—of antibiotics generally—in the public consciousness, it’s likely to be Alexander Fleming. It was considerably easier for Fleming to become the first hero of the antibiotic age if his great discovery were understood to be one he himself recognized immediately, rather than one about which he was mistaken—which was apparently the case, at least for a few months. The story that better fits the facts, one that was persuasively argued by the physiologist Robert Scott Root-Bernstein, is that Fleming hadn’t been doing a staph experiment at all; instead of testing a number of different pathogens, he was actually observing a number of different fungi. He was, therefore, surprised by the accidental introduction of the staph colonies, and not the other way around.
Which leaves unanswered the experiment’s goal, about which Fleming was famously unhelpful. Experiments need hypotheses, after all. If his goal was to observe staph colonies under different conditions, what were they? If, instead, his objective was something different, the problem vanishes. Root-Bernstein’s answer? Fleming was seeking a new source for lysozyme.
In 1928, lysozyme was still Fleming’s only notable discovery; even after he had become world famous, it remained so important to him that he felt obliged to observe, in his Nobel Lecture in 1945, that “Penicillin was not the first antibiotic I happened to discover. In 1922, I described lysozyme, a powerful antibacterial ferment which had a most extraordinary lytic [i.e., destructive] effect on some bacteria.” And molds were an extremely promising source for antibacterial compounds like lysozyme. As early as 1876, John Tyndall described the effects of the mold: “On the 13th [December 13, 1875] a thick blanket of Penicillium” that had formed on meat “assumed a light brown colour, as if by a faint admixture of clay . . . the slime of dead or dormant Bacteria, the cause of their quiescence being the blanket of Penicillium. I found no active life in this tube, while all the others swarmed with Bacteria.” Joseph Lister himself had noted that bacteria grown in samples that included molds—formally, the one known as P. glaucum—failed to grow. It is suggestive that Fleming’s original notes show that he thought the original bacteria-inhibiting fungus was P. rubrum, not, as the mycologist Charles Thorn later showed, P. notatum. This is a lot easier to explain if Fleming was testing a number of different molds, in an ongoing search for something he knew existed—lysozyme—rather than something never before seen. He had been working diligently since 1922 examining mucus, sputum, blood, plasma, eggs, snail slime, flowers, and even root vegetables, looking for lysozyme, and the best explanation for the inconsistencies in Fleming’s years-later account is that he initially believed that he had found, in the Penicillium mold, not a new antibacterial compound, but an old one.
However dubious his later recollections of the discovery, Fleming deserves enormous credit for recognizing the potential of the compound he first called “mould juice” and, even more, for the experiments that followed. He and his assistant, Stuart Craddock, became penicillin farmers, cultivating crop after crop of Penicillium, and fertilizing them with protein from the heart of a bull. With sufficient quantities to begin testing, they established where the juice was effective—it killed not just staphylococci, but also streptococci, and a number of other bacteria—and where not—typhus, for example, was immune to it. And they established that it was harmless to nonbacterial cells. Though it would be more than thirty years before the mechanism was understood, the reasons for penicillin’s effectiveness against some, but not all, bacteria (and its lack of toxicity toward animal cells) were the same.
Since 1884, biologists had known that some varieties of bacteria stained a distinctive color when exposed to certain dyes, usually gentian violet. Such bacteria were named Gram-positive, for Hans Christian Gram, the Danish biologist who had discovered the phenomenon; those that didn’t take the stain were, predictably enough, Gram-negative.
When bacteria reproduce, they behave like a water balloon with a string tied around the middle: The original cell divides in half, while the cell wall is stre
tched and twisted. Penicillin (and related compounds) chemically weakens the cell walls of the bacteria as it splits—this is why penicillin only acts on bacteria when they’re dividing—but only for Gram-positive bacteria that are unprotected by the lipopolysaccharide outer membrane: staph and strep, but not typhus.* And not animal cells, which have membranes but not walls, and are therefore safe from the actions of penicillin.
Fleming and Craddock could demonstrate these facts empirically without knowing their underlying mechanisms (Fleming, in particular, was convinced that the compound was, like lysozyme, an enzyme). They could purify the “mould juice” and distill it, though not to the point that they were able to remove an unpredictable number of toxic impurities, nor did their fluids ever reach a concentration of more than 1 percent. They could even test it on a sinus infection afflicting Craddock. Unaccountably, though, Fleming never tried it on an infected animal. In the words of another researcher, “All Fleming had to do to demonstrate the curative effect of penicillin was to inject .5 ml of his culture fluid in to a 20 g mouse infected with a few streptococci or pneumococci. . . . He did not perform this obvious experiment for the simple reason that he did not think of it.”
One possible reason for the failure to test the fluid on a test animal was the difficulty of working with it; nothing Fleming and Craddock did could solve the problem of penicillin’s instability: Within days, sometimes hours, the stuff, evaporated now into syrup, would lose its effectiveness. As a result, though Fleming would return to penicillin research occasionally over the following three years, he actually spent more time during the 1930s on lysozyme. As late as 1940 he wrote of penicillin, “The trouble of making it” even as a local antiseptic “seemed not worthwhile.” He had run up against the wall separating bacteriology from biochemistry, and St. Mary’s had no one with the training needed to hurdle it. Craddock later recalled that “we knew very little when we began” using the classic technique of dissolving the compound in a solution of acetone (sometimes ether) and allowing it to evaporate. “We knew just a little more when we had finished.”*
St. Mary’s deficiency in well-educated chemists was both absolute and relative, especially as compared to Germany. Because German bacteriological research was largely taking place in industrial chemistry laboratories, the level of expertise in processes that occurred at the molecular level was almost unimaginably high. St. Mary’s Inoculation Department was probably Britain’s most sophisticated and successful bacteriological research facility; in May 1932, the Dean of St. Mary’s, Sir Charles Wilson (later Lord Moran) appealed to England’s greatest newspaper mogul, Lord Beaverbrook, asking for the £100,000 needed to build St. Mary’s into a world-class institution. Beaverbrook did come through with a generous contribution, around £60,000, but that was probably less than Klarer and Mietzsch spent just producing test compounds for Gerhard Domagk. Competing with I. G. Farben with nothing but donations from Britain’s aristocrats was a bit like a prep school taking the field against the New York Yankees.
The German dye conglomerates were even able to transform physicians into adequate chemists; in the case of Paul Ehrlich, brilliant ones. It was no accident that the argument at the core of Ehrlich’s 1908 Nobel Lecture supposed that the future of microbiology would be chemical rather than observational. For decades few outside Germany listened.
Or, if they did, they did not understand. Almroth Wright, despite his very impressive skills, was poorly equipped to appreciate the importance of chemical analysis and synthesis. Worse, Wright’s conviction that any successful attack on bacterial pathogens would emerge from the immune system rendered him uninterested in hiring competent chemists. In consequence, when Domagk’s sulfa drugs ignited a revolution in medicine in 1934, Fleming’s 1929 paper “On the Antibacterial Action of Cultures of a Penicillium” was all that existed to record his most important contribution to humanity’s war on infectious disease.
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At his death in March 1902, Cecil John Rhodes, the English-born founder of the British South Africa Company, was one of the wealthiest and most celebrated men in the world. He had built a hugely successful business empire—among other things, he founded De Beers Consolidated Mines, then and now the world’s largest diamond mining concern—alongside one of the more traditional sort: the eponymous colony, later independent country, he christened Rhodesia. However, since Rhodesia was renamed Zimbabwe* in 1980 by an administration that found his brand of colonialism more than a little offensive, the Rhodes name lives on today only in institutions founded after his death: Rhodes University in South Africa, and, of course, the Rhodes Scholarships.
The scholarship, which funds two or three years of study at one of the University of Oxford’s residential colleges, is awarded annually to college graduates from current and former British colonies, the United States, and—when world wars don’t intervene—Germany. As of this writing, there have been 7,600 Rhodes Scholars, including dozens of men and women who are even more celebrated than their benefactor: Nobel Prize winners, generals, a few professional athletes, cabinet members, senators, governors, Canadian and Australian prime ministers, and even one U.S. president. It’s a close call which of them has had the greatest impact on history, but there’s little doubt about the first Rhodes Scholar to change the world, a physician who departed Australia for the journey that brought him to Magdalen College in January 1922. His name was Howard Florey.
Florey was then twenty-three years old, the youngest of five children born in Adelaide to a first-generation Australian mother and an English émigré father. He had excelled at both St. Peter’s Collegiate School and at the University of Adelaide in every academic subject except math,* and at an exhausting number of athletic pursuits, including tennis, cricket, and football. His father’s death in 1918, while Florey was studying for his medical degree, freed him to apply for, and accept, the scholarship that brought him and sixty-one others to Oxford,* a freshly minted MD ready to begin his studies at the university’s Department of Pathology.
Pathology—broadly speaking, the study of the causes of disease—was, for obvious reasons, a young discipline in 1922, no older than the discoveries of Koch and Pasteur fifty years before. Oxford had started teaching it as a course in 1894, and achieved departmental status only in 1901. The same year Florey arrived in Oxford, the pathology department received a gift in the amount of £100,000 from the trustees of the estate of Sir William Dunn, a Scottish merchant banker and politician who had, like Cecil Rhodes himself, made a fortune in nineteenth-century South Africa. Though the planning and construction of the Sir William Dunn School of Pathology took four years—it wouldn’t open its doors until 1927—Florey’s timing could scarcely have been better.
In 1923, the young Australian earned First-Class Honours from the School of Physiology and the Francis Gotch Medal awarded to the department’s most promising researcher. In his notebook of that year, the secretary of the Rhodes Trust, Sir Francis Wylie, described Florey as “a first-rate man—ranks with our best.” Wylie wasn’t the only one to recognize his talent. One of Florey’s instructors, Sir Charles Sherrington, nominated him for the John Lucas Walker Studentship at Cambridge’s Gonville and Caius College in 1923, which paid a stipend of £300 a year—around £15,000, or $24,000, today—plus another £200 for equipment.
Florey’s second year in England was productive. He published four papers on a variety of topics, served as medical officer for an Arctic expedition, and, despite what even Florey himself recognized as a less than appealing personality—in 1923, he described himself in a letter to his future wife, Ethel Reed, as “developing into a rather nasty product”—even acquired friends; one of them, Charles Sutherland Elton, would become one of the founders of modern population ecology. He had found a mentor in Sherrington, who wasn’t just professor of physiology at Oxford, but, in 1923, president of the Royal Society, the world’s first and most distinguished scientific association, which meant that his endorsement was
about as good as it got for an ambitious young researcher.*
During his third year he made his first connection with the Rockefeller Foundation.
Established in 1913 by the Rockefeller family “to promote the well-being of humanity throughout the world,” in 1923 the foundation was the world’s largest philanthropic enterprise, with a special interest in medicine and health. It had already established the world’s first School of Public Health at Johns Hopkins University, and a dozen more public health universities around the world, working to eradicate parasitical diseases like malaria and yellow fever.
There were a number of reasons behind the decision of the world’s wealthiest family to embark on a crusade to give away millions of dollars. One was surely to repair some serious image problems. After decades of building the Standard Oil trusts, and accusations of brutal competitive tactics in order to corner the entire oil industry, John D. Rockefeller, Sr., was not the most admired man in America. Well-meaning (and well-publicized) philanthropy could reverse some of this, but even there, the path was fraught. The behavioral and social sciences, including anything that touched on the nature of industrial relations, were strictly forbidden, especially after the 1914 Ludlow strike—better known as the Ludlow Massacre—in which dozens of miners and their families were killed at the Colorado mine owned by John D. Rockefeller, Jr. Pure science was the ticket: the purer, the better.
The really novel aspect of the foundation, though, was how the money was disbursed: Rockefeller, who had neither the time nor the inclination to decide on the foundation’s grantees (and in any case his involvement was widely regarded as the next thing to poisonous), wanted experts doing the selection. Scientists would recommend other scientists, the best and the brightest that could be found. One of the foundation’s executives, Wickliffe Rose, spent nearly a year in Europe asking the continent’s most prominent researchers for nominees that might deserve grants from the foundation’s International Education Board in order to—his words—“make the peaks higher” and let the results flow down the mountain to everyone else.* So-called circuit riders of the Rockefeller Foundation traveled the world, checkbook in hand, looking to identify the “future leaders in science,” and both Cambridge and Oxford were regular stops on their journeys.