Rare diseases are defined as diseases that afflict no more than one person in two thousand, and there is a paradox at their heart, which is that although each disease doesn’t affect many people, collectively they affect a lot. Altogether there are about seven thousand rare diseases—so many that about one person in seventeen in the developed world has one, which isn’t very rare at all. But, sadly, so long as a disease affects only a small number of people, it is unlikely to get much research attention. For 90 percent of rare diseases, there are no treatments at all.

  A second category of disorders that have become more common in modern times, and represent a much greater risk for most of us, is what Professor Daniel Lieberman of Harvard calls mismatch diseases—that is, diseases brought on by our indolent and overindulgent modern lifestyles. The idea, roughly, is that we are born with the bodies of hunter-gatherers but pass our lives as couch potatoes. If we want to be healthy, we need to eat and move about a little more like our ancient ancestors did. That doesn’t mean we have to eat tubers and hunt wildebeest. It means we should consume a lot less processed and sugary foods and get more exercise. Failure to do that, however, is what is giving us the disorders like type 2 diabetes and cardiovascular disease that are killing us in great numbers. Indeed, as Lieberman notes, medical care is actually making things worse by treating the symptoms of mismatch diseases so effectively that we “unwittingly perpetuate their causes.” As Lieberman puts it with chilling bluntness, “You are most likely going to die from a mismatch disease.” Even more chillingly, he believes that 70 percent of the diseases that kill us could easily be preventable if we would just live more sensibly.

  * * *

  —

  When I met Washington University’s Michael Kinch in St. Louis, I asked him what he believed was the greatest disease risk to us now.

  “Flu,” he said without hesitation. “Flu is way more dangerous than people think. For a start, it kills a lot of people already—about thirty to forty thousand every year in the United States—and that’s in a so-called good year. But it also evolves very rapidly, and that’s what makes it especially dangerous.”

  Every February, the World Health Organization and the Centers for Disease Control get together and decide what to make the next flu vaccine from, usually based on what’s going on in eastern Asia. The problem is that flu strains are extremely variable and really hard to predict. You are probably aware that all flus have names like H5N1 or H3N2. That is because every flu virus has two types of proteins on its surface—hemagglutinin and neuraminidase—and these account for the H and N in their names. H5N1 means that the virus combines the fifth known iteration of hemagglutinin with the first known iteration of neuraminidase, and for some reason that is a particularly nasty combination. “H5N1 is the version commonly known as bird flu, and it kills between 50 to 90 percent of victims,” says Kinch. “Luckily, it isn’t readily transmissible between humans. So far this century, it has killed about four hundred people—roughly 60 percent of those it has infected. But look out if it mutates.”

  Based on all the available information, the WHO and CDC announce their decision on February 28, and all the flu vaccine manufacturers in the world begin working on the same strain. Says Kinch, “From February to October they make the new flu vaccine, in the hope that we will be ready for the next big flu season. But when a really devastating new flu emerges, there’s no guarantee that we will actually have targeted the right virus.”

  In the 2017–18 flu season, to take one recent example, people who had been vaccinated were only 36 percent less likely to get flu than those who hadn’t been vaccinated. In consequence, it was a bad year for flu in America, with a death toll estimated at eighty thousand. In the event of a really catastrophic epidemic—one that killed children or young adults in large numbers, say—Kinch believes we wouldn’t be able to produce vaccine fast enough to treat everyone, even if the vaccine was effective.

  “The fact is,” he says, “we are really no better prepared for a bad outbreak today than we were when Spanish flu killed tens of millions of people a hundred years ago. The reason we haven’t had another experience like that isn’t because we have been especially vigilant. It’s because we have been lucky.”

  *1 Because of the similarity of symptoms and difficulty of diagnosis, it is sometimes lumped in with chronic fatigue syndrome (CFS) but is really quite different. CFS (formally myalgic encephalomyelitis) tends to affect individuals, while epidemic neuromyasthenia hits populations.

  *2 When talking of diseases, people often use “infectious” and “contagious” interchangeably, but there is a difference. An infectious disease is one caused by a microbe; a contagious disease is one transmitted by contact.

  21 WHEN THINGS GO VERY WRONG: CANCER

  We are bodies. They go wrong.

  —TOM LUBBOCK, UNTIL FURTHER NOTICE, I AM ALIVE

  I

  CANCER IS THE malady most of us fear more than any other, yet much of that dread is fairly recent.*1 In 1896, when the newly founded American Journal of Psychology asked people to name the health crises they most feared, hardly any mentioned cancer. Diphtheria, smallpox, and tuberculosis were the most worrying afflictions, but even lockjaw, drowning, being bitten by a rabid animal or caught in an earthquake were more fearsome to the average person than cancer.

  Partly this was because people in the past often didn’t live long enough to get cancer in great numbers. As a colleague told Siddhartha Mukherjee, author of The Emperor of All Maladies, a history of cancer, “The early history of cancer is that there is very little early history of cancer.” It isn’t that cancer didn’t exist at all, but more that it didn’t register with people as something probable and fearful. In that sense it was rather like pneumonia now. Pneumonia is still the ninth most common cause of death, yet few of us greatly fear dying from it because we tend to associate it with frail elderly people who are about to shuffle off anyway. So it was for a very long time with cancer.

  All that changed in the twentieth century. Between 1900 and 1940, cancer jumped from eighth place to second place (just behind heart disease) as a cause of death, and it has cast a long shadow over our perceptions of mortality ever since. Today some 40 percent of us will discover we have cancer at some point in our lives. Many, many more will have it without knowing it and will die of something else first. Half of men over sixty and three-quarters over seventy, for instance, have prostate cancer at death without being aware of it. It has been suggested, in fact, that if all men lived long enough, they would all get prostate cancer.

  * * *

  —

  Cancer in the twentieth century became not only the great dread but the great stigma. A survey of physicians in America in 1961 found that nine out of ten did not inform patients when they had cancer because the shame and horror of it were so great. Surveys in Britain at about the same time found that roughly 85 percent of cancer patients wished to know if they were dying but that between 70 and 90 percent of doctors declined to tell them anyway.

  We tend to think of cancer as something we catch, like a bacterial infection. In fact, cancer is entirely internal, a case of the body turning on itself. In 2000, a landmark paper in the journal Cell listed six attributes in particular that all cancer cells have, namely:

  They divide without limit.

  They grow without direction or influence from outside agents like hormones.

  They engage in angiogenesis, which is to say they trick the body into giving them a blood supply.

  They disregard any signals to stop growing.

  They fail to succumb to apoptosis, or programmed cell death.

  They metastasize, or spread to other parts of the body.

  What it comes down to really is cancer is, appallingly, your own body doing its best to kill you. It is suicide without permission.

  “That’s why cancers aren’t contagious,” says Dr. Josef Vormoor, founding clinical director of pediatric hemato-oncology at the new Princess Máxima Center for childhood cancers in Utrecht, the Netherlands. “They are you attacking you.”

  Vormoor is an old friend, whom I first met when he was in a previous post as director of the Northern Institute for Cancer Research at Newcastle University in England. He joined the Princess Máxima Center shortly before its opening in the summer of 2018.

  Cancer cells are just like normal cells except that they are proliferating wildly. Because they are so seemingly normal, the body sometimes fails to detect them and doesn’t invoke an inflammatory response as it would with a foreign agent. That means that most cancers in their early stages are painless and invisible. It is only when tumors grow big enough to press on nerves or form a lump that we become aware that something is wrong. Some cancers can quietly accrete for decades before they become evident. Others never become evident at all.

  Cancer is quite unlike other maladies. It is often relentless in its attacks. Victory against it is nearly always hard won and often at great cost to the victim’s overall health. It will retreat under an onslaught, regroup, and return in a more potent form. Even when seemingly defeated, it may leave behind “sleeper” cells that can lie dormant for years before springing to life again. Above all, cancer cells are selfish. Normally, human cells do their job, then die on command when instructed to by other cells for the good of the body. Cancer cells don’t. They proliferate entirely in their own interests.

  “They have evolved to avoid detection,” says Vormoor. “They can hide from drugs. They can develop resistance. They can recruit other cells to help them. They can go into hibernation and wait for better conditions. They can do any number of things that make it hard for us to kill them.”

  Something we have only recently realized is that before cancers metastasize, they are able to prepare the ground for an invasion in distant target organs, probably through some form of chemical signaling. “What this means,” Vormoor says, “is that when cancer cells spread to other organs, they don’t just turn up and hope for the best. They already have a base camp in the destination organ. Why certain cancers go to certain organs, often in distant parts of the body, has always been a mystery.”

  We need to remind ourselves from time to time that these are brainless cells we are considering here. They are not willfully malevolent. They are not plotting to kill us. All they are doing is what all cells try to do—survive. “The world is a challenging place,” says Vormoor. “All cells have evolved a repertoire of programs that they use to help protect themselves from DNA damage. They are just doing what they are programmed to do.”

  Or as one of Vormoor’s colleagues, Olaf Heidenreich, explained it to me, “Cancer is the price we pay for evolution. If our cells couldn’t mutate, we would never get cancer, but we also couldn’t evolve. We would be fixed forever. What this means in practice is that although evolution is sometimes tough on the individual, it’s beneficial for the species.”

  Cancer is actually not one disease, but a suite of more than two hundred with lots of different causes and prognoses. Eighty percent of cancers, known as carcinomas, arise in epithelial cells—that is, the cells that make up the skin and the linings of organs. Breast cancers, for instance, don’t just grow randomly within the breast, but normally begin in the milk ducts. Epithelial cells are assumed to be particularly susceptible to cancers because they divide rapidly and often. Only about 1 percent of cancers are found in connective tissue; these are known as sarcomas.

  Cancer is above all an age thing. Between birth and the age of forty, men have just a one in seventy-one chance of getting cancer and women one in fifty-one, but over sixty the odds drop to one in three for men and one in four for women. An eighty-year-old person is a thousand times more likely than a teenager to develop cancer.

  Lifestyle is a huge factor in determining which of us get cancer. More than half of cases, by some calculations, are caused by things we can do something about—smoking, drinking to excess, and overeating primarily. The American Cancer Society found a “significant association” between being overweight and incidence of cancer of the liver, breast, esophagus, prostate, colon, pancreas, kidney, cervix, thyroid, and stomach—just about everywhere, in short. How exactly weight tips the balance is not at all understood, but it certainly seems to.

  Environmental exposures are also a significant source of cancers—more perhaps than most of us realize. The first person to notice a connection between environment and cancers was a British surgeon, Percivall Pott, who in 1775 noted that scrotal cancer was disproportionately prevalent among chimney sweeps—indeed, was so particular to the profession that the disorder was called chimney sweep’s cancer. Pott’s investigation into their plight, in a work called Chirurgical Observations: Relative to the Cataract, the Polypus of the Nose, the Cancer of the Scrotum, the Different Kinds of Ruptures, and the Mortification of the Toes and Feet, was notable not only for identifying an environmental source for a cancer but in showing some compassion for the poor chimney sweeps, for even in that hard and neglectful age they were a forlorn group. From earliest childhood, Pott recorded, sweeps were “frequently treated with great brutality, and almost starved with cold and hunger; they are thrust up narrow and sometimes hot chimnies, where they are bruised, burned, and almost suffocated; and when they get to puberty, become peculiarly liable to a most noisome, painful, and fatal disease.” The cause of the cancer, Pott discovered, was an accumulation of soot in the sweeps’ scrotal folds. A good wash once a week stopped the cancer from arising, but most sweeps didn’t get a weekly wash, and scrotal cancer remained a problem until late in the nineteenth century.

  No one knows, because it is essentially impossible to determine, to what extent environmental factors contribute to cancers now. More than eighty thousand chemicals are produced commercially in the world today, and by one calculation 86 percent of them have never been tested for their effects on humans. We don’t even know much about the good or neutral chemicals around us. As Pieter Dorrestein of the University of California at San Diego told a journalist from the journal Chemistry World in 2016, “If one asks the question what are the ten most abundant molecules in the human habitat, no one can answer.” Of the things that might harm us, only radon, carbon dioxide, tobacco smoke, and asbestos have been studied really extensively. The rest is mostly speculation. We inhale a lot of formaldehyde, which is used in flame retardants and the glues that hold together our furniture. We also produce and breathe in a lot of nitrogen dioxide, polycyclic hydrocarbons, semi-organic compounds, and miscellaneous particulates. Even the cooking of food and the burning of candles can throw off particulates that may do us no good at all. Although no one can say to what extent pollutants in air and water contribute to cancers, it has been estimated that it may be as much as 20 percent.

  Viruses and bacteria cause cancers, too. The World Health Organization in 2011 estimated that 6 percent of cancers in the developed world but 22 percent in low- and middle-income countries are attributable to viruses alone. This was once a very radical idea. In 1911, when Peyton Rous, a recently qualified researcher at the Rockefeller Institute in New York, found that a virus caused cancer in chickens, the discovery was universally dismissed. In the face of opposition and even some ridicule, Rous dropped the idea and turned to other research. It was not until 1966, more than half a century after his discovery, that he was formally vindicated with the award of a Nobel Prize. We now know that pathogens are responsible for cervical cancer (caused by the human papillomavirus), Burkitt’s lymphoma, hepatitis B and C, and several others. Altogether, it has been estimated, pathogens may account for a quarter of all cancers globally.*2

  And sometimes cancer just seems to be cruelly random. About 10 percent of men and 15 percent of women who get lung cancer are not smokers, have not been exposed to known environmental hazards, or have not faced any other increased risks, as far as can be told. They are just, it seems, very, very unlucky, but whether they are unlucky in a fateful sense or a genetic one is usually impossible to say.

  One thing is common to all cancers, however. Treatment is rough.

  II

  IN 1810, THE English novelist Fanny Burney, while living in France, developed breast cancer at the age of fifty-eight. It is almost impossible to imagine how horrifying this must have been. Two hundred years ago, every form of cancer was horrible, but breast cancer especially so. Most victims suffered years of torment and often unspeakable embarrassment as a tumor slowly devoured their breast and replaced it with an open hole from which seeped foul fluids that made it impossible for the poor victim to mix with others, sometimes even with her own family. Surgery was the only possible treatment, but in the days before anesthetics it was at least as painful and distressing as the cancer itself and was nearly always lethal.

  Burney was told that her only hope was to undergo a mastectomy. She recounted the ordeal—“a terror that surpasses all description”—in a letter to her sister Esther. Even now it makes painful reading. On a September afternoon, Burney’s surgeon, Antoine Dubois, came to her house with six assistants—four other doctors and two students. A bed had been moved to the middle of the room and space around it cleared for the team to work.

  “M. Dubois placed me upon the mattress, and spread a cambric handkerchief upon my face,” Burney reported to her sister. “It was transparent, however, and I saw through it that the bedstead was instantly surrounded by seven men and my nurse. I refused to be held; but when, bright through the cambric, I saw the glitter of polished steel—I closed my eyes. When the dreadful steel was plunged into the breast—cutting through veins—arteries—flesh—nerves—I needed no injunctions to restrain my cries. I began a scream that lasted intermittingly during the whole time of the incision—and I almost marvel that it rings not in my ears still, so excruciating was the agony….I felt the instrument—describing a curve—cutting against the grain, if I may say so, 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.”