Arrival of the Fittest: Solving Evolution's Greatest Puzzle

by Andreas Wagner

  Figure 4 shows how we can organize this information. The left side of the figure stands for a list of five thousand reactions—written as chemical equations. To avoid clutter I wrote out the molecules in only one of them—the sucrose-splitting reaction—but simplified all others to a single letter. Let’s consider one organism, such as E. coli or a human, and mark a “1” next to a reaction if our organism can catalyze this reaction—it has a gene making an enzyme for it. Otherwise we’ll mark a “0.” The result is a long list of ones and zeroes like that in the figure, a compact way to specify a metabolism.

  Bacteria such as E. coli can make all twenty amino acids in proteins, whereas metabolic cripples like us humans can make only twelve of them. We lack the necessary enzymes and reactions for the remaining eight. The figure’s shorthand way of describing a metabolism is ideal for expressing differences like this: Because we lack some reactions, our list of reactions contains some zeroes where that of E. coli contains ones.

  A list like this is also an extremely compact way to write an organism’s metabolic genotype—the part of the genome encoding its metabolism—because an organism’s list of reactions is ultimately encoded in its DNA. You can also think of the list as a text written in an alphabet with only two letters, and without spaces or punctuation marks, like this: “1001 . . . 0110 . . . 0010.” The first letter in such a text might correspond to the sucrose-splitting reaction, which is present (“1”) in this example, whereas the second reaction might be one of those needed to synthesize an essential amino acid—it is absent (“0”) in this example text but could be present (“1”) in another organism’s genotype—and so on.

  It is a text in a library vast beyond imagination, the library of all possible metabolisms.

  The number of texts in that library can be calculated with the same arithmetic that computed the size of the universal library of books. Because each reaction in the known universe of reactions can be either present or absent in a metabolism, there are two possibilities (present or absent) for the first reaction, two for the second reaction, and so on, for each reaction in the universe. To calculate the total number of texts, we multiply the number 2 by itself as many times as there are reactions in our universe. For a universe of 5,000 reactions, there are 25000 possible metabolisms, 25000 texts written in the alphabet of zero and one, each of them standing for a different metabolism. This number is greater than 101500, or a 1 with 1,500 trailing zeroes. While not quite as large as the number of texts in the universal library of human books, it is still much larger than the number of hydrogen atoms in the universe. The metabolic library is also hyperastronomical.

  And just as the universal library contains all meaningful books, the library of metabolisms contains all “meaningful” metabolisms—those that allow an organism to survive—and many more, because not all metabolisms are meaningful, just as not all books are. Some metabolisms cannot procure energy, or they fail to manufacture important molecules. These are like books where some chapters, paragraphs, or sentences are coherent but the book as a whole does not make sense. And many other metabolic texts are gibberish. These are metabolisms with disjointed reaction sequences dead-ending on molecules useless to life, the equivalent of books containing only meaningless character strings.

  If you wandered through the universal library of books long enough, you would find books that surprise you. They contain novel thoughts, ideas, and inventions. The genotypic texts in the universal metabolic library are no different. They can encode metabolisms with never-before-seen chemical abilities, novel phenotypes that manufacture new molecules or use new fuels. In short, innovations.

  Because metabolism is as old as life itself, evolving life has explored this library ever since it originated. A billion years ago, nature had already discovered unimaginably many metabolic phenotypes, enough of them that it might have stopped finding innovative metabolic texts long since. But far from resting on its early laurels, evolution is still discovering such texts, much faster than we can decipher them, in billions and trillions of organisms alive today. Some of these texts appeared less than a hundred years ago—a mere moment in evolutionary time.

  Consider pentachlorophenol, a nasty molecule that humans first produced in the 1930s. It is used in antifouling paint to coat ships’ hulls, and also as an insecticide, fungicide, and disinfectant—in short, to kill life. Pentachlorophenol also damages our kidneys, blood, and nervous system, and it causes cancer. But despite its noxious nature, life has found ways not only to tolerate pentachlorophenol but to thrive on it. The aptly named bacterium Sphingobium chlorophenolicum can extract both energy and carbon from it, using pentachlorophenol as its only food source. To do so, its genome encodes four enzyme-catalyzed reactions that convert pentachlorophenol into molecules that are as digestible as glucose—the equivalent of transforming a chemical weapon into a chocolate bar.3

  The combination of these reactions is unique to S. chlorophenolicum, but the reactions themselves are not. Each of them occurs in hundreds if not thousands of other organisms. Two of them help recycle superfluous amino acids in some bacteria, whereas the other two disarm toxic molecules produced by some fungi and insects—molecules that happen to resemble pentachlorophenol.4 Like a garage mechanic building a sprinkler system out of an alarm clock, a bicycle pump, and some PVC pipe, evolution has created in S. chlorophenolicum a new arrangement of chemical reactions catalyzed by enzymes that individually exist in other organisms. In other words, metabolic innovation is combinatorial.

  Innovations that allow organisms to feed on highly toxic, man-made molecules are not rare. The bacterium Burkholderia xenovorans happily feeds on the now outlawed polychlorinated biphenyls, which were widely used in making plastics and in the electrical industry.5 Other bacteria readily digest chlorobenzene, a toxic organic solvent used in chemical laboratories.6 And even more striking are the bacteria that feed on the very antibiotics designed to kill them.7 Some of these antibiotics are man-made, so bacteria did not encounter them until recently.

  Just as nature can convert poisons into food, it also came up with ingenious ways of managing its waste. Ammonia (NH3), for example, isn’t just the gas in household cleaners with the sharp, unpleasant odor that makes your eyes burn, but a highly toxic waste product of animal metabolism. Because ammonia dissolves in water, fish can just excrete it into the water surrounding them and forget about it—the fish equivalent of peeing in the swimming pool. But when animals first conquered land more than three hundred million years ago, they did not have this luxury. They needed to prevent toxic ammonia gas from poisoning their blood.

  The solution lay in a metabolic text that contains the instructions for converting ammonia into the less toxic molecule urea, which we secrete to this day in our urine. This metabolic innovation involves five common chemical reactions, each one independently useful to organisms long before the need to detoxify ammonia appeared.8

  When exactly this innovation appeared is unknown, but clues are easy to find. Even though modern teleosts—bony fish—have no need to detoxify ammonia, their ancestors already harbored a chemical blueprint for making urea, still seen in cartilaginous fish like sharks and rays that swam through the oceans long before modern fish appeared. However, the title character of Jaws uses urea for a different purpose than the humans hunting it—for nitrogen storage, buoyancy, or as a counterweight to the salt in seawater. (You might think that the DNA of bony fish should contain some remnant of this innovation, if it had already originated in their distant ancestors. And that’s indeed the case: The text for the urea cycle still exists in bony fish, even though they rarely express its chemical meaning. They are a bit like adults who learned a language while infants and can still recognize some of its words.)9

  Detoxifying your waste is good, but recycling it is even better, and nature excels at that too. The nitrogen waste of animals—ammonia or urea—fertilizes plants. The very oxygen we breathe is a waste product of photosynthesis.10 And every gram of feces is teeming with
billions of bacteria feeding on the molecules in it: One man’s waste is a bacterium’s treasure. Each one of these bacteria harbors a metabolic text, ancient or recent, to break down molecules, extract energy and chemical elements, and build new life from them.

  Innovative metabolic texts are just as ubiquitous in extreme environments—extremely hot, extremely cold, excessively dry, highly caustic, exceedingly radioactive, super-salty, and so on—as in temperate ones. Bacteria in particular can thrive in boiling water and in ice, in highly corrosive sulfuric acid and in crushing oceanic depths. To survive, they had to innovate, and many of their innovations—you guessed it—are metabolic.

  Without these innovations, extreme environments would kill bacteria just as easily as they kill us. Too much salt, for example, kills cells, because it forces water out through osmosis and prevents enzymes from doing their job—they need water as a lubricant. To clog this drain, metabolism produces molecules with exotic names such as ectoine and glycine betaine that cannot leave a cell as easily as water does, and that can stand in for water molecules lost through osmosis. They keep proteins lubricated. To make these molecules, cells need only a few extra enzyme-catalyzed chemical reactions that start with common molecules like the amino acid aspartate. Add these reactions to a metabolism, and you have a leg up in the most hostile environment. Halophilic bacteria—the name comes from the Greek for “salt-loving”—can survive salt concentrations of 30 percent, ten times higher than the seawater that kills us when we drink it. They can even live around and inside salt crystals.11

  Extreme environments are no picnic, but life can be even harder if you face predators and parasites, and especially if escaping them is not an option. Any ordinary plant would be an immovable feast for many organisms, from insects and worms tunneling through the soil to slugs and other herbivores aboveground. Because plants can’t so much as twitch in their own defense, they develop chemical weapons, molecules so toxic that animals avoid them. Plants are not alone in using chemical warfare, but they are especially adept at it, perhaps because they are, literally, rooted to one spot.

  These defensive molecules are metabolic innovations, because they require new combinations of chemical reactions to synthesize them. One of them is the nicotine produced by tobacco plants that some of us blissfully inhale through cigarettes, even though it is so toxic that some farmers use it as an insecticide. But plants had the idea first, as a group of German scientists recently showed. When they artificially lowered the amount of nicotine that tobacco plants produce, insects developed a voracious appetite for the plants. They attacked the plants more often, ate more leaves, and grew faster. The plants, in turn, lost three times more leaves than normal plants to their attackers.12

  Nicotine is only the best known of more than three thousand similar alkaloids—a catchall term for organic molecules built around nitrogen atoms, including caffeine and morphine—that plants use in chemical defense. And although they are numerous, alkaloids are only one among several kinds of chemical warfare molecules. Others include the astringent tannins that make your mouth feel dry and shriveled when you eat unripe fruit.13 Tannins bind very tightly to plant proteins and prevent our gut from digesting these proteins, which discourages us from feeding on them in the first place. Cyanogenic glycosides are especially nasty chemical defense molecules that are produced in cassava or manioc, the important African and South American food plant.14 Unless you remove these glycosides by cooking or soaking, they release hydrogen cyanide, the active ingredient of the Zyklon B pesticide piped into the “showers” at Nazi extermination camps like Auschwitz-Birkenau. If you ever thought of nature as that idyllic place, the next best thing to the Garden of Eden, a tutorial on chemical warfare in plants will quickly dispel that myth.

  Biochemical warfare molecules like these are metabolic innovations, add-ons to an existing metabolism manufactured by new sequences of chemical reactions that start from common biomass molecules and transform them into potent poisons. Each one requires specific passages of text in a metabolic genotype.

  Some of nature’s ways to find new metabolic texts are familiar, because they dominate in large multicellular animals like us. They include the changes accompanying sexual reproduction, which shuffles chromosomes like decks of cards, so that each of our children starts with a new deal. Then there are the spontaneous mutations in a DNA’s letter sequence, arising through chance events such as when photons of ultraviolet radiation smash into the genome, or through highly reactive oxygen radicals that are by-products of chemical reactions and burst the chemical bonds of nearby DNA.

  Neither way to explore the metabolic library is very effective. Since the shuffling of sexual reproduction occurs between highly similar genomes—two human genomes share 99.9 percent of their DNA letter sequence—it is not the most effective way to create new metabolisms.15 It is like trying to write a new play by changing thirty words in Hamlet. And while mutations can create new proteins, including new enzyme catalysts, they are rare, which means the process is rather slow.

  And there is one more reason why metabolic innovation is not swift in large, multicellular animals. A new way of using energy or building organic structures can make its value known only at the speed that it spreads throughout a population, and animals that produce a new generation every few decades—or even every few months—can’t innovate any more rapidly than that.

  All this doesn’t mean that animals like us are completely impoverished when it comes to metabolic innovations. Our bodies, for example, can disarm drugs—like the widely used aspirin, known to chemists as acetylsalicylic acid—through a metabolic process called glucuronidation that renders them less toxic and excretable in urine. Cats and some other carnivores like hyenas lack this enzyme.16 (Consult a vet before medicating your pet hyena with aspirin.) You may ask why our bodies have this enzyme, which evolution created long before the company Bayer first marketed aspirin in the 1890s. The clue lies in aspirin’s name itself, which comes from an old name for a plant called meadowsweet, Spiraea ulmaria. This and many other plants have been used since antiquity for pain relief. What is more, plants containing salicylic acid were part of our ancestors’ diets, such that our omnivoric bodies—unlike those of carnivores like hyenas—needed a way to detoxify it.

  Within the multicellular world, humans are far from the pinnacle of metabolic creation, however, because many animals beat us in other aspects of metabolism. Humans cannot produce vitamin C, and must therefore drink it with a morning glass of orange juice, whereas dogs can make their own. And although we can extract calories from the seeds of grasses like wheat and maize, cows are better at digesting the cellulose in their stalks. To be fair, however—credit where it is due—that miracle of metabolism isn’t really a bovine innovation, but a microbial one: It is the bacteria in the four-stomached cows that convert gigantic cellulose molecules into easily digested glucose.

  Which is a hint that the real geniuses of innovation are the smallest organisms on the planet: bacteria.

  This isn’t just because bacteria produce new generations in minutes rather than years, and so can improve their genetic toolkits much faster than we. The innovation advantage of bacteria goes much deeper than that. To grasp how big it is, imagine a teenage boy trying to make his high school basketball team, even though he’s only a shade over five feet tall. Hard work and exercise can only take him so far. He just doesn’t have the right genes—not like his best friend, who can practically touch the rim on his tiptoes.

  A bacterium wanting the bacterial equivalent of a forty-inch vertical leap isn’t limited by the genes bequeathed it by previous generations. If, in some science-fiction movie, perhaps, the two basketball-playing friends had the same innovation equipment as bacteria, the process would look something like this. Our two characters are dining in their favorite restaurant when a slender hollow tube begins to grow out of the taller boy’s body, blindly groping toward the shorter. As soon as it connects, this tube injects a random fragment of the talle
r guy’s DNA text into the other body, and if this DNA contains the right genes, the high school basketball team gets a new power forward.

  This is an example of horizontal gene transfer, a phenomenon tragically unavailable to disadvantaged humans but rampant in microbes. Sometimes when two bacteria are in proximity, one of them will extrude a slender stalklike hollow tube in the direction of the other. When the tube docks, it shrinks in length, draws the two cells closer, and through the tunnel thus created, one cell transfers DNA to its neighbor.

  This transfer resembles sex as we know it, because a penislike tube transfers genetic material from one organism to another. But bacterial and human sex are quite different. Their sex, unlike ours, does not serve reproduction. And it doesn’t even shuffle a whole genome, but usually just transfers a few genes.

  Bacteria can acquire new genes in other ways too. Some absorb DNA from other cells after they die, rupture, and spill their molecular innards. As boneheaded as a person who would rather eat books—surely a great source of fiber—than read them, they use some of this DNA as food. Occasionally, though, the eaten DNA becomes hitched to their genome and helps make new proteins.17

  Gene transfer can also take advantage of viruses, those tiny lifeless particles whose DNA can enslave cells many times their size.18 While viruses reprogram a cell into a helpless factory that clones its viral masters, small pieces of the cell’s DNA can fuse with the viral genome. These pieces piggyback on newly minted viruses that leave the cell, and get injected along with the viral genome into the next hapless victim. In this scenario, one of our basketball-playing friends might simply have to sneeze on the other, whereupon his talent could be transferred to his teammate’s newly improved genome.