by Isaac Asimov
In this way, individual bacteria give rise to colonies which can then be cultured separately and tested to see what disease they produce in an experimental animal. The technique not only made it possible to identify a given infection but also permitted experiments with various possible treatments to kill specific bacteria.
With his new techniques, Koch isolated a bacillus that causes anthrax and, in 1882, another that causes tuberculosis. In 1884, he also isolated the bacterium that causes cholera. Others followed in Koch’s path. In 1883, for instance, the German pathologist Edwin Klebs isolated the bacterium that causes diphtheria. In 1905, Koch received the Nobel Prize in medicine and physiology.
Chemotherapy
Once bacteria had been identified, the next task was to find drugs that would kill a bacterium without killing the patient as well. To such a search, the German physician and bacteriologist Paul Ehrlich, who had worked with Koch, now addressed himself. He thought of the task as looking for a “magic bullet” which would not harm the body but strike only the bacteria.
Ehrlich was interested in dyes that stain bacteria—an area that had an important relationship to cell research. The cell in its natural state is colorless and transparent so that little detail within it could be seen. Early microscopists had tried to use dyes to color the cells, but it was only after Perkin’s discovery of aniline dyes (see chapter 11) that the technique became practical. Though Ehrlich was not the first to use synthetic dyes in staining, he worked out the techniques in detail in the late 1870s and thus led the way to Flemming’s study of mitosis and Feulgen’s study of DNA in the chromosomes (see chapter 13).
But Ehrlich had other game in mind, too. He turned to these dyes as possible bactericides. A stain that reacted with bacteria more strongly than with other cells might well kill the bacteria, even when it was injected into the blood in a concentration low enough not to harm the cells of the patient. By 1907, Ehrlich had discovered a dye, called trypan red, which would stain trypanosomes, the organisms responsible for the dreaded African sleeping sickness, transmitted via the tsetse fly. Trypan red, when injected in the blood in proper doses, can kill trypanosomes without killing the patient.
Ehrlich was not satisfied: he wanted a surer kill of the microorganisms. Assuming that the toxic part of the trypan-red molecule was the azo combination—that is, a pair of nitrogen atoms (–N=N–)—he wondered what a similar combination of arsenic atoms (–As=As–) might accomplish. Arsenic is chemically similar to nitrogen but much more toxic. Ehrlich began to test arsenic compounds one after the other almost indiscriminately, numbering them methodically as he went. In 1909, a Japanese student of Ehrlich’s, Sahachiro Hata, tested compound 606, which had failed against the trypanosomes, on the bacterium that causes syphilis. It proved deadly against this microbe (called a spirochete because it is spiral-shaped).
At once Ehrlich realized he had stumbled on something more important than a cure for trypanosomiasis, which after all was a limited disease confined to the tropics. Syphilis had been a hidden scourge of Europe for more than 400 years, ever since Columbus’s time. (Columbus’s men are supposed to have brought it back from the Caribbean Indians; in return, Europe donated smallpox to the Indians.) Not only was there no cure for syphilis, but prudishness had clothed the disease in a curtain of silence that let it spread unchecked.
Ehrlich devoted the rest of his life (he died in 1915) to the attempt to combat syphilis with compound 606, or, as he called it, Salvarsan (“safe arsenic”; its chemical name is arsphenamine). It could cure the disease, but its use was not without risk, and Ehrlich had to bully hospitals into using it correctly.
With Ehrlich, a new phase of chemotherapy came into being. Pharmacology, the study of the action of chemicals other than foods (that is “drugs”) upon organisms, finally came into its own as a twentieth-century adjunct of medicine. Arsphenamine was the first synthetic drug, as opposed to the plant remedies such as quinine or the mineral remedies of Paracelsus and those who imitated him.
SULFA DRUGS
Naturally, the hope at once arose that every disease might be fought with a little tailored antidote all its own. But for a quarter of a century after Ehrlich’s discovery, the concocters of new drugs had little luck. About the only success of any sort was the synthesis by German chemists of plasmochin in 1924 and of atabrine in 1930; they could be used as substitutes for quinine against malaria. (These drugs were very helpful to Western troops in jungle areas during the Second World War, when the Japanese held Java, the source of the world supply of quinine, which, like rubber, had moved from South America to Southeast Asia.)
In 1932 came a breakthrough. A German chemist named Gerhard Domagk had been injecting various dyes into infected mice. He tried a new red dye called Prontosil on mice infected with the deadly hemolytic streptococcus. The mice survived! He used it on his own daughter, who was dying of streptococcal blood poisoning. She survived also. Within three years, Prontosil had gained worldwide renown as a drug that could stop the strep infection in man.
Oddly, Prontosil did not kill streptococci in the test tube—only in the body. At the Pasteur Institute in Paris, Jacques Trefouel and his co-workers decided that the body must change Prontosil into some other substance that takes effect on the bacteria. They proceeded to break down Prontosil to the effective fragment, named sulfanilamide. This compound had been synthesized in 1908, reported perfunctorily, and forgotten. Sulfanilamide’s structure is:
It was the first of the “wonder drugs.” One after another bacterium fell before it. Chemists found that, by substituting various groups for one of the hydrogen atoms on the sulfur-containing group, they could obtain a series of compounds, each of which had slightly different antibacterial properties. Sulfapyridine was introduced in 1937; sulfathiazole, in 1939; and sulfadiazine, in 1941. Physicians now could choose from a whole platoon of sulfa drugs for various infections. In the medically advanced countries, the death rates from bacterial diseases—notably, pneumococcal pneumonia—dropped dramatically.
Domagk was awarded the Nobel Prize in medicine and physiology in 1939. When he wrote the usual letter of acceptance, he was promptly arrested by the Gestapo; the Nazi government, for peculiar reasons of its own, refused to have anything to do with the Nobel Prizes. Domagk felt it the better part of valor to refuse the prize. After the Second World War, when he was at last free to accept the honor, Domagk went to Stockholm to receive it officially.
THE ANTIBIOTICS
The sulfa drugs had only a brief period of glory, for they were soon put in the shade by the discovery of a far more potent kind of antibacterial weapon—the antibiotics.
All living matter (including human beings) eventually returns to the soil to decay and decompose. With the dead matter and the wastes of living creatures go the germs of the many diseases that infect those creatures. Why is it, then, that the soil is usually so remarkably clean of infectious germs? Very few of them (the anthrax bacillus is one of the few) survive in the soil. A number of years ago, bacteriologists began to suspect that the soil harbors microorganisms or substances that destroy bacteria. As early as 1877, for instance, Pasteur had noticed that some bacteria died in the presence of others. And if the suspicion were correct, the soil would offer a large variety of organisms that might bring death to others of their kind. It is estimated that each acre of soil contains about 2,000 pounds of molds, 1,000 pounds of bacteria, 200 pounds of protozoa, 100 pounds of algae, and 100 pounds of yeast.
One of those who conducted a deliberate search for bactericides in the soil was the French-American microbiologist René Jules Dubos. In 1939, he isolated from a soil microorganism called Bacillus brevis a substance, tyrothricin, from which he isolated two bacteria-killing compounds that he named gramicidin and tyrocidin. They turned out to be peptides containing D-amino acids—the mirror images of the ordinary L-amino acids that make up most natural proteins.
Gramicidin and tyrocidin were the first antibiotics produced as such. But an antibiotic that wa
s to prove immeasurably more important had been discovered—and merely noted in a scientific paper—twelve years earlier.
The British bacteriologist Alexander Fleming one morning found that some cultures of staphylococcus (the common pus-forming bacterium), which he had left on a bench, were contaminated with something that had killed the bacteria. There were little clear circles where the staphylococci had been destroyed in the culture dishes. Fleming, being interested in antisepsis (he had discovered that an enzyme in tears, called lysozome, had antiseptic properties), at once investigated to see what had killed the bacteria, and discovered that it was a common bread mold, Penicillium notatum. Some substance, which he named penicillin, produced by the mold was lethal to germs. Fleming dutifully published his results in 1929, but no one paid much attention at the time.
Ten years later the British biochemist Howard Walter Florey and his German-born associate, Ernst Boris Chain, became intrigued by the almost forgotten discovery and set out to try to isolate the antibacterial substance. By 1941, they had obtained an extract that proved effective clinically against a number of gram-positive bacteria (bacteria that retain a dye developed in 1884 by the Danish bacteriologist Hans Christian Joachim Gram).
Because wartime Britain was in no position to produce the drug, Florey went to the United States and helped to launch a program that developed methods of purifying penicillin and speeding up its production by the mold.
In 1943, five hundred cases were treated with penicillin; and, by the war’s end, large-scale production and use ‘of penicillin were under way. Not only did penicillin pretty much supplant the sulfa drugs, but it became (and still is) one of the most important drugs in the entire practice of medicine. It is effective against a wide range of infections, including pneumonia, gonorrhea, syphilis, puerperal fever, scarlet fever, and meningitis. (The range of effectivity is called the antibiotic spectrum.) Furthermore, it has practically no toxicity or undesirable side effects, except in penicillin-sensitive individuals.
In 1945, Fleming, Florey, and Chain shared the Nobel Prize in medicine and physiology.
Penicillin set off an almost unbelievably elaborate hunt for other antibiotics. (The word was coined in 1942 by the Rutgers University bacteriologist Selman Abraham Waksman.)
In 1943, Waksman isolated from a soil mold of the genus Streptomyces the antibiotic known as streptomycin. Streptomycin hit the gram-negative bacteria (those that easily lose the Gram stain). Its greatest triumph was against the tubercle bacillus. But streptomycin, unlike penicillin, is rather toxic and must be used with caution.
For the discovery of streptomycin, Waksman received the Nobel Prize in medicine and physiology in 1952.
Another antibiotic, chloramphenicol, was isolated from molds of the genus Streptomyces in 1947. Chloramphenicol attacks not only gram-positive and gram-negative bacteria but also certain smaller organisms—notably those causing typhus fever and psittacosis (parrot fever). But its toxicity calls for care in its use.
Then came a whole series of broad-spectrum antibiotics, found after painstaking examination of many thousands of soil samples—Aureomycin, Terramycin, Achromycin, and so on. The first of these, Aureomycin, was isolated by Benjamin Minge Duggar and his co-workers in 1944 and was placed on the market in 1948. These antibiotics are called tetracyclines, because in each case the molecule is composed of four rings side by side. They are effective against a wide range of infections with the result that infectious diseases have fallen to cheeringly low levels. (Of course human beings left alive by our continuing mastery over infectious disease have a much greater chance of succumbing to a metabolic disorder. Thus, in the last eighty years, the incidence of diabetes, the most common such disorder, has increased tenfold.)
RESISTANT BACTERIA
The chief disappointment in the development of chemotherapy has been the speedy rise of resistant strains of bacteria. In 1939, for instance, all cases of meningitis and pneumococcal pneumonia showed a favorable response to the administration of sulfa drugs. Twenty years later, only half the cases did. The various antibiotics also became less effective with time. It is not that the bacteria “learn” to resist but that resistant mutants among them flourish and multiply when the “normal” strains are killed off. Mutation is, ordinarily, a slow process; and in the eukarotes, the multicellular ones particularly, variation and change are brought about much more quickly by the constant shuffling of genes and chromosomes in each generation. Bacterial transformation is swift through mutation alone, however, because bacteria multiply so quickly. Uncounted numbers arise from a few progenitors; and though the percentage of useful mutations, such as those capable of giving rise to an enzyme that destroys an otherwise effective chemotherapeutic agent, is very low, the absolute numbers of such mutations is fairly high.
Furthermore, the genes necessary for the production of such enzymes are often found in plasmids and are transferred from bacterium to bacterium, making the spread of resistance even more rapid.
The danger of resistant strains of bacteria is greatest in hospitals, where antibiotics are used constantly, and where the patients naturally have below-normal resistance to infection. Certain new strains of staphylococci resist antibiotics with particular stubbornness. This hospital staph is a serious worry in maternity wards, for instance, and attained headline fame in 1961, when an attack of pneumonia, sparked by such resistant bacteria, nearly ended the life of screen star Elizabeth Taylor.
Fortunately, where one antibiotic fails another may still attack a resistant strain. New antibiotics, and synthetic modifications of the old, may hold the line in the contest against mutations. The ideal thing would be to find an antibiotic to which no mutants are immune. Then there would be no survivors of that particular bacterium to multiply. A number of such candidates have been produced. For instance, a modified penicillin, called Staphcyllin, was developed in 1960. It is partly synthetic; and because its structure is strange to bacteria, its molecule is not split and its activity ruined by enzymes such as penicillinase (first discovered by Chain), which resistant strains use against ordinary penicillin. Consequently, Staphcyllin is death to otherwise resistant strains; it was used to save Taylor’s life, for instance. Yet strains of staphylococcus, resistant to synthetic penicillins, have also turned up. Presumably, the merry-go-round will go on forever.
Additional allies against resistant strains are various other new antibiotics and modified versions of old ones. One can only hope that the stubborn versatility of chemical science will manage to keep the upper hand over the stubborn versatility of the disease germs.
PESTICIDES
The same problem of the development of resistant strains arises in the battle with our larger enemies, the insects, which not only compete dangerously for food but also spread disease. The modern chemical defenses against insects arose in 1939, with the development by the Swiss chemist Paul Muller of the chemical dichlorodiphenyltrichloroethane, better known by its initials, DDT. Muller was awarded the Nobel Prize in medicine and physiology for this feat in 1948.
By then, DDT had come into large-scale use, and resistant strains of houseflies had developed. Newer insecticides—or, to use a more general term that will cover chemicals used against rats or against weeds, pesticides—must continually be developed.
In addition, there are critics of the overchemicalization of our battle against other, nonhuman forms of life. Some critics are concerned lest science make it possible for an increasingly large segment of the population to remain alive only through the grace of chemistry; they fear that if ever our technological organization falters, even temporarily, great carnage will result as populations fall prey to the infections and diseases from which they have been kept safe by chemical fortification and to which they lack natural resistance.
As for the pesticides themselves, the American science-writer Rachel Louise Carson published a book, Silent Spring, in 1962 that dramatically brought to the fore the possibility that our indiscriminate use of chemicals might kill
harmless and even useful species along with those we are actually attempting to destroy. Furthermore, Carson maintained that to destroy living things without due consideration might lead to a serious upsetting of the intricate system whereby one species depends on another and, in the end, hurt more than it helps humanity. The study of this interlinking of species is termed ecology, and there is no question but that Carson’s book encouraged a new hard look at this branch of biology.
The answer, of course, is not to abandon technology and give up all attempts to control insects (the price in disease and starvation would be too high) but to find methods that are more specific and less damaging to the ecological structure generally.
For instance, insects have their enemies. Those enemies, whether insect-parasites or insect eaters, might be encouraged. Sounds and odors might be used to repel insects or to lure them to their death. Insects might be sterilized through radiation. In each case, every effort should be made to zero in on the insect being fought.
One hopeful line of attack, led by the American biologist Carroll Milton Williams, is to make use of the insects’ own hormones. Insects molt periodically and pass through two or three well-defined stages: larva, pupa, and adult. The transitions are complex and are controlled by hormones. Thus, one called juvenile hormone prevents formation of the adult stage until an appropriate time. By isolating and applying the juvenile hormone, the adult stage is held back to the point where the insect is killed. Each insect has its own juvenile hormone and is affected only by its own. A particular juvenile hormone might thus be used to attack one particular species of insect without affecting any other organism in the world. Guided by the structure of the hormone, biologists may even prepare synthetic substitutes that will be much cheaper and do the job as well.