What did Cardinal Richelieu, Heinrich Heine, Frédéric Chopin, Anton Chekhov, Franz Kafka, George Orwell, and Eleanor Roosevelt have in common? They all died of tuberculosis because the treatments available until about fifty years ago probably did little to prolong sufferers’ lives. Ryan’s story of the discovery of the antibiotics and other agents used against tuberculosis makes as exciting reading as Paul de Kruif’s Microbe Hunters, which must have lured more idealistic young people into medical research than any other book ever written. In earlier times a clean, mild climate was often prescribed, but Chopin wrote ruefully from his villa in Mallorca:
I have been sick as a dog the last two weeks; I caught cold in spite of 18 degrees C. of heat, roses, oranges, palms, figs and three most famous doctors on the island. One sniffed at what I spat up, the second tapped where I spat it from, the third poked about and listened how I spat it. One said I had died, the second that I am dying, the third that I shall die…. All this has affected the “Preludes” and God knows when you will get them.
Perhaps the common fear of consumption was the source of the German Romantic poets’ preoccupation with early death, which Schubert set to music in his Winterreise, with tears streaming down his cheeks. Later in the century, both Verdi’s opera La Traviata and Puccini’s La Bohème end with the heroine’s death from consumption. In her recent book Living in the Shadow of Death, Sheila Rothman has reconstructed the tragic lives of consumptives in nineteenth-century New England from collections of their letters. The disease gradually drained all energy from Deborah Fiske, an enterprising and intelligent young woman, until she could barely manage even to give directions to the servants looking after her household. She died in 1844, aged thirty-eight. Since consumption was not regarded as contagious, Deborah Fiske never seems to have worried that her husband might catch it, which of course he did.
Some patients, Ms. Rothman tells us, sought better health in California, Arizona, or Florida, where they were often exploited by ruthless employers or cheated by the people who ran bogus sanatoriums. Jeffries Wyman, a New Englander whose forebears had settled in Massachusetts before the arrival of the Mayflower, contracted tuberculosis in 1833 as a medical student at Harvard, but he did not succumb to the disease until he had reached his sixties. He combined his duties of professor of anatomy at Harvard with winter expeditions of biological exploration in Florida’s Everglades which restored his health. In 1871 he wrote to his brother: “I have not been sick a day since leaving Hibernia, have slept with and without the tent, have gained strength, have taken long rows in the boat once of nine and twice of ten miles each without fatigue. My cough has not gone but is greatly diminished and my appetite is always good.” However, in 1872 he reported that he had had several hemorrhages and that “the trouble is there where it has been and I see no reason why I should ever be free from it again.”
Except for peaks during the Crimean War and the First and the Second World Wars, mortality from tuberculosis in Britain declined throughout the second half of the nineteenth and the first half of this century; by 1947 it had fallen to about one eighth of what it is estimated to have been in 1800, even in the absence of any effective treatment. We do not know exactly when the decline started; it is generally attributed to improving standards of living, but these actually deteriorated during much of the nineteenth century as a result of the movement of large numbers of people from the country to overcrowded slums in the new industrial towns.
Natural selection may have played its part in the decline: the disease may have killed those genetically least resistant before they reached reproductive age, so that a gradually increasing fraction of the population inherited enough resistance to survive infection. It is sometimes alleged that vaccination and the newly introduced antibiotics and drugs had little effect on the decline of deaths from tuberculosis, which was merely continuing its historic downward trend. In fact the pace of that trend became over fifty times faster and the annual number of new infections declined twice as fast as they had done before they were introduced. In 1935, nearly 70,000 people died from tuberculosis in England and Wales; in 1947, just after antibiotics were introduced, 55,000 died; in 1990 that number was reduced to 330. Similar reductions have been achieved in the United States and other industrialized countries.
This spectacular success inspired ambitious plans to eradicate the disease in underdeveloped countries, where its incidence remains many times larger than in developed ones. With the assistance of the International Union against Tuberculosis and help from the US and other richer countries, some very poor countries in Africa, including Mozambique in the middle of its civil war, developed highly effective national programs for the control of tuberculosis. On the other hand, in 1990 the annual mortality rate for tuberculosis in sub-Saharan Africa was still about 1,500 times greater than that in England. In many African countries the incidence of tuberculosis looked as if it was just beginning to drop when the AIDS epidemic struck. This has been ruinous for all health services, including those for the control of tuberculosis, because AIDS suppresses the natural immune system. In many Asian countries that lack effective programs for controlling their already very high tuberculosis rates, the explosion of the AIDS epidemic could lead to disaster; in Western industrialized countries resistance to antibiotics has recently caused a resurgence of tuberculosis.
Ryan’s book begins with Robert Koch’s announcement on March 24, 1882, to the German Physiological Society in Berlin of his discovery of the rod-shaped tubercle bacilli. Koch detected these tiny, elusive bacteria partly thanks to his invention of a new method of staining, but he might not have spotted them if Carl Zeiss, the founder of the great optical firm in Jena, had not presented him with the first of the newly developed oil immersion lenses, which enormously improved the power of Koch’s microscope. Articles in the New York Tribune and the London Times hailed Koch’s discovery and looked forward to an early vaccine against tuberculosis, but this did not emerge until many years later. The immediate benefit of Koch’s discovery was the final proof that tuberculosis is contagious.1 According to René and Jean Dubos, American doctors still doubted this even ten years afterward,2 but before the end of the century many countries were reducing the spread of the disease by isolating tuberculosis patients in sanatoriums and forbidding spitting in public places.
Early in the century, Albert Calmette, a pupil of Louis Pasteur, and Camille Guérin at Lille discovered that virulent tubercle bacilli from cows lost their deadly sting after being cultured for eleven years in 231 successive solutions that contained ox bile. Animals infected with these attenuated bacilli became immune to tuberculosis. Calmette and Guérin made these bacilli into the vaccine now known as BCG (for Bacilli Calmette-Guérin). They first used it in 1921 on a child whose mother had died of tuberculosis in childbirth, but it came into disrepute in 1930 after 73 out of 249 children vaccinated with it in Lübeck had died. Their deaths were later proved to have been caused by contamination of the vaccine with virulent bacilli. Scandinavian countries therefore resumed BCG vaccination in 1938, but in England doubts lingered on because most of the evidence for the effectiveness of BCG remained anecdotal until 1950, when the Medical Research Council’s Tuberculosis Research Unit began a countrywide trial of its safety and effectiveness.
Of over 16,000 children between fourteen and fifteen and a half years old, half, chosen at random, were vaccinated with BCG and half were left unvaccinated. During the next twenty years 248 of the unvaccinated children and only 62 of the vaccinated ones developed the disease.3 Two trials in the United States, one on twenty-year-old American Indians and the other on infants in Chicago, and another trial in Haiti also proved to be highly effective, but others in the United States, in Puerto Rico, and in Southern India showed little or no evidence that BCG offered protection against tuberculosis. Studies in several other countries showed that between 53 and 74 percent of the people vaccinated did not contract tuberculosis, and a much higher proportion were protected against tubercular meningitis. There is no satisfactory explanation for the contradictory results of the trials, 4 but some researchers now believe that previous infection with common and harmless bacteria related to Mycobacterium tuberculosis rendered many children in Puerto Rico and Southern India immune. In consequence, there was only a small difference in the incidence of tuberculosis between those children who had been vaccinated and those who had not.
Early in this century German chemists were prominent in the fight against infectious diseases. Paul Ehrlich discovered Salvarsan, his “magic bullet” against syphilis in 1910. The next great discovery in Germany, which led to the isolation of sulfanilamide, was made by Gerhard Domagk at Elberfeld in 1935.
In his search for antibacterial agents, Domagk was driven by his memories of World War I As a medical student he worked at a hospital on the Russian front and he could never forget the terrible suffering of the young soldiers infected with gas gangrene. After the war, he took a medical degree, and when he was only thirty-two he was appointed director of research in experimental pathology and bacteriology at the laboratories of the giant chemical firm I.G. Farbenindustrie at Elberfeld, a post which he held for the rest of his working life. The firm asked Domagk to make a wide-ranging survey of chemical agents that could be used against bacterial infections. An Englishman who visited Domagk was shown “enormous laboratories in which they did nothing but take compound after compound and test its ability to deal with infections in animals caused by a variety of organisms.” For several years this work yielded no clear results.
Ryan claims that one of the firm’s chemists, Joseph Klarer, synthesized over six hundred compounds until at last he hit upon the winner, but this is not borne out by Leonard Colebrook’s authoritative memoir of Domagk.5 According to him, two chemists, Fritz Mietsch and Klarer, gave Domagk in 1932 a red compound which they had synthesized several years earlier as a “fast” dye for leather. This was Prontosil, the forerunner of the sulfanilamides. Even though the dye failed to stop the growth of bacteria in cultures, it killed lethal streptococci in animals and brought about miraculous recoveries in some mortally ill human patients.
Domagk did not publish his findings until 1935, when Prontosil had been patented. Within a few weeks of his publication Jacques Tréfouél and his colleagues at the Pasteur Institute in Paris found that the active component in Prontosil was sulfanilamide, a colorless molecule split from the larger molecule of Prontosil, which made the patent worthless.
I had been under the impression that the Hungarian physician Ignaz Semmelweiss had done away with puerperal fever in 1861, when he wrote that midwives and doctors must wash their hands before attending childbirths; but I learned from Ryan’s book that thousands of women still died from it every year in the 1930s. Colebrook recalls the dramatic impact of Domagk’s discovery on mortality from puerperal fever and other infectious diseases. It opened up an immense field for therapeutic advance.
The haemolytic streptococcus [which Prontosil killed] played a major role in the heavy and tragic mortality of puerperal and acute rheumatic fevers, of countless septicaemic conditions resulting from war wounds [and civilian injuries—including burns], as well as of erysipelas (a skin infection) and the numerous acute inflammatory conditions of the respiratory tract and the ear—the latter being chiefly responsible for the immeasurable miseries of deafness….
In England it was quickly found that cerebro-spinal meningitis (which had usually proved fatal) could readily be arrested and cured. Pneumonia, too,—“the captain of the men of death”—was similarly brought under control. And the dreaded venereal disease, gonorrhoea, usually cleared up in a few days.6
The original sulfanilamide was not very effective in curing pneumococcal pneumonia, but a modification, sulphapyridine, introduced in the early Forties, proved highly effective. It cured Winston Churchill’s pneumonia in North Africa in 1943.
On October 26, 1939, some weeks after Germany’s attack on Poland, Domagk received a telegram that he had been awarded the Nobel Prize for Physiology or Medicine. Hitler had forbidden Germans to accept Nobel prizes after the Norwegian Parliament had awarded the peace prize to the imprisoned German pacifist Carl von Ossietzky, even though the prize for medicine is awarded by the Medical Karolinska Institute in Stockholm. Perhaps because Domagk had not indignantly refused the prize as an insult to the Führer, the Gestapo arrived to arrest him, and armed soldiers took him to the town prison for interrogation. He was kept there for a week, fearing for his life. After his release the Gestapo arrested him once more and ordered him to sign a letter declining the prize. In 1947, Domagk was finally able to travel to Stockholm to receive the Nobel medal, but without the accompanying check; the money had been returned to the general funds.
The sulfanilamides failed to kill tubercle bacilli. They also had unpleasant and dangerous side-effects, including vomiting, skin rashes, and damage to the liver, kidneys, and bone marrow. But their discovery stimulated many chemists and microbiologists to search for other antibacterial drugs. One of them was Selman Waksman, who had arrived in the United States in 1910 from a small Jewish town in the Ukraine. By 1939 he was head of a leading laboratory for soil microbiology at Rutgers Agricultural College in New Jersey. His research covered subjects ranging from nitrogen-fixing bacteria and the taxonomy of fungi to the use of human feces for compost. He was aware of reports that some virulent bacteria, including tubercle bacilli, do not survive for long in soil.
According to his memoirs, the outbreak of the Second World War in September 1939 made him switch the work of his laboratory to a search for antibacterial agents produced by micro-organisms in soil. This work bore fruit five years later when Waksman’s graduate student Albert Schatz extracted a compound from the fungus Actinomyces griseus, which stopped the growth of many virulent bacteria, including tubercle bacilli cultured in test tubes. This compound was the new antibiotic, streptomycin.
I could not help being struck by the contrast between Alexander Fleming, the reticent and inhibited Scotsman who discovered penicillin, and the dynamic go-getter Selman Waksman. Fleming found in 1929 that the broth in which he had cultured his mold Penicillium notatum inhibited the growth of the streptococci and staphylococci that infected wounds, and also of the organisms responsible for gonorrhea, meningitis, and diphtheria. The broth was harmless to white blood cells; it could be injected with impunity into mice and rabbits, and the mold itself could be eaten without ill effects. Having carried out these experiments, Fleming unaccountably failed to take the obvious next step—the step that Ernst Chain and Howard Florey were to take eleven years later when they decided to find out whether an injection of Fleming’s broth would protect mice from lethal infection. The spectacular success of their experiment encouraged them to turn their Oxford laboratory into a factory to make enough penicillin for human trials. Fleming could have done all this eleven years earlier.
By contrast, two physicians from the Mayo Clinic, Dr. William H. Feldman and Dr. H. Corwin Hinshaw, maintained regular contact with Waksman throughout his search for antibacterial agents. Within a few weeks of Schatz’s discovery, Waksman sent them ten grams of streptomycin for animal tests. In Feldman’s words:
The results suggested that, despite its many impurities, this new substance was well tolerated at a therapeutic level sufficient to exert a marked suppressive effect on otherwise irreversible tuberculous infection in guinea pigs. However, despite the marked suppressive effect on the pathogenesis of the infection, it was recorded that streptomycin had not destroyed all of the tubercle bacilli in the tissues of the treated animals and that, therefore, under the conditions imposed, the action of the drug was essentially bacteriostatic rather than bacteriocidal [that is, it prevented bacteria from multiplying, but didn’t destroy them].7
On the strength of Feldman and Hinshaw’s experiments with only four guinea pigs, Waksman persuaded the nearby pharmaceutical firm Merck to call a board meeting. At first the board members hesitated to support efforts to isolate and manufacture streptomycin, but the company’s founder, George Merck, joined the meeting, and took the courageous and farsighted decision to put fifty people to work on streptomycin immediately.
Although streptomycin stopped the growth of tubercle bacilli without killing them, it still seemed to bring about spectacular cures of terminally ill patients. In 1945 news of these results prompted the British Medical Research Council to use the limited supplies of streptomycin then available in England for a controlled double-blind clinical trial. Philip d’Arcy Hart, who set up the trial, chose 107 patients with acute pulmonary tuberculosis; in each case doctors had decided that the only possible treatment was bed rest. Fifty-five patients, chosen at random, were treated with the available streptomycin and prescribed bed rest. The other fifty-two simply stayed in bed. At the end of six months four of the treated and fourteen of the untreated had died; the lungs of twenty-eight of the treated and of only four of the untreated had improved.
However, five years later the hopes raised by these results were shattered; by that time thirty-two of the treated and thirty-five of the untreated patients had died. Clearly streptomycin alone was not going to cure tuberculosis; Feldman and Hinshaw had already discovered that tubercle bacilli resistant to streptomycin began to emerge after only four weeks of treatment. Streptomycin also damaged the inner ear, and prolonged treatment with large doses of it could cause deafness. In 1948, a course of streptomycin injections gave George Orwell a remission that enabled him to finish Nineteen Eighty-Four, but he developed such severe allergic reactions against the drug that treatment had to be discontinued after only fifty days. He suffered a relapse and died in January 1950. Still, Waksman received the Nobel Prize in 1952 “for his discovery of streptomycin, the first antibiotic effective against tuberculosis,” a discovery which stimulated the immensely fruitful search for other micro-organisms in soil that secrete antibiotics.
But Albert Schatz, the real discoverer of streptomycin, and the first author listed on the original publications, got no prize. He was the son of poor Jewish farmers in Connecticut and had studied soil microbiology to find ways of increasing the yields on his father’s unproductive farm. He embarked on the search for antibiotics only because Waksman made it a condition of his meager offer of $40 a month to work in his laboratory; but then Schatz threw himself into the research, testing hundreds of different soil micro-organisms for antibacterial activity. After slaving away for three and a half months, Schatz found in the throat of an infected chicken and in a compost heap fungi which stopped the growth of several virulent bacteria, including some known to resist penicillin.
Against the advice of his colleagues, and apparently not on Waksman’s instructions, he then tested the effects of the fungus on tubercle bacilli and was elated to discover that it inhibited their growth in cultures. He next devised a way of extracting the active compound from cultures of the fungus. The discovery was published unglamorously in the Proceedings of the Society for Experimental Biology and Medicine of 1944 under the joint authorship of Schatz and Waksman, but in the subsequent publicity Schatz’s contribution was soon forgotten.
In his rather pedestrian and humorless autobiography,8 Waksman reproduced the text of a lecture he delivered at the Mayo Clinic in October 1994. Announcing the great discovery he declared: “In September 1943, my assistants and I succeeded in isolating in our laboratory an organism that produced an antibiotic…,” when Waksman himself had sat in his office while Schatz toiled away in a basement laboratory. He said not a word in the lecture about Schatz, or about René Dubos or H. Boyd Woodruff, whose earlier discoveries of soil antibiotics that proved too toxic for clinical use had prepared the way for the discovery of streptomycin. Instead, Waksman used throughout the lecture the plural majestatis “We.” The ethics of scientific and medical research have now been elevated to an academic subject, to which an entire new journal is to be devoted, but no one seems to care about what I regard as the First Commandment: “Thou shalt not take the credit for thy junior collaborators’ work,” a commandment whose observance would avoid much injustice and bitterness.
Isolated from one another by the war, but stimulated by Domagk’s discovery of Prontosil, Domagk and other scientists in Europe and the US also searched for a drug that would work against tuberculosis. One was the biochemist Jorgen Lehmann, the son of a Danish professor of theology, who headed the pathology department of Sahlgren’s Hospital in Gothenburg, Sweden. Ryan describes him as an eccentric, imaginative genius who had already made his name showing that dicoumarol—a chemical compound extracted from spoiled sweet clover and marketed under the name warfarin—was an effective anticlotting agent. In 1940, he read a report that salicylic acid, a compound related to but not, as Ryan incorrectly writes, identical to aspirin, makes tubercle bacilli respire—i.e., take in oxygen—faster than normally. This showed that the bacilli ate the compound and that a chemically modified version of it might poison them.
According to Ryan, Lehmann quickly and intuitively perceived the correct modification:
Chance therefore had nothing to do with it. PAS [para-aminosalicylic acid] did not come from the screening of many chemical manipulations of the aspirin molecule. Like a real-life Sherlock Holmes, he had solved the puzzle logically from the facts which were available to him.
Lehmann’s own report in the Lancet showed that he used a more conventional approach.9 At his suggestion, chemists at the Swedish pharmaceutical firm Ferrosan synthesized about fifty different derivatives of salicylic acid, one of which, PAS, inhibited the growth of tubercle bacilli in cultures. In this paper, Lehmann reported that guinea pigs tolerated the compound well and that two tuberculosis patients treated with it showed marked improvement. (Ryan appears to have been told that Lehmann had also submitted a two-page article to Nature, that this was first rejected, but later accepted for publication in the spring of 1946. I could not find this article. The meager results reported in the Lancet article do not tally with the spectacular improvements in several patients which Ryan was told had been achieved by the time of its publication.)
Swedish medical colleagues at first received Lehmann’s discovery with disbelief, but this soon proved unjustified. In 1952, a study by the British Medical Research Council showed that PAS when taken alone was indeed less effective than streptomycin taken alone, but treatment with both almost completely prevented the emergence of streptomycin-resistant strains after prolonged treatment. For the first time tuberculosis could be cured. As the news of the efficacy of PAS against tuberculosis spread, the Ferrosan company vastly increased its production to meet the huge, worldwide demand. Lehmann’s discovery of PAS was just as important as Schatz and Waksman’s of streptomycin, and was made at the same time, even though it was published two years later. Lehmann was yet another scientist unjustly denied the Nobel Prize, for reasons that we shall not know until 2002, when the Nobel files for 1952 will finally be open to inspection.
At Elberfeld, Domagk continued his search for an anti-tuberculosis drug throughout the war, regardless of the town’s destruction by Allied bombers. By 1945 he had found an effective compound called Conteben and traveled around war-ravaged Germany under terrible hardships to convince his skeptical colleagues of its therapeutic value against tuberculosis. The efforts of Domagk and others to improve on Conteben led to the discovery of one of the most potent anti-tubercular drugs yet found: isoniazid.
By the early Fifties, then, there were several powerful anti-TB drugs on the market—conteben, isoniazid, PAS, and streptomycin, but no single one cured all patients because it took many months’ treatment to clear the body of the bacilli, and drug-resistant mutants were liable to emerge much sooner. A combination of drugs offered better hopes. Suppose, for example, the probability of the emergence of a bacillus with its resistance against any one of the drugs were one in a million, then the probability of the emergence of a bacterium with resistance against two drugs in combination would be one in a million million, and against three in combination, one in a million million million. The British Medical Research Council therefore began a long series of trials designed to discover the right combination, and dose, of drugs that would prevent the emergence of resistant strains.10 Another trial, in India, showed no difference between the time needed to cure patients who took the drugs while resting in sanatoriums and those who carried on relatively normal lives at home. These findings led to the gradual closing of the world’s tuberculosis sanatoriums, including those in Davos, the setting of Thomas Mann’s Magic Mountain. They have long been converted into hotels.
The Medical Research Council’s trials were designed according to statistical analyses made by Bradford Hill and, later, by Ian Sutherland; they have been crucial to the near-eradication of tuberculosis in developed and many underdeveloped countries throughout the world. They were the first to evaluate the efficacy of treatments free from human bias and according to rigorous mathematical criteria, and they have helped to transform clinical practice from an art into a science. Ryan fails to appreciate this.
By 1980 the annual incidence of new cases of tuberculosis—not deaths from it—in the Western industrial countries had dropped to about one in ten thousand. Yet only ten years later the Centers for Disease Control in Atlanta, Georgia, warned that tuberculosis was not only reappearing but was out of control in the US. By 1991 there were 4000 new cases of tuberculosis in New York alone. AIDS is believed to be the chief culprit. Many of us, myself included, contracted tuberculosis in childhood, recovered, and have since been immune; but apparently tubercle bacilli survive in our scar tissues for years or even decades, and we are safe only as long as they are kept in check by our immune systems. When AIDS destroys this, the dormant bacilli revive.
Immigration from underdeveloped countries where tuberculosis has never been suppressed is another source of infection. In 1990 the Center for Disease Control reported the incidence of tuberculosis among foreign-born persons in the United States to be thirteen times higher than among native Americans. In a new book, Silent Travelers, Alan M. Kraut writes that the number of active tuberculosis cases in New York City rose from 2,545 in 1989 to 3,673 in 1991. The incidence rose by 56 percent among African-Americans, 52.3 percent among Hispanic residents, and 46.9 percent among Asians, compared to 13.2 percent among native whites.
In the United States as a whole, the incidence rose by nearly 10 percent between 1989 and 1990, but the accompanying graph shows no evidence that new immigrants are largely responsible for these increases.
In London, one in fifty of the homeless has tuberculosis, but this is mainly a consequence of poverty rather than of AIDS. Malnutrition and exposure make the homeless susceptible to infection; sleeping in crowded shelters promotes infection, and the movement of infected people from shelter to shelter causes it to spread.
The bacilli of some recent patients have proved resistant to all commonly used drugs and antibiotics, often because patients failed to comply with the prolonged combined drug regimen11—isoniazid, rifampicin, and pyrazinamide for six months—that is essential for a cure. Others foolishly treat themselves with single anti-tuberculosis drugs that pharmacies in some countries sell over the counter or they are prescribed inadequate drug treatments by incompetent doctors. In the United States, about half the cases of tuberculosis that resist the commonly used drugs can still be cured by special combinations of drugs, but at a cost of about $200,000 for each patient. Stephen E. Weis and others report that drug resistance and relapse among tuberculosis patients are mostly owing to non-compliance with the prescribed drug regimens, and therefore can be drastically reduced by treatment under direct observation by local health departments. In a trial in Tarrant Country, Texas, directly observed therapy reduced the rate of relapse from 20.9 to 5.5 percent and the rate of multidrug-resistant relapse from 6.1 to 0.9 percent even though many of the patients were alcoholics, drug users, homeless, or psychiatric cases.12 Kraut recommends rigorous public health measures to combat the spread of the disease, not just in New York, but throughout the United States. Ryan and others plead for worldwide campaigns.
K. M. Citron at the Brompton Hospital in London has written that “BCG vaccination of the newborn usually protects against serious forms of tuberculosis, is safe and cheap and should be used in developing countries where tuberculosis is most prevalent.”13 Many reports confirm that it prevents both tuberculosis that has disseminated, or spread over several organs, in children, as well as meningitis. Others believe the most important task to be an intensive search for new vaccines that would be effective worldwide for both adults and children. Molecular biologists are trying to make better vaccines by using recombinant DNA technology.
Alexander Pope advised:
Be not the first by whom the new are tried,
Nor yet the last to lay the old aside.
Most doctors in Ryan’s story seem to have paid more attention to the first rather than the second line. The often maligned drug industries come out well. Domagk’s search for active compounds remained fruitless for many years, yet the managers of I. G. Farben continued to put huge resources at his disposal. They made no profit from Prontosil, because the active principle turned out to be a split-product of the dye, or from Conteben, because the victorious Allies confiscated their patent rights. George Merck turned his international patent rights on the manufacture of streptomycin over to Rutgers University, so that any firm could make it if they paid royalties to Rutgers. Ferrosan employed a mere seventy-five people when they took up the synthesis of PAS, which proved cumbersome and uneconomical until one of the company’s chemists invented a quick and cheap method of making it. Its risk paid off. By 1964 it was selling 3000 tons per year.
p class=”initial”>Ryan’s book makes excellent reading because he combines accounts of his characters’ achievements with their personal histories, gleaned from diaries, documents, and interviews with their contemporaries. He reminds us how precarious our lives used to be before the discovery of antibiotics, when a cut finger or a sore throat could be deadly, and he emphasizes that our battle against deadly bacteria can rarely be finally won, because natural selection leads to the multiplication of mutants which can overcome our best defenses.
Micro-organisms that resist antibiotics have become a common problem of many hospitals. Among them are the hemolytic streptococci, which give rise to puerperal fever and wound infections, staphylococci causing boils, and klebsiella, which are responsible for a particularly virulent form of pneumonia. Penicillin-resistant gonorrhea is common in Africa and Southeast Asia and affects about one case in ten in the United Kingdom. In the US, complacency and financial cuts have let the once excellent state and local systems of communicable-disease surveillance crumble, so that new and antibiotic-resistant infections may spread undiagnosed and unreported. The Centers for Disease Control in Atlanta plan to reverse this trend by strengthening surveillance, by opening centers for the discovery of new infections, and by starting a global warning system for disease migration.14 We also need to discover new antibiotics and vaccines all the time, if Ryan’s heroes are not to have battled in vain.
Toward the end of Domagk’s life the biochemist Otto Warburg told him that he deserved monuments in each valley and on every mountain. Domagk replied that no one is interested any longer in diseases that can be cured. Tuberculosis must now be removed from the list of those diseases; it presents a renewed deadly menace to mankind,15 not only in the third world, where it is the leading cause of death, but everywhere.
May 26, 1994
This had already been shown in 1865 by Jean Antoine Villemin who transferred pus from human patients to rabbits which then developed tuberculosis. Comptes Rendues de l’Académie des Sciences 61 (1865), p. 1012. ↩
R.J. Dubos and J. Dubos, The White Plague: Tuberculosis, Man and Society (London: Gollancz, 1953). ↩
Philip d’Arcy Hart and I. Sutherland, “BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and adult life,” in British Medical Journal, Vol. 2 (1977), pp. 293–295. ↩
K.M. Citron, “BCG vaccination against tuberculosis: international perspectives,” in British Medical Journal, Vol. 306 (January 23, 1993), p. 222. ↩
Leonard Colebrook, “Gerhardt Domagk,” Biographical Memoirs of Fellows of the Royal Society, Vol. 10 (1964), pp. 39–50. ↩
Leonard Colebrook, “Gerhardt Domagk,” p. 40. ↩
W.H. Feldman, “Streptomycin: some historical aspects of its development as a chemotherapeutic agent in tuberculosis,” American Review of Tuberculosis, Vol. 69 (1964), pp. 850–868. ↩
Selman Waksman, My Life with Microbes (London: The Scientific Book Club, 1958). ↩
J. Lehmann, “Para-aminosalicylic acid in the treatment of tuberculosis,” Lancet, Vol. 1 (January 5, 1946), pp. 15–16. ↩
See for example British Medical Journal, Vol. 1 (February 19, 1955), pp. 435–445. The Medical Research Council scientists who planned and organized the trials were Philip D’Arcy Hart, Wallace Fox, Marc Daniels, Dennis Mitchison, and Ian Sutherland. The trial reported in this paper was carried out with 558 patients in fifty-one hospitals of the National Health Service. ↩
Between 1986 and 1990, 46.4 percent of tuberculosis patients in New York failed to complete the prescribed six months of chemotherapy. ↩
See “The Effect of Directly Observed Therapy on Rates of Drug Resistance and Relapse in Tuberculosis,” New England Journal of Medicine (April 28, 1994), pp. 1179–1184. The same issue also contains a report on a workshop recently held at Rockefeller University on pathogenic bacteria that are resistant to multiple antibiotics, with recommendations for preventing the emergence of such bacteria. ↩
Citron, “BCG vaccination against tuberculosis,” p. 222. ↩
For a full discussion of resistance to antibiotics see Science, April 15, 1994, pp. 360–393. ↩
B. R. Bloom and C. J. L. Murray, “Tuberculosis: Commentary on a reemergent killer,” Science, No. 257 (1992), pp. 1055–1064. This is an excellent, authoritative review on the present situation in the US and elsewhere. ↩