The Evolutionary Arms Race Remember the Red Queen in Alice in Wonderland?



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The Evolutionary Arms Race



  • Remember the Red Queen in Alice in Wonderland?

  • “A slow sort of country!”, said the Queen. “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.”

  • Microbes and humans are locked in a perpetual evolutionary arms race

  • Each side must continually evolve in response to evolutionary changes in the other

  • Leigh Van Valen’s Red Queen hypothesis says that organisms are doomed to extinction if they can’t keep pace with evolutionary changes in the organisms they interact with

  • Van Valen thinks that coevolution in response to changes in other organisms is even more critical than evolution in response to changes in the physical environment

  • And I think he’s probably right, especially where our coevolution with microbes is concerned…


  • Coevolution shapes our relationship with the microbial world

  • Coevolution occurs when an evolutionary change in one organism leads to an evolutionary change in another organism that interacts with it

  • Each side must match the other, advantage for advantage

  • It’s the ultimate high stakes poker game – the stakes are life and death!

  • We thought we were winning that game in the 1940’s, thanks to penicillin

  • This new “magic bullet” would save us once and for all from our microbial foes

  • Penicillin is produced in nature by the fungi in the genus Penicillium

  • It was the wonder drug of the day - and its discovery was a happy accident…


  • Sir Alexander Fleming is usually credited with discovering penicillin in 1928

  • But Ernest Duchesne actually beat Fleming to the punch by over thirty years

  • Duchesne was a French medical student at l’Ecole du Service de Santé Militaire de Lyon (the Military Health Service School of Lyon, in France)

  • The story goes that he happened to notice that the Arab stable boys, at the Army Hospital stables, were intentionally storing their saddles in damp, dark rooms, to encourage mold to grow on them

  • They explained that the moldy saddles helped saddle sores to heal better

  • He tested an extract from the mold on sick guinea pigs, and cured them all!

  • This species of Penicillium, Penicillium glaucum , (now renamed Penicillium expansum), was effective against E. coli bacteria, and could even kill the Salmonella bacterium that causes typhoid fever (which Fleming’s species, Penicillium notatum, couldn’t do)

  • Duchesne’s 1897 dissertation was titled “Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes”

  • He wasn’t the first person in history to make the connection between infection and mold

  • The practice was widespread in antiquity

  • Pliny the Elder, for example, recommends using mushrooms for wounds

  • Egyptian beer was actually therapeutic, and commonly used to treat wounds!

  • Both the beer, and the yeast preparation used to make it, contained the antibiotic tetracycline


  • We’ve extracted tetracycline from several Nubian and Egyptian mummies, and the evidence suggests it was absorbed over a period of several years during their lifetime

  • Bread was made by exposing it to the air to pick up yeast cells, which also exposed it to contamination by other microbes


  • Using partially baked bread in the brewing process probably introduced spores of the bacterium Streptomyces, which later produced the antibiotics


  • While the bacterium doesn’t make a lot of antibiotic in the bread itself, it really turns it on in the more challenging environment of brewing beer

  • And yes, the ancient Egyptians seem to have been well aware of the beneficial health effects of drinking their native brew


  • It was a much less alcoholic and much more nutritious drink than the one we make today, more like a thick soup, and they used it medicinally for everything from mouthwash to feminine hygiene!

  • So Duchesne wasn’t the first person to make the connection between natural antibiotics and infection


  • Regarding Duchesne’s work, Pasteur says that the same species of mold studied by Duchesne was “used for centuries by the peasants in the steppes of Russia and the plains of Brittany and was reputed to heal sores contracted in the fields”

  • Lister even used an extract of Penicillium glaucum in 1884 to cure one of his patients

  • One of Pasteur’s students was a well-loved and inspiring teacher named Gabriel Roux, who became Duchesne’s’s mentor

  • And, stable stories to the contrary, it was Roux who suggested that Duchesne look at the competition between bacteria and fungi – a novel idea, at the time

  • Roux was an expert on fungi, director of the Lyon municipal water quality laboratory

  • He knew that fungal spores could be cultured from distilled water, but not from city tap water or city fountains

  • There must be a microorganism in the city water that competed with the fungus and destroyed it

  • Many people beat Duchesne to the punch …

  • But Duchesne, to his credit, was the first one to actually experiment on the problem, and to publish his results – which were completely ignored

  • The Pasteur Institute didn’t even bother acknowledging that they had received his dissertation

  • And his army service intervened, preventing him from continuing his work

  • He died at the age of 37, probably from tuberculosis – his wife had died from it 8 years earlier

  • Fast forward thirty-two years later, Fleming was culturing staph bacteria in his lab, and happened to notice that a fuzzy blue-green mold had infected one of his plates, and seem to be killing nearby clumps of bacteria

  • He isolated the mold and cultured it, and observed that it killed several different kinds of bacteria

  • Penicillin is a very effective killer

  • It doesn’t actually kill bacteria outright, as we generally believe, but it keeps them from reproducing, which amounts to the same thing in the end

  • It stops them from forming new cell walls when they divide, so the local population quickly dies out of bacterial “old age”

  • Fleming published his discovery in 1929, but it was not until 1939 that a team at Oxford University, headed by Howard Florey and Ernst Boris Chain, was able to fully explore its antibiotic properties

  • Fleming, Florey and Chain shared the 1945 Nobel prize for their research on penicillin

  • By the early 1940’s, clinical trials were underway, and mass production of the new wonder drug began just in time for the D-Day invasion

  • Talk about good timing…

  • Many lives were saved in World War 2 by – strangely enough - a bad supermarket melon

  • Producing penicillin in large quantities turned out to be a major challenge

  • Some strains were easier to work with or more productive than others

  • Fleming had worked with Penicillium notatum, a relatively stubborn species

  • People scoured the world for different strains or species to test in the lab

  • Army pilots brought back soil samples from around the globe

  • But it was the little town of Peoria that saved the day!

  • The USDA research lab in Peoria was at the forefront of penicillin research

  • They instructed their staff to keep a weather eye out for any unusual molds in grocery stores, or in their refrigerators

  • Lab tech Mary Hunt hit pay dirt in 1943, bringing in a moldy supermarket melon, with a fungus that had a “a pretty, golden look” to it

  • The species turned out to be Penicillium chrysogenum, and it doubled the level of penicillin production

  • Penicillin was soon followed by other new wonder drugs

  • Gerhard Domagk discovered Prontosil, the first sulfa drug, in 1935

  • In 1943, Selman Waksman isolated streptomycin from soil bacteria, receiving the 1952 Nobel Prize for his efforts

  • Tetracyclines, a new family of wonder drugs that includes aureomycin and terramycin, were isolated from Streptomyces soil bacteria in 1945

  • The synthetic form of the drug, the first natural antibiotic to be chemically modified, was patented in 1955 by Lloyd Conover


  • Called simply Tetracycline, it paved the way for a new generation of human-altered antibiotics, and soon became a perennial favorite

  • When I was an undergraduate, in the late 1960’s, it was the universal panacea at our university health clinic


  • Everybody left the clinic with a generous supply of pharmaceutical company samples

  • But bacteria quickly evolved resistant strains to every new antibiotic we could invent

  • Including penicillin…

  • In its heyday, it was widely touted as a cure-all

  • Not only would it cure disease, it would cure body odor and bad breath!

  • Drug stores sold penicillin soaps, penicillin mouthwash, even penicillin soda pop - What were we thinking?

  • The ad blitz for wonder drugs continues to this day - prescription drugs can now be advertised on TV

  • Although if you really listen to all those side effects, it makes most of them a bit less appealing…appealing…If death occurs, discontinue use immediately…

  • The fine print on the label may warn of the dangers of antibiotic resistance

  • But the warning comes far too late…

  • Antibiotics are becoming less and less effective against more and more diseases

  • By the late 1980’s microbial resistance had reached alarming proportions

  • But that didn’t stop the medical establishment from continuing to over-prescribe antibiotics

  • Nor did it stop agribusiness from feeding them to cattle and poultry

  • Indiscriminate use of antibiotics has created new strains of super germs, microbes that are immune to even our strongest magic bullets

  • Fleming himself predicted the evolution of bacteria resistant to penicillin – prophetic words!

  • Gonorrhea (Neisseria gonorrhoeae) became resistant to penicillin by 1970

  • It became resistant to tetracycline in the 1980’s, and has continued to stay one step ahead of our best attempts to fight it

  • A strain evolved in South Vietnam in the 1980’s that took the battle a step further

  • It is not only resistant to penicillin, it actively attacks it and destroys it!

  • We call such strains MDR, multiple drug resistant, if they resist several drugs

  • We call them XDR, extensively drug resistant, if they resist most or all drugs

  • Consider our most powerful wonder drug, vancomycin

  • It’s the best drug to treat infections of enterococci bacteria (gut bacteria)

  • Enterococci cause 10-12% of all hospital acquired infections

  • If you get a resistant strain of enterococci, the results are often fatal

  • A 1993 study in a New York City hospital found 42 deaths per 100 infected patients!

  • Resistant strains of enterococci were seen in France in 1988

  • They had spread to the US and Great Britain by 1989

  • And the gut bacteria even transferred their resistance to staph and strep bacteria!

  • There are many ways for bacteria to evolve resistance to antibiotics

  • Change cell wall permeability to exclude the drug

  • Alter the surface of the cell membrane (disguise)

  • Alter the binding site that the drug attaches to

  • Use bacterial enzymes to neutralize the drug

  • All of these changes can be inherited by the bacteria, and bacteria can evolve resistance very quickly

  • The pace of microbial evolution is extremely rapid

  • Bacteria evolve a thousand times faster than we do!

  • Our time to first reproduction is measured in decades, but E. coli can divide every 20 minutes

  • In the case of viruses, a typical HIV victim is fighting 10 billion new viruses a day!!

  • Our only salvation is our clever and complex immune system, which we’ll discuss at length later on

  • One of the secrets of bacterial success is a little snippet of DNA called a plasmid

  • Plasmids are like tiny computer programs that code for a particular trait, like resistance to an antibiotic

  • A plasmid evolved by any one bacterium can soon be passed to billions of others

  • It’s like the bacterial equivalent of file sharing over the internet, or downloading new apps to a smart phone

  • When bacteria reproduce by conjugation, which is as close to sex as they get, they become connected by tiny tubes, and can exchange DNA


  • Included in that genetic information are many plasmids

  • Plasmids are short strands of DNA that form a tiny loop

  • About 5% of bacterial DNA is in the form of plasmids

  • Basic bacterial chromosomes have all the essential information required for survival and reproduction

  • The plasmids are usually lagniappe, as we call it in New Orleans – a little something extra…

  • Each bacterium can have up to several hundred copies of each plasmid, and freely distributes them to other bacteria

  • And with a little help from humans, plasmids can be carried around the globe in a matter of hours

  • Many of these bacterial plasmids carry genes that confer resistance to antibiotics

  • Now you might be asking yourself, what is a bacterium doing with an antibiotic?

  • Or a fungus, for that matter?

  • Here is where we get a little short-sighted, a little too smug – because we usually think the battle is all about us

  • But these powerful drugs didn’t evolve so bacteria could war against us

  • It evolved from their continual war with one another

  • And we are relative latecomers to this particular battlefield

  • Microbes have been competing with one another for billions of years

  • And that vast arena of evolutionary conflict has yielded some very exotic and effective chemical weapons, organic compounds that kill a wide array of microorganisms

  • Nobody is above the fray…

  • In 1952, penicillin could cure virtually 100% of infections due to Staphylococcus

  • By 1982, barely 10% of staph infections were killed by penicillin

  • One strain of staph had evolved a special plasmid, beta-lactamase plasmid, that gave it resistance to penicillin

  • And this plasmid quickly passed into the general staph population

  • In the late 1960’s, doctors switched to methicillin, another drug in the penicillin family

  • By the late 1980’s, strains had emerged that were resistant to methicillin

  • These are usually referred to as MRSA strains, which stands for methicillin resistant Staphylocccus aureus

  • This is one of the most dangerous microbes in hospitals today (we call it HA-MRSA, for hospital acquired) – and it also appears in the general community (CA-MRSA, for community acquired)

  • Symptoms vary with the strain and the area that is infected

  • It usually appears as a skin infection, like a rash, or pimples, or spider bites – the rash progresses to painful large boils filled with pus

  • In some cases, the infections proceeds rapidly, moving from the skin to the internal organs, bloodstream, and joints, and the victim may die

  • These resistant strains are especially bad for patients with stressed immune systems, like burn patients, and patients in IC wards

  • Hospital outbreaks have became more common, with 17,000 to 18,000 deaths or more per year

  • Fortunately, increased awareness, better hand washing, and more thorough screening of patients has led to a 16% decline in cases in recent years (2005-2008)

  • By early 1990’s, vancomycin was the only effective antibiotic for staph infections

  • Unfortunately, Vancomycin is one of the most expensive antibiotics on the market

  • This constant game of one up-manship is getting more expensive with each new round

  • By the 1980’s, resistant strains of bacteria were costing hospitals an additional $30 billion per year!!

  • Poor people, who make up a large share of the population in many nations, simply can’t afford it…

  • The 1990’s saw super-strains of staph appear, resistant to almost every drug, thanks to plasmid exchange

  • And as if deadly staph weren’t bad enough, resistant Streptococcus strains soon began to emerge

  • Most strep infections up to 1950 were Strep type A

  • Strep A strains were vulnerable to penicillin

  • Penicillin knocked Strep A populations way back, allowing the competing Strep B strains to take over

  • By 1970, strep B was raging around the world

  • It has been especially hard on neonatal care units, 75% fatality under two months of age

  • Resistant Strep A can cause streptococcal toxic shock syndrome (STSS)

  • Among its many victims was Jim Henson, creator of the muppets…

  • One of the most terrifying resistant strains of Strep A is the strain that causes streptococcal gangrene

  • The press soon dubbed the disease with a more fitting moniker

  • They called it the flesh-eating bacteria…

  • The disease causes gangrene as the bacteria eats its way under the skin, following a traumatic bruise or wound

  • By the time the victim realizes something is wrong, it may already be too late

  • The result is often a choice between amputation or death

  • There are 10,000 to 15,000 cases of group A streptococcal infection each year in US

  • “Necrotizing fasciitis” , or flesh eating, occurs in about 5% to 10% of these victims

  • The fatality rate is about 30%!

  • One young mother miraculously beat the odds after a 5 year ordeal

  • Sandy Wilson acquired it in the hospital maternity ward

  • She lost her spleen, gall bladder, appendix, part of her stomach and all of her intestines

  • After 40 operations, she is finally recovering, though she has to take immunosuppressant drugs the rest of her life, thanks to her transplants

  • Once unique to streptococcus strains, the production of flesh-eating toxins has now spread to staphylococcus strains

  • As if that weren’t bad enough, another drug resistant Strep A strain to worry about is rheumatic fever

  • It used to be a widespread and debilitating disease, hitting children between the age of 5 and 15, and typically leaving them crippled and arthritic, or with a bad heart…

  • Your mother or grandmother would remember it

  • It had mostly faded away by the early 1950’s

  • By the 1970’s rheumatic fever had all but disappeared from the developed nations

  • But a 1985 outbreak in Salt Lake City, was followed by a resurgence across the US

  • Where did it come from?

  • It never really went away…

  • In the Less Developed Countries, rheumatic fever and other strep infections have always been rampant

  • These nations form a constant reservoir of new infection

  • The lack of diagnostic labs in Less Developed Countries leads to heavy and indiscriminate use of antibiotics

  • Many prescription drugs are available over the counter, and self-prescription is the norm

  • Such populations form a breeding ground for resistant strains of common microbes

  • Not that it’s all that safe right here at home…

  • In 1983, dozens of young Hopi Nation children became ill, with severe bloody diarrhea

  • The infection was due to Salmonella, a bacterium that causes food poisoning

  • The disease resisted treatment with any conventional antibiotic

  • It was traced back to an adult Hopi under treatment for a chronic urinary infection

  • The patient had been taking several antibiotics over a long period of time

  • His intestinal bacteria had gradually acquired immunity to all these antibiotics

  • The E. coli in the patient’s stomach passed these resistant genes to the Salmonella strain as plasmids

  • Resistant hospital strains often turn out to be more virulent than non-resistant strains

  • Madagascar hospitals encountered a highly virulent resistant strain of Shigella

  • It was resistant to all seven of the most commonly used antibiotics!

  • Shigella patients treated with antibiotics experienced such intense symptoms, they often died from the complications

  • A nice example of microbial ecology at work…

  • The antibiotics probably killed off most or all of the species that would have normally competed with Shigella in the gut

  • Chalk it up to symbiosis…

  • There are three types of symbiosis:

  • Mutualism – each partner benefits the other

  • Commensalism – one partner is helped, and the other is neither helped nor hindered, and

  • Parasitism – in which one partner benefits at the expense of the other

  • The hidden cost of antibiotics is that they are indiscriminate killers of bacteria

  • They kill the normal bacterial symbionts that live within us

  • Our normal intestinal bacteria are mostly commensal species

  • Bacteria in our mouth, throat, and gut compete with other bacterial species for food, nutrients, and attachment points

  • If you remove their natural competitors by using antibiotics, resistant strains of microbes have a free reign

  • CDC (2013) estimates 23,000 deaths per year due to antibiotic resistant strains

  • CDC (2007) – 100,000 deaths per year from resistant hospital acquired infections

  • “Just in case” (prophylactic) prescription of antibiotics is a big part of the problem

  • Pediatricians have come to routinely prescribe antibiotics for any undiagnosed infection

  • But antibiotics have no effect on viruses, they merely select for resistant bacteria

  • For example, Amoxicillin is routinely given to children with fever, without any actual diagnosis (“the pink stuff” from day care)

  • When the only tool you have is a hammer, every problem looks like a nail…

  • And incidentally, if you do take an antibiotic, don’t stop taking it just because you’re starting to feel better

  • No matter how foul it may taste, drain it to the dregs

  • Otherwise you leave behind a generation of resistant bacterial survivors

  • Prophylactic use of antibiotics for healthy cattle has contributed to the evolution of MDR strains

  • In June 2003 McDonald’s announced it was phasing out use of antibiotics in cattle from its suppliers

  • That affects over 2.5 billion pounds of chicken, beef, poultry

  • A bold move, which hopefully other fast food franchises will follow!

  • The European Union has also banned their use, and in the US the FDA is moving to ban such additives as well

  • What lessons can we learn from antibiotic resistance?

  • Limit their use whenever possible, and don’t prescribe antibiotics unless the disease is known - they don’t work on viruses

  • Break up prescription patterns to avoid a constant selection pressure on one drug

  • Use the full dosage, to completely kill the bacteria

  • Don’t feed massive amounts of antibiotics to cattle or poultry

  • Retire certain antibiotics altogether, to allow vulnerable strains to re-emerge


  • The basic problem is coevolution

  • Bacteria have a remarkable ability to quickly counteract any new chemical weapons evolved by their competitors – which is both good news and bad news for us

  • As Pasteur and Joubert predicted in 1877, speaking about the arms race between different kinds of microbes: “These facts may, perhaps, justify the greatest hope from the therapeutic point of view”

  • And they were right – most of our hopes are still pinned on the chemical weapons that microbes evolved to use on one another


  • We need all the hope we can get…

  • We are up against an enemy that never sleeps, an enemy that has been sharpening its combat skills for billions of years

  • And all we have managed to do with our wonder drugs is to accelerate the pace of this evolutionary arms race, by exposing billions of bacteria at a time to the same chemical attack…

  • A sure-fire technique for creating resistant strains

  • But the evolutionary arms race isn’t just about weapons

  • As in any conflict, strategy is the ultimate key to victory

  • And the coevolution of man and microbes has created a wealth of strategies on both sides of the battlefield

  • In our next lecture we’ll look at the various strategies we’ve evolved to defend ourselves against microbial invasions, and the counter strategies evolved by microbes to thwart our defenses



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