by Isaac Asimov
Early in the 1920s, Landsteiner (the discoverer of blood groups) carried out a series of experiments that clearly showed antibodies to be very specific indeed. The substances he used to generate antibodies were not antigens but much simpler compounds whose structure was well known. They were arsenic-containing compounds called arsanilic acids. In combination with a simple protein, such as the albumin of egg white, an arsanilic acid acted as an antigen: when injected into an animal, it gave rise to an antibody in the blood serum. Furthermore, this antibody was specific for the arsanilic acid; the blood serum of the animal would clump only the arsanilic-albumin combination, not albumin alone. Indeed, sometimes the antibody could be made to react with just an arsanilic acid, not combined with albumin. Landsteiner also showed that very small changes in the structure of the arsanilic acid would be reflected in the antibody. An antibody evoked by one variety of arsanilic acid would not react with a slightly altered variety.
Landsteiner coined the name haptens (from a Greek word meaning “to bind”) for compounds, such as the arsanilic acids, that can give rise to antibodies when they are combined with protein. Presumably, each natural antigen has a specific region in its molecule that acts as a hapten. On that theory, a germ or a virus that can serve as a vaccine is one that has had its structure changed sufficiently to reduce its ability to damage cells but still has its hapten group intact, so that it can cause the formation of a specific antibody. In the early 1980s, a group headed by Richard A. Lerner prepared a synthetic vaccine by using a synthetic protein modeled on the Au virus. This synthetic vaccine immunized guinea pigs against the disease.
It would be interesting to learn the chemical nature of the natural haptens. If that could be determined, it might be possible to use a hapten, perhaps in combination with some harmless protein, to serve as a vaccine giving rise to antibodies for a specific antigen. That would avoid the necessity of resorting to toxins or attenuated viruses, which always carries some small risk.
Just how does an antigen evoke an antibody? Ehrlich believed that the body normally contains a small supply of a1 the antibodies it may need, and that when an invading antigen reacts with the appropriate antibody, this stimulates the body to produce an extra supply of that particular antibody. Some immunologists still adhere to that theory or to modifications of it. Yet.it seems highly unlikely that the body is prepared with specific antibodies for a1 the possible antigens, including unnatural substances such as the arsanilic acids.
The alternate suggestion is that the body has some generalized protein molecule that can be molded to fit any antigen. The antigen, then, acts as a template to shape the specific antibody formed in response to it. Pauling proposed such a theory in 1940. He suggested that the specific antibodies are varying versions of the same basic molecule, merely folded in different ways. In other words, the antibody is molded to fit its antigen as a glove fits the hand.
By 1969, however, the advance of protein analysis had made it possible for a team under Gerald Maurice Edelman to work out the amino-acid structure of a typical antibody made up of well over 1,000 amino acids. For this work, he received a share of the 1972 Nobel Prize for physiology and medicine.
J. Donald Capra went on to show that there were hypervariable regions in the amino-acid chain. Apparently, the relatively constant sections of the chain serve to form a three-dimensional structure that holds the hypervariable region, which can itself be designed to fit a particular antigen by a combination of changes in particular amino acids within the chain and by changes in geometrical configuration.
By the act of combination, an antibody can neutralize a toxin and make it impossible for it to participate in whatever reactions serve to harm the body. An antibody might also combine with regions on the surface of a virus or a bacterium. If it has the capacity to combine with two different spots, and one is on the surface of one microorganism and the other on the surface of a second, an antibody can initiate the process of agglutination in which the microorganisms stick together and lose their ability to multiply or to enter cells.
The antibody combination may serve to label cells it involves, so that phagocytes more easily engulf it. The antibody combination may also serve to activate the complement system which can then utilize its enzyme components to puncture the wall of the intruding cell and thus destroy it.
The very specificity of antibodies is a disadvantage in some ways. Suppose a virus mutates so that its protein has a slightly different structure. The old antibody for the virus often will not fit the new structure. It follows that immunity against one strain of virus is no safeguard against another strain. The virus of influenza and of the common cold are particularly susceptible to minor mutations—one reason that we are plagued by frequent recurrences of these diseases. Influenza, in particular, will occasionally develop a mutant of extraordinary virulence, which may then sweep a surprised and non immune worldas happened in 1918 and, with much less fatal result, in the Asian flu pandemic of 1957.
A still more annoying effect of the body’s oversharp efficiency in forming antibodies is its tendency to produce them even against a harmless protein that happens to enter the body. The body then becomes sensitized to that protein and may react violently to any later incursion of the originally innocent protein. The reaction may take the form of itching, tears, production of mucus in the nose and throat, asthma, and so on. Such allergic reactions are evoked by the pollen of certain plants (causing hay fever), by certain foods, by the fur or dandruff of animals, and so on. An allergic reaction may be acute enough to cause serious disablement or even death. The discovery of such anaphylactic shock won for the French physiologist Charles Robert Richet the Nobel Prize in medicine and physiology in 1913.
In a sense, every human being is more or less allergic to every other human being. A transplant, or graft, from one individual to another will not take, because the receiver’s body treats the transplanted tissue as foreign protein and manufactures antibodies against it. The person-to-person graft that will work best is from one identical twin to the other. Since their identical heredity gives them exactly the same proteins, they can exchange tissues or even a whole organ, such as a kidney.
The first successful kidney transplant took place in December 1954 in Boston, from one identical twin to another. The receiver died in 1962 at the age of thirty of coronary artery disease. Since then, hundreds of individuals have lived for months and even years with kidneys transplanted from other than identical twins.
Attempts at transplanting other organs, such as the lungs or the liver, have been made, but what most caught the public fancy was the heart transplant.
The first reasonably successful heart transplants were conducted in December 1967 by the South African surgeon Christiaan Barnard. The fortunate receiver—Philip Blaiberg, a retired South African dentist—lived for many months on someone else’s heart.
For a while afterward, heart transplants became the rage, but the furor by late 1969 had died down. Few receivers lived very long, for the problems of tissue rejection seemed overwhelming, despite massive attempts to solve the reluctance of the body to incorporate any tissue but its own.
The Australian bacteriologist Macfarlane Burnet had suggested that embryonic tissues might be immunized to foreign tissues and that the free-living animal might then tolerate grafts of that tissue. The British biologist Peter Medawar demonstrated this to be so, using mouse embryos. The two men shared in the 1960 Nobel Prize in medicine and physiology as a result.
In 1962, a French-Australian immunologist, Jacques Francis Albert Pierre Miller, working in England, went even further and discovered what may be the reason for this ability to work with embryos in order to make future toleration possible. He discovered that the thymus gland (a piece of tissue which until then had had no known use) was the tissue capable of forming antibodies. If the thymus gland was removed from mice at birth, those mice died after three or four months out of sheer incapacity to protect themselves against the environment. If the thymu
s was allowed to remain in the mice for three weeks, it already had time to bring about the development of antibody-producing cells in the body, and might then be removed without harm. Embryos in which the thymus has not yet done its work may be so treated as to “learn” to tolerate foreign tissue; the day may yet come when, by the way of the thymus, we may improve tissue toleration, when desirable, perhaps even in adults.
And yet, even if the problem of tissue rejection were surmounted, there would remain serious problems. After all, every person who receives a living organ must receive it from someone who is giving it up, and the question arises when the prospective donor may be considered dead enough to yield up his or her organs.
In that respect it might prove better if mechanical organs were prepared which would involve neither tissue rejection nor knotty ethical issues. Artificial kidneys became practical in the 1940s, and it is possible for patients without natural kidney function to visit a hospital once or twice a week and have their blood cleansed of wastes. It makes for a restricted life even for those fortunate enough to be serviced, but it is preferable to death.
In the 1940s, researchers found that allergic reactions are brought about by the liberation of small quantities of a substance called histamine into the blood-stream. This led to the successful search for neutralizing antihistamines, which can relieve the allergic symptoms but, of course, do not remove the allergy. The first successful antihistamine was produced at the Pasteur Institute in Paris in 1937 by the Swiss-born chemist Daniel Bovet, who for this and subsequent researches in chemotherapy was awarded the Nobel Prize in physiology and medicine in 1957.
Noting that sniffling and other allergic symptoms were much like those of the common cold, pharmaceutical firms decided that what works for one ought to work for the other, and, in 1949 and 1950, flooded the country with antihistamine tablets. (The tablets turned out to do little or nothing for colds, and their vogue diminished.)
Allergies do their maximum harm when the body becomes allergic to one or another of its own proteins. Ordinarily, the body adjusts to its own proteins in the course of its development from a fertilized egg; but on occasion, some of this adjustment is lost. The reason may be that the body manufactures antibodies against a foreign protein that, in some respects, is uncomfortably close in structure to one of the body’s own; or it may be that with age enough changes take place in the surface of certain cells that they begin to seem foreign to the antibody cells; or certain obscure viruses which, on infection, do little or no harm to the cells ordinarily, may produce subtle changes in the surface. The result is autoimmune disease.
In any case, autoimmune responses figure more commonly in human disorders than had been realized until recently. While most autoimmune diseases are uncommon, it may be that rheumatoid arthritis is one. Treatment for such diseases is difficult, but hope naturally improves if we know the cause and, therefore, the direction in which to look for effective treatment.
In 1937, thanks to the protein-isolating techniques of electrophoresis, biologists finally tracked down the physical location of antibodies in the blood. The antibodies were located in the blood fraction called gamma globulin.
Physicians have long been aware that some children are unable to form antibodies and therefore are easy prey to infection. In 1951, doctors at the Walter Reed Hospital in Washington made an electrophoretic analysis of the plasma of an eight-year-old boy suffering from a serious septicemia (“blood poisoning”) and, to their astonishment, discovered that his blood had no gamma globulin at all. Other cases were quickly discovered. Investigators established that this lack is due to an inborn defect of metabolism which deprives the person of the ability to make gamma globulin; it is called agammaglobulinemia. Such persons cannot develop immunity to bacteria. They can now be kept alive, however, by antibiotics. Surprisingly enough, they are able to become immune to virus infections, such as measles and chickenpox, after having the disease once. Apparently, antibodies are not the body’s only defense against viruses.
In 1957, a group of British bacteriologists, headed by Alick Isaacs, showed that cells, under the stimulus of a virus invasion, liberates a protein that has broad antiviral properties. It counters not only the virus involved in the immediate infection but other viruses as well. This protein, named interferon, is produced more quickly than antibodies are and may explain the antivirus defenses of those with agammaglobulinemia. Apparently its production is stimulated by the presence of RNA in the double-stranded variety found in viruses. Interferon seems to direct the synthesis of a messenger-RNA that produces an antivirus protein that inhibits production of virus protein but not of other forms of protein. Interferon seems to be as potent as antibiotics and does not activate resistance. It is, however, fairly species-specific. Only interferon from humans and from other primates will work on human beings.
The fact that human, or near-human, interferon is required and that human cells produce it in only trace quantities, has made it impossible for a long time to obtain the material in amounts sufficient to make it clinically useful.
Beginning in 1977, however, Sydney Pestka at the Roche Institute of Molecular Biology worked on methods for purifying interferon. This was done, and interferon was found to exist as several closely allied proteins. The first alpha-interferon to be purified had a molecular weight of 17,500 and consisted of a chain of 166 amino acids. The amino-acid sequence of a dozen different interferon species were worked out, and there were only relatively minor differences among them.
The gene responsible for the formation of interferon was located and, by means of recombinant-DNA techniques, was inserted into the common bacterium Escherichia coli. A colony of these bacteria was thus induced to form human interferon in very pure form, so that it could be isolated and crystallized. The crystals could be analyzed by X rays, and the three-dimensional structure determined.
By 1981, enough interferon was on hand for clinical trials. No miracles resulted but it takes time to work out appropriate procedures.
New infectious diseases occasionally make their appearance. The 1980s saw a frightening one called acquired immune deficiency syndrome (AIDS) in which the immune mechanism breaks down and a simple infection can kill. The disease, attacking chiefly male homosexuals, Haitians, and those receiving blood transfusions, is spreading rapidly and is usually fatal. So far it is incurable, but in 1984, the virus causing it was isolated in France and in the United States and that is a first step forward.
Cancer
As the danger of infectious diseases diminishes, the incidence of other types of disease increases. Many people who a century ago would have died young of tuberculosis or diphtheria or pneumonia or typhus now live long enough to die of heart disease or cancer. That is one reason heart disease and cancer have become, respectively, the number-one and the number-two killers in the Western world. Cancer, in fact, has succeeded plague and smallpox as a universal fear. It is a nightmare hanging over all of us, ready to strike anyone without warning or mercy. Three hundred thousand Americans die of it each year, while 10,000 new cases are recorded each week. The incidence has risen 50 percent since 1900.
Cancer is actually a group of many diseases (about 200 types are known), affecting various parts of the body in various fashions. But the primary disorder is always the same: disorganization and uncontrolled growth of the affected tissues. The name cancer (the Latin word for “crab”) comes from the fact that Hippocrates and Galen fancied the disease spreading its ravages through diseased veins like the crooked, outstretched claws of a crab.
Tumor (from the Latin word meaning “grow”) is by no means synonymous with cancer but applies to harmless growths such as warts and moles (benign tumors) as well as to cancers (malignant tumors). The cancers are variously named according to the tissues affected. Cancers of the skin or the intestinal linings (the most common malignancies) are called carcinomas (from the Greek word for “crab”); cancers of the connective tissues are sarcomas; of the liver, hepatoma; of glands generall
y, adenomas; of the white blood cells, leukemia; and so on.
Rudolf Virchow of Germany, the first to study cancer tissue under the microscope, believed that cancer was caused by the irritations and shocks of the outer environment. This is a natural thought, for it is just those parts of the body most exposed to the outer world that are most subject to cancer. But when the germ theory of disease became popular, pathologists began to look for some microbe as the cause of cancer. Virchow, a staunch opponent of the germ theory of disease, stubbornly insisted on the irritation theory. (He quit pathology for archaeology and politics when it turned out that the germ theory of disease was going to win out. Few scientists in history have gone down with the ship of mistaken beliefs in quite so drastic a fashion.)
If Virchow was stubborn for the wrong reason, he may have been so in the right cause. There has been increasing evidence that some environments are particularly conducive to cancer. In the eighteenth century, chimney sweeps were found to be more prone to cancer of the scrotum than other people were. After the coal-tar dyes were developed, workers in the dye industries showed an above-average incidence of cancers of the skin or bladder. It seemed that something in soot and in the aniline dyes must be capable of causing cancer. Then, in 1915, two Japanese scientists, K. Yamagiwa and K. Ichikawa, discovered that a certain coal-tar fraction could produce cancer in rabbits when applied to the rabbits’ ears for long periods. In 1930, two British chemists induced cancer in animals with a synthetic chemical called dibenzanthracene (a hydrocarbon with a molecule made up of five benzene rings). This does not occur in coal tar; but three years later, it was discovered that benzpyrene (also containing five benzene rings but in a different arrangement), a chemical that does occur in coal tar, can cause cancer.
Quite a number of carcinogens (cancer producers) have now been identified. Many are hydrocarbons made up of numerous benzene rings, like the first two discovered. Some are molecules related to the aniline dyes. In fact, one of the chief concerns about using artificial dyes in foods is the possibility that in the long run such dyes may be carcinogenic.
