by Isaac Asimov
In short, the answer to the fact that scientific advance may sometimes have damaging side effects, is not to abandon scientific advance, but to substitute still more advance—intelligently and cautiously applied.
HOW CHEMOTHERAPY WORKS
As to how the chemotherapeutic agents work, the best guess seems to be that each drug inhibits some key enzyme in the microorganism in a competitive way. This action is best established in the case of the sulfa drugs. They are very similar to para-aminobenzoic acid (generally written “p-aminobenzoic acid”), which has this structure:
P-aminobenzoic acid is necessary for the synthesis of folic acid, a key substance in the metabolism of bacteria as well as other cells. A bacterium that picks up a sulfanilamide molecule instead of p-aminobenzoic acid can no longer produce folic acid, because the enzyme needed for the process is put out of action. Consequently, the bacterium ceases to grow and multiply. The cells of the human patient, on the other hand, are not disturbed; they obtain folic acid from food and do not have to synthesize it. There are no enzymes in human cells to be inhibited by moderate concentrations of the sulfa drugs in this fashion.
Even where a bacterium and the human cell possess similar enzymes, there are other ways of attacking the bacterium selectively. The bacterial enzyme may be more sensitive to a given drug than the human enzyme is, so that a certain dose will kill the bacterium without seriously disturbing the human cells. Or a drug of the proper design may be able to penetrate the bacterial cell membrane but not the human cell membrane. Penicillin, for instance, interferes with the manufacture of cell walls, which bacteria possess but animals cells do not.
Do the antibiotics also work by competitive inhibition of enzymes? Here the answer is less clear. But there is good ground for believing that at least some of them do.
Gramicidin and tyrocidin, as I mentioned earlier, contain the “unnatural” D-amino acids. Perhaps these jam up the enzymes that form compounds from the natural L-amino acids. Another peptide antibiotic, bacitracin, contains ornithine; this may inhibit enzymes from making use of arginine, which ornithine resembles. There is a similar situation in streptomycin: its molecule contains an odd variety of sugar which may interfere with some enzyme acting on one of the normal sugars of living cells. Again, chloramphenicol resembles the amino acid phenylalanine; likewise, part of the penicillin molecule resembles the amino acid cysteine. In both of these cases the possibility of competitive inhibition is strong.
The clearest evidence so far of competitive action by an antibiotic involves puromycin, a substance produced by a Streptomyces mold. This compound has a structure much like that of nucleotides (the building units of nucleic acids), and Michael Yarmolinsky and his co-workers at Johns Hopkins University have shown that puromycin, competing with transfer-RNA, interferes with the synthesis of proteins. Again, streptomycin interferes pith transfer-RNA, forcing the misreading of the genetic code and the formation of useless protein. Unfortunately, this form of interference makes it toxic to other cells besides bacteria, because it prevents their normal production of necessary proteins. Thus puromycin is too dangerous a drug to use, and streptomycin is nearly so.
BENEFICENT BACTERIA
Naturally, human attention focuses on those bacteria that are pathogenic and (in our selfish judgment) do harm. These are, however, a minute fraction of the total number. It has been estimated that, for every harmful bacterium, there are 30,000 that are harmless, useful, or even necessary. If we go by species, then out of 1,400 identified species of bacteria, only about 150 cause disease in human beings or in those plants and animals that we have cultivated or domesticated.
Consider, for instance, the fact that, at each moment, countless organisms are dying, and that relatively few of them serve as food for other organisms at the level of ordinary animals. Less than 10 percent of fallen leaves, and less than 1 percent of dead wood, are eaten by animals. The rest falls prey to fungi and bacteria. Were it not for these decomposers, especially the popularly named decay bacteria, the world of life would choke on the ever-increasing accumulation of indigestible fragments which would contain within themselves an ever-increasing fraction of those elements necessary for life. And, in the not distant end, there would be no life at all.
Cellulose, in particular, is indigestible to multicellular animals and is the most common of all the structures produced by life. Even though animals such as cattle and termites seem to live on cellulose-rich food such as grass and wood, they do so only through innumerable bacteria that live in their digestive tracts. It is these bacteria that decompose the cellulose and restore it to an active role in the overall life cycle.
Again, all plant life requires nitrogen, out of which to build up amino acids and proteins. Animal life also requires nitrogen and obtains it (already built up into amino acids and proteins) from the plant world. Plant life obtains it from nitrates in the soil. The nitrates, however, are inorganic salts which are soluble in water. If it were merely a question of nitrates, these would be leached out of the soil by rainfall, and the land would become unproductive. On land at least, plant life would be impossible, and only such animals could exist as fed on sea life.
Where do the nitrates come from, then, since there are always some present in the soil despite the action of millions of years of rainfall? The obvious source is the nitrogen of the atmosphere, but plants and animals have no means of making use of gaseous nitrogen (which is quite inert chemically) and of “fixing” it in the form of compounds. There are, however nitrogen-fixing bacteria that are capable of converting atmospheric nitrogen into ammonia. Once that is formed, it is easily converted into nitrates by nitrifying bacteria. Without such activity by bacteria (and by blue-green algae), land life would be impossible.
(Of course, human beings-thanks to modern technology, such as the Haber process, as described in chapter II—are also capable of fixing atmospheric nitrogen, but were able to do so only after land life had existed for some hundreds of millions of years. By now, the industrial fixation of nitrogen has reached such a point that there is some concern about whether natural processes of denitrification—the reconversion of nitrates to gaseous nitrogen by still other bacteria—can keep pace. The overaccumulation of nitrates in rivers and lakes can encourage the growth of algae and the death of higher organisms such as fish, to the overall detriment of a balanced ecological system.)
Microorganisms of various sorts (including bacteria) have been of direct use to human beings from prehistoric times. Various yeasts (single-celled fungi that are eukaryotic) readily convert sugars and starches to alcohol and carbon dioxide and have therefore been used, from remote antiquity, to ferment fruit and grain into wine and beer. The production of carbon dioxide has been used to convert wheat Hour into the soft and puffy breads and pastries we are accustomed to.
Molds and bacteria produce other changes that convert milk into yogurt or into any of a myriad of cheeses.
In modern times, we have industrial microbiology where specific strains of molds and bacteria are cultivated in order to produce substances of pharmaceutical value—such as antibiotics, vitamins, or amino acids—or of industrial value, such as acetone, butyl alcohol, or citric acid.
With the use of genetic engineering (as mentioned in the previous chapter), bacteria and other microorganisms might make more efficient capacities they already possess—such as nitrogen fixation—or develop new capacities—such as the ability to oxidize hydrocarbon molecules under the proper conditions and thus clean up oil spills. They might also gain the capacity to produce desirable substances such as various blood fractions and hormones.
Viruses
To most people it may seem mystifying that the wonder drugs have had so much success against the bacterial diseases and so little success against the virus diseases. Since viruses, after all, can cause disease only if they reproduce themselves, why should it not be possible to jam the virus’s machinery just as we jam the bacterium’s? The answer is simple and, indeed, obvious once you r
ealize how a virus reproduces itself. As a complete parasite, incapable of multiplying anywhere except inside a living cell, the virus has very little, if any, metabolic machinery of its own. To make copies of itself, it depends entirely on materials supplied by the cell it invades—as it can do with great efficiency. One virus within a cell can become 200 in 25 minutes. And it is therefore difficult to deprive the virus of those materials or jam the machinery without destroying the cell itself.
Biologists discovered the viruses only recently, after a series of encounters with increasingly simple forms of life. Perhaps as good a place as any to start this story is the discovery of the cause of malaria.
NONBACTERIAL DISEASE
Malaria has, year in and year out, probably killed more people in the world than any other infectious ailment, since until recently about 10 percent of the world’s population suffered from the disease, which caused 3 million deaths a year. Until 1880, it was thought to be caused by the bad air (mala aria in Italian) of swampy regions. Then a French bacteriologist, Charles Louis Alphonse Laveran, discovered that the red-blood cells of malaria-stricken individuals were infested with parasitic protozoa of the genus Plasmodium. (For this discovery, Laveran was awarded the Nobel Prize in medicine and physiology in 1907.)
In 1894, a British physician named Patrick Manson, who had conducted a missionary hospital in Hong Kong, pointed out that swampy regions harbor mosquitoes as well as dank air, and he suggested that mosquitoes might have something to do with the spread of malaria. A British physician in India, Ronald Ross, pursued this idea and, in 1897, was able to show that the malarial parasite does indeed pass part of its life cycle in mosquitoes of the genus Anopheles (see figure 14.2). The mosquito picks up the parasite in sucking the blood of an infected person and then passes it on to any person it bites.
Figure 14.2. Life cycle of the malarial microorganism.
For his work, bringing to light for the first time the transmission of a disease by an insect vector, Ross received the Nobel Prize in medicine and physiology in 1902. It was a crucial discovery of modern medicine, for it showed that a disease might be stamped out by killing off the insect carrier. Drain the swamps that breed mosquitoes; eliminate stagnant water; destroy the mosquitoes with insecticides—and you can stop the disease. Since the Second World War, large areas of the world have been freed of malaria in just this way, and the total number of deaths from malaria has declined by at least one third from its maximum.
Malaria was the first infectious disease traced to a nonbacterial microorganism (a protozoan in this case). Very shortly afterward, another non bacterial disease was tracked down in a similar way. It was the deadly yellow fever, which as late as 1898, during an epidemic in Rio de Janeiro, killed nearly 95 percent of those it struck. In 1899, when an epidemic of yellow fever broke out in Cuba, a United States board of inquiry, headed by the bacteriologist Walter Reed, went to Cuba to investigate the causes of the disease.
Reed suspected a mosquito vector, such as had just been exposed as the transmitter of malaria. He first established that the disease could not be transmitted by direct contact between the patients and doctors or by way of the patient’s clothing or bedding. Then some of the doctors deliherately let themselves be bitten by mosquitoes that had previously bitten a man sick with yellow fever. They got the disease, and one of the courageous investigators, Jesse William Lazear, died. But the culprit was identified as the Aedes aegypti mosquito. The epidemic in Cuba was checked, and yellow fever is no longer a serious disease in the medically advanced parts of the world. The cause of yellow fever is non-bacterial, but non-protozoan, too. The disease agent is something even smaller than a bacterium.
As a third example of a non bacterial disease, there is typhus fever. This infection is endemic in North Africa and was brought into Europe via Spain during the long struggle of the Spaniards against the Moors of North Africa. Commonly known as plague, it is very contagious and has devastated nations. In the First World War, the Austrian armies were driven out of Serbia by the typhus when the Serbian army itself was unequal to the task. The ravages of typhus in Poland and Russia during that war and its aftermath (some 3 million persons died of the disease) did as much as military action to ruin those nations.
At the turn of the twentieth century, the French bacteriologist Charles Nicolle, then in charge of the Pasteur Institute in Tunis, noticed that although typhus was rife in the city, no one caught it in the hospital. The doctors and nurses were in daily contact with typhus-ridden patients, and the hospital was crowded; yet there was no spread of the disease there. Nicolle considered what happened when a patient came into the hospital, and it struck him that the most significant change was a thorough washing of the patient and removal of his lice-infested clothing. Nicolle decided that the body louse must be the vector of typhus. He proved the correctness of his guess by experiments. He received the Nobel Prize in medicine and physiology in 1928 for his discovery. Thanks to his finding, and the discovery of DDT, typhus fever did not repeat its deadly carnage in the Second World War. In January 1944, DDT was brought into play against the body louse. The population of Naples was sprayed en masse, and the lice died. For the first time in history, a winter epidemic of typhus (when the multiplicity of clothes, not removed very often, made louse-infestation almost certain and almost universal) was stopped in its tracks. A similar epidemic was stopped in Japan in late 1945 after the American occupation. The Second World War became almost unique among history’s wars in possessing the dubious merit of killing fewer people by disease than by guns and bombs.
Typhus, like yellow fever, is caused by an agent smaller than a bacterium, and we must now enter the strange and wonderful realm populated by subbacterial organisms.
SUBBACTERIA
To get some idea of the dimensions of objects in this world, let us look at them in order of decreasing size. The human ovum is about 100 micrometers (100 millionths of a meter, or about 1/250 inch) in diameter and is just barely visible to the naked eye. The paramecium, a large protozoan which in bright light can be seen moving about in a drop of water, is about the same size. An ordinary human cell is only 1/10 as large (about 10 micrometers in diameter) and is quite invisible without a microscope. Smaller still is the red-blood corpuscle—some 7 micrometers in maximum diameter. The bacteria, starting with species as large as ordinary cells, drop down to a tinier level: the average rod-shaped bacterium is only 2 micrometers long, and the smallest bacteria are spheres perhaps no more than 0.4 micrometers in diameter. They can barely be seen in ordinary microscopes.
At this level, organisms apparently have reached the smallest possible volume into which can be crowded all the metabolic machinery necessary for an independent life. Any smaller organism cannot be a self-sufficient cell and must live as a parasite. It must shed most of the enzymatic machinery as excess baggage, so to speak. It is unable to grow or multiply on any artificial supply of food, however ample; hence it cannot be cultured, as bacteria can, in the test tube. The only place it can grow is in a living cell, which supplies the enzymes that it lacks. Such a parasite grows and multiplies, naturally, at the expense of the host cell.
The first subbacteria were discovered by a young American pathologist named Howard Taylor Ricketts. In 1909, he was studying a disease called Rocky Mountain spotted fever, which is spread by ticks (blood-sucking arthropods, related to the spiders rather than to insects). Within the cell’s infected hosts, he found inclusion bodies which turned out to be very tiny organisms, now called rickettsia in his honor. Ricketts and others soon found that typhus also is a rickettsial disease. In the process of establishing a proof of this fact, Ricketts himself caught typhus, and died in 1910 at the age of thirty-nine.
The rickettsia are still big enough to be attacked by antibiotics such as chloramphenicol and the tetracyclines. They range in diameter from about 0.8 to 0.2 micrometers. Apparently they possess enough metabolic machinery of their own to differ from the host cells in their reaction to drugs. Antibiotic
therapy has therefore considerably reduced the danger of rickettsial diseases.
At the lowest end of the scale, finally, come the viruses. They overlap the rickettsia in size; in fact, there is no actual dividing line between rickettsia and viruses. But the smallest viruses are small indeed. The virus of yellow fever, for instance, is only 0.02 micrometers in diameter. The viruses are much too small to be detected in a cell or to be seen under any optical microscope. The average virus is only 1/1,000 the size of the average bacterium.
A virus is stripped practically clean of metabolic machinery. It depends almost entirely upon the enzyme equipment of the host cell. Some of the largest viruses are affected by certain antibiotics; but against the run-of-the-mill viruses, drugs are helpless.
The existence of viruses was suspected many decades before they were finally seen. Pasteur, in his studies of hydrophobia, could find no organism in the body that could reasonably be suspected of causing the disease. Rather than decide that his germ theory of disease was wrong, Pasteur suggested that the germ in this case was simply too small to be seen. He was right.
In 1892, a Russian bacteriologist, Dmitri Iosifovich Ivanovski, was studying tobacco-mosaic disease, a disease that gives the leaves of the tobacco plant a mottled appearance. He found that the juice of infected leaves could transmit the disease when placed on the leaves of healthy plants. In an effort to trap the germs, he passed the juice through porcelain filters with holes so fine that not even the smallest bacterium could pass through. Yet the filtered juice still infected tobacco plants. Ivanovski decided that his filters must be defective and were actually letting bacteria through.
