Coincidental killers

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Coincidental killers

A colorized transmission electron micrograph of Escherichia coli bacteria. Photo courtesy Elizabthe H White/CDC

We assume that microbes evolved to attack humans when actually we are just civilian casualties in a much older war

Ed Yong is an award-winning science writer. His blog Not Exactly Rocket Science is hosted by National Geographic, and he has been published in Wired, Nature, New Scientist, The Guardian and The Times.

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The classic novel by H G Wells, The War of the Worlds (1898) – a tale of England besieged by Martian conquerors – ends not with a rousing and heroic victory but an accidental one. The aliens subjugate humanity with heat rays and black smoke but, at the height of their victory, they die. Their machines come to a standstill amid the ruins of a deserted London, and the birds pick at their rotting remains. The cause of their downfall? Bacteria. As the novel’s unnamed narrator says, they were ‘slain, after all man's devices had failed, by the humblest things’.

Wells’s logic was simple. Humans have immune systems that protect us from the infectious germs that we’ve been exposed to since our earliest origins. We still get diseases, but at least we can put up a fight. The Martians, despite their technological superiority, could not. ‘There are no bacteria in Mars,’ the narrator explains, ‘and directly these invaders arrived, directly they drank and fed, our microscopic allies began to work their overthrow.’

When I first read the book about two decades ago, this final twist seemed like a cop-out. It comes out of nowhere – a sort of deus ex microbia rescue – and, besides, Earth’s microbes could not possibly grow in an alien body. But more recently, I have come to realise that Wells, writing at the close of the 19th century, was inadvertently hinting at a truth about bacteria that even today’s microbiologists sometimes forget: these organisms can become lethal through evolutionary accidents.

In the novel, bacteria did not evolve to cripple the aliens. They evolved to target humans and other animals. The invaders unexpectedly stepped into the crossfire, and succumbed. The same can happen to us. Many of the bacteria and fungi that afflict us with severe diseases are not aiming at us at all. Instead, they have evolved to thrive in harsh environments or to fend off other microbes. It just so happens that these same adaptations allow them to thrive in our bodies or to fend off our immune systems.

Consider Streptococcus pneumoniae, a common bacterium that lives in our noses and airways. It is typically harmless but it can sometimes flip from passive passenger to active killer, causing pneumonia, meningitis, sepsis, and other illnesses. This typically happens in people with weakened immune systems, and it’s often the fault of strains that have thick coats of complex sugar molecules that protect them from our immune systems.

But in 2007 Elena Lysenko, then at the University of Pennsylvania School of Medicine, found that there is more to this story than strong microbe meets compromised host. S.pneumoniae shares our airways with other bacteria such as Hemophilus influenzae. These species do not make for happy neighbours, and H.influenzae has been known to marshal its host’s white blood cells to attack its competitor. This strategy usually works. When Lysenko incubated the two microbes together in mice, she found the rodents usually ousted S.pneumoniae from their airways, leaving H.influenzae to rule alone.

But the thickly armoured strains of S.pneumoniae are impervious to white blood cells, and can stand their ground. Their armour would normally be a liability – they take so much energy to make that their owners get outcompeted by strains that make lighter and less costly coats. But with H.influenzae mobilising an immune army, a thick coat suddenly becomes worthwhile. And by coincidence, those coats make these strains better at invading deeper parts of the respiratory system, and causing serious disease. In defending itself from a competitor, S.pneumoniae inadvertently becomes an armoured killer.

Its virulence – its ability to cause disease – is not an adaptation against its host. It is a side effect, a fluke. It kills through coincidence.

In the late 17th century, the Dutch scientist Antonie van Leeuwenhoek created a new type of microscope lens and brought an entire world of tiny organisms into focus. Looking at his own dental plaque, he wrote: ‘I then most always saw with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving.’ These little creatures were intriguing but seemingly unimportant, and few others picked up the baton from van Leeuwenhoek. That changed in the 19th century, when Louis Pasteur and Robert Koch proved that some of these microbes were behind important diseases.

That framing has stuck. Microbes are everywhere, but we take their presence on phones, keyboards, and toilet seats as a sign of filth and squalor. They fill our bodies, helping us to digest our food and safeguard our health, but we view them as adversaries to be drugged and conquered.

This antagonism is understandable. Aside from those of us with access to microscopes, most people will never see microbes with their own eyes. And so we tend to identify microbes with the disease-causing minority among them, the little buggers that trigger the tickling mist of a sneeze or the pustule on otherwise smooth skin. We become aware of their existence when they threaten our lives, and for much of our history, that threat was substantial. Epidemics of smallpox, cholera, tuberculosis, and plague have traumatised humanity, and the fear of these diseases has contaminated our entire culture, from our religious rites to Hollywood films such as Contagion (2012) or Outbreak (1995).

When microbes aren’t killing us, we are largely oblivious to them. So, we construct narratives of hosts and pathogens, heroes and villains, us and them. Those that cause disease exist to reproduce at our expense, and we need new ways of resisting them. And so we study how they evolve to outfox our immune system or to spread more easily from one person to another. We identify genes that allow them to cause disease and we label those genes as ‘virulence factors’. We place ourselves at the centre of their world. We make it all about us.

We might think of antibiotics as modern inventions, but they’re actually weapons that bacteria have been using against each other for aeons

But a growing number of studies show that our anthropocentric view is sometimes unjustified. The adaptations that allow bacteria, fungi and other pathogens to cause us harm can easily evolve outside the context of human disease. They are part of a microbial narrative that affects us, and can even kill us, but that isn’t about us. This concept is known as the coincidental evolution hypothesis or, as the Emory University microbiologist Bruce Levin described it in 2008, the ‘shit happens’ hypothesis.

This hypothesis does not apply to all infections, and is almost certainly irrelevant to viruses, which always need to reproduce in a host. Nor does it apply to the many bacteria and fungi, such as Staphylococcus aureus or Candida albicans, that are long-standing human pathogens and well-adapted to us. But it does explain some weird aspects of many diseases.

Why, for example, would bacteria harm the hosts that they depend on for survival? In some cases, the answer is obvious: they cause symptoms such as sneezing or coughing that help them to spread. But what about S.pneumoniae? Strains that sit harmlessly in a host’s airways are already capable of spreading to another individual. The virulent forms, which descend deeper into the respiratory tract, are actually less contagious. The same goes for bugs such as Hemophilus influenzae and Neisseria meningitidis, which can inflame the protective membranes around the brain and lead to life-threatening cases of bacterial meningitis. In doing so, they risk capsizing their own ship without any hope of boarding a new one.

The coincidental evolution hypothesis helps to resolve these paradoxes. It tells us that at least some human diseases have nothing to do with us at all.

The coincidental evolution hypothesis explains a number of other recent discoveries about microbes. Scientists have found antibiotic resistance genes in bacteria that have been frozen for 30,000 years, or isolated in million-year-old caves. We might think of antibiotics as modern inventions, but they’re actually weapons that bacteria have been using against each other for aeons, or at least well before Alexander Fleming noticed a funky mould in a Petri dish in 1928. Antibiotic resistance genes evolved as part of this ancient war, but they also help today’s microbes to deal with the medicines that we mass-produce.

Likewise, many of the ‘virulence genes’ that help pathogens to cause disease have counterparts in marine microbes with no track record of infecting humans. And some supposedly pathogenic bacteria were often common parts of the environment. ‘These organisms become accidental pathogens,’ says the microbiologist Arturo Casadevall from Yeshiva University in New York. ‘They’ll still be there even if you remove all the animals from the planet. And yet, evolution selected for just the right combination of traits to cause disease in humans.’

We fear lions and tigers and bears; bacteria have to contend with phage viruses, nematode worms, and predatory amoebas

Vibrio cholerae, the bacterium that causes cholera, is a good example. Scientists used to regard it as a human pathogen that spreads when the faeces of infected people seep into water supplies. We now know that it’s mainly a marine species that attaches itself to the shells of small crustaceans, and occasionally makes its way into our water supply. ‘In the last decade, people have begun to accept that a lot of these opportunistic pathogens that people assumed were only in the environment transiently between human hosts are actually environmental bacteria that occasionally end up in humans,’ says Diane McDougald from the University of New South Wales, who studies V.cholerae.

Many of the pathogens we fear most are mere tourists on the human body. Their real homes are oceans, caves, or soils. To understand them, we need to understand them within their natural ecology. Soil, for example, is an extreme habitat for a microbe: harsh and constantly changing. It can quickly oscillate from flood to drought, from scalding heat to freezing cold, and total darkness to intense solar radiation. It’s rife with other competing microbes, and crawling with hungry predators. We fear lions and tigers and bears; bacteria have to contend with phage viruses, nematode worms, and predatory amoebas.

All of these conditions can lead to adaptations that make microbes accidentally suited for life in a human host. We are, after all, just another environment. A thick capsule that shields a microbe from dehydration could also shield it from our immune system. A spore that is adapted for travelling through the air can be easily inhaled into a respiratory tract.

Scientists have demonstrated many of these coincidental adaptations by exposing bacteria to a natural threat and showing that they then become better at infecting humans and other mammals. Escherichia coli, for example, is a common gut bacterium, and a darling of laboratory scientists. In its natural environments, whether the soil or the gut of a mammal, it is menaced by predatory amoebas, which threaten to engulf and digest it. In 2010, the French scientist Frantz Depaulis and colleagues found an E.coli strain called 536 that resists these predators, with genes that protect it from the amoebas’ digestive enzymes and allow it to scavenge nutrients such as iron. Rather than being disintegrated, it actually grows inside its would-be predator and eventually kills it from within.

Many of these protective genes also allow strains of the mostly harmless E.coli to cause severe illness in humans, mice and other mammals. This makes perfect sense. Many of our immune cells, like macrophages, engulf and digest microbes just as amoebas do, so an amoeba-proof bacterium is also a macrophage-proof one. By adapting to their natural predators, strains of E.coli are coincidentally pre-adapted to foil our immune system.

The coincidental evolution hypothesis might be irksome to some. What are the odds that an adaptation to one challenge would perfectly predispose an organism to another? The answer, it seems, is: pretty high. Evolution, however, is all about small probabilities manifesting through long timescales and large numbers – and microbes have both. They have been living on the planet for billions of years, and there are countless legions of them.

Casadevall likes to say that each microbe holds a different hand of cards – adaptations that allow it to cope with its environment. Most of these combinations are meaningless to us. A bacterium might be able to resist being digested by other cells, but it might not be able to grow at 37 degrees Celsius. It might grow at the right temperature, but it might not be able to tolerate our slightly alkaline pH levels. But that doesn’t matter. There are so many microbes out there that some of them will end up with a hand that lets them muscle their way into our game. ‘If you take all the microbial species in the world and imagine that they have these traits randomly, you can find pathogenic microbes for practically anything,’ says Casadevall.

we’re not central actors in the dramas that affect our lives. We are just passers-by

This inevitability paints the rise of new infectious diseases in a new light. The past few decades have seen the rise of terrifying new fungi, such as the chytrid fungus that is massacring the world’s amphibians, or the one behind the White-nose syndrome that has killed millions of North American bats. ‘People ask where these came from,’ says Casadevall. ‘It may just be that their virulence was generated by selection forces that have nothing to do with the hosts they ended up with.’

The same rationale explains why human explorers should be cautious if we ever encounter a planet with microbial life. ‘Most people in infectious disease think that if there are microbes in Mars, what do we have to worry about?’ says Casadevall. ‘They won’t have the right proteins for causing diseases in humans. But if you had enough microbes, there might be pathogens there.’

If that’s the case, these infections might continue being virulent for a long time. ‘When I was a student, parasitologists would tell you that disease was a primitive state in the relationship between a parasite and its host,’ says Levin. ‘Everyone eventually evolves to niceness and co-operation, with symbiosis and mutualism as the endpoints.’ But if virulence is coincidental to begin with, there might not be much of an evolutionary pressure for the inadvertent pathogen to change its ways.

There is something unsatisfying, almost nihilistic, about this idea. It deprives us of answers. As Casadevall wrote in a review, it says that virulence can arise by chance, ‘in a process that has no explanation, except for that it happened’. According to this outlook, we’re not central actors in the dramas that affect our lives. We’re not even bit players. We are just passers-by, walking outside the theatre and getting hit by flying props.

The most important parts of a microbe’s world are, after all, other microbes. They’ve been dealing with each other for billions of years before we came along. When we step into the crossfire of this ancient war, we risk becoming collateral damage. Like Wells’s Martians, we too can be laid low by coincidence.

Read more essays on biology, epidemiology and human evolution


  • Brant

    Great article that shows the limits of our tendency to anthropomorphize our tiny cohabitants.

  • Guest

    This is a fantastic article Ed.

  • Lynn Wilhelm

    What a fantastic article, Ed.

    I especially love this line, "We are just passers-by, walking outside the theatre and getting hit by flying props."

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  • Mike Lewinski

    Although 40 years old now, Lewis Thomas' book The Lives of a Cell: Notes of a Biology Watcher is excellent and worth a read on this subject:

    Some bacteria are only harmful to us when they make exotoxins, and they only do this when they are, in a sense, diseased themselves. The toxins of diphtheria bacilli and streptococci are produced when the organisms have been infected by bacteriophage; it is the virus that provides the code for toxin. Uninfected bacteria are uninformed. When we catch diphtheria it is a virus infection, but not of us. Our involvement is not that of an adversary in a straightforward game, but more like blundering into someone else's accident.


    The microorganisms that seem to have it in for us in the worst way--the ones that really appear to wish us ill--turn out on close examination to be rather more like bystanders, strays, strangers in from the cold. They will invade and replicate if given the chance, and some of them will get into our deepest tissues and set forth in the blood, but it is our response to their presence that makes the disease. Our arsenals for fighting off bacteria are so powerful, and involve so many different defense mechanisms, that we are in more danger from them than from the invaders. We live in the midst of explosive devices; we are mined.

  • someone

    Thanks for the excellent article.

  • AstridH

    Excellent article, Ed. Instead of an anthropocentric view of the world, we should try an ecocentric one.

  • Jayarava

    One thing not mentioned in this article is that, at least in theory, any bacteria can exchange genetic material with any other bacteria. Thus adaptations for survival can be passed on throughout bacterial colonies and across "species". And bacteria seldom exist in mono-cultures. Usually a bunch of them live in loosely symbiotic relationships.

    We may think we are the highest life form on the planet, but really bacteria are the champions.

  • Roy Niles

    "Evolution, however, is all about small probabilities manifesting through long timescales and large numbers – and microbes have both." Actually evolution of living entities is driven by their intelligent reaction to accidents, and coincidence always has an accidental cause. Microbes in other words would not evolve without the accidents that allow them to acquire newer purposes.

  • Sarah

    Very interesting article and comments too. There is a whole world of bacteria I really know nothing about. I'm looking forward to reading more.

  • Jonathan Dunn

    In the materialist reductionist view, agency doesn't even exist - absolutely everything is an "accident". The particle doesn't know it's part of an atom ... and so on up to the neuron that doesn't know it's part of a brain. The parts just respond to local causes, which somehow add up to the eye-of-the-beholder spectacle of the seemingly conscious intelligent being. Through the eye of physics, the scenario of a diligent clockmaker working over a table is a staggeringly complex "accident" - the carbon, oxygen, etc in his body just behave as they would in the bog nearby.

    • fromthepoisonwell

      You can still differentiate between accidents (events without purposes) and events caused by purposes (conscious, goal-driven sentiments) while being a materialist and reductionist. As a compatibilist, I even believe in free will while still being a materialistic determinist.
      The clockmaker, though a large collection of atoms, is still working towards an end and with purpose when building the clock, even if you just view his consciousness as a jumble of biochemistry, grey-matter structures, and neurons; you can still recognize purpose. I'd argue he's still conscious even if the parts are all only responding to local causes. He's self aware whether his atoms are or not. Just like the clock, at the simplest level he may be made up of atoms and small parts, but he's still ticking.

      Tangentially, I'm still torn on whether or not I think it's fair to consider microbes purposive (this article didn't really have a problem with that, even if that was implied/stated: anthropomorphizing is fine by me), but I just found a very interesting old essay arguing against just that, among other things. Though some of it is less-good and even terrible (quotes from Ayn Rand just aren't okay hahaha and I can see people taking issue with the idea that, "On the physical level, the functions of all living organisms, from the simplest to the most complex [...] are actions generated by the organism itself and directed to a single goal: the maintenance of the organism's life." I sure as hell did.), I did find it very interesting. The differentiation between goal-oriented behavior and purpose was a useful way of defining them that I'd never seen before.

      • Jonathan Dunn

        Materialists often say they believe in consciousness but what materialists forget to do generally is look for *proof* of consciousness. The prime merit of the materialist is looking for evidence and for mechanisms. You can believe your neighbor is conscious all day but you'll never get proof. It's just a belief. What kind of a materialist are you if you sprinkle all kind of unmeasurable ghosts on top of your mechanisms? Everyone has beliefs.

        Moreover if you are confident that his behaviors are made up of nothing besides the interactions of smaller pieces then you don't *need* consciousness. There's no room for it. If consciousness doesn't *do* anything, then there's no evidence for it. If the composite pieces and their interactions *do* all of the *doing* in what your neighbor is *doing* then there's no gap to stuff in consciousness, and there's no gap that needs consciousness stuffed into it.

        Is sand falling through the funnel in a hourglass "consciously working toward the end" of filling the bottom compartment? Why or why not? How could you tell? What experiment could you perform to determine objectively whether or not a person's purposes are different from the sand's?

  • Durwin

    I'd hate to have a job in biological science with the name Lysenko.

  • dadawdawd

    the entire freaking universe is not about us?!?
    now - about that whole god/devil thing......

    • Milo

      Um, your response to that one line shows a huge flaw in your ability to reason. So long as the human brain has this reflexive ability that seemingly no other living creature shares, then that 'whole GOD/devil thing' becomes extremely important to the human species in way that it is not to the cockroach, or the chimpanzee. (Though we do know some animal species do have a sense of guilt--dogs, for example.)

  • Milo

    Presumably, there will be a time when humans with their prescience will not exist on planet earth; there will be no species on planet earth with that sense of prescience. But there will be plants, and animals, and microbes until the last days of planet earth as the sun grows into a red giant--still some billions of years away.

  • flowirin

    Wonderful article. Thank you.

  • The Wet One

    That was awesome.

    As a former student of microbiology, it was most enlightening and put my former understanding of the world in question. A good thing.

    So not only are we walking, talking and living hotels for microbes, we're also the innocent victims of drive by shootings of the little buggers.

    Truly, microbes rule the world.