How Medicine Is Unlocking the Evolution of Disease, Accident by Accident
Plague Time: How Stealth Infections Cause Cancers, Heart Disease, and Other Deadly Ailments
by Paul W. Ewald
Free Press, 288 pp., $25
Cancer: The Evolutionary Legacy
by Mel Greaves
Oxford University Press, 276 pp., $27.50
The Rise and Fall of Modern Medicine
by James Le Fanu, M.D.
Carroll & Graf, 512 pp., $26
Fanny Burney was a contemporary of Jane Austen. In her time, Burney was the more popular novelist, and even today one of her novels, Evelina, is still in print, a Penguin classic. Burney moved in very rarefied circles -- she was second keeper of the Robes (one of those delightfully silly titles court aristocracy revels in) to Queen Charlotte, George III's wife, until she married a French general, Alexander d'Arblay, and moved to Paris in 1800. In 1810, she began to suffer from a pain in her right breast, which became so severe in 1811 that she was unable to use her right arm. She consulted M. Dubois, the Empress Josephine's obstetrician. M. Dubois advised rest, but the pain continued to augment, and the "spot" on the breast continued to harden. M. Dubois then consulted a famous surgeon, Baron Larry, who had distinguished himself at the battle of Borodino by dispatching 200 amputations in 24 hours. Larrey recommended the always-hazardous course of surgery.
The surgery was performed on September 30, 1811, and Burney described it in a letter to her sister nine months later -- a letter that took her three months to write, and which, she wrote, "I dare not revise, nor read, the recollection is so painful." The letter is almost unique -- a view of a major medical procedure from the perspective of a patient, rather than a doctor; and a patient, in this case, of extraordinary literary gifts. I must skip the acutely described lead-in to the operation -- her growing pain, her consultations with doctors, her fear of the operation, her desperate sensation that the evil was deep, "so deep I often thought that if it could not be dissolved, it could only with life be extirpated."
Burney was told to prepare some charpie, a linen especially made for surgical dressings, so as to have it on hand for the operation. By a ruse, she contrived to get her husband out of the house on the appointed day, because she knew that, in spite of his military background, he was too sensitive to deal with her pain. Larry arrived with six other doctors, dressed in black, at her house. Burney was given a wine cordial, probably wine infused with laudanum. Two nurses and the maid came to watch the preparations, but the maid and one of the nurses, dreading what was to come, ran off. Burney was made to lie on a mattress, and a handkerchief was put over her face, apparently in the feeble hope that, by not seeing her operation, she would somehow feel it less. But she could see through the semi-translucent tissue, which is how she caught a gesture from the surgeon that signified that he was planning on cutting off the whole breast. She was unprepared for this, and protested, but to no avail. The operation then proceeded:
When the dreadful steel was plunged into the breast -- cutting through veins -- arteries -- flesh -- nerves -- I needed no injunctions not to restrain my cries. I began a scream that lasted unintermittingly during the whole time of the incision -- & I almost marvel that it rings not in my Ears still! so excruciating was the agony. When the wound was made, & the instrument was withdrawn, the pain seemed undiminished, for the air that suddenly rushed into those delicate parts felt like a mass of minute but sharp & forked poniards, that were tearing the edges of the wound -- but when again I felt the instrument -- describing a curve -- cutting against the grain, if I may so say, while the flesh resisted in a manner so forcible as to oppose and tire the hand of the operator, who was forced to change from the right to the left -- then, indeed, I thought I must have expired. I attempted no more to open my Eyes, -- they felt as if hermettically shut, & so firmly closed, that the Eyelids seemed indented into the Cheeks. The instrument this second time withdrawn, I concluded the operation over -- Oh no! presently the terrible cutting was renewed -- & worse than ever, to separate the bottom, the foundation of this dreadful gland from the parts to which it adhered -- Again all description would be baffled -- yet again all was not over, -- Dr Larry rested but his own hand, & -- Oh heaven! I then felt the Knife rackling against the breast bone -- scraping it!
The operation lasted for 17 and a half minutes, and left Burney too weak to move. That night she went into convulsions, but was given some elixer calmante, probably an opiate. The next morning she was better, and was served a little chicken broth. The surgeon, who had removed all the "peccant atoms," as Burney calls them (in our more colorless vocabulary, we call these cancerous cells), apparently didn't miss any. Burney lived for another 20 years. It is interesting to think that, as much as we are impressed by the ghastliness of her situation, she at least did not go into the operation after having experienced the dubious benefits of chemotherapy, nor go out of it having to take anything more toxic than chicken soup. If she could compare her experience to modern therapies for breast cancer, I wonder which she would choose.
What sickens the modern reader is the incredible painfulness of it all. The knife "rackling" against the breastbone haunts the mind much more than any of the bogeymen dreamt up by the gothic novelists who were Burney's contemporaries. Yet if we get past the pre-modernity of Doctor Dubois' "pain management strategy," the account is strangely familiar. We still respond surgically to breast cancer; we still argue over whether mastectomy or lumpectomy (the removal of the infected area only) is more advantageous; and we still don't know what this evil is, where it comes from, or why it emerges.
In Paul Ewald's newest book, Plague Time: How Stealth Infections Cause Cancers, Heart Disease, and Other Deadly Ailments, he advances some bold answers to all these questions. The book presents the heretical thesis that cancers, as well as other chronic illnesses, like heart disease and even mental illnesses like schizophrenia, are infectious diseases. This thesis is contrary to the research agenda of the Eighties and Nineties, which was driven by the assumption that these illnesses, unlike infectious illnesses, arise in the absence of a pathogen, with the causative agent blamed variously on genetics or the environment.
Paul Ewald is a brilliant, and sometimes screwy, evolutionary biologist at Amherst College. It should be emphasized that he is not a virologist. His 1994 book, Evolution of Infectious Disease, was mindblowing, although controversial. In that book Ewald announced that he wanted to bring together The Origin of Species and the Physicians' Desk Reference -- that, in other words, he felt that the evolutionary dynamic of microbes had been neglected and misunderstood in the medical world. His latest book begins by popularizing this idea. Let's call this Ewald's Brilliant Idea Number One, or (ô la Dave Eggers) EBINO.
The best way to understand Ewald's insight is to ask yourself a question: What does a cold virus want? Usually we are very species-centric about our diseases. The sneezing caused by a rhinovirus, the diarrhea caused by Vibrio cholerae, the warts caused by herpes -- these are all symptoms we want to get rid of. And our doctors want to get rid of them too. So asking what the microbe wants seems rather perverse. But if we want to understand infection, Ewald says, we have to look at it from a microbe's eye-view. Microbes are like humans, and like all living things in one way: They want to replicate. Given this hard-wired goal, Ewald says, we should look at how the microbe transmits itself -- which means looking at its life-cycle -- and we should look at the physical characteristics of the pathogen (which part of the body it prefers, whether it can survive outside its preferred environment, etc.). If you have a good grasp of these two features, you can tell what selection pressures the microbe is under -- what dangers it faces, what strategies it uses to overcome those dangers, how it keeps on keepin' on.
The common cold that, dear reader, you no doubt suffered at least once this winter, just wanted other common colds to proliferate. To do this, it might have made you miserable, but it didn't immobilize you. Rather, you probably decided to mask certain of the symptoms, using cold remedies, and went to work, didn't you? From the rhinovirus' point of view, that was precisely what you were supposed to do. Because to get out of you, and to get into other hosts, it needs you to infect people. It doesn't need to knock you off your feet, but it definitely needs to keep you sneezing, and wiping the mucous away, and touching people with that hand.
But let's say you're a plasmodium falciparum, the agent of malaria. What do you want? Well, your life cycle isn't confined to human beings. You are transmitted to human beings via mosquitoes. The mosquitoes get the falciparum from humans, and transmit it to other humans. What you want is for mosquitoes to get a bite to the human epidermis somehow. To do this, humans have to be incapacitated severely. It's best to have them lying down, unwilling to move. Unwilling to raise their hands and brush away the mosquitoes, actually. Let's say that in this process, 20% of your human hosts die. Is this going to be a big tragedy? Not really. Since you are a microbe cycling between mosquitoes and humans, unless there's some evolutionary disadvantage to not killing this many humans, you can continue to ignore a certain amount of host casualties.
The rhinovirus likes the respiratory tract. The syphilis spirochete likes the genitals. STDs have a problem rhinoviruses don't have. Although we have to breathe, we don't have to have sex -- no matter what your boyfriend told you. In order to transmit, STDs have to wait around in the host body, sometimes for long periods of time. To do this, they have to evolve protection from the host's immune system. As Ewald puts it, "they have to act like criminals living in a town that is heavily patrolled by the police."
Ewald goes over this ground only in order to make a big segue to his Brilliant Idea Number Two (EBINT). Notice something about those STDs -- since they have to hang around in your body for long periods of time, it might be possible that other infectious bugs hang around your body for long periods of time. Like all scientists, Ewald is impressed with a good story. The stories of the Eighties that were on the margins while the spotlight was being taken by genetic research were about chronic illnesses -- peptic ulcer, for instance -- that were turning out to be microbe-related. These diseases -- Ewald labels them "stealth diseases," which is a little too Madison Avenue for my taste -- might include artherothrombosis, Alzheimer's, and schizophrenia. They certainly include cervical cancer.
Many people are still unaware that cervical cancer is an STD. In one of the best passages in his book, Ewald explains why human papilloma viruses (HPV) can "ratchet up their harmfulness in response to greater opportunities for sexual transmission." It is a perfect example of using evolutionary means to explain the "stealthiness" of a stealth disease.
So why is it that I finished Plague Time feeling vaguely unsatisfied?
Ewald applies his idea in a one-size-fits-all fashion. Why should I think that, because a bacterium causes peptic ulcer, another one causes Alzheimer's? A further aggravation is that Ewald is too eager to pass EBINT off as some radical, avant-garde idea, which leads him to take, at times, the aggrieved tone of factitious victimage that we expect from an after-dinner speech by Clarence Thomas, not from a tenured scientist. It simply isn't true that the establishment is "against" Ewald's germ theory. It is increasingly against monocausal explanations of chronic illness.
If Ewald is boastful and sometimes careless, Mel Greaves is the Alistair Cooke of cancer researchers -- genial, learned, a little armchair-ish. Greaves is a professor at London's Institute of Cancer Research. His book covers the gamut of cancers. He seems to believe in a pluralistic answer to the enigma of cancer causation in contrast to the approach of pioneers like Lewis Thomas, who thought that all cancers would eventually be discovered to be related. Greaves isn't the kind of guy who is going to give you one brilliant idea.
If Fanny Burney were to read the book, she would of course turn to the chapter on breast cancer. The estrogen-like molecules in some industrial pollutants as well as the estrogen in oral contraceptives have been fingered as henchmen of the Crab. Greaves, however, is curious about endogamous estrogen, the stuff that the body produces on its own. The story he tells is speculative, but it brings out an evolutionary viewpoint oddly unmentioned by Ewald: human evolution.
Greaves' premise is that the first hominid women, who came out of the African jungle around five million years ago, had developed an ovulation cycle that went with having a first period at around 16, an early pregnancy at around 18 or 19, a long period of breast-feeding (maybe as much as 27 months), six or more children, and a shorter life span. Contrast this with the average Swedish woman today. The first period will come at around 12 and a half. The first pregnancy will come at around 30. The period of breast-feeding will last maybe 3 months. And of course the life span will be almost 75 to 80 years, on average. Even granting that our reconstruction of the "primitive woman" is speculative, the difference between the number of ovulatory cycles is striking: For primitive Eve, it is 145; for the Swede, about 440. Throw into this the increase in life span, which would allow the effects of the ovulatory differential to accumulate after menopause.
Greaves does not promote his theory as the complete and full explanation of breast cancer, but it does fit with certain epidemiological curiosities that aren't explained by the virus theory. It was noticed, as long ago as the 18th century, that nuns had a high rate of breast cancer. It was also noticed that, contrary to the pattern of most diseases, breast cancer seemed biased toward the upper class. One of the keys to Greaves' theory is breast-feeding. Breast-feeding has been linked to a reduction of the hormones in the bloodstream that stimulate the ovulatory cycle. It is a sort of natural contraceptive device. Among the !Kung tribe, for instance, where artificial contraception hardly exists, the birth spacing is governed by the amount of time women spend breast-feeding.
James Le Fanu is, like Greaves, a British doctor. He has a polemical case to make in The Rise and Fall of Modern Medicine. The "rise" is what propelled medicine in its "golden age," from 1940 to 1980. The "fall" is what happened since. The term "fall" might startle the layman. What about all the genetic therapies and new discoveries that Time magazine, on slow news weeks, is always hyperventilating about? Le Fanu isn't having any of it. What happened in the golden age was revolutionary, while what is happening now, Le Fanu implies, is hype and nonsense.
Compare the drug discoveries of the Nineties (Prozac, Viagra, perhaps AZT) to what happened in the Forties: In 1941, penicillin was discovered, as well as the pap smear for cervical cancer. In 1944, kidney dialysis was discovered. In 1948, lens transplants for cataracts were first done. In 1949, cortisone was discovered. In 1950, the cure for tuberculosis was discovered, as was the link between smoking and lung cancer. Or think of what life would be like now if the pill, organ transplants, and hip replacements just didn't exist. These things, or at least the technology that made these things possible, were discovered in three years, between 1960 and 1963.
Le Fanu goes through the "rise" by presenting 10 significant moments of medical history, starting with penicillin. We all have a cinematic idea of what medical research is about -- first you search for a cause of a disease, than you find a cure. In Le Fanu's view, we can forget this story. Most of the great discoveries of the past 50 years happened by accident, as substances were discovered that cured diseases of unknown causation by unknown means. For Le Fanu, penicillin is the great model.
Here's how Alexander Fleming discovered penicillin: He found some contaminating mold growing on a petri dish of staphylococchi he had left standing by a window. The mold had sprouted there, on its own, and was destroying the bacteria. But this account understates the element of accident. Other scientists could never reproduce the discovery as Fleming recounted it because, as a matter of fact, penicillium won't usually grow that way. Someone finally discovered that the temperature of London at the end of July, 1928, when Fleming's discovery was made, had been exceptionally cool. This allowed a spore, floating up from the laboratory on the floor below, which was investigating fungi, to grow. Then, the temperature returned to normal, and that allowed the staphylococchi to grow. Penicillin, in other words, was as improbable as the "chance meeting of an umbrella and a sewing machine on a dissecting table," to quote Lautreamont's line which, in June of 1928, surrealists in Paris were proclaiming as an aesthetic principle. Probably Fleming never heard of André Breton, but they were brothers under the skin. As Le Fanu succinctly puts it, "The therapeutic revolution of the post-war years was not ignited by a major scientific insight, rather the reverse: it was the realization by doctors and scientists that it was not necessary to understand in any detail what was wrong, but that synthetic chemistry blindly and randomly would deliver the remedies."
The "fall" of modern medicine is, in some way, the natural consequence of a run of luck. How often can you discover revolutionary molds in your petri dishes? Into the vacuum moved two new medical paradigms, the gene school and the social school of disease.
As for the "wonders" of biotechnology, Le Fanu claims they are simply a repetition of what was already done in the golden age. Since the first triumph of genetically engineered medicine was insulin, Le Fanu examines the motivations which went into the invention of "human insulin," and finds them financial rather than medical. His final verdict on genetic engineering is that, while it is a technically "dazzling" way of making drugs, it is "severely constrained by the fact that the only things that genes can make are proteins." Thus, the only gene drugs we are likely to see are those where a protein is deficient, or those where a sufficient dosage of protein might influence a disease.
This is, of course, a spiritedly one-sided account of genetic medicine. Le Fanu ignores the problems the first wave of drugs, from the golden age, encountered as they diffused through the medical system. Take, briefly, Factor VIII. Factor VIII is used by hemophiliacs, who suffer from an inability of the circulatory system to produce a protein that promotes clotting. Factor VIII was made by concentrating hundreds of units of plasma. This was all very well in the Sixties, when it was first produced and distributed. But something very bad happened in the Seventies and Eighties. The blood system was contaminated with a new virus nobody knew about -- HIV. Hemophiliacs were taking a drug that literally magnified their risk beyond that of any other sector of the population. The result was that half of the hemophiliacs in the USA were infected with AIDS. The proportions are even larger in Germany and France. The genetic engineering of Factor VIII tells us a different story from the one Le Fanu favors -- the "fall" side of medical history is cleaning up a mess from the golden age. The whole sorry story of Factor VIII is told, at some length, in Douglas Starr's wonderful 1998 book, Blood: An Epic History of Medicine and Commerce.
If Le Fanu is scathing about genetic engineering, he is vitriolic about the Social Theory of disease. This theory derives its inspiration from the way cigarettes were fingered as carcinogenic: The statistical link was discovered before the mechanics of it were clear. The Social Theorists, relying on comparative epidemiology tables, have attributed most disease to diet and other environmental factors. The centerpiece of the theory was the supposed link between cholesterol and heart disease, "proving" that the Western diet was the cause of the rise of cardiac disease. Ancel Keys, a Minnesota dietician, was the moving force behind the theory that cholesterol was the culprit. For Le Fanu, the absurdity is that, even at the height of the vogue for the cholesterol explanation, the central mystery of coronary thrombosis -- the thrombosis itself -- was left unexplained. Le Fanu thinks the explanation is now at hand -- like Ewald, he thinks it is probably about an infectious disease, chlamydia pneumoniae.
Reviewing science books, even popular ones, puts an unspoken burden on the reviewer. I'm a layman, and laymen (and women) are usually left out of medical research, except in one way -- it is about us. We get sick. We die, or we don't. "Age is a sicknesse, and Youth is an ambush; and we need so many Phisicians, as may make up a Watch, and spie every inconvenience," John Donne observed. Unfortunately, for every "inconvenience" the physician treats, for every advance in technology, Nature counterbalances with new opportunities for disease. If Factor VIII was a marvelous weapon against hemophilia, it was also, in retrospect, a marvelously quick and efficient pipeline for HIV, and for Hepatitis B. If we extend our life spans, we become more vulnerable to "stealth" diseases. If we depend too much on a proven methodology, we are going to miss infectious diseases that don't correspond to the canonical model. As Le Fanu, with his marvelously denunciatory crankiness, writes, "Genuine progress, optimistic and forward-looking, is always to be welcomed, but progress as ideological necessity leads to obscurantism, falsehood and corruption."