The great geneticist Theodosius Dobzhansky wrote that in nature nothing makes sense unless we bear in mind that natural selection reigns supreme. In Africa, one of the sources of poverty is a cattle disease caused by a parasite, the trypanosome. The disease is transmitted by the tsetse fly. When this fly stings a cow, the trypanosomes penetrate into her blood, where they are recognized as foreign invaders by some of her white blood cells. Alarmed by that signal, these particular white cells divide and multiply, and their descendants secrete antibodies into the blood that kill the parasites. Alas, not quite all of them. A few survive because genetic mutations have dressed them up in new coats unrecognized by the cow’s antibodies; these survivors now divide and multiply, and force the cow’s immune system to begin the fight all over again. The same battle repeats itself every few weeks.
The Dutch molecular biologist Piet Borst discovered the genetic mechanism that enables the trypanosomes to take up a multitude of different disguises. He found that their chromosomes contain a repertoire of genetic “cassettes,” each capable of directing the manufacture of a different protein coat; mutations can activate such cassettes in turn by inserting them into the same “cassette player.” None of these new coats can fool the cow’s defenses for long because early in life the genes that code for its antibodies have been shuffled in about a hundred million different ways, allowing the cow to make about a hundred million different antibodies, each secreted by a different population of white blood cells. This profligacy ensures that the cow can make antibodies not only against the trypanosomes in all their different guises, but also against all other conceivable infections.
The mutations that change the trypanosomes’ coats, and the shuffling of the genes that gives rise to millions of different antibodies, are chance events. Natural selection causes those of the cow’s white cells that by chance recognize the trypanosomes, and those of the trypanosomes that escape recognition at first, to divide and multiply. The Darwinian struggle between the white cells and the trypanosomes ensures the survival of the population of parasites and also that of their host, the cow, but she becomes emaciated and a poor producer of milk, to the detriment of the farmer.
White blood cells like those that respond to the trypanosomes are the soldiers that spring to an animal’s defense on infection. Robert S. Desowitz’s book introduces the layman to their different uniforms, weapons, and tactics, and to the systems of command that control them, including, surprisingly, our state of mind. The vicious cold that struck you just before your final exams may have penetrated your defenses because mental stress and exhaustion had already made your immune system crumble. Experiments on rats suggest that the immune response can even be suppressed by a conditioned reflex, as if, after a series of exams, the mere sight of another examination paper could suppress it.
The book introduces us to some of the classic experiments on the microorganisms that attack us and our natural defenses against them. Its title, The Thorn in the Starfish, is taken from a discovery made in 1882 by the Russian biologist Elie Metchnikoff. Here is his own account of it:
I was resting from the shock of the events which provoked my resignation from the University [of Odessa] and indulging enthusiastically in researches in the splendid setting of the Straits of Messina.
One day when the whole family had gone to a circus to see some extraordinary performing apes, I remained alone with my microscope, observing the life in the mobile cells of a transparent starfish larva, when a new thought suddenly flashed across my brain. It struck me that similar cells might serve in the defense of the organism against intruders. Feeling that there was in this something of surpassing interest, I felt so excited that I began striding up and down the room and even went to the sea-shore to collect my thoughts.
I said to myself that, if my supposition were true, a splinter introduced into the body of a starfish larva, devoid of blood vessels or of a nervous system, should soon be surrounded by mobile cells as is to be observed in a man who runs a splinter into his finger. This was no sooner said than done.
There was a small garden in our dwelling, in which we had a few days previously organized a “Christmas tree” for the children on a little tangerine tree: I fetched from it a few rose thorns and introduced them at once under the skin of some beautiful starfish larvae as transparent as water.
I was too excited to sleep that night in the expectation of the results of my experiment, and very early the next morning I ascertained that it had fully succeeded.
That experiment formed the basis of the phagocyte theory [phagocytes are the mobile cells he had observed], to the development of which I devoted the next twenty-five years of my life.
As so often, a discovery of great benefit to man was made by observing the humblest of creatures. Soon afterward Metchnikoff went to Paris in order to work out its medical implications in Pasteur’s new laboratory. He then found himself embattled with Paul Ehrlich, the German pioneer of immunology who championed the role of the antibodies in the body fluids and belittled that of Metchnikoff’s bacteria-devouring phagocytes. In reality both proved vital. (Desowitz tells us that Ehrlich’s work initiated a “novalike” explosion of research, which made me wonder if our senses have become so blunted by superlatives that an explosion of mere dynamite slides off unnoticed and only an event capable of blowing up the entire solar system provides a cliché powerful enough to stir us.)
Desowitz supplies health-conscious Americans with recipes for keeping their immune systems vigorous to a ripe old age by taking essential trace metals in addition to their vitamin pills but he warns that these measures will be to no avail to heavy smokers. In Britain, cigarette advertisements have to display the warning, “Smoking may damage your health”; Mrs. Thatcher is said to have dismissed one of her ministers because he prepared legislation that would have prohibited the advertisements altogether. Smoking is the prime cause of lung cancer and one of the prime causes of cardiovascular disease. Desowitz describes other consequences of smoking that are less widely known. One is a depression of the immune system that makes smokers more liable to contract infections; another is paralysis of the tiny hairs lining the windpipe and the lungs that push out dust and bacteria; yet another is perversion of enzymes meant to remove or repair damaged lung tissue, so that they destroy the lung tissue instead and cause the agonizing disease of emphysema.
Allergic reactions may have evolved originally to rid animals of parasitic worms. The antibodies elicited by their presence in the gut do not attack the worms directly, but cause the release of irritants such as histamine that make the host’s gut expel the worms. These same antibodies are activated “by mistake” in hay fever, asthma, and other allergic diseases that plague us. Smoking relieves two allergic conditions, asthma and ulcerative colitis, at least in some of the sufferers. Apparently these patients benefit by the suppression of the immune system that smoking produces.
Vaccination mobilizes the immune system against diseases before they attack us. Its inventor, the English physician Edward Jenner, first tried it in 1778, not on “informed volunteers” but on children recruited from the workhouse. He inoculated them with the cowpox, and afterward his nonphysician nephew Henry Jenner tried to infect them with smallpox pus to see whether they were protected; he also used a non-inoculated child as a “control.” Desowitz was perplexed by the contradiction between Jenner’s religious faith and such ruthless experiments on ignorant children, until an Oxford historian explained to him that these children would have been beyond the protection of the Established Church’s God because they had committed the sin of being born poor; paupers were then considered as fair game as guinea pigs are now. Desowitz writes that the government of Bavaria made vaccination compulsory as early as 1807. It took until 1871 for compulsory vaccination to be made effective in Jenner’s native England, and nearly two hundred years for it finally to be made available to virtually every man, woman, and child in the world. New ways of killing people have always been adopted with alacrity, but ways of preventing illness have sometimes taken centuries to be implemented.
Vaccination may have saved even more lives than antibiotics. The author writes:
In 1921 there were in America some 200,000 cases of diphtheria; in 1934, 250,000 cases of whooping cough; in 1941, 900,000 cases of measles; in 1952, 21,000 cases of polio; and in 1968, 150,000 cases of mumps. By 1982 the widespread immunizations given to children had reduced the yearly incidences to 3 cases of diphtheria, 1,500 cases each of measles and whooping cough, 5,000 cases of mumps, and 7 cases of polio (three of which were caused by the vaccine, a rare untoward occurrence). All this and more (tetanus and rubella are also included in the standard immunizing regime) for a total cost of about ten dollars per child for all immunizations. There has never been a greater bargain.
In 1974 the Surgeon General of the United States announced national goals for the continuing immunization of America—goals that were projected to be achieved by 1990. That program is not only working, it is ahead of schedule. It is just possible that by 1990, or shortly thereafter, measles and polio will become extinct in the United States—historical curiosities.
It is sad that this splendid program is now threatened by budget cutters and by huge damages awarded against pharmaceutical firms whose vaccines have accidentally caused illness or death. Courts should realize that it is no more possible to manufacture an absolutely safe vaccine than it is to make a faultless car, and the public must accept a minimum of risk in return for the immense benefits; otherwise pharmaceutical firms will give up the manufacture of vaccines, since zero risk can be bought only at infinite expense.
Further great advances in vaccination are now in the offing. By 1990 most children in the United States should be vaccinated against mumps, measles, and rubella, and measles might soon be eradicated worldwide, just like smallpox. There already exists a vaccine against hepatitis B, a widespread killer and cause of liver cancer, but it costs $100 a shot. Leprosy still affects about 12 million people. Large-scale clinical trials of vaccines against it are being carried out in Venezuela, India, and Malawi. Research on a vaccine against malaria has become possible since M.J. Friedman in America and G. Pasvol in Britain found out how to culture the malaria parasite in human red blood cells, but there are many technical difficulties still to be overcome. The brightest hope lies in genetically engineering the vaccinia (cowpox) virus, formerly used for vaccination against smallpox, so that it also displays on its surface the markers of other diseasecausing organisms, such as the hepatitis B virus and the malaria parasite. A single shot of this genetic composite should be cheap and would immunize against a variety of diseases. For the distant future, the author forecasts vaccination even against some of the more common cancers.
Of the 90 million children now born in the world each year, 15 million die during their first year of life, and 6 million of these die from preventable infectious diseases, mostly in the third world. In addition to the 15 million dead, 180,000 children become lamed by polio. Much more illness could be prevented cheaply by worldwide vaccination, and Desowitz makes a passionate plea for its being put into effect: mothers in an African village mourn their children as deeply as mothers do in the Western world. I was much taken by Desowitz’s imagined “day in the life of a tropical vaccinator,” a warm-hearted story of a Candide of the third world who sets out from his district health center to vaccinate the children in a distant village against diphtheria, measles, whooping cough, and tetanus. So far only a quarter of the third world’s children have received the combined vaccine, even though it costs only 70 cents per child. Candide’s collection excludes smallpox, because that scourge of mankind had already been eradicated by the World Health Organization in what must have been one of the greatest achievements of international cooperation ever. It is quite remarkable that the organization got everyone at risk vaccinated in even the remotest corners of the globe despite the negligence, irresponsibility, incompetence, and corruption that are typical of many countries and frustrate the author’s Candide at every step.
Some vaccines may be rendered ineffective by malnutrition, which is widespread especially among children in the third world. For undernourished children only the vaccines against smallpox, measles, and polio work, while those against typhoid, mumps, diphtheria, and yellow fever offer no protection. They could be made effective by giving the children a diet high in protein just before and for one or two weeks after vaccination. According to the author, “This modest expedient appears simple enough on paper but is probably mostly impossible in the field as any despairing administrator of a famine-relief program is well aware.” The World Health Organization has laid down minimal nutritional requirements for people of all ages, but these may be inadequate for many among the undernourished quarter of the world’s population, because their intestines are infested by parasites that snatch the food from them and so irritate their bowels that even their minimal rations are poorly absorbed.
In the United States, Desowitz writes, “the Third World may be only a few blocks or a short bus ride away.” According to him, the Physicians’ Task Force on Hunger in America found children suffering from protein-deficiency diseases such as kwashiorkor, making their tummies swell and their bottoms shrink, diseases that were believed to be confined to the tropics. Other children displayed stunted growth, lethargy, and vitamin deficiencies. These children of the American poor, immunologically impoverished and susceptible to infection, are no longer protected by the government-sponsored immunization programs.
When will there be an effective vaccine against AIDS? Desowitz has no answer to this vexing question, but he supplies much interesting and useful information about AIDS. A new disease first came to be suspected in 1979 when a rare form of pneumonia, normally found only in small infants, was diagnosed among five male homosexuals in Los Angeles. Seven years later, 28,000 people in the United States were diagnosed as having AIDS, and 270,000 are forecast for 1991, with a total of 180,000 deaths projected for the twelve-year period, nearly four times the number caused by the Vietnam War.
The AIDS virus was first identified in 1983 by Luc Montagnier at the Pasteur Institute in Paris and named lymphadenopathy-associated virus (LAV). Desowitz prefers to call it human T cell leukemia virus III, a name coined by Robert Gallo at the National Cancer Institute in Bethesda, Maryland, in the belief that it is related to the T cell leukemia viruses. The name now commonly used is human immunodeficiency virus, HIV for short. Desowitz deals at length with the evidence that this virus really is the cause of AIDS, and that the presence of antibodies against it proves people to be carriers of AIDS. He provides detailed descriptions, not fit for the drawing room, of the habits of male homosexuals. Apparently ten different partners in a day and a hundred in a month used to be common, but a recent drastic fall in the incidence of rectal gonorrhea in San Francisco indicates a drop in promiscuity that may slow the spread of AIDS.
AIDS is not catching like a cold, and is normally transmitted by blood transfusions, shared syringes, abrasive, mostly homosexual sex, or across the placenta from an infected mother to her embryo, and rarely by monogamous heterosexual intercourse. Against that, Desowitz cites the worrying finding that a small fraction of AIDS patients in Haiti are just such monogamous people. Some experts believe AIDS to have long been endemic in Africa and to have remained unnoticed, but the author dismisses this view on the grounds that the symptoms are so striking and unique that not even the most obtuse physician could have missed them. On the other hand, examinations of frozen samples of human serum taken in Central Africa in 1959 have shown one sample to contain antibodies against the AIDS virus, whereas AIDS-positive sera have not been found among American or European samples of serum frozen at that time.
Viruses related to the two known AIDS viruses have been found in African monkeys, which made people wonder if transmission from monkeys to man might have initiated the AIDS epidemic. Desowitz dismisses this possibility on the grounds that he has never heard of an African ravishing a monkey, but in a recent issue of The Lancet F. Noireau quotes a book by the anthropologist A. Kashamura on the sex habits and cultures of the people near the Great African Lakes: “To rouse a man or a woman to intense sexual activity, one injects into their thighs, their public region or their back the blood of a male monkey, for a man, or a female one, for a woman.” The book was written before the emergence of AIDS.1 The description is likely to be authentic because Kashamura is a native of the Great Lakes region and wrote the book about the customs of his own people. Noireau concludes that “these magic practices would constitute an efficient experimental transmission model and could be responsible for the emergence of AIDS in man.”2
What hope is there of halting the spread of AIDS or saving its victims? According to Desowitz, “We can’t look forward to the chemotherapeutic magic bullet pill for succour. Chemotherapy research has yet to gift mankind with any practical effective drug to combat any viral disease—let alone AIDS.” In fact a highly effective drug against the herpes family of viruses has been on the market for several years. It is called Acyclovir and was discovered in 1977 by Gertrude Elion, Howard Schaeffer, and D.J. Bauer at the Wellcome Research Laboratories. It relieves the pain and prevents the aftermath of shingles, that tormenting disease of the elderly. Drug firms are now synthesizing hundreds of chemical analogues of Acyclovir in the hope that one of them might prove active against AIDS.
Research on all aspects of AIDS is accelerating. The Public Health Service has asked for $351 million in 1987 and $471 million in 1988 for its support, but the author dismisses this:
Undoubtedly all the new money will buy a mass of information. A small amount of it may even be therapeutically applicable, but the bulk will be the minutiae beloved by scientists.
Such disparagement is unfair to the many good scientists who have put their current work aside to study the AIDS virus and its attack on the immune system. In the short space of four years since the virus’s discovery, they have deciphered its genes, characterized its mode of replication, provided an inventory of its component molecules, and identified the type of white blood cell that harbors it. These are not useless minutiae but the essential preliminaries to a rational therapy. Development of a vaccine against AIDS is difficult because the virus mutates rapidly, possibly even to the extent of differing slightly in each person. Moreover, once a person has been infected, the presence of antibodies against the virus does not prevent the development of the disease, perhaps because the chromosome of the AIDS virus becomes integrated with the chromosomes of the white blood cells of its host, so that the virus becomes part of the host’s own genetic system. It now looks as though many of those whose sera contains antibodies against the AIDS virus may never develop the disease, possibly because of some genetic factor, but it is too early to be certain of this.
In the United States AIDS research is coordinated by the National Institutes of Health, who have enlisted some of the best brains in virology, molecular biology, and biochemistry to work on the problem. There is good hope that these outstanding scientists will find ways of preventing the spread of the terrible disease and of saving its victims. In Britain, the Medical Research Council, a government agency similar to the National Institute of Health, is mobilizing research for vaccines and drugs against AIDS. Similar efforts are underway in other European countries and will soon become worldwide.
The strength of Desowitz’s book springs from his compassion and wide medical experience in many parts of the world. For example, his description of smokers’ emphysema does not end with the analysis of its microscopic manifestations but with the recall of an old friend, the head technician of the London School of Tropical Medicine, who was a chain smoker and succumbed to the disease. His discussion of epidemiology in the tropics goes beyond statistics to the daily problems of poor’ people’s lives. To the layman in the US the book offers much sensible advice about vaccination, diet, and life style, and to anyone concerned about public health much challenging information about preventable disease. Desowitz tries to make laymen understand how the immune system works at the cellular level, but I was disappointed that he stops short of explaining its intriguing molecular mechanism, whose unraveling has been one of the greatest recent triumphs of molecular biology.
The book’s weaknesses are occasional errors, especially in biochemistry; a practical physician’s disdain for basic biomedical science that “has not cured anybody,” but has in fact been responsible for many of the medical advances described here, such as the Salk and Sabin vaccines against polio; and occasional lapses from the popular to the fatuous, such as the author’s final imaginary conversation with two visitors and two colleagues, who claim that the conquest of malaria is purely a question of money, or when he suggests that Pasteur might have delayed a crucial experiment because an exasperated Mrs. Pasteur might have said, “What, Louis, you are going to the laboratory today? This is the weekend you promised to clean out the closets.” How can any American who has lived in Europe imagine that a woman of the French bourgeoisie of the last century would have dared to ask her husband to demean himself with a task that she would have left to her maid? Even today few Frenchmen will handle a duster.
A little further on, we read that Pasteur was “as frugal as any budget-conscious researcher today.” This conjures up a Pasteur counting his research grants, rather than a man who lived during a Spartan time when organized state support for biological science hardly existed and scientists had to improvise with primitive tools often paid for out of their own pockets. The author writes about “a bacteria”; he would not tell us that he is married to “a women,” so why deny the poor bacterium its singular? Laymen would have found it helpful if, in addition to the footnotes explaining technical terms, the book had also included a glossary. However, these are minor faults in what may be the first book that explains our natural defenses against infection lucidly to the layman.
October 8, 1987