PROLOGUE

World Enough, and Time

In the spring of 1904, Ernest Rutherford, a thirty-two-year-old New Zealand–born physicist then working at McGill University in Canada, gave a lecture at the world’s oldest scientific organization, the Royal Society of London for Improving Natural Knowledge. His subject was radioactivity and the age of the earth.

At that time, scientists had long since forsworn the biblical accounts asserting that the earth was only six thousand years old. The most widely accepted dates had been calculated by another physicist—William Thomson, better known as Lord Kelvin—who had used the equations of thermodynamics and the earth’s heat conductivity to estimate that the planet was somewhere around twenty million years old.

In geology, that’s not a lot of time, and the implications were profound. The earth’s geological features could not have appeared within this duration if processes like volcanism and erosion proceeded at today’s rate.1 But the real victim of Kelvin’s estimate was Charles Darwin’s theory of evolution by natural selection. Darwin had described himself as “greatly troubled at the short duration of the world according to Sir W. Thomson.”2 He knew that organisms had not changed much since the last ice ages, and from such little change he inferred that the amount of time needed to create all organisms—alive today or preserved in fossils—must be truly enormous.3 Twenty million years was not enough time to create life’s diversity.

But Rutherford, who had discovered the phenomenon of radioactive half-life only a few years before, knew that Kelvin was wrong, by at least several orders of magnitude. As he later recalled:

I came into the room, which was half dark, and presently spotted Lord Kelvin in the audience and realized that I was in for trouble at the last part of the speech dealing with the age of the earth, where my views conflicted with his. . . . The discovery of the radio-active elements, which in their disintegration liberate enormous amounts of energy, thus increases the possible limit of the duration of life on this planet, and allows the time claimed by the geologist and biologist for the process of evolution.4 (emphasis added).

And that was that. Kelvin died in 1907. Rutherford won the Nobel Prize in 1908, and by the 1930s his radiometric methods had shown that the earth was around 4.5 billion years old. Darwin’s theory was saved, since the processes of random mutation and selection now had the time needed to create life’s enormous complexity and diversity.

Or did they?

Consider the peregrine falcon, Falco peregrinus, one of nature’s great predators and an organism of marvelous perfection. Its powerful musculature, matched with an extremely lightweight skeleton, makes it by far the fastest animal on earth, able to reach more than 200 miles per hour in one of its characteristic dives. All that speed translates into enormous kinetic energy when the falcon strikes its prey in midair with razor-sharp talons. If that impact alone does not deliver death, the falcon can sever the spinal column of its prey with a conveniently notched upper beak.5

Before moving in for the kill, F. peregrinus needs to track down its prey. The targeting mechanism is a pair of eyes with full-color binocular vision, possessing resolving power more than five times greater than a human’s, which means that a peregrine can see a pigeon at distances of more than a mile.6 Like many predators, the falcon has an eye with a nictitating membrane—a third eyelid—a bit like a windshield wiper that removes dirt while keeping the eye moist during a high-speed chase. The falcon’s eyes also harbor more photoreceptors, the rods that capture images in very low light, and the cones that provide color vision. 7 Its photoreceptors render even long-wavelength ultraviolet light visible.

A marvel indeed. But even more marvelous is knowing that every one of those brilliant adaptations is the sum of innumerable tiny steps, each one preserved by natural selection, each one a change in a single molecule. The deadly beak and talons of F. peregrinus are built from the same raw material as its feathers, the protein molecules known as keratin, the human versions of which make up your hair and nails.8 For color vision, those extraordinary eyes depend on opsins, protein molecules in the eyes’ rods and cones. Crucial for their remarkable acuity are their lenses, composed of transparent proteins known as crystallins.9

The first vertebrates to use crystallins in lenses did so more than five hundred million years ago, and the opsins that enable the falcon’s vision are some seven hundred million years old.10 They originated some three billion years after life first appeared on earth. That sounds like a helpfully long amount of time to come up with these molecular innovations. But each one of those opsin and crystallin proteins is a chain of hundreds of amino acids, highly specific sequences of molecules written in an alphabet of twenty amino acid letters. If only one such sequence could sense light or help form a transparent cameralike lens, how many different hundred-amino-acid-long protein strings would we have to sift through? The first amino acid of such a string could be any one of the twenty kinds of amino acids, and the same holds for the second amino acid. Because 20 × 20 = 400, there are there are 400 possible strings of two amino acids. Consider also the third amino acid, and you have arrived at 20 × 20 × 20, or 8,000, possibilities. At four amino acids we already have 160,000 possibilities. For a protein with a hundred amino acids (crystallins and opsins are much longer), the numbers multiply to a 1 with more than 130 trailing zeroes, or more than 10130 possible amino acid strings. To get a sense of this number’s magnitude, consider that most atoms in the universe are hydrogen atoms, and physicists have estimated the number of these atoms as 1090, or 1,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000. This is “only” a 1 with 90 zeroes. The number of potential proteins is not merely astronomical, it is hyperastronomical, much greater than the number of hydrogen atoms in the universe.11 To find a specific sequence like that is not just less likely than winning the jackpot in the lottery, it is less likely than winning a jackpot every year since the Big Bang.12 In fact, it’s countless billions of times less likely. If a trillion different organisms had tried an amino acid string every second since life began, they might have tried a tiny fraction of the 10130 potential ones. They would never have found the one opsin string. There are a lot of different ways to arrange molecules. And not nearly enough time.

When the seventeenth-century lyric poet Andrew Marvell bemoaned, “Had we but world enough, and time” to avoid the “deserts of vast eternity” that lay before him, he was attempting to unlock his mistress’s bedchamber, not the secrets of nature. But he was on to something. Common wisdom holds that natural selection, combined with the magic wand of random change, will produce the falcon’s eye in good time. This is the mainstream perspective on Darwinian evolution: A tiny fraction of small and random heritable changes confers a reproductive advantage to the organisms that win this genetic lottery and, accumulating over time, such changes explain the falcon’s eye—and, by extension, everything from the falcon itself to all of life’s diversity.

The power of natural selection is beyond dispute, but this power has limits. Natural selection can preserve innovations, but it cannot create them. And calling the change that creates them random is just another way of admitting our ignorance about it. Nature’s many innovations—some uncannily perfect—call for natural principles that accelerate life’s ability to innovate, its innovability.

For the d last fifteen years, I have been privileged to help uncover these principles, first in the United States and later, joined by a group of highly talented researchers, in my laboratory at the University of Zürich in Switzerland. Using experimental and computational technologies unimagined by Darwin or Rutherford, our goal is not to discover individual innovations, but to find the wellsprings of all biological innovation. What we have found so far already tells us that there is much more to evolution than meets the eye. It tells us that the principles of innovability are concealed, even beyond the molecular architecture of DNA, in a hidden architecture of life with an otherworldly beauty.

These principles are the subject of this book.

CHAPTER ONE

What Darwin Didn’t Know

Sallie Gardner was the world’s first movie star. Her graceful debut in 1878 launched cinema itself, though she was only six years old. Sallie, you see, happened to be the Thoroughbred horse that the English-born photographer Eadweard Muybridge shot in full gallop with his zoopraxiscope, an array of twenty-four cameras along her path, to settle a pressing question that undoubtedly keeps many people awake at night: Does a galloping horse ever lift all four legs off the ground? (The answer is yes.) His grainy, jerky silent movie, all of a second long, is worlds apart from the high-definition digital surround-sound cinematography taken for granted in the early twenty-first century. Yet the time separating Muybridge’s photographic study from modern movies spans just over a century, a stretch not much longer than the time since Darwin published The Origin of Species, only nineteen years before Sallie Gardner’s star turn.

During the same time, biology has been transformed by a revolution even more dramatic than the cinematic one.1 This revolution has revealed a world as inaccessible to Darwin as outer space was to cavemen. And it has helped to answer the single most important question about evolution, the question that Darwin and generations of scientists after him did not, could not touch: How does nature bring forth the new, the better, the superior? How does life create?

You might be puzzled. Wasn’t that exactly Darwin’s great achievement, to understand that life evolved and to explain how? Isn’t that his legacy? Yes and no. Darwin’s theory surely is the most important intellectual achievement of his time, perhaps of all time. But the biggest mystery about evolution eluded his theory. And he couldn’t even get close to solving it. To see why, we first need to take a look at what Darwin knew and what he didn’t, what was new about his theory and what wasn’t, and why only now, more than a century later, can we begin to see how the living world creates.

Germs of thought about an evolving natural world existed long before Darwin. No fewer than twenty-five hundred years ago, the Greek philosopher Anaximander—better known as the great-grandfather of the heliocentric worldview—thought that humans emerged from fish. The fourteenth-century Muslim historian Ibn Khaldun thought that life progressed gradually from minerals to plants to animals. Much later, the nineteenth-century French anatomist Etienne Geoffroy Saint-Hilaire deduced from fossilized reptiles that they had changed over time.2 The Viennese botanist Franz Unger argued in 1850, just a few years before Darwin published The Origin of Species in 1859, that all other plants descend from algae.3 And the French zoologist Jean-Baptiste Lamarck postulated that evolution occurred through use and disuse of organs. Some of the earliest thinkers even seem prescient about evolution, until you dig a bit and find some bizarre nuggets, such as Anaximander’s notion that early humans lived inside fish until puberty, when their hosts burst and released them. Beliefs that are alien to today’s science persisted well into Darwin’s era. According to one of them, shared by many from the ancient Greeks to Lamarck, simple organisms are spontaneously created from inanimate matter like wet mud.4

Just as evolution had its proponents, it had equally vocal opponents well into Darwin’s era. And no, I do not mean people like today’s young earth creationists—half literate and wholly ignorant—who believe that earth was created on a Saturday night in October of 4004 BC (and that Noah’s Ark could have saved more than a million species, but Noah somehow forgot the huge dinosaurs, perhaps forgivably so, considering that he was six hundred years old). I mean scientific leaders of the time. One of them was the French geologist Georges Cuvier, the founder of paleontology, literally the science of “ancient beings” (think dinosaurs).5 He discovered that the fossils embedded in older rocks are quite different from those in younger rocks, which resemble today’s life. Yet he thought that each species had essential, immutable characteristics, and could only vary in superficial traits. Another example is Carl Linnaeus, who lived a mere century before Darwin. He is the father of our modern system for classifying life’s diversity, yet until late in life he did not believe in evolution’s great chain of living beings.6

Christian beliefs are the best-known reason for such resistance. To Cuvier, life’s diversity wasn’t evidence of evolution but of the Creator’s great talents. Another reason, however, has even deeper roots. It goes back all the way to the Greek philosopher Plato, whose influence on Western philosophy is so great that the twentieth-century philosopher Alfred North Whitehead demoted all of European philosophy to “a series of footnotes to Plato.”7 Plato’s philosophy was deeply influenced by the ideal, abstract world of mathematics and geometry. It maintains that the visible, material world is but a faint, fleeting shadow of a higher reality, which consists of abstract geometric forms, such as triangles and circles. To a Platonist, basketballs, tennis balls, and Ping-Pong balls share an essence, their ball-like shape. It is this essence—perfect, geometric, abstract—that is real, not the physical balls, which are as fleeting and changeable as shadows.

The goals of scientists like Linnaeus and Cuvier—to organize the chaos of life’s diversity—are much easier to achieve if each species has a Platonic essence that distinguishes it from all others, in the same way that the absence of legs and eyelids is essential to snakes and distinguishes them from other reptiles. In this Platonic worldview, the task of naturalists is to find the essence for each species. Actually, that understates the case: In an essentialist world, the essence really is the species.8 Contrast this with an ever-changing evolving world, where species incessantly spew forth new species that can blend with each other.9 The snake Eupodophis from the late Cretaceous period, which had rudimentary hind legs, and the glass lizard, which is alive today and lacks legs, are just two of many witnesses to the blurry boundaries of species. Evolution’s messy world is anathema to the clear, pristine order that essentialism craves. It is thus no accident that Plato and his essentialism became the “great antihero of evolutionism,” as the twentieth-century zoologist Ernst Mayr called it.10

In the controversy between Darwinists and their opponents, fossils like Eupodophis were mere boulders in a mountain of evidence that helped Darwin’s supporters gain the upper hand.11 At Darwin’s time, systematists had already classified thousands of living species and unveiled deep similarities among them. Geologists had discovered that the earth’s surface was roiling, incessantly creating, folding, and crushing layers of rock. Paleontologists had discovered countless extinct species, some in young rocks and similar to the life we know, others in ancient rocks and very different. Embryologists had shown that organisms as different as a freely paddling shrimp and a barnacle clamped to a ship’s hull can have deeply similar embryos.12 Explorers, Darwin among them, had found many intriguing patterns of biogeography. Small islands have fewer species, opposite shores of the same continent harbor very different faunas, Europe and South America host completely different mammals.13

A special creation of each species would leave all these threads of knowledge in a messy tangle. Darwin, one of the greatest synthesizers of all time, wove them into the beautiful fabric of his theory. He threw the gauntlet at creationists by claiming that all life shares a common ancestor, and thereby dismissed biblical Genesis from the debate table.

That was Darwin’s first great insight. The second one was the central role of natural selection, an insight inspired by the spectacular success of animal and plant breeders.14 The Origin’s entire first chapter marvels at the diversity of domestic dogs, pigeons, crop plants, and ornamental flowers that human breeders had produced. It is indeed stunning to think that humans could create Great Danes, German shepherds, greyhounds, bulldogs, and Chihuahuas, all from a common lupine ancestor, and all within mere centuries. Darwin realized that natural selection is not so different from such human selection, except that it operates on a much grander scale, and over eons of time. Nature incessantly creates new variants of organisms, most inferior, a few of them superior, and all of these variants must pass through the sieve of natural selection. Only individuals best adapted to their environment survive, procreate, and give rise to further variants. Given enough time, this process helps explain all of life’s diversity, so much so that the geneticist Theodosius Dobzhansky could say in 1973 that “nothing in biology makes sense except in the light of evolution.”

From the very beginning, that light shone more brightly on some of life’s mysteries than on others. One of them was left in especially deep shadows: the mechanism of heritability. Without some mechanism that guarantees faithful inheritance from parents to offspring, adaptations—a bird’s wing, a giraffe’s neck, a snake’s fangs—cannot persist over time. And without inheritance, selection would be powerless. Darwin himself had no idea why children resemble their parents, and his frankness in admitting ignorance is disarming. “The laws governing inheritance are for the most part unknown,” he said in the Origin.15

Darwin’s theory was a bit like that first movie of a galloping horse, revolutionary when compared to still photography, but only a modest step on the path to full-length feature films. The next step on biology’s path—explaining inheritance—was already made by the time Darwin died, but he did not know it. Nor did any other prominent scientist, although decisive experiments had already started in 1856, three years before Darwin published the Origin.16 Even the scientist who performed these experiments would not live to see the avalanche of progress he triggered, which would eventually engulf all of biology.

That scientist was the Austrian monk Gregor Mendel, who studied in Vienna and entered St. Thomas Abbey in Brno, where he would experiment on more than twenty thousand pea plants before he became abbot. For his experiments, he deliberately chose pea plants that differed in several discrete features: One plant might produce smoothly round yellow peas, whereas the other would produce wrinkly green peas, but none with in-between color or shape. Other pea plants differed sharply in flower color, pod shape, or stem length. Mendel cross-fertilized these plants and analyzed their offspring, thousands and thousands of plants.

What he saw was that these features often do not blend in the offspring.17 The offspring’s first or second generation produces either round or wrinkly peas, but none with an intermediate shape. And different features can be inherited independently, such that the offspring might sport combinations—round and green, wrinkly and yellow—that neither parent harbored. The causes of inheritance behaved like discrete and indivisible particles. Each parent carried two particles responsible for traits like roundness or color, but would pass only one of them on to its offspring. Different features were inherited through different kinds of particles, and could thus combine and recombine independently.

Mendel worked in an academic backwater far from the intellectual currents of his time. And he committed the error that snuffed many an academic career, then and now: He published little and in the wrong place—in his case a local naturalist journal.18 And as bad luck would have it, the abbot who succeeded him would burn Mendel’s papers after his death. But thirty-four years after its publication in 1865, Mendel’s sleeping beauty of a discovery would be roused by the Dutch botanist Hugo de Vries, who independently performed experiments similar to those of Mendel. Historians still argue whether he truly rediscovered Mendel’s laws, or whether he learned about Mendel’s work during his own experiments and tried to hide his knowledge.19 The searing disappointment of having not just been scooped, but scooped by three decades, could certainly explain the impulse to rewrite history. Be that as it may, rediscovered Mendel’s laws were, and from then on they spread like wildfire. They became the basis of a whole new branch of biology, the science of genetics. Traits that behave as Mendel described exist in many plants and animals, including humans. Some of our Mendelian traits are as odd as the consistency of ear wax (wet or dry), but others are as important as the major blood groups (A or B), or diseases like sickle-cell anemia.

As it turns out, de Vries was to receive a consolation prize. He is the grandfather of the word gene, whose importance endures in both science and popular culture. De Vries had called the particles of inheritance that Mendel had described “pangenes,” and a few years later the Danish geneticist Wilhelm Ludvig Johannsen would simply drop the “pan.”20

Johannsen contributed two further important words to the language of modern biology. He coined the word genotype and distinguished it from the phenotype. In today’s language, a genotype comprises all genes of an organism, all its DNA, whereas the phenotype comprises everything else you could observe about the organism: its size, its color, whether it has a tail, or feathers, or a carapace. To see this distinction is crucial, because it allows us to tell cause from effect when organisms change. Take the word mutation, which was already used two hundred years earlier for any dramatic change in an organism’s appearance. In the early twentieth century, it was sometimes applied to Mendel’s units of inheritance, and sometimes to the organism (phenotype), leading to endless confusion about causes and effects of change.21 A century later we know that mutations change a genotype, like the mutations that altered the blueprint of light-sensing opsin proteins in some of our distant animal ancestors. Such genotypic change can cause changes in a phenotype, and some changed phenotypes become innovations—novel and useful features—like our ability to see the world in color.

Only once we have distinguished between genotype and phenotype can we ask a question crucial to understand life’s innovability: How do mutations cause changes in phenotypes and bring forth innovations? Because that was the other great mystery left unanswered at the time of Darwin’s death: Where do innovations come from? Where do the new variants come from that selection needs? And especially those variants that improve an organism, help it survive a little longer, appear sexier to a mate, or have more babies? One could answer this question with a vacuous platitude: New variants arise randomly, by chance. This platitude is still used today, but Darwin was already familiar with it. And he knew that it explains exactly nothing. He opened the chapter on laws of variation in the Origin like this:

I have hitherto sometimes spoken as if the variations . . . had been due to chance. This, of course, is a wholly incorrect expression, but it serves to acknowledge plainly our ignorance of the cause of each particular variation.

This is not a small problem, because natural selection is not a creative force. It does not innovate, but merely selects what is already there. Darwin realized that natural selection allows innovations to spread, but he did not know where they came from in the first place.

To appreciate the magnitude of this problem, consider that every one of the differences between humans and the first life forms on earth was once an innovation: an adaptive solution to some unique challenge faced by a living being. It might have been the challenge of converting the light energy from the sun into living matter. Or the challenge of converting another living thing into food. Or simply of moving from one place to another. Every square meter of the earth’s surface, every cubic meter of the oceans, every meadow, forest, and desert, every city and suburb is packed to the limits with organisms, and each organism exhibits countless such innovations. Fundamental ones like photosynthesis and respiration. Protective ones like reptilian scales and insulating feathers. Supportive ones like connective tissue and skeletons. Some are complex, with hundreds of moving parts, others are not. But no matter how large or small, from the ten feet of a blue whale’s tail fluke to the ten microns of a bacterium’s flagellum, every single one exists because, at some point since life’s origin, the right variation occurred.

Selection did not—cannot—create all this variation. A few decades after Darwin, Hugo de Vries expressed it best when he said that “natural selection may explain the survival of the fittest, but it cannot explain the arrival of the fittest” (emphasis added).22 And if we do not know what explains its arrival, then we do not understand the very origins of life’s diversity.

Life can innovate, it has innovability. What is more, it can innovate while preserving what works through faithful inheritance. It can explore the new while preserving the old. It can be progressive and conservative at the same time. And through the early twentieth century, biologists had no idea how that is possible. As we shall see, there is no way they could have known. Another century of discoveries was needed before the experimental and computational toolbox of biology became powerful enough to tackle this question.

In fact, looking back, it is remarkable that early-twentieth-century scientists could even distinguish genotypes from phenotypes. They were as ignorant about the material basis of Mendelian inheritance as Muybridge was of color photography. It was not even clear whether genes were intangible concepts, like gravity, or physical objects that could be isolated from a body and studied.23 Only later would it become clear that genes were very physical, lying on chromosomes and consisting of DNA.

Even before the discovery of genes’ physical reality, Mendel’s discovery fanned the flames under an old controversy that had simmered since Darwin. Discrete, granular, particulate inheritance flies in the face of an obvious fact that all of us are familiar with. If a six-foot-tall man and a five-foot-tall woman have children, then discrete inheritance demands that their children should be as tall as either parent—five or six feet—but never in between.24 But we all know that the children’s heights lie on a continuum, as do the shapes of their faces, the color of their skin, the contours of their bones, and so on. Naturalists since Darwin found such continuous, blending inheritance everywhere around them, in the yield of crops, the weight of eggs, the sizes of leaves—in brief, in most features of organisms.25 This kind of variation is clearly important in nature.

The controversy raged around the question of which kind of variation, continuous or discrete, was more important for evolution. The naturalist or gradualist school of thought—Darwin was an early adherent—emphasized the small, continuous variation that we see all around us. The other school—“Mendelists,” “mutationists,” or “saltationists”—believed in the large, discrete variants that Mendel had studied. In a cartoon version of this dispute, a gradualist would imagine that the many petals of a garden rose emerged from its five-petaled ancestors through gradual additions of petals over many generations. A mutationist, on the other hand, would argue that the multifoliate rose could have appeared in a single saltational “macromutation” from this ancestor.26

Looking back, this debate seems just as important as the question that kept medieval scholastics busy: How many angels can dance on the head of a pin? But it just about pierced the heart of Darwinism. For the Mendelists believed less in natural selection than in the power of mutations to bring forth new traits. In their view, the real drivers behind life’s evolution were large mutations that created individuals far outside the norm of their species. “Hopeful monsters” is what the German-born zoologist Richard Goldschmidt would call them, citing as one of his examples the benthic flatfish that live on the ocean floor, which have both eyes on the same side of the head.27

Although the Mendelists would turn out to be wrong—most evolutionary change does indeed occur gradually and involves natural selection—they did have a point. The real mystery of evolution is not selection, but the creation of new phenotypes. But they were born too early. They could speculate wildly, but had no way to solve the mystery, and the controversy between the two camps continued well into the twentieth century until powerful new insights would dissolve it. That process began when a long-known fact became newly appreciated: Genetic change happens not just in individuals, but in populations.

The white-bodied peppered moth is a perfectly inconspicuous insect whose white wings are sprinkled with flecks of black. Against a background of tree bark and lichen, this mottled pattern camouflages the moth against ravenous birds. In some moths, a gene affecting wing color can mutate to produce a dark-colored wing. This mutation is usually bad news for a moth, because mutant moths are no longer camouflaged, and birds can rapidly pick them off. But in nineteenth-century England the Industrial Revolution gave the dark mutant moths a much-needed break. During this time, air pollution became so severe that it wiped out most lichen and turned tree bark black. Now the dark moths were well hidden, and the white moths had turned into bird food.

If natural selection mattered, we would expect that the black moths would become more frequent over time. They would sweep through a moth population, whereas white moths would become rare. This is indeed what happened in nineteenth-century England, as the proportion of black moths in the population rose from 2 percent in 1848 to 95 percent by 1895.28 But this information isn’t nearly as important as the questions it triggers: Can we predict how rapidly they sweep through the population? Or conversely, if we have observed how fast they sweep, can we infer how strongly the dark color affects fitness, a moth’s chances of remaining hidden from birds? These were quantitative, mathematical questions, new to evolutionary thinking. And they created a new quantitative discipline within biology: population genetics.

One of the central insights of population genetics is to view a population not just as a collection of distinct organisms but as a collective pool of genes. The genes that determine a moth’s wing color, for example, have different forms—the technical term is alleles—responsible for light or dark wings, that occur in different proportions or frequencies in the population. Imagine that at any one time, equal numbers of both types of alleles were present in a population of organisms, and that some new factor—a new predator, or a change in pollution—allowed moths with darker wings to live longer, and so produce more offspring. Their advantage need not be huge, but even a merely 1 percent increase in the dark-winged allele, from 50 percent to 51 percent in the first generation, could accumulate over time and allow the dark-winged variants to occupy a larger and larger percentage of the population. That’s how natural selection works: It changes allele frequencies, and thus the appearance of individuals over time.

This was revolutionary. The study of life, which had largely depended on the same tools since Aristotle—close observation and dissection in the field and laboratory, recorded in sketchbooks and notes—began to embrace the mathematics of differential equations and the analysis of variance. Through the minds of intellectual giants such as Sewall Wright, J. B. S. Haldane, and the statistician R. A. Fisher, population genetics developed into a theory that could answer precise, quantitative questions about natural selection. At the same time, naturalists studied the frequencies of alleles in wild populations such as that of the peppered moth, and experimentalists created evolution in action in the laboratory, by studying laboratory populations of small, rapidly breeding animals such as fruit flies. The mathematical theory was the mortar that helped join these observations into an intellectual edifice.

The new evidence from population genetics showed that variation covered a broad spectrum, with “pure” Mendelian variation at one extreme, and continuous variation at the other. Mendelian phenotypes—wing color, pea shape—are influenced by one gene with large effects. Continuously varying phenotypes like height are influenced by multiple genes, each with a tiny effect. Population genetics showed that natural selection affects both kinds of genes. But truly surprising was how powerfully selection could affect them. If a dark-wing allele decreased a moth’s chance to be eaten by a few percent, it could wipe out the light-wing allele within a few dozen moth generations. And both naturalists and experimentalists found far more genes in their populations with small effects than with large ones. Mendel clearly had chosen his peas very carefully, because Mendelian traits that are influenced by a single gene comprise a tiny fraction of all traits.29 Most evolution is gradual and does not make large jumps.30

By the 1930s, the concept of natural selection, the nature of inheritance, and population thinking had been synthesized into a body of knowledge known as the modern synthesis, named after an eponymous book by the biologist Julian Huxley.31 Despite its name, the synthesis will soon be a century old. But unlike most centenarians, it shows no signs of senescence. Augmented by mathematical refinements and modern data, it is unbroken, and by some measures stronger than ever, playing an increasingly important role in understanding human biology—helping to reconstruct human origins, trace human migrations, and understand genetic diseases. If this edifice of knowledge were a physical building, it would rival everything architects have conceived, from the palaces of Angkor Wat and the mausoleum of the Taj Mahal to the great Gothic cathedrals of the thirteenth century. It is a grand achievement of the human mind.

There is, however, a dirty secret behind its success. The architects of the modern synthesis focused on the genotype at the expense of the organism and its phenotype. They neglected the marvelous complexity of organisms with their trillions of cells, each inhabited by billions of molecules whose functions are themselves incredibly complex. And they neglected how all this complexity unfolds from a single fertilized cell, and how genes contribute to this unfolding. By neglecting this complexity, the architects of the modern synthesis effectively ignored its product: the organism itself. They did so knowingly, since they wanted to understand how gene frequencies change over time. In focusing on the genotype, they simplified an organism’s phenotype down to simpler quantities, such as fitness, the average number of genes a typical individual transmits to the next generation. (Fitter organisms contribute more genes to the next generation’s gene pool.) What is more, they also assumed that individual genes play a simple role in determining fitness, for example that fitness is the sum total of many small gene effects.

Don’t get me wrong. It is hard to see how the modern synthesis could not have ignored the organism. The price of understanding is always abstraction, neglecting most of a staggeringly complex world to understand one tiny fragment of it. Take it from another theorist, Albert Einstein, who knew what he was talking about when he said that “everything should be made as simple as possible, but no simpler.”32 The modern synthesis was just as simple as it needed to be to answer thousands of questions about the evolution of genes and genotypes. Its very success in understanding natural selection in action was built on getting rid of organismal complexity. But whenever a theory is successful, it is also easy to forget its limitations, and this is exactly what happened in the heyday of the modern synthesis, when the grandeur of life’s evolution became redefined and demoted to a “change in allele frequency within a gene pool.”33 The principal limitation—a high price to pay—was the inability to answer the second great question the Origin had left open: Where do innovative phenotypes come from? The modern synthesis could explain how innovations spread, but not how they originate.

To say that all evolutionists had thrown the organism under the bus, however, would be unfair to a minority of them, those who compared how the complexity of different organisms unfolds in their embryos. But these embryologists, whose forebears had helped Darwin to recognize the common ancestry of all living things, were sidelined by the modern synthesis and its advocates, who had no need for the embryo. In 1932, one year before he would win the Nobel Prize for showing how genes are organized into chromosomes, the fly geneticist Thomas Hunt Morgan would say that it does not matter much “whether you choose an ape or the foetus of an ape as the progenitor of the human race.”34

But even though population geneticists ruled in biology’s halls of power, some embryologists in the back rows kept heckling the opinion leaders, pointing out that they were ignoring the very thing they were trying to explain. Their voices got louder toward the end of the twentieth century. That’s when evolutionary developmental biology, or “evo-devo,” emerged as a new research discipline, one that aims to integrate embryonic development, evolution, and genetics. Evo-devo produced fantastic insights into how genes cooperate, like orchestra musicians, to make embryonic development possible.

So far, though, these insights have not yet added up to a theory rivaling the modern synthesis. And only theory can turn a heap of facts into a tower of knowledge. The culprit is once again the enormous phenotypic complexity of whole organisms. Even today, we struggle to fully understand the phenotype of even the simplest organisms, and hundreds of thousands of biologists laboring over many decades have still not fully understood how genes help shape this phenotype.35 Where the modern synthesis has a theory without phenotypes, the embryologists have phenotypes without a theory.

Evo-devo, however, has taught us an important lesson. To understand innovability we cannot ignore the complexity of phenotypes. We must embrace it. And even though we do not yet understand all of an organism’s complexity, we now understand the parts of the phenotype that ultimately bring forth all innovations. This is where the next chapters will take us.

The same century that led biology from Darwin to Mendel and the modern synthesis also gave birth to biochemistry, a science that had been conceived more than seven thousand years earlier, when humans started to produce beer and wine. The mechanism by which yeasts transform sugar into ethanol remained mysterious, however, until Louis Pasteur showed, three years before Darwin’s Origin, that living organisms cause fermentation. And even that truth was toppled a few decades later, when Eduard Buchner proved in 1897 that fermentation does not require living organisms, because yeast extracts containing no living cells can ferment sugar. His discovery helped dispel vitalism, the notion that life required an enigmatic vital force and obeys laws different from those of the inanimate world.

To teach us that life is based on prosaic chemistry is important, but Buchner is even better remembered as a pioneer in the discovery of enzymes, those gigantic protein molecules consisting of dozens to thousands of amino acids.36 They can speed up chemical reactions that cleave, join, or rearrange atoms up to a billionfold. Biochemistry honors Buchner to this day by using his naming system for enzymes, adding the suffix -ase to the chemical reaction they catalyze. An enzyme that can process the sugar sucrose would be sucrase, one processing lactose would be lactase, and so on.

His discoveries also spun off another branch of biochemistry. It focused not on enzymes but on the reactions they catalyzed, and would unveil a new chemical world, that of metabolism with its bewildering complexity. Broadly speaking, an organism’s metabolism—the word itself comes from the Greek for “change”—comprises two sorts of chemical transformations. The first kind cleaves energy-rich molecules such as the sugar glucose to extract energy from them. The second uses this energy to transform nutrient molecules into a cell’s own molecular building blocks, which comprise dozens of molecules like the amino acids in proteins. Along the way, a metabolism must also manage a body’s waste, disarming toxic molecules into harmless ones. Taken together, these tasks are complex and require more than a thousand chemical reactions—and the enzymes that catalyze them—in order to build and maintain our bodies.37

The discovery that protein enzymes help build our phenotype is a monumental insight of twentieth-century biochemistry. (It also led to a key insight about life’s creativity: Even the largest changes in an organism result from alterations in individual molecules.) But this discovery was dwarfed by an even greater one: the chemical structure of our genes.

Its story also begins at Darwin’s time, in 1869, the same year as the fifth edition of The Origin of Species.38 That is when the Swiss chemist Friedrich Miescher first identified a new mysterious substance, different from protein.39 He called it Nuklein, but its chemical structure would not become clear until decades later. Not until 1910 would we know that the substance—by then renamed deoxyribonucleic acid (DNA)—contains the four bases adenine (A), cytosine (C), guanine (G), and thymine (T), molecules that we now call the four letters of the DNA alphabet. And it would be 1944 before biologists realized that DNA is the stuff of inheritance. In that year Oswald Avery showed that DNA from a disease-causing strain of the bacterium Streptococcus pneumoniae helps another, harmless strain kill mice.40

Less than a decade later, James Watson and Francis Crick would reveal that DNA is a supremely beautiful molecule. Its two strands form the famed double helix, a twisted ladder in which two paired bases from opposite strands make up each rung. In each rung, two bases are always paired, A always with T, and C always with G. This structure also suggests how DNA could be copied, and thus how inheritance works at the level of molecules.41 Genes had turned out to be so much more than Johannsen had thought.

It had taken seventy years to get from Muybridge’s zoopraxiscope to color television—to get from recording individual black-and-white images on silver plates to encoding color images as electric signals, transmitting them wirelessly, and displaying them on cathode-ray tubes. During the same seventy years, biology had also progressed dramatically and embraced new discoveries just as enthusiastically. It had married the mathematics of population genetics and birthed the modern synthesis. It had revealed the function of enzymes and discovered the structure of DNA (brought to us at about the same time as color television). It had incorporated the knowledge of chemistry that would become essential to understanding the origins of innovation. It wasn’t there yet. But it was getting closer.

FIGURE 1.

Watson and Crick’s discovery rang in the age of molecular biology. Within the next twelve years, biologists would learn that DNA is transcribed into the closely related ribonucleic acid (RNA), which is then translated, three nucleotide letters at a time, into a protein string of amino acids (figure 1). This translation follows a genetic code in which most of the sixty-four possible three-letter words encode a single amino acid. Only a few words are set aside to signal the beginning and the end of a protein string.

Knowing the DNA letter sequence of a gene, a child could predict the amino acid sequence of a protein. But this is where simplicity ends. Proteins fold into intricate three-dimensional shapes that wobble and vibrate. To understand how they perform their tasks, such as to accelerate chemical reactions, both the shapes and their vibrations need to be known. And to this day we are unable to predict either one from the underlying amino acid string, so complex and subtle are the rules underlying this folding. To be sure, experiments to identify protein folds were already under way in the 1950s, beginning with the oxygen-storing globin proteins of our blood and muscles.42 But these experiments were laborious and could take years. Whereas finding the amino acid string encoded by a DNA letter sequence is as easy as looking up a word in a dictionary, predicting a protein fold is much harder—a bit like translating a poem by Yeats into Chinese.

This is not good news for anyone hoping to understand where innovative phenotypes come from. Understanding an organism’s phenotypes—any of its aspects, whether the color of a wing, the acuity of an eye, or the strength of a bone—comes down to understanding the molecules that build a body, the smallest building blocks of the phenotype. If we cannot predict their shape, it is impossible to travel the road from the genotype all the way to the phenotype. But that road is where nature innovates. Without understanding its twists and turns, its speed limits and traffic signs, we know little more about innovability than Darwin.

And it gets worse, because proteins don’t operate on their own. They cooperate like worker bees in solving a complex task. Take the protein hormone insulin, a messenger molecule produced by the pancreas that commands your liver cells to absorb and process glucose. Insulin cannot enter the liver directly. Instead, it binds to a protein on a liver cell’s surface, the insulin receptor. In response, this receptor modifies another protein inside the cell, which starts a chain of handshakes between further proteins that, eventually, turn on the genes needed to process glucose. At every moment of our existence, thousands of such molecular signals crisscross our body and are processed inside cells. Since Watson and Crick’s discovery, molecular biologists have increasingly studied processes like these. Pulling on a few loose strands, they have unearthed the molecular webs that allow us to eat, move, see, hear, think, taste, sleep, and do just about everything else we do.

But we got more than we asked for. Thousands of man-years have already been poured into this endeavor, and the end is not near. To the contrary, the more we learn, the more strands of this web become evident, the more complex and tangled it seems. The road from genotype to phenotype extends to the horizon and beyond.

Throughout the twentieth century, many evolutionary biologists were undistracted by all this complexity. Basking in the glow of the modern synthesis, they were blissfully focused on the genotype. And this focus became even greater after Watson and Crick’s work had stirred the ocean of our ignorance, and after new technology to read the letter sequence of DNA molecules had been developed. This technology spawned a new research field known as molecular evolutionary biology, whose subject was variation in amino acid and DNA strings. The earliest incarnation of this technology was about as inefficient as Muybridge’s zoopraxiscope—a year’s work would reveal no more than a few hundred letters. By the mid-1980s, however, its efficiency had increased more than tenfold, enough to read short sequences of DNA from multiple individuals in a population.43

When molecular evolutionists took advantage of this technology, they discovered something nobody had expected: enormous amounts of genetic variation, everywhere, even in organisms that had not changed for many millennia.

One early molecular evolution study focused on alcoholdehydrogenase, an enzyme that helps detoxify ethanol. We have a gene for it, and so do fruit flies. No one knows whether they get as high on fermented fruit as any Skid Row wino, but they certainly are attracted to it, and they need this enzyme to prevent alcohol poisoning. In 1983, Martin Kreitman from Harvard University found that the DNA from a small sample of fruit flies contained more than forty-three different DNA text variants in this gene.44 Similar variants occur in humans. One of them causes a form of alcohol intolerance where blotches erupt on the faces and bodies of sensitive individuals, a condition so widespread among people with Asian ancestry that it is known as “Asian flush.”45

But what Kreitman did not find in the alcoholdehydrogenase gene was even more telling. Most of the mutations in this gene were silent. They changed the DNA sequence, but not the amino acid sequence of alcoholdehydrogenase. This is possible because the genetic code is redundant, because more than one three-letter word can encode the same amino acid. And it was surprising. Even with a redundant code, there should have been many more amino-acid-changing mutations, because mutations tend to sprinkle genes randomly with letter changes. Something had happened to these mutations.

The something was natural selection. Because these changes impaired the enzyme, natural selection had weeded them out long before Kreitman got to see them.

Kreitman’s discovery and others like it illustrate a fact that is easily overlooked: The revolutions in evolutionary thought are different from other scientific revolutions. Whereas the revolution of quantum physics in the early twentieth century, for example, gave rise to a worldview incompatible with that of classical physics, revolutions in evolutionary biology leave core elements of previous theories intact.46 Rather than overturning the past, they deepen and sharpen it. They add layers of clarity and resolution, as well as new dimensions. The film Seabiscuit added color, music, dialogue, and the sound of hoofbeats to the first recording of Sallie Gardner’s ride, but it didn’t invalidate Muybridge’s revelation about the nature of galloping. Where Darwin used the natural world to infer the power of selection, the modern synthesis could see it in the ebb and flow of gene frequencies, and molecular evolutionists found it in DNA signatures, such as the excess of silent mutations. In doing so, they dissolved a fog of confusion that Darwin left behind. (Some of the fog, because the molecular revolution taught us more about genotypic than phenotypic change, the heart of the origination problem.)

The amount of variation Kreitman found in the alcoholdehydrogenase gene is not unusual. Animal and plant populations are chock-full of genetic variation. Genetic variants even occur in populations of living fossils whose phenotypes have not changed for many millions of years, such as the coelacanth, a strange fish thought to be extinct until a live specimen was found in 1939.47 Their abundance raised questions that occupy molecular evolutionists to this day. Do most of them matter for phenotypic evolution? Are they necessary or irrelevant for life’s innovations? Their mere existence underlines how hard it is to understand phenotypic innovation and how it emerges from genetic change.