Epidemics: Reading #1


Sonia Shah

The Logic of Pandemics

From: Pandemic  (2016) ― Chapter 9 [excerpts]


[1] There's no straightforward record of the ancient pandemics that plagued us. They can be discerned only obliquely, by the contours of the long shadows they've cast. But according to evolutionary theory and a growing body of evidence from genetics and other fields, pandemics and the pathogens that cause them have shaped fundamental aspects of what it means to be human, from the way we reproduce to the way we die. They shaped the diversity of our cultures, the outcomes of our wars, and lasting ideas about beauty, not to mention our bodies themselves and their vulnerability to the pathogens of today. Their powerful and an­cient influence informs the specific ways modern life provokes pandem­ics the way the tides shape the currents.


[2] Disease is intrinsic to the fundamental relationship between microbes and their hosts. All it takes to confirm that is a brief tour through the history of microbial life and a peek inside our own bodies. Humans dominate the planet in modern times, but in the past, it was the microbes that ruled. By the time our earliest ancestors, the first multicellular organisms, clambered out of the sea around 700 million years ago, microbes had been colonizing the planet for nearly 3 billion years. They had radiated into every available habitat. They lived in the sea, in the soil, and deep inside Earth's crust. . .


[3] For the microbes, our bodies were simply another niche to fill, and as soon as we formed, they radiated into the new habitats our bodies provided. Microbes colonized our skin and the lining of our guts. They incorporated their genes into ours. Our bodies were soon home to 100 trillion microbial cells, more than ten times the number of human cells; one-third of our genomes were spiked with genes that originated in bacteria.


[4] Did our ancestors willingly play host to the intruding microbes that colonized their interiors? Possibly. But probably not. For like the outsized military of an insecure state, we developed a swollen arsenal of weaponry to surveil, police, and destroy microbes. We shed layers of skin to rid ourselves of the microbes that would colonize its surface. We constantly blinked our eyelids to wash microbes off our eyeballs. We produced a bacteria-killing brew of hydrochloric acid and mucus in our stomachs to repel microbes that might attempt to colonize their interiors. Every cell in our body developed sophisticated methods of protecting itself from microbial invasion, and the capacity to kill itself if it failed . . .


[5] We call these culprits "pathogens," but really they are just microbes doing the same thing they do everywhere else: feeding, growing, and spreading. And they do so relentlessly. That's their nature. Under optimal conditions, microbes double their numbers every half hour. They never age. So long as there's enough food around, they won't die unless something kills them. That is to say, they will predictably exploit the resources available to them to the fullest extent possible. If that results in epidemics and pandemics, so be it.


[6] The logic of microbial life and our immune defenses conjure up a pandemic-scarred past. But there's more. Evolutionary biologists and geneticists interpret certain anomalies, such as unusual signatures in our DNA and strange behaviors that are otherwise difficult to explain, as clues, too. For a growing number of experts, they're as suggestive as the trembling hands of a seemingly unscathed trauma victim would be to a criminal detective: only a violent, pandemic-plagued past could explain them. These anomalies are not what most people would consider either strange or hard to justify. They are two fundamental parts of our life cycle: sexual reproduction and death. We take them as given. But for evolutionary bi­ologists, they are puzzling developments in our evolution that demand explanation . . .


[7] It is in light of selfish gene theory that sexual reproduction and death come to seem confounding, for neither sex nor death is a particularly efficient means of disseminating genes, given the alternatives. Consider sexual reproduction. At one time, all life on the planet reproduced asexually (by cloning or other methods). There were no sexually reproducing creatures. But at some point in the history of evolution, sexual reproduction emerged. And yet, from the point of view of our genes, it was a vastly inferior strategy compared to other methods of reproduction. Organisms that clone themselves pass on 100 percent of their genes to their offspring. Sexual reproducers must not only partner up with another individual to reproduce, but both parents lose half of their genes in the bargain, for the resulting child inherits half of its genes from each parent.


[8] To survive, the first sexually reproducing organisms would have had to outcompete the cloners, who dominated the resources and habitats of the planet. But how could they? In the 1970s, the evolutionary biologist William Hamilton created a computer model to simulate what that contest looked like. The simulation set up a population in which half of the individuals practiced cloning and half paired up and had sex. (Imagine a clan of all-female Amazons who replicate themselves without males, alongside a tribe of females who could reproduce only with the help of a male.) Everyone was equally subject to the kind of random deaths that befall populations in the wild, like being attacked by predators or frozen in an ice storm. The model then calculated the reproductive success of the two tribes, counting the number of offspring they each produced.


[9] The cumulative effect of the two different reproductive strategies didn't take long to reach its logical conclusion. Every time Hamilton ran the model, the sexual reproducers rapidly went extinct. Random deaths in the sexually reproducing tribe resulted in a disproportionate loss to the mating pool (as anyone who has tried to find a date after the age of forty can understand intuitively). Not so for the cloners, who maintained their vigorous rate of replication regardless of random losses. It didn't matter that the offspring of the sexually reproducing tribe were more genetically diverse and therefore more resilient to long-term changes in the environment. The burden of random deaths was too immediate to allow those benefits to manifest themselves.


[10] Thus sexual reproduction should have been an experiment that failed. And yet it didn't. Eventually, the reproductive strategy of our distant ancestors spread throughout the animal kingdom, including in us, many years later, in whom it became a central preoccupation. It was Hamilton who offered a startling explanation that solved the mystery: sex evolved because of pathogens. Sexual reproduction requires a profound genetic sacrifice, he noted, but the payback is that the offspring of sexual reproducers are genetically distinct from their parents. That was no advantage in surviving hostile weather or predators, Hamilton observed, but it was a huge advantage in surviving pathogens. That's because pathogens, unlike the weather or predators, refine their attacks on us. 


[11] Imagine a pathogen that first strikes when you're a baby. As you develop, the pathogen goes through hundreds of thousands of generations. By the time you're an adult (if you've survived the ravages of the pathogen) and are ready to reproduce, the pathogen has become far better at attacking you than you are at defending yourself against it. While your genetic makeup has stayed the same, the pathogen's has evolved. But individuals who clone themselves provide pathogens exact replicas of the target they've already gotten so good at stalking. They endow their offspring with the worst possible chances of surviving the pathogen's appetites. Much better, in that case, Hamilton theorized, to produce offspring that are genetically distinct from you, even if that means forsaking half of your own genes.


[12] Scientists have shown how refined pathogens' attacks become over time by experimentally transferring the pathogens of an old individual into a young one. One study cited by the evolutionary zoologist Matthew Ridley focused on long-lived Douglas fir trees, which are routinely attacked by scale insects. (Although scale insects are not microbes, they are disease-causing organisms just like microbial pathogens.) In the wild, old trees are more heavily infected than young ones. This is not because the old trees are weaker than the young ones, as one might think. The old are more heavily infested because their pathogens have had more time to adapt to them. When scientists transplanted the scale insects of an old tree onto a young tree, the young tree suffered the same heavy burden of disease as its elders. It's easy to see how, with pathogens like that around, sexual reproduction would provide a better chance at survival than cloning.


[13] Since Hamilton first articulated his theory about pathogens and the evolution of sex, a large body of supportive evidence has accumulated. Biologists have found that species that practice both sexual and nonsexual reproduction will switch between the two depending on the presence of pathogens. When raised in a lab devoid of their usual pathogens, or in the presence of pathogens that are altered in such a way that they cannot evolve, the roundworm Caenorhabditis elegans will mostly replicate without sex. But when stalked by pathogens, it will reproduce sexually instead. In other experiments, scientists altered roundworms so that they cannot sexually reproduce. When they reared these worms with pathogens, the nematodes went extinct within twenty generations. In contrast, when they allowed roundworms to practice sexual reproduction, they survived alongside their pathogens indefinitely. Withstanding pathogens seems to require the special benefits provided by sexual reproduction.


[14] By forcing the evolution of sex, pathogens may have forced an ad­ditional adaptation: death. The notion that death is some optional thing that can "evolve" may seem counterintuitive. The idea that deterioration and death are inevitable is central to how most of us think about life. We think of the body as a kind of machine that inevitably wears out over time. Individual parts fail and the damage accumulates. Finally, after some critical threshold is passed, the entire machine stops working. Thus we say that nobody can "cheat death." We even equate the word "aging," which is simply the passing of time, with diminishment. (What we really mean is what biologists call "senescence," a gradual deterioration of function proceeds with the passing of time and ultimately leads to death.)


[15] But senescence and death are not inevitable facets of life. There are examples of immortality all around us. Microbes live forever. Trees don't deteriorate with time. On the contrary, as they age they get stronger and more fertile. For microbes and many plants, immortality is the rule, not the exception. There are even some animals that don't age: clams and lobsters, for example. Death, for them, is caused solely by external factors, not internal ones. One way the human body is distinctly different from a machine is that it can repair itself. After we exercise, we repair ourselves from the damage we've inflicted to our muscles. When our bones are broken or skin ruptured, we grow new bone tissue and new skin. (There are even reports of people regrowing severed fingers.)? Our cells have a wide range of ways they repair themselves from insult. Other animals have this capacity to self-repair. Worms rebuild their severed wriggling bodies. Starfish regrow their arms. Lizards regrow their tails. Such repairs actually make us stronger, not weaker.


[16] Scientists have found that far from being an inherently inevitable process, senescence is controlled by particular genes, variously called "suicide genes" or "death genes." Their job is to progressively turn off the processes of self-repair that keep our bodies in good condition. They're like a host switching off the lights at the end of a party. It happens at a certain time, no matter what. The discovery of these genes dates back to the 1970s, when scientists found that removing certain glands from a female octopus could postpone her otherwise inevitable death. Normally, a female octopus will stop eating and die, like clockwork, ten days after she finishes tending her eggs. But surgically removing the glands that control maturation and breeding resulted in an octopus that behaved quite differently. After laying her eggs, she resumed eating and survived for another six months. Scientists have similarly pinpointed genes with no known purpose other than to trigger deterioration and death in worms and flies. When those genes are experimentally inactivated, death is delayed. The worms and flies live on . . .


[17] Both Hamilton's theory about the evolution of sex and the adaptive theory of aging are versions of what's called the "Red Queen Hypothesis," which has revolutionized modern biology. It's named after a scene in Lewis Carroll's Through the Looking Glass. Alice collapses to the ground after a vigorous bout of running with the Red Queen, only to find they'd made no progress at all. "You'd generally get to somewhere else," Alice says, "if you ran very fast for a long time, as we've been doing." The Red Queen explains the logic of why they did not: "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"


[18] What does this mean for our epidemic past and future? According to classic natural selection theory, as articulated in 1859 by Charles Darwin and as taught in high school biology classes around the world, pathogens and their victims adapt to each other over time, evolving to­ward a less fractious relationship. The Red Queen Hypothesis says otherwise. For every adaptation on the part of one species, it holds, there's a counter-adaptation on the part of its rival. What that means is that pathogens and their victims don't evolve toward greater harmony: they evolve increasingly sophisticated attacks on each other. They're like spouses in a bad marriage. They run "very fast and for a long time," but they don't "get to somewhere else."


[19] And that leads to the same conclusion as arguments about the nature of microbes and the immune system and the evolution of sex and death. That is, that the relationship between pathogens and their victims does not evolve toward greater accommodation. On the contrary, it's a continuous battle in which each side evolves increasingly more sophisticated ways to crack the other's defenses. This suggests that epidemics are not necessarily contingent on specific historic conditions at all. Even in the absence of canals and planes and slums and factory farms, pathogens and their hosts are locked in an endless cycle of epidemics. Far from being historical anomalies, epidemics are a natural feature of life in a microbial world.


[20] These theories about sex, death, and pathogens were not formulated to reveal the extent of our long entanglement with pathogens. They were attempts to resolve theoretical problems in natural selection, the corner­stone theory of modern biology. But strange patterns in our genes, and the way geneticists and other scientists have tried to understand what they mean, support their theoretical claims. One of those strange patterns has to do with the nature of gene­tic diversity among us. Colloquially, we say that each of us is "genetically unique," but that's actually not accurate. In fact, we all have the same genes. Each of us has genes that tell the body how to build a nose or how to shape an ear, for example. (A gene is simply a specific segment of DNA where instructions for specific traits are stored.) What we have are different variants of the same gene, for the sequence of chemicals in that segment varies from individual to individual. Your variant, for example, may call for an attached earlobe and mine for a hanging one.


[21] Sex and mutations introduce new variants and combinations into our genomes at a regular clip. But it's a messy process with no direction. It's like blindly throwing a wrench at a bicycle. Most of the time, new variants are downright unhelpful. The genome is degraded by the variant just as the bicycle would be. Sometimes, the variant is neutral and there's no noticeable effect at all. Very rarely, a random variant will happen to coincide with events that make it useful. Over time, unhelpful genetic variants are methodically weeded out while the beneficial ones come to dominate. And so, when geneticists compare the genomes of a bunch of different people at a given moment in time, they expect to find a certain degree of genetic variation, but not a huge amount. And yet, when geneticists zoom in to one part of the genome, they find a singular anomaly. It's the part of the genome where certain pathogen-recognition genes lie. These genes provide instructions for building what are called human leukocyte antigens (HLA), proteins that signal to the immune system when a cell has been infected. (They do this by binding to a fragment of the pathogen and displaying it on the surface of the cell, like a flag.) On this one part of the genome, we've maintained a huge number of variants among us. Our HLA or pathogen-recognition genes are more diverse, in fact, than any other part of the genome, by two orders of magnitude. So far, more than twelve thousand variants have been discovered.


[22] There are two possible explanations for it. Either each of those twelve thousand variants is neutral and thus the variation is meaningless— which is hard to believe given the sheer number of variants— or some powerful force has reversed the normal pressures that reduce variation, making it somehow advantageous for us to maintain a vast library of old genetic variants.


[23] That force may be pathogens causing repeated cycles of epidem­ics. To cause repeated epidemics in the same population, a pathogen must switch between different strains to evade detection, like a thief using different disguises to repeatedly rob the same bank. Retaining a large number of pathogen-detection genes among us ensures that there'll always be a few individuals who can suss out the latest disguise. Each pathogen-detection gene variant thus neither fully dies out nor sweeps into dominance. We carry them around with us, like a treasure chest full of specialized detection tools handed down from generation to generation. What's more, we've been doing this for millennia. We have a lot of old genes in our genomes, genes for useful traits like eyes and brains and backbones, which we share with other species. Our pathogen-recognition genes are on par with these. Some of the pathogen-recognition genes embedded in modern people's genomes are 30 million years old. They've survived among us even as we've split off into different species multiple times. That suggests that pathogens have been cyclically causing epidemics, dying down, then lashing out again for geological eons.


[24] Our genomes also contain clues about a specific pandemic in our past. This one struck the hominid line (of which Homo sapiens are the sole survivors) around 2 million years ago. The evidence lies in a gene that controls the production of a particular compound called a sialic acid. Over the course of three hundred thousand years— a heartbeat in evolutionary time— every individual who produced this sialic acid died out or failed to reproduce, leaving behind only those who didn't produce the sialic acid, because they had variant of the gene that inactivated it.


[25] What could have caused such a dramatic change so quickly? . . . A pandemic caused by a pathogen that invaded cells using the particular sialic acid that was lost could have killed off all the individuals who produced it, leaving only those who didn't. It was probably some form of malaria, noting that the malaria parasite Plas­modium reichenowi, which today causes malaria in chimpanzees, binds to the lostsialic acid, which is called N-Glycolylneuraminic acid, or Neu5Gc. That malaria-like pandemic had profound consequences for the survivors. Their cells, unlike those of every other primate and all other vertebrates, no longer produced Neu5Gc. That meant that any attempt at conception between a survivor and anyone who hadn't lived through the pandemic would have failed. The survivor's immune system would register Neu5Gc-laden sperm cells, or those of a developing fetus, as foreign and attack them; as Varki's experiments on genetically engineered mice have shown, survivors could reproduce only with each other. A new species would have been born. Indeed, according to fossil evi­dence, the first upright, walking hominid species, Homo erectus, diverged from their predecessors, the ape-like Australopithecus, right around the time when New5Gc was lost. If Varki is right, our first pandemic helped make us human.


[26] The striking thing about these findings about ancient pandemics is that the paradoxical observations they're based on were made in the course of unrelated inquiries. Both the discovery of our lost sialic acid and that of the diversity in our pathogen-recognition genes were flukes. Varki discovered the lost sialic acid in 1984, when he administered horse serum to a patient with bone-marrow failure and found that the patient's immune system reacted to the sialic acids in it. He spent decades figuring out why, stumbling upon the story of the ancient pandemic in the process. Scientists discovered the diversity in our pathogen-recognition genes in the course of attempting organ transplants. Unless the donor and recipient shared identical pathogen-recognizing HLA genes, surgeons found, the recipient's immune system would attack the donor's organ as if it were pathogenic. Attempts to match donors and recipients according to their HLA genes revealed the vast scale of variation among us. And yet despite the happenstance nature of these discoveries, both led to conclusions that jibed with the theories of evolutionary biologists . . .


[27] Ancient epidemics and pandemics have cast a long shadow upon us. While connections between our genetic adaptations to ancient epidemics and our vulnerability to modern pathogens have only recently been detectable, thanks to advances in genetic research, scientists expect that many more such connections exist and are yet to be found. It may be that much of our vulnerability to the pathogens of today— and tomorrow— is shaped by how our ancestors survived the pathogens of the past.


[28] Given the outsize role pathogens and pandemics have played in our evolution, it stands to reason that they've probably helped shape our behavior, too. According to psychologists, historians, and anthropologists, they have. The evolutionary psychologists Corey L. Fincher and Randy Thornhill theorize that culture itself— the differentiation of populations into behaviorally and geographically distinct groups— originated as a behavioral adaptation to an epidemic-filled past.


[29] The theory starts with the idea of "immune behaviors." These are social and individual practices that help people elude pathogens, such as avoiding certain landscape features like wetlands or swamps, or practicing certain culinary rituals, like adding spices with antibacterial properties to foods. These behaviors are not necessarily purposely designed to protect people from pathogens; people may not have even been aware that they helped do so. But immune behaviors, once developed, stick around because the people who indulge in them are less vulnerable to infectious diseases. The behaviors, passed down through the generations, become entrenched.


[30] Suggestively, in places where there are more pathogens, there are more ethnic groups (among traditional peoples), and vice versa. Of all the various factors that could potentially predict the level of ethnic diversity in a given region, pathogen diversity is one of the strongest. And in experiments, people who are made more aware of pathogens express greater allegiance to their ethnic group, suggesting that biases toward one's own group, the basis of cultural difference, is indeed linked to fear of disease. In a 2006 study, anthropologists found that eliciting people's fears of contagion (for example, by indicating that a glass of milk they were about to drink was spoiled) heightened their ethnocentrist attitudes, compared to people whose fears of contagion were not thus heightened.


[31] The differentiation of cultural groups by pathogens also dictated the outcome of confrontations between them. Groups of people have been able to vanquish other groups by wielding what McNeill calls an "im­munological advantage." They simply introduce pathogens to which they've adapted but against which their rivals have no immunity. It happened in West Africa three thousand years ago, when Bantu-speaking of the continent, bringing the pathogen with them. They rapidly defeated the hundreds of other linguistic groups believed to have populated the region in what historians call the "Bantu expansion." Immunological advantages allowed the people of ancient Rome to repel invading armies from northern Europe, who perished from the Roman fevers to which locals had adapted. The protection afforded by Rome's immunological advantage rivaled those of a standing army. "When unable to defend herself by the sword," the poet Godfrey of Viterbo noted in 1167, "Rome could defend herself by means of the fever."


[32] Most famously, Europeans conquered the Americas starting in the fifteenth century by decimating native peoples with the Old World pathogens to which they had no immunity. Smallpox introduced by Spanish explorers killed the Incas in Peru and nearly half the Aztecs in Mexico. The disease spread throughout the New World, destroying na­tive populations ahead of European settlement. Meanwhile, the people of tropical Africa repeatedly repelled the forays of European colonizers, who were felled by the malaria and yellow fever to which locals had adapted. (One unhappy result was the development of the brutal Atlantic triangle trade of the sixteenth to nineteenth centuries. Having failed to establish colonies in sub-Saharan Africa, Europeans carried captives from Africa across the ocean to the Americas to serve as slave labor on their sugar plantations.) These and other confrontations, decided by the immunological distinctions among us, continue to reverberate through modern society today. . .


[33] Another curious facet of attractiveness and mate choice that may have originated as a strategy to survive ancient epidemics has to do with pathogen-recognizing HLA genes. Choosing a mate with pathogen-recognition genes different from your own improves the chances that your children will be able to survive a broad range of pathogens. Indeed, couples whose pathogen-recognition genes differ enjoy greater reproductive success than couples whose pathogen-recognition genes are more similar. (They suffer fewer spontaneous abortions and their chil­dren are more closely spaced in age, suggesting that they experience few miscarriages.)


[34] Of course, the composition of other people's pathogen-recognition genes can influence our choices about mates only if we can somehow distinguish between people with similar pathogen-recognition genes and those with exotic pathogen-recognition genes. Although most people are unaware of it, it turns out that we can. Numerous studies have shown that people, like other animals, can sense the composition of others' pathogen-recognition genes by scent. (Precisely how pathogen-recognition genes influence body odor is unclear. It may revolve around how the proteins coded by the genes bind to cells or affect the bacterial fauna in the body that create odors.) And people have preferences based on those odors. In one study, subjects whose pathogen-recognition genes had been typed were asked to wear cotton T-shirts for two nights in a row (while refraining from using perfumes in soaps or other products and eating foods that produced strong odors). The T-shirts were then stuffed into unlabeled jars, which were presented to the subjects to sniff. Each preferred the scent of those T-shirts worn by people whose pathogen-recognition genes differed the most from their own.


[35] That's not to say we choose mates based solely, or even in part, on their body odor, of course. But it's quite possible that we had to in our epidemic-plagued past. To this day we can sniff out the difference and feel a twinge of residual desire based on it. Microbes have exerted a similarly powerful influence on us via their perch from inside our bodies. Scientists are just starting to unravel the mysteries of the microbes that live in and on us, collectively known as the microbiome. So far, they've found that they're often invisible puppet masters, too, with critical processes such as that of brain development in mammals, sex in insects, and immunity in mice triggered solely by the presence of certain microbes.  The microbes that live in human guts influence our risk of developing obesity, depression, and anxiety. They may play a role in controlling our behavior as well. Experimentally ridding mice of their microbes altered their behavior in suggestive ways, reducing both their anxiety responses and ability to perform tasks requiring memory; exposing one mouse to the microbes of another led it to behave in ways that mimic the other.


[37] All of which is to say that our vaunted sense of individuality is an illu­sion. Animals like us, as the evolutionary biologist Nicole King has said, have never been single organisms. For better or worse, we're "host-microbe ecosystems." Microbes shape us from without and also from within. That is to say, pathogens and pandemics are not solely the products of modern life. They're part of our biological heritage. The predicament we find ourselves in today, on the threshold of a new pandemic, is hardly exceptional. It's of a piece with hundreds of millions of years of evolution.


[38] In many ways, we remain as diminished by pathogens today as we were eons ago. Globally, we've conquered barely more than a handful. New pathogens encroach upon us by the hundreds, threatening a pandemic. Meanwhile, old ones continue to exact their pounds of flesh: nearly all of all deaths in people under the age of forty-five are due to infectious disease.


[39] And yet at the same time, our prospects have never been better. Consider the fact that of the three existential challenges faced by all species, pathogens are just one. Our conquest over the other two— predators and Earth's often hostile climate— has been nearly complete. We've been incrementally transforming hostile climes to suit our needs and comforts since our ancestors tamed fire one million years ago, ban­ishing the night and the cold the way our central heating systems and hermetically sealed glass windows do today. Our battle with predators was settled when we walked out of Africa one hundred thousand years ago and into the world's continents, rapidly driving every other large mammal— and the predators that hunted them—into extinction. We rid our habitats of the American lions, the mastodon, the mammoths, the saber-toothed cats, and the other hominids such as Neanderthals that might have preyed upon us. Our sole predators left now are other humans.