The Coming Plague

by Laurie Garrett

  The following year, 1981, David Golde at UCLA found a patient who was suffering from a particularly aggressive type of blood cancer, hairy-cell leukemia, so named because the damaged white blood cells appeared “hairy” under the microscope. Golde discovered that something in the blood of this patient was capable of producing the “hairy” effect on human T-cell lymphocytes grown in the laboratory. Golde named the patient’s cell line MO.18

  Several scientists wondered why Golde’s cell line grew so well in test tubes, since heretofore it had been nearly impossible to raise human T cells in the laboratory. Robert Gallo and UCLA’s Irvin Chen both thought the lab growth capability plus evidence that “something” from the MO cells could transform other human lymphocytes indicated that an infectious cancer-causing agent was involved.

  The hunt was on.

  Chen discovered a second cancer-causing retrovirus in the MO cells, which was dubbed HTLV-II (Gallo’s first virus was then redesignated HTLV-I).19 Chen concluded that HTLV-II had no oncogene, however, and the cancerous behavior of the MO cells seemed to be caused by a defective form of the virus that had emerged in the laboratory as a result of culturing conditions. The finding was confirmed within weeks in three other laboratories. 20

  The impact of these findings was striking. The U.S. National Cancer Institute, for example, would quickly shift resources toward cancer virology, encouraging scientists to search for other cancer-causing human viruses and to further elucidate the link between oncogenes and microbes.

  “We have found oncogenes. We have sequenced those oncogenes. And we have learned that we have these genes in our human genomes normally. That’s both frightening and exciting,” National Cancer Institute director Dr. Vincent De Vita said in 1981. “We’ve put one billion dollars into viral oncology research. Jim Watson asked me to say was it useful or not. What value would I place on it? Every nickel we’ve spent or committed so far has been worth it. We’ve had dividends beyond imagination.”

  That year De Vita ordered all the work in the NIH’s Frederick Laboratory facility switched to the pursuit of links between viruses, oncogenes, and cancer. Thanks to the new molecular biology technologies, it was now possible to conduct such searches with a reasonable degree of speed and efficiency. One segment of known DNA or RNA from, for example, HTLV-I could be used as a probe to search quickly for the presence of its genetic mates in all sorts of animal and human cells.

  The notion that cancer could result from a contagious process was extraordinary, particularly in view of how hard cancer patients and scientists had fought for centuries to dispel precisely that notion. Ever since medical science had learned to differentially diagnose cancer, people had feared the disease’s victims. Prejudice and shame often went hand in hand with the biological horrors of cancer.

  That cultural perspective had begun to shift in the 1960s when the public recognized the link between cancer and a host of chemical toxins, particularly those contained in smoked tobacco. While fears of contagion were erased, they were replaced by apprehension and a considerable amount of anger directed at the sources of chemical carcinogens.21 During the mid-1970s, most Western countries had erected government infrastructures devoted to the regulation and control of human exposure to such chemical carcinogens, monitoring food, water, air pollution, pesticides, auto emissions, industrial waste, housing materials, and so on.

  By the time molecular biologists zeroed in on oncogenes and retroviruses, the political and consumer power of the environmental movement was quite considerable, particularly in North America and the Scandinavian countries. That explains Michael Bishop’s hesitancy to overemphasize the role of viruses in causation of human cancers. His “keyboard” metaphor for triggering oncogenes with a variety of carcinogens—hormones, chemicals, and microbes—was an important way to reconcile the previous emphasis on chemical origins of cancer with the new insights into viral mechanisms of pathogenesis.

  In years to come epidemiologists would strive to understand how such viruses were spread, who gave HTLV-I, for example, to whom. Japanese and German researchers would discover antibodies to HTLV-I in African monkeys and chimpanzees, as well as hunters in Kenya.22 It would quickly be apparent that HTLV-I infections of human beings were clustered in populations not only in Japan23 and the Caribbean24 but also in Surinam25 and Italy.26

  Harvard Medical School virologist Bernard Fields, who tried to perform studies of viral disease agents simultaneously on the micro, laboratory level and the macro, clinical scale, wondered just how relevant all this gene jumping was to human health. He likened viruses to spaceships on a voyage in to a hostile environment. Their payload—the viral DNA or RNA, replete with all its jumping gene and transposing potential—was hidden inside a delivery system that, in Fields’s analogy, included propulsion and navigation systems and a protective capsule capable of withstanding the viral equivalent of an Apollo spacecraft’s heated reentry into Earth’s atmosphere. To gain access to its target cells in the human bloodstream, liver, brain, or whatever organ it was designed to infect, the virus had first to pass through significant hostile territory: the skin, intestinal lining, mucosal barriers in the reproductive tract, protective linings of the nose, mouth, and lungs, and the blood/brain barrier that barred entry to the central nervous system. Fields sought to keep concerns about the newly discovered viruses in check, insisting that the tiniest of microbes would die out if they mutated radically because they would, in the process of mutation, damage their vital payload and delivery systems.

  A few scientists focused their attention on the origins of such viruses. Gallo, for example, forwarded the hypothesis that the HTLV-I and HTLV-II viruses made their way around the world along the shipping routes pioneered by Magellan and slave traders. He and Yamamoto asserted that the viruses originated in African monkeys, spread somehow into the human population, and then found their way around the world via sexual transmission between slaves.27 An alternative theory was that the virus originated in Africa and was carried by Portuguese sailors to the port city of Kyushu during the sixteenth century.28

  A few months before the discovery of HTLV-II was publicly announced, the U.S. National Cancer Institute and the Tokyo Cancer Institute held their 1982 annual Japanese-American cancer meeting, focusing on HTLV-I. The Japanese had trouble narrowing the pool of HTLV-I researchers down to the limit of seven participants who could attend the elite gathering. Research on HTLV-I had exploded in Japan, with over a dozen large laboratories attacking the scientific problem.

  For the Americans, the reverse was the case. Besides Gallo and his staff at the National Cancer Institute, nobody was devoting much attention to HTLV-I, and many leading cancer experts in January 1982 pooh-poohed the significance of the virus. Since the meeting was to be chaired by the Americans, the National Cancer Institute was at pains to find a leader for the gathering who was generally familiar with cancer-causing retroviruses. The institute selected Harvard virologist Myron “Max” Essex, who was one of the world’s experts on the feline leukemia virus (FeLV), a retrovirus that caused cancer in cats.29 The Rhode Island-born Yankee was both a trained veterinarian and microbiologist. At the time the Japanese-American meeting took place, Essex was the newly-appointed Chair of the Department of Cancer Biology at the Harvard School of Public Health.

  As the meeting unfolded it was clear that the Japanese were studying HTLV-I at a feverish pace, and had made impressive strides in elucidating the relationship between the virus and genesis of hairy-cell leukemia.

  Gallo was not happy.

  “I can’t even get people in my own lab interested in working on this virus,” Gallo told Essex. “Nobody in the U.S. is taking this thing seriously, but the Japanese are working like crazy on it. They’re pulling ahead of us.”

  Essex acknowledged that the range and quality of data that various Japanese
scientists had presented were quite good. Gallo leaned over and looked earnestly into Essex’s eyes.

  “Max, you’ve got to get involved.”

  Essex protested that his lab was already overwhelmed with work on other cancer-causing viruses, notably FeLV and hepatitis B,30 which produced liver tumors. But Gallo’s insistence won him over.

  Essex applied the tools his lab had developed for studying T-lymphocyte responses to the cat virus to answer questions about how the human immune system reacted to HTLV-I. He soon demonstrated that, as was the case with FeLV in cats, humans infected with HTLV-I had aberrant immune systems. In particular, their T cells were suppressed or deficient in number, leading to an overall inadequacy of the entire immune system.31

  Researchers from the Tokyo Cancer Institute showed that 100 percent of the Japanese islanders who had hairy-cell leukemias were infected with HTLV-I. But about 12 to 15 percent of the adult residents of the area were also infected, without having cancer: they did, however, suffer a range of immune system disorders.

  Essex was convinced that these striking similarities between HTLV-I and FeLV pointed to some distant time when the viruses moved between host species. Similarly, he was convinced that hepatitis B viruses in various animal species all evolved from a common ancestor: the genes of the human virus were over 40 percent identical to those of a liver-cancer-causing virus found in, of all things, woodchucks.32

  In both species, it would later be shown, the virus caused nearly all hepatocellular carcinomas; perhaps 100 percent of such tumors in the woodchucks and about 90 percent of those in human beings. Worldwide surveillance would eventually reveal that millions of people were infected with the hepatitis B virus, about 15 percent were chronically ill, and as a result, perhaps five million developed liver cancer every year.33 Hepatitis B was not a retrovirus, of course, but a large virus whose genetic material was in organized segments of DNA. Scientists had no idea how the virus caused cancer, and there was no clear link between hepatitis B and any known oncogenes.

  By 1980 there was also strong evidence linking some other DNA viruses to human cancer. As early as the 1960s, Denis Burkitt, a British physician working in Uganda, had noticed that a certain type of lymphoma was extremely common in East Africa, and that its distribution in the human population seemed to follow a clustering pattern: whole families or villages might be afflicted in one area, while virtually no cases of the cancer could be found in a nearby village. He hypothesized that the disease was caused by a transmissible virus.34 British researchers Michael Epstein and Y. M. Barr discovered a new type of herpes virus in cells from Burkitt’s lymphoma patients.35 The tumor was dubbed Burkitt’s lymphoma, the virus Epstein-Barr virus or EBV. Like hepatitis B, EBV was a fairly large DNA virus and scientists could find no immediate explanation for how it caused the lymphomas. Similarly, human papillomavirus was linked to genital cancers, particularly cervical carcinoma.36

  Though much about the connection between viruses and cancer remained obscure, it was an accepted tenet of biology by 1982 that viruses could directly, or perhaps through intermediary chemicals or host genes, cause the changes in cells that were the hallmarks of cancer. It was also generally accepted that such viruses might take years to produce clinically noticeable symptoms in those humans or animals who were infected. Thus, the concept of slow viruses had emerged—an idea epidemiologists found extremely challenging because of the difficulty of showing that a population of people have cancer today due to a virus they were exposed to ten or twenty years ago.

  The remarkable genetic similarities between oncogenes found in all animals, humans, even insects seemed to signal a commonly shared point of vulnerability in a huge range of the planet’s fauna. If a virus adapted to infect, for example, a monkey and deftly switch on the simian’s oncogene, could it not also, with some evolutionary or rapid mutation, gain the ability to enter human cells and switch on the nearly identical Homo sapiens oncogene?

  Given the slow pace of the disease process produced by such viruses, and the ability of some to hide inside animal or human DNA, these microbes were extremely difficult to detect.

  How many more might exist in nature?

  How many types of cancer might prove to be caused by such viruses? Were there other diseases slow viruses might be causing right under the medical establishment’s nose?

  In a very short time scientists would unearth frightening answers to their collective inquiry.

  9

  Microbe Magnets

  URBAN CENTERS OF DISEASE

  When one comes into a city to which he is a stranger, he ought to consider its situation, how it lies as to the winds and the rising of the sun; for its influence is not the same whether it lies to the north or to the south, to the rising or to the setting sun. These things one ought to consider most attentively, and concerning the waters which the inhabitants use, whether they be marshy and soft, or hard and running from elevated and rocky situations, and then if saltish and unfit for cooking; and the ground, whether it be naked and deficient in water, or wooded and well-watered, and whether it lies in a hollow, confined situation, or is elevated and cold …

  From these things he must proceed to investigate everything else. For if one knows all these things well, or at least the greater part of them, he cannot miss knowing, when he comes into a strange city, either the diseases peculiar to the place, or the particular nature of the common diseases, so that he will not be in doubt as to the treatment of the diseases, or commit mistakes, as is likely to be the case provided one had not previously considered these matters. And in particular, as the season and year advances, he can tell what epidemic disease will attack the city, either in the summer or the winter, and what each individual will be in danger of experiencing from the change of regimen.

  —Hippocrates, On Airs, Waters, and Places, c. 400 B.C.1

  I

  In 6000 B.C. there were fewer humans on earth than now occupy New York and Tokyo. Earth’s roughly 30 million prehistoric residents were scattered over vast expanses of the warmer parts of the planet, and few of them ever ventured far from their birthplace. According to what little archaeological information and scientific conjecture is available, their microbial threats came primarily from parasites in their food and water or were carried by local insects.

  Over the next 4,000 years the human population slowly increased and people congregated around rivers, ocean ports, and sites of rich food resources. Trade routes emerged, connecting the nascent urban centers, and the city’s residents thrived off their merchants’ exploits and the taxes they levied on their poorer rural subjects.

  By the time the Egyptians ceased building pyramids, around 2000 B.C., there were several cities with thousands of inhabitants each: Memphis, Thebes, Ur—the religious or political capitals of empires. And by 60 B.C. the vast empires of Rome and China boasted urban centers of tens of thousands of people, which functioned as the hubs of trade and culture for the planet’s 300 million residents.

  By 5 B.C. Rome’s 1 million residents consumed 6,000 tons of grains a week. After the fall of the Roman Empire, no city would again attain such a size for 1,800 years, when London would become the largest metropolis in history up to that time.2

  Cities afforded the microorganisms a range of opportunities unavailable in rural settings. The more Homo sapiens per square mile, the more ways a microorganism could pass from one hapless human to another. People would pass the agent to other people in hundreds of ways every minute of every day as they touched or breathed upon one another, prepared food, defecated or urinated into bodies of water with multiple uses, traveled to distant places taking the microbes with them, built centers for sexual activity that allowed microbes to exploit another method of transmission, produced prodigious quantities of waste that could serve as food for rodent and insect vectors, dammed rivers and unwittingly left cisterns of rain water about to create breeding pools for diseas
e-carrying mosquitoes, and often responded to epidemics in hysterical ways that ended up assisting the persistent microbes.

  Cities, in short, were microbe heavens, or, as British biochemist John Cairns put it, “graveyards of mankind.”3 The most devastating scourges of the past attained horrific proportions only when the microbes reached urban centers, where population density instantaneously magnified any minor contagion that might have originated in the provinces. And microbes successfully exploited the new urban ecologies to create altogether novel disease threats.

  Warfare, trade, the occasional need to put down local peasant uprisings during times of elevated taxation or famine, religious pilgrimages, and the seductive lure of the city for adventurous youth guaranteed that continuous cycles of new microbial invasions would beset urban populations which generally lacked protective immunity.

  The microbes’ transmissive success was guaranteed among a city’s poor, and every urban center had its marginalized neighborhoods where malnourished, immunodeficient people lived in high-density squalor. Urban poverty and disease went hand in hand not only because insufficient diets weakened people’s immune systems but also because of their living conditions. If the Roman patricians occasionally suffered dysentery because of bacteria in the aqueducts, the plebeians downstream were guaranteed a doubled exposure due to the additional bacterial burden of the patrician’s contaminated waste.

  The life expectancy of ancient Rome’s populace was far shorter than that of the Empire’s citizens in rural Mediterranean or North African areas. Only about one of every three Roman residents saw the ripe old age of thirty, compared with 70 percent of their rural counterparts. Virtually nobody in the city lived to eighty, whereas about 15 percent of the pastoral citizens attained that goal.4