Or even four billion dollars.
Okay, maybe five billion tops; but that’s my final offer.
“Bitter Resistance”
Two hundred thousand bacteria could easily lurk under the top half of this semicolon; but for the sake of focussing on a subject that’s too often out of sight and out of mind, let’s pretend otherwise. Let’s pretend that a bacterium is about the size of a railway tank car.
Now that our fellow creature the bacterium is no longer three microns long, but big enough to crush us, we can get a firmer mental grip on the problem at hand. The first thing we notice is that the bacterium is wielding long, powerful whips that are corkscrewing at a blistering 12,000 RPM. When it’s got room and a reason to move, the bacterium can swim ten body-lengths every second. The human equivalent would be sprinting at forty miles an hour.
The butt-ends of these spinning whips are firmly socketed inside rotating, proton-powered, motor-hubs. It seems very unnatural for a living creature to use rotating wheels as organs, but bacteria are serenely untroubled by our parochial ideas of what is natural.
The bacterium, constantly chugging away with powerful interior metabolic factories, is surrounded by a cloud of its own greasy spew. The rotating spines, known as flagella, are firmly embedded in the bacterium’s outer hide, a slimy, lumpy, armored bark. Studying it closely (we evade the whips and the cloud of mucus), we find the outer cell wall to be a double-sided network of interlocking polymers, two regular, almost crystalline layers of macromolecular chainmail, something like a tough plastic wiffleball.
The netted armor, wrinkled into warps and bumps, is studded with hundreds of busily sucking and spewing orifices. These are the bacterium’s “porins,” pores made from wrapped-up protein membrane, something like damp rolled-up newspapers that protrude through the armor into the world outside.
On our scale of existence, it would be very hard to drink through a waterlogged rolled-up newspaper, but in the tiny world of a bacterium, osmosis is a powerful force. The osmotic pressure inside our bacterium can reach 70 pounds per square inch, five times atmospheric pressure. Under those circumstances, it makes a lot of sense to be shaped like a tank car.
Our bacterium boasts strong, highly sophisticated electrochemical pumps working through specialized fauceted porins that can slurp up and spew out just the proper mix of materials. When it’s running its osmotic pumps in some nutritious broth of tasty filth, our tank car can pump enough juice to double in size in a mere twenty minutes. And there’s more: because in that same twenty minutes, our bacterial tank car can build in entire duplicate tank car from scratch.
Inside the outer wall of protective bark is a greasy space full of chemically reactive goo. It’s the periplasm. Periplasm is a treacherous mess of bonding proteins and digestive enzymes, which can yank tasty fragments of gunk right through the exterior hide, and break them up for further assimilation, rather like chemical teeth. The periplasm also features chemoreceptors, the bacterial equivalent of nostrils or taste-buds.
Beneath the periplasmic goo is the interior cell membrane, a tender and very lively place full of elaborate chemical scaffolding, where pump and assembly-work goes on.
Inside the interior membrane is the cytoplasm, a rich ointment of salts, sugars, vitamins, proteins, and fats, the tank car’s refinery treasure-house.
If our bacterium is lucky, it has some handy plasmids in its custody. A plasmid is an alien DNA ring, a kind of fly-by-night genetic franchise which sets up work in the midst of somebody else’s sheltering cytoplasm. If the bacterium is unlucky, it’s afflicted with a bacteriophage, a virus with the modus operandi of a plasmid but its own predatory agenda.
And the bacterium has its own native genetic material. Eukaryotic cells — we humans are made from eukaryotic cells — possess a neatly defined nucleus of DNA, firmly coated in a membrane shell. But bacteria are prokaryotic cells, the oldest known form of life, and they have an attitude toward their DNA that is, by our standards, shockingly promiscuous. Bacterial DNA simply sprawls out amid the cytoplasmic goo like a circular double-helix of snarled and knotted Slinkies.
Any plasmid or transposon wandering by with a pair of genetic shears and a zipper is welcome to snip some data off or zip some data in, and if the mutation doesn’t work, well, that’s just life. A bacterium usually has 200,000 or so clone bacterial sisters around within the space of a pencil dot, who are more than willing to take up the slack from any failed experiment in genetic recombination. When you can clone yourself every twenty minutes, shattering the expected laws of Darwinian heredity merely adds spice to life.
Bacteria live anywhere damp. In water. In mud. In the air, as spores and on dust specks. In melting snow, in boiling volcanic springs. In the soil, in fantastic numbers. All over this planet’s ecosystem, any liquid with organic matter, or any solid foodstuff with a trace of damp in it, anything not salted, mummified, pickled, poisoned, scorching hot or frozen solid, will swarm with bacteria if exposed to air. Unprotected food always spoils if it’s left in the open. That’s such a truism of our lives that it may seem like a law of physics, something like gravity or entropy; but it’s no such thing, it’s the relentless entrepreneurism of invisible organisms, who don’t have our best interests at heart.
Bacteria live on and inside human beings. They always have; bacteria were already living on us long, long before our species became human. They creep onto us in the first instants in which we are held to our mother’s breast. They live on us, and especially inside us, for as long as we live. And when we die, then other bacteria do their living best to recycle us.
An adult human being carries about a solid pound of commensal bacteria in his or her body; about a hundred trillion of them. Humans have a whole garden of specialized human-dwelling bacteria — tank-car E. coli, balloon-shaped staphylococcus, streptococcus, corynebacteria, micrococcus, and so on. Normally, these lurkers do us little harm. On the contrary, our normal human-dwelling bacteria run a kind of protection racket, monopolizing the available nutrients and muscling out other rival bacteria that might want to flourish at our expense in a ruder way.
But bacteria, even the bacteria that flourish inside us all our lives, are not our friends. Bacteria are creatures of an order vastly different from our own, a world far, far older than the world of multicellular mammals. Bacteria are vast in numbers, and small, and fetid, and profoundly unsympathetic.
So our tank car is whipping through its native ooze, shuddering from the jerky molecular impacts of Brownian motion, hunting for a chemotactic trail to some richer and filthier hunting ground, and periodically peeling off copies of itself. It’s an enormously fast-paced and frenetic existence. Bacteria spend most of their time starving, because if they are well fed, then they double in number every twenty minutes, and this practice usually ensures a return to starvation in pretty short order. There are not a lot of frills in the existence of bacteria. Bacteria are extremely focussed on the job at hand. Bacteria make ants look like slackers.
And so it went in the peculiar world of our acquaintance the tank car, a world both primitive and highly sophisticated, both frenetic and utterly primeval. Until an astonishing miracle occurred. The miracle of “miracle drugs,” antibiotics.
Sir Alexander Fleming discovered penicillin in 1928, and the power of the sulfonamides was recognized by drug company researchers in 1935, but antibiotics first came into general medical use in the 1940s and 50s. The effects on the hidden world of bacteria were catastrophic. Bacteria which had spent many contented millennia decimating the human race were suddenly and swiftly decimated in return. The entire structure of human mortality shifted radically, in a terrific attack on bacteria from the world of organized intelligence.
At the beginning of this century, back in the pre-antibiotic year of 1900, four of the top ten leading causes of death in the United States were bacterial. The most prominent were tuberculosis (“the white plague,” Mycobacterium tuberculosis) and pneumonia (*Streptococcus pneumoniae,* Pneu
mococcus). The death rate in 1900 from gastroenteritis (*Escherichia coli,* various Campylobacter species, etc.) was higher than that for heart disease. The nation’s number ten cause of death was diphtheria (*Corynebacterium diphtheriae*). Bringing up the bacterial van were gonorrhea, meningitis, septicemia, dysentery, typhoid fever, whooping cough, and many more.
At the end of the century, all of these festering bacterial afflictions (except pneumonia) had vanished from the top ten. They’d been replaced by heart disease, cancer, stroke, and even relative luxuries of postindustrial mortality, such as accidents, homicide and suicide. All thanks to the miracle of antibiotics.
Penicillin in particular was a chemical superweapon of devastating power. In the early heyday of penicillin, the merest trace of this substance entering a cell would make the hapless bacterium literally burst. This effect is known as “lysing.”
Penicillin makes bacteria lyse because of a chemical structure called “beta-lactam.” Beta-lactam is a four-membered cyclic amide ring, a molecular ring which bears a fatal resemblance to the chemical mechanisms a bacterium uses to build its cell wall.
Bacterial cell walls are mostly made from peptidoglycan, a plastic-like molecule chained together to form a tough, resilient network. A bacterium is almost always growing, repairing damage, or reproducing, so there are almost always raw spots in its cell wall that require construction work.
It’s a sophisticated process. First, fragments of not-yet-peptided glycan are assembled inside the cytoplasm. Then the glycan chunks are hauled out to the cell wall by a chemical scaffolding of lipid carrier molecules, and they are fitted in place. Lastly, the peptidoglycan is busily knitted together by catalyzing enzymes and set to cure.
But beta-lactam is a spanner in the knitting-works, which attacks the enzyme which links chunks of peptidoglycan together. The result is like building a wall of bricks without mortar; the unlinked chunks of glycan break open under osmotic pressure, and the cell spews out its innards catastrophically, and dies.
Gram-negative bacteria, of the tank-car sort we have been describing, have a double cell wall, with an outer armor plus the inner cell membrane, rather like a rubber tire with an inner tube. They can sometimes survive a beta-lactam attack, if they don’t leak to death. But gram-positive bacteria are more lightly built and rely on a single wall only, and for them a beta-lactam puncture is a swift kiss of death.
Beta-lactam can not only mimic, subvert and destroy the assembly enzymes, but it can even eat away peptide-chain mortar already in place. And since mammalian cells never use any peptidoglycans, they are never ruptured by penicillin (although penicillin does sometimes provoke serious allergic reactions in certain susceptible patients).
Pharmaceutical chemists rejoiced at this world-transforming discovery, and they began busily tinkering with beta-lactam products, discovering or producing all kinds of patentable, marketable, beta-lactam variants. Today there are more than fifty different penicillins and seventy-five cephalosporins, all of which use beta-lactam rings in one form or another.
The enthusiastic search for new medical miracles turned up substances that attack bacteria through even more clever methods. Antibiotics were discovered that could break-up or jam-up a cell’s protein synthesis; drugs such as tetracycline, streptomycin, gentamicin, and chloramphenicol. These drugs creep through the porins deep inside the cytoplasm and lock onto the various vulnerable sites in the RNA protein factories. This RNA sabotage brings the cell’s basic metabolism to a seething halt, and the bacterium chokes and dies.
The final major method of antibiotic attack was an assault on bacterial DNA. These compounds, such as the sulphonamides, the quinolones, and the diaminopyrimidines, would gum up bacterial DNA itself, or break its strands, or destroy the template mechanism that reads from the DNA and helps to replicate it. Or, they could ruin the DNA’s nucleotide raw materials before those nucleotides could be plugged into the genetic code. Attacking bacterial DNA itself was the most sophisticated attack yet on bacteria, but unfortunately these DNA attackers often tended to be toxic to mammalian cells as well. So they saw less use. Besides, they were expensive.
In the war between species, humanity had found a full and varied arsenal. Antibiotics could break open cell walls, choke off the life-giving flow of proteins, and even smash or poison bacterial DNA, the central command and control center. Victory was swift, its permanence seemed assured, and the command of human intellect over the realm of brainless germs was taken for granted. The world of bacteria had become a commercial empire for exploitation by the clever mammals.
Antibiotic production, marketing and consumption soared steadily. Nowadays, about a hundred thousand tons of antibiotics are manufactured globally every year. It’s a five billion dollar market. Antibiotics are cheap, far cheaper than time-consuming, labor-intensive hygienic cleanliness. In many countries, these miracle drugs are routinely retailed in job-lots as over-the-counter megadosage nostrums.
Nor have humans been the only mammals to benefit. For decades, antibiotics have been routinely fed to American livestock. Antibiotics are routinely added to the chow in vast cattle feedlots, and antibiotics are fed to pigs, even chickens. This practice goes on because a meat animal on antibiotics will put on poundage faster, and stay healthier, and supply the market with cheaper meat. Repeated protests at this practice by American health authorities have been successfully evaded in courts and in Congress by drug manufacturers and agro-business interests.
The runoff of tainted feedlot manure, containing millions of pounds of diluted antibiotics, enters rivers and watersheds where the world’s free bacteria dwell.
In cities, municipal sewage systems are giant petri-dishes of diluted antibiotics and human-dwelling bacteria.
Bacteria are restless. They will try again, every twenty minutes. And they never sleep.
Experts were aware in the 1940s and 1950s that bacteria could, and would, mutate in response to selection pressure, just like other organisms. And they knew that bacteria went through many generations very rapidly, and that bacteria were very fecund. But it seemed that any bacteria would be very lucky to mutate to successfully resist even one antibiotic. Compounding that luck by evolving to resist two antibiotics at once seemed well-nigh impossible. Bacteria were at our mercy. They didn’t seem any more likely to resist penicillin and tetracycline than a rainforest can resist bulldozers and chainsaws.
However, thanks to convenience and the profit motive, once-miraculous antibiotics had become a daily commonplace. A general chemical haze of antibiotic pollution spread across the planet. Titanic numbers of bacteria, in all niches of bacterial life, were being given an enormous number of chances to survive antibiotics.
Worse yet, bacteriologists were simply wrong about the way that bacteria respond to a challenge.
Bacteria will try anything. Bacteria don’t draw hard and fast intellectual distinctions between their own DNA, a partner’s DNA, DNA from another species, virus DNA, plasmid DNA, and food.
This property of bacteria is very alien to the human experience. If your lungs were damaged from smoking, and you asked your dog for a spare lung, and your dog, in friendly fashion, coughed up a lung and gave it to you, that would be quite an unlikely event. It would be even more miraculous if you could swallow a dog’s lung and then breathe with it just fine, while your dog calmly grew himself a new one. But in the world of bacteria this kind of miracle is a commonplace.
Bacteria share enormous amounts of DNA. They not only share DNA among members of their own species, through conjugation and transduction, but they will encode DNA in plasmids and transposons and packet-mail it to other species. They can even find loose DNA lying around from the burst bodies of other bacteria, and they can eat that DNA like food and then make it work like information. Pieces of stray DNA can be swept all willy-nilly into the molecular syringes of viruses, and injected randomly into other bacteria. This fetid orgy isn’t what Gregor Mendel had in mind when he was discovering the roots of classical genet
ic inheritance in peas, but bacteria aren’t peas, and don’t work like peas, and never have. Bacteria do extremely strange and highly inventive things with DNA, and if we don’t understand or sympathize, that’s not their problem, it’s ours.
Some of the best and cleverest information-traders are some of the worst and most noxious bacteria. Such as Staphylococcus (boils). Haemophilus (ear infections). Neisseria (gonorrhea). Pseudomonas (abcesses, surgical infections). Even Escherichia, a very common human commensal bacterium.
When it comes to resisting antibiotics, bacteria are all in the effort together. That’s because antibiotics make no distinctions in the world of bacteria. They kill, or try to kill, every bacterium they touch.
If you swallow an antibiotic for an ear infection, the effects are not confined to the tiny minority of toxic bacteria that happen to be inside your ear. Every bacterium in your body is assaulted, all hundred trillion of them. The toughest will not only survive, but they will carefully store, and sometimes widely distribute, the genetic information that allowed them to live.
The resistance from bacteria, like the attack of antibiotics, is a multi-pronged and sophisticated effort. It begins outside the cell, where certain bacteria have learned to spew defensive enzymes into the cloud of slime that surrounds them — enzymes called beta-lactamases, specifically adapted to destroy beta-lactam, and render penicillin useless. At the cell-wall itself, bacteria have evolved walls that are tougher and thicker, less likely to soak up drugs. Other bacteria have lost certain vulnerable porins, or have changed the shape of their porins so that antibiotics will be excluded instead of inhaled.
Inside the wall of the tank car, the resistance continues. Bacteria make permanent stores of beta-lactamases in the outer goo of periplasm, which will chew the drugs up and digest them before they ever reach the vulnerable core of the cell. Other enzymes have evolved that will crack or chemically smother other antibiotics.
Essays. FSF Columns Page 17