It’s a Microbial World After All
The realm of infectious disease is so ripe and attractive as a backdrop for contemplating the catastrophic decimation of populations of species because of its very nature of the microbial world.
We live on a planet dominated—in terms of species biomass—by microbes. This ubiquity is not accidental but the result of the causal forces responsible for the nature of life. The earth was formed 4.6 billion years ago, and life began 1 billion years later. For the majority of that time, life on earth was exclusively microbial species. Mammals represent only a sliver of that nearly 4-billion-year epoch, with humans representing just a sliver of a sliver.
What that microbial multi-billion-year advantage has done is allow microbes time to evolve and diversify to inhabit every niche of this planet, including areas inhospitable to any other form of life. Such environs including radiation-laden environments and undersea heat vents, which are home to extremophile bacteria that are “extreme” in a manner very different than human extreme sports participants.
Viewing the planet in this context, you can see how foolish it is to try and over sterilize one’s life with antibacterial hand sanitizer, respect the 5-second rule for food dropped on the floor, and memorize articles cataloging the density of “germs” in various public locations. Everything is germy and always will be.
Even the human body, soon after birth, becomes virtually melded to its microbial colonizers. These constitute the human microbiota or human microbiome. This patina of microbes has become so essential for life that disruption or alteration of the microbiome has been linked with adverse health outcomes such as Clostridium difficile infection, gastro-esophageal reflux disease (GERD) and possibly will help unravel the mysteries of autism.
We are really unable to live without bacteria. The symbiotic relationship we have with bacteria provides essential physiological support for our life. From synthesizing the vitamin K needed for adequate blood clotting to fending off potential nefarious bacteria by leaving them no space to set up shop, our microbiome is our protector. A disrupted microbiome is not conducive to good health.
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Bacteria, though mere single-celled organisms, are not simple in any sense. They possess many sophisticated genetic and metabolic components. For example, certain bacteria can flip a genetic switch when they sense enough others of their species are present to constitute a quorum. Such quorum sensing provides a massive survival advantage to bacteria that possess the faculty, which, in effect, allows a bacterial colony to operate like a super-organism reminiscent of the societal structure advocated in Plato’s Republic. These bacterial super-organisms can take the form of a biofilm, an impregnable slime layer, that in the certain setting such as the infection of a prosthetic hip, can stymie the power of antibiotics to the great detriment of the patient.
In fact, if looked at from the perspective of an alien race, as I frequently say, the Earth could be described as a planet of bacteria with a spattering of other species that, as Eula Biss puts it in her excellent book, bacteria use to travel about. Of course, this is hyperbole, because bacteria, though ubiquitous, cannot be thought to dominate the planet in the manner in which humans do but it is a perspective that is based on significant and under-appreciated facts.
A similar analysis could be applied to other major members of the microbial world such as fungi and protozoa. It is more complicated with viruses, of which a quadrillion quadrillion exist on earth, because viruses exist on the chasm between animate and inanimate. As such, they do not have the a “life” cycle akin to bacteria or fungi. In fact, some hypotheses have been put forward postulating that viruses are devolved bacteria that have given up some of the trappings of life and the related energy upkeep costs in favor of a simpler existence. In fact, there exist some viruses which are endogenously present in our DNA and are literally part of us, along for the ride of life.
Standing on the Shoulders of Darwin
The veracity of Darwin’s observations and inductions, which coalesced from hypothesis into the theory of evolution by natural selection, are — in the modern context — apparent to anyone who just looks with an active mind. However, there is no better setting in which to witness evolution unravel real time than in the microbial world where the equivalent of world wars and a struggle for existence are occurring continuously.
Any microbe has to fight for its life, competing for sources of food in order to survive, reproduce, and flourish. Some environments are luscious resource-replete locales in which life is relatively easy with little effort required to meet needs. However, situations can be temporary and drastically change for any number of reasons, including cleaning out the fridge some bacteria call home.
Because of the sheer number of bacteria and their ability to reproduce rapidly, mutations will occur routinely. Some mutations may not be beneficial, some will have no effect, and some will be advantageous. Advantageous mutations could allow a microbe to utilize a new food source, withstand extremes of temperature, expand an ecological niche, or develop a weapon to use against competitors.
All of this dynamism of evolution is occurring all the time in the microbial world, irrespective of humans. Remember, humans have only existed for a brief segment of the time that microbes have flourished on this planet. It is only when humans and other organisms appeared that this evolution had implications for health.
For instance, the weapons some bacteria evolve to use against each other and other microbes, sometimes take the form of what we know as antibiotics. Antibiotics are the missiles microbes use against each other to keep outsiders away from their niche and its treasures. In response to these weapons, some bacteria develop anti-weapons systems or antimicrobial resistance mechanisms—naturally, in order to survive.
Antibiotic resistance is often framed as a novel threat because of the role of injudicious antibiotic prescribing (which is a real issue). However, antibiotic resistance is truly almost as old as the planet itself. It has been detected in bacteria that reside within caves in which no human has set foot and also in tribes of remote peoples who have never received an antibiotic prescription. Following this line of reasoning, it becomes clear that our tit-for-tat war with microbes is doomed to end in failure if an antibiotic arms race is our chosen tactic, for the microbes can evolve much faster than we can develop new antibiotics, which ultimately are often derived from them. We are playing on their field using tools they themselves developed.
It is important to recognize that evolutionary pressures do not always select for more virulent or dangerous microbes and, in some cases, may select for less virulence. It all depends on the context. For example, the bacterium that causes the diarrheal illness cholera might be very deadly in one setting but in another much milder. For instance, it has been hypothesized that the level of sanitation has an influence on the volume of the diarrhea produced by Vibrio cholerae, which is spread via the fecal-oral route. In certain situations, voluminous diarrhea gives it the best chance to pass from person-to-person where in others just a little diarrhea can go a long way.
The forces of evolution are manifest in the microbial world and, because of the magnitude of reproduction achievable by microbes (compare the 20-minute doubling time of an E.coli cell vs. that of a human) have real-time consequences for disease and health. Accordingly, these forces play a major role in how we think about and respond to these threats. Conversely, even though we are also indisputable products of evolution, our reproductive time leaves us woefully without an ability to rapidly develop an intrinsic species level adaption, though over centuries, we do fairly well—and better than the Christmas Island rat—as I will discuss at several later points in the book.
There are three touchstone infectious disease emergencies in our species’ past (and present) that highlight important threads that I will draw out and integrate throughout the book. A context-setting thumbnail sketch of each follows.
The Black Death and the Power to Reshape Society
The Black Death, which occurred in the 14th century, is arguably the most important infectious disease outbreak in history. Not only did it shake medical foundations to their core, but it also literally reshaped societal structure in medieval Europe by culling a large swath (1/3rd!) of the population.
The Black Death was an outbreak of plague, a disease caused by infection with the flea-associated bacteria Yersina pestis. This bacteria spreads from fleas to humans and then between humans when it reaches the lungs. It has always been well recognized in its bubonic form in which the lymph nodes in the groin and armpit become markedly swollen.
There have been countless books written about the Black Death as well as extemporaneous accounts such as Boccaccio’s The Decameron and I don’t seek to recapitulate the intricate details. For our purposes, it is important to realize that The Black Death, by killing 1/3 of Europe’s population, is a touchstone in understanding how infectious diseases impact history, world events, geopolitics, and national security. No war or weapon (save biological ones) could ever deliver such a blow as this tiny bacterium did.
With one-third of Europe’s population dead, labor shortages abounded and because of the demand for labor and its reduced supply, it is thought that peasant laborers were able to change the terms of employment via The Peasant’s Revolt—an event that dramatically changed the structural relationship between landlords and their tenants who worked the land. The other element of The Black Death worth emphasizing is the deadly anti-Semitism that sought to blame European Jews for the outbreak. Jews were repeatedly accused of having poisoned wells and were consequently killed in large numbers using horrific means. Societal disruption during such an existential crisis, how The Black Death clearly must have been viewed by those experiencing it, is a major factor in infectious disease outbreaks. You might think that humans have jettisoned something as prejudicial and arbitrary as blaming certain members of society for a disease outbreak, but in large part they haven’t. Just recall HIV/AIDS, Ebola, and even the 2009 H1N1 influenza pandemic, in which North Americans faced stigma.
Malaria: This Leaves a Mark
If something killed half of all humans that ever lived, it is safe to say it is something that would leave its mark on history both literally and figuratively on the human genome. Such is the “achievement” of malaria.
This mosquito-borne scourge of mankind, caused by the Plasmodium species of parasites, still kills at an amazing clip of 1 million humans per year. Though most of the industrial world is now free of malaria—thanks in part to DDT—the planet on the whole is still malarious. In areas in which malaria is endemic, it exacts an enormous toll on the people, robbing parents of their children, confining productive people to their beds, and diverting precious resources to beat back what could’ve been just a problem of the past, as it is in many parts of the world.
Because of the incredible ability of malaria to cull the population of humans, it can be thought of as a Darwinian selection pressure on the population. In other words, because of the myriad, often subtle, genetic differences (i.e., mutations) that exist between humans there may be some that, for whatever reason, are advantageous to those who are infected with malaria. Such an advantage may be that the possessor of the mutation is unable to be infected by the malaria parasite or has only a mild case if infected. Over time those that are resistant to dying from malaria would have more of a chance to reproduce and pass on the protective genes to their offspring. As more and more time passes, a proportion of the population who descended from these “mutants” would exist and be able to flourish in an area that other humans would find inhospitable.
The above is a brief explanation for why such mutations as the one that causes sickle cell anemia was preserved by natural selection. In this case, if one possesses just one of two mutant genes and is only a carrier, they are resistant to malaria and not affected by sickle cell anemia (whereas those with both genes mutated suffer the effects of sickle cell anemia). The offspring of carriers, who would have at least a 50% chance of inheriting the gene from one of its parents, would be evolutionarily privileged in malarious areas where those not so preferred would have a higher chance of succumbing to malaria. Similar mechanics underlie the propagation of other malaria-resistant genetic diseases such as glucose-6-phosphate deficiency (G6PD), thalassemia, hereditary spherocytosis, hereditary elliptocytosis, and the Duffy blood group. To indelibly concretize the point, one just has to superimpose maps of where malaria has been present on the planet and where these genetic mutations are highly prevalent and see the perfect overlap.
The lesson I draw from such a prolific killing machine as malaria is that even when it appears bleak—a 50% kill rate of the human population can’t be described, even if you’re a glass half-full type, as anything but bleak—there is inherent resiliency in humans derived from their genomes.
1918: The Great Influenza
For most of human history, globalization was not fathomable as people tended to locate in one geographic area and not move far from it because of the cost, difficulty, and danger incurred when leaving one’s enclave. That all changed with Christopher Columbus’ path-breaking, heroic, and pioneering voyage of 1492. Indeed, I believe our modern perspective of “a small world”, when viewed in terms of fundamentals, can be traced back to that pregnant voyage that changed so many things.
Fast-forward 400 or so years in the future to the early 20th century and we find ourselves in the midst of the world’s first global conflict in which nations, literally separated by oceans, are engaged in an unprecedented war with each other.
Inserted into the melee was the influenza virus.
This small virus, which hadn’t even been discovered, embarked on a killing spree that dwarfed war casualties. It charted up to 50 to 100 million deaths in its deadly yearlong circumnavigation of the globe, aided by mass global troop movements. By comparison HIV is estimated to have killed 39 million people in its decades of existence.
While debate exists to the original origin of this virus—Kansas vs. China vs. somewhere else—this pandemic concretized for many the ability of an infectious disease, in the modern era, to literally wreak havoc.
There are many books that have been written about this incident detailing the utter calamity the human race was in during the pandemic with shortages, curfews, closures, masks, casket piles, mass graves, and the like becoming a normal part of life. With “just” an estimated 1-2.5% fatality rate with infection, the sheer scope of the respiratory virus’s infectiousness exacted a staggering toll killing about 5% of the extant population of 1 billion humans on Earth in what is really just a blink of time.
Though fictional portrayals of a post-apocalyptic world inhabited by zombies, monsters, and mystery abound in popular culture, one need not delve into the world of science-fiction fantasy to understand pandemics and infectious disease emergencies. One can simply study the course of The Black Death, malaria, and the 1918 influenza pandemic to see worst case scenarios.
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From the above it should, hopefully, be apparent that the human race has been through major infectious disease emergencies that took a horrendous toll on the species who, not knowing the power that laid within their genes, must have thought the end of the universe was at hand (and for those who succumbed indeed it was the end). However, the human race persisted—even in an era before widespread availability of effective supportive medical care, not to mention vaccines, antibiotics, and antivirals. These were not even close to existential or “x-risks” even though they were the biggest foes our ancestors faced from the microbial world.
With these basic facts and a little bit of history at hand, we can now turn to unraveling the alchemy of a pandemic pathogen — the first lens for how I evaluate every infectious disease outbreak.