Asimov's New Guide to Science

by Isaac Asimov

  Immune Reactions

  Viruses are our most formidable living enemy (except human beings themselves). By virtue of their intimate association with the body’s own cells, viruses have been all but invulnerable to attack by drugs or any other artificial weapon. And yet we have been able to hold our own against them, even under the most unfavorable conditions. The human organism is endowed with impressive natural defenses against disease.

  Consider the Black Death, the great plague of the fourteenth century. It attacked a Europe living in appalling filth, without any modern conception of cleanliness and hygiene, without plumbing, without any form of reasonable medical treatment—a crowded and helpless population. To be sure, people could flee from the infected villages, but the fugitive sick only spread the epidemics faster and farther. Nonetheless, three fourths of the population successfully resisted the infections. Under the circumstances, the marvel is not that one out of four died, but that three out of four survived.

  There is clearly such a thing as natural resistance to any given disease. Of people exposed to a serious contagious disease, some will have a relatively mild case, some will be very sick, some will die. There is also such a thing as complete immunity—sometimes inborn, sometimes acquired. A single attack of measles, mumps, or chickenpox, for instance, will usually make one immune to that particular disease for the rest of one’s life.

  All three of these diseases, as it happens, are caused by viruses. Yet they are comparatively minor infections, seldom fatal. Measles, the most dangerous of the three, usually produces only mild symptoms, at least in a child. How does the body fight off these viruses and then fortify itself so that the virus it has defeated never troubles it again? The answer to that question forms a thrilling episode in modern medical science, and for the beginning of the story we must go back to the conquest of smallpox.

  SMALLPOX

  Up to the end of the eighteenth century, smallpox was a particularly dreaded disease, not only because it was often fatal but also because those who recovered were permanently disfigured. A light case would leave the skin pitted; a severe attack could destroy all traces of beauty and almost of humanity. A very large proportion of the population bore the marks of smallpox on their faces. And those who had not yet caught it lived in fear of its striking.

  In the seventeenth century, people in Turkey began to infect themselves deliberately with mild forms of smallpox, in the hope of making themselves immune to severe attack. They would have themselves scratched with the serum from blisters of a person who had a mild case. Some people developed only a light infection; others suffered the very disfigurement or death they had sought to avoid. It was risky business, but it is a measure of the horror of the disease that people were willing to risk the horror itself in order to escape from it.

  In 1718, the famous beauty Lady Mary Wortley Montagu learned about this practice when she went to Turkey with her husband, sent there briefly as the British ambassador, and she had her own children inoculated. They escaped without harm. But the idea did not catch on in England, perhaps partly because Lady Montagu was considered a notorious eccentric. A similar case, across the ocean, was that of Zabdiel Boylston, an American physician. During a smallpox epidemic in Boston, he inoculated 241 people, of whom 6 died. He underwent considerable criticism for this.

  Certain country folk in Gloucestershire had their own idea about how to avoid smallpox. They believed that a case of cowpox, a disease that attacked cows and sometimes people, would make a person immune to both cowpox and smallpox. This was wonderful, if true, for cowpox produced hardly any blisters and left hardly any marks. A Gloucestershire doctor, Edward Jenner, decided that there might be some truth in this folk “superstition.” Milkmaids, he noticed, were particularly likely to catch cowpox and apparently also particularly likely not to be pockmarked by smallpox. (Perhaps the eighteenth-century vogue of romanticizing the beautiful milkmaid was based on the fact that milkmaids, having clear complexions, were indeed beautiful in a pockmarked world.)

  Was it possible that cowpox and smallpox were so alike that a defense formed by the body against cowpox would also protect against smallpox? Very cautiously Dr. Jenner began to test this notion (probably experimenting on his own family first). In 1796, he decided to chance the supreme test. First he inoculated an eight-year-old boy named James Phipps with cowpox, using fluid from a cowpox blister on a milkmaid’s hand. Two months later came the crucial and desperate part of the test. Jenner deliberately inoculated young James with smallpox itself.

  The boy did not catch the disease. He was immune.

  Jenner called the process vaccination, from vaccinia, the Latin name for cowpox. Vaccination spread through Europe like wildfire. It is one of the rare cases of a revolution in medicine that was adopted easily and almost at once—a true measure of the deadly fear inspired by smallpox and of the eagerness of the public to try anything that promised escape. Even the medical profession put up only weak opposition to vaccination—though its leaders put up such stumbling blocks as they could. When Jenner was proposed for election to the Royal College of Physicians in London in 18l3, he was refused admission, on the ground that he was not sufficiently up on Hippocrates and Galen.

  Today smallpox seems to have been wiped out as an active disease for lack of enough people who have not been rendered immune by vaccination and can serve as hosts. There has not been a single case of smallpox in the United States since 1949 or anywhere in the world since 1977. Samples of the virus still exist in some laboratories for purposes of research, and accidents may yet happen.

  VACCINES

  Attempts to discover similar inoculations for other severe diseases got nowhere for more than a century and a half. It was Pasteur who made the next big step forward. He discovered, more or less by accident, that he could change a severe disease into a mild one by weakening the microbe that produced it.

  Pasteur was working with a bacterium that caused cholera in chickens. He concentrated a preparation so virulent that a little injected under the skin of a chicken would kill it within a day. On one occasion, he used a culture that had been standing for a week. This time the chickens became only slightly sick and recovered. Pasteur decided that the culture was spoiled and prepared a virulent new batch. But his fresh culture failed to kill the chickens that had recovered from the dose of “spoiled” bacteria. Clearly, the infection with the weakened bacteria had equipped the chickens with a defense against the fully potent ones.

  In a sense, Pasteur had produced an artificial “cowpox” for this particular “smallpox.” He recognized the philosophical debt he owed to Jenner by calling his procedure vaccination, too, although it had nothing to do with vaccinia. Since then, the term has been used quite generally to mean inoculations against any disease, and the preparation used for the purpose is called a vaccine.

  Pasteur developed other methods of weakening (or attenuating) disease agents. For instance, he found that culturing anthrax bacteria at a high temperature produced a weakened strain that would immunize animals against the disease. Until then, anthrax had been so hopelessly fatal and contagious that as soon as one member of a herd came down with it, the whole herd had to be slaughtered and burned.

  Pasteur’s most famous victory, however, was over the virus disease called hydrophobia, or rabies (from a Latin word meaning “to rave,” because the disease attacks the nervous system and produces symptoms akin to madness). A person bitten by a rabid dog would, after an incubation period ofa month or two, be seized by violent symptoms and almost invariably die an agonizing death.

  Pasteur could find no visible microbe as the agent of the disease (of course, he knew nothing of viruses), so he had to use living animals to cultivate it. He would inject the infectious fluid into the brain of a rabbit, let it incubate, mash up the rabbit’s spinal cord, inject the extract into the brain of another rabbit, and so on. Pasteur attenuated his preparations by aging and testing them continuously until the extract could no longer cause noticeable d
isease in a rabbit. He then injected the rabbit with hydrophobia in full strength and found the animal immune.

  In 1885, Pasteur got his chance to try the cure on a human being. A nine-year-old boy, Joseph Meister, who had been severely bitten by a rabid dog, was brought to him. With considerable hesitation and anxiety, Pasteur treated the boy with inoculations of successively less and less attenuated virus, hoping to build up resistance before the incubation period had elapsed. He succeeded. At least, the boy survived. (Meister became the gatekeeper of the Pasteur Institute and, in 1940, committed suicide when the Nazi army in Paris ordered him to open Pasteur’s crypt.)

  In 1890, a German army doctor named Emil von Behring, working in Koch’s laboratory, tried another idea. Why take the risk of injecting the microbe itself, even in attenuated form, into a human being? Assuming that the disease agent causes the body to manufacture some defensive substance, would it not serve just as well to infect an animal with the agent, extract the defense substance that it produces, and inject that substance into the human patient?

  Von Behring found that this scheme did indeed work. The defensive substance turned up in the blood serum, and von Behring called it antitoxin. He caused animals to produce antitoxins against tetanus and diphtheria. His first use of the diphtheria antitoxin on a child with the disease was so dramatically successful that the treatment was adopted immediately and proceeded to cut the death rate from diphtheria drastically.

  Paul Ehrlich (who later was to discover the “magic bullet” for syphilis) worked with von Behring and probably calculated the appropriate antitoxin dosages. Later he broke with von Behring (Ehrlich was an irascible individual who found it easy to break with anyone) and alone went on to work out the rationale of serum therapy in detail. Von Behring received the Nobel Prize in medicine and physiology in 1901, the first year in which it was awarded. Ehrlich also was awarded that Nobel Prize, sharing it with a Russian biologist in 1908.

  The immunity conferred by an antitoxin lasts only as long as the antitoxin remains in the blood. But the French bacteriologist Gaston Ramon found that, by treating the toxin of diphtheria or tetanus with formaldehyde or heat, he was able to change its structure in such a way that the new substance (called toxoid) could safely be injected in a human patient. The antitoxin then made by the patient himself lasts longer than that from an animal; furthermore, new doses of the toxoid can be injected when necessary to renew immunity. After toxoid was introduced in 1925, diphtheria lost most of its terrors.

  Serum reactions were also used to detect the presence of disease. The best-known example of this is the Wasserman test; introduced by the German bacteriologist August von Wasserman, in 1906, for the detection of syphilis. This was based on techniques first developed by a Belgian bacteriologist, Jules Bordet, who worked with serum fractions that came to be called complement. This has turned out to be a complex system made up of a number of interrelated enzymes. For his work, Bordet received the Nobel Prize in medicine and physiology in 1919.

  Pasteur’s laborious wrestle with the virus of rabies showed the difficulty of dealing with viruses. Bacteria can be cultured, manipulated, and attenuated on artificial media in the test tube. Viruses cannot; they can be grown only in living tissue. In the case of smallpox, the living hosts for the experimental material (the cowpox virus) were cows and milkmaids. In the case of rabies, Pasteur used rabbits. But living animals are, at best, an awkward, expensive, and time-consuming medium for culturing microorganisms.

  In the first quarter of this century, the French biologist Alexis Carrel won considerable fame with a feat that was to prove immensely valuable to medical research—keeping bits of tissue alive in the test tube. Carrel had become interested in this sort of thing through his work as a surgeon. He had developed new methods of transplanting animals’ blood vessels and organs, for which he received the Nobel Prize in medicine and physiology in 1912. Naturally, he had to keep the excised organ alive while he was getting ready to transplant it. He worked out a way to nourish it, by perfusing the tissue with blood and supplying the various extracts and ions. As an incidental dividend, Carrel, with the help of Charles Augustus Lindbergh, developed a crude mechanical heart to pump the blood through the tissue.

  Carrel’s devices were good enough to keep a piece of embryonic chicken heart alive for thirty-four years—much longer than a chicken’s lifetime. Carrel even tried to use his tissue cultures to grow viruses—and he succeeded in a way. The only trouble was that bacteria also grew in the tissues; and in order to keep the virus pure, such tedious aseptic precautions had to be taken that it was easier to use animals.

  The chick-embryo idea, however, was in the right ball park, so to speak. Better than just a piece of tissue would be the whole thing—the chick embryo itself. A chick embryo is a self-contained organism, protected by the egg shell, equipped with its own natural defenses against bacteria, and cheap and easy to come by in quantity. And, in 1931, the pathologist Ernest William Goodpasture and his co-workers at Vanderbilt University succeeded in transplanting a virus into a chick embryo. For the first time, pure viruses could be cultured almost as easily as bacteria.

  The first great medical victory by means of the culture of viruses in fertile eggs came in 1937. At the Rockefeller Institute, bacteriologists were still hunting for further protection against the yellow-fever virus. It was impossible to eradicate the mosquito completely, after all, and infected monkeys maintained a constantly threatening reservoir of the disease in the tropics. The South-African bacteriologist Max Theiler at the institute set out to produce an attenuated yellow-fever virus. He passed the virus through 200 mice and 100 chick embryos until he had a mutant that caused only mild symptoms yet gave rise to complete immunity against yellow fever. For this achievement Theiler received the 1951 Nobel Prize in medicine and physiology.

  When all is said and done, nothing can beat culture in glassware for speed, control of the conditions, and efficiency. In the late 1940s John Franklin Enders, Thomas Huckle Weller, and Frederick Chapman Robbins at the Harvard Medical School went back to Carrel’s approach. (He had died in 1944 and was not to see their success.) This time they had a new and powerful weapon against bacteria contaminating the tissue culture—the antibiotics. They added penicillin and streptomycin to the supply of blood that kept the tissues alive, and found that they could grow viruses without trouble. On impulse, they tried the poliomyelitis virus. To their delight, it flourished in this medium. It was the breakthrough that was to conquer polio, and the three men received the Nobel Prize in medicine and physiology in 1954.

  The poliomyelitis virus could now be bred in the test tube, instead of solely in monkeys (which are expensive and temperamental laboratory subjects). Large-scale experimentation with the virus became possible. Thanks to the tissue-culture technique, Jonas Edward Salk of the University of Pittsburgh was able to experiment with chemical treatment of the virus, to learn that polio viruses killed by formaldehyde could still produce immune reactions in the body, and to develop his now-famous Salk vaccine.

  Polio’s sizable death rate, its dreaded paralysis, its partiality for children (so that it has the alternate name of infantile paralysis), the fact that it seems to be a modern scourge with no epidemics on record prior to 1840, and particularly the interest attracted to the disease by its eminent victim, Franklin Delano Roosevelt, made its conquest one of the most celebrated victories over a disease in all human history. Probably no medical announcement ever received such a Hollywood-premiere type of reception as did the report, in 1955, of the evaluating committee that found the Salk vaccine effective. Of course, the event merited such a celebration—more than do most of the performances that arouse people to throw ticker tape and trample one another. But science does not thrive on furor or wild publicity. The rush to respond to the public pressure for the vaccine apparently resulted in a few defective, disease-producing samples of the vaccine slipping through, and the subsequent counterfuror set back the vaccination program against the disease.r />
  The setback was, however, made up, and the Salk vaccine was found effective and, properly prepared, safe. In 1957, the Polish-American microbiologist Albert Bruce Sabin went a step further. He made use not of dead virus (which, when not entirely dead, could be dangerous) but of strains of living virus, incapable of producing the disease itself, but capable of bringing about the production of appropriate antibodies. Such a Sabin vaccine could be taken by mouth, moreover, and did not require the hypodermic. The Sabin vaccine gained popularity first in the Soviet Union and then in eastern European countries; but by 1960, it came into use in the United States as well, and the fear of poliomyelitis has lifted.

  ANTIBODIES

  What does a vaccine do, exactly? The answer to this question may some day give us the chemical key to immunity.

  For more than half a century, biologists have known the body’s main defenses against infection as antibodies. (Of course, there are also the white-blood cells called phagocytes, which devour bacteria—as was discovered in 1883 by the Russian biologist I1ya Hitch Mechnikov, who later succeeded Pasteur as the head of the Pasteur Institute in Paris and shared the 1908 Nobel Prize in medicine and physiology with Ehrlich. But phagocytes are no help against viruses and seem not to be involved in the immunity process I am considering.) A virus, or indeed almost any foreign substance entering into the body’s chemistry, is called an antigen. The antibody is a substance manufactured by the body to fight the specific antigen: it puts the antigen out of action by combining with it.

  Long before the chemists actually ran down an antibody, they were pretty sure the antibodies must be proteins. For one thing, the best-known antigens were proteins, and presumably it would take a protein to catch a protein. Only a protein could have the subtlety of structure necessary to single out and combine with a particular antigen.