The Gene
Fisher realized that the careful mathematical modeling of hereditary traits might resolve this rift. Mendel had discovered the discontinuous nature of genes, Fisher knew, because he had chosen highly discrete traits and crossed pure-breeding plants to begin with. But what if real-world traits, such as height or skin color, were the result of not a single gene, with just two states—“tall” and “short,” “on” and “off”—but of multiple genes? What if there were five genes that governed height, say, or seven genes that controlled the shape of a nose?
The mathematics to model a trait controlled by five or seven genes, Fisher discovered, was not all that complex. With just three genes in question, there would be six alleles or gene variants in total—three from the mother and three from the father. Simple combinatorial mathematics yielded twenty-seven unique combinations of these six gene variants. And if each combination generated a unique effect on height, Fisher found, the result smoothened out.
If he started with five genes, the permutations were even greater in number, and the variations in height produced by these permutations seemed almost continuous. Add the effects of the environment—the impact of nutrition on height, or sunlight exposure on skin color—and Fisher could imagine even more unique combinations and effects, ultimately generating perfectly smooth curves. Consider seven pieces of transparent paper colored with the seven basic colors of the rainbow. By juxtaposing the pieces of paper against each other and overlapping one color with another, one can almost produce every shade of color. The “information” in the sheets of paper remains discrete. The colors do not actually blend with each other—but the result of their overlap creates a spectrum of colors that seems virtually continuous.
In 1918, Fisher published his analysis in a paper entitled “The Correlation between Relatives on the Supposition of Mendelian Inheritance.” The title was rambling, but the message was succinct: if you mixed the effects of three to five variant genes on any trait, you could generate nearly perfect continuity in phenotype. “The exact amount of human variability,” he wrote, could be explained by rather obvious extensions of Mendelian genetics. The individual effect of a gene, Fisher argued, was like a dot of a pointillist painting. If you zoomed in close enough, you might see the dots as individual, discrete. But what we observed and experienced in the natural world from afar was an aggregation of dots: pixels merging to form a seamless picture.
The second reconciliation—between genetics and evolution—required more than mathematical modeling; it hinged on experimental data. Darwin had reasoned that evolution works via natural selection—but for natural selection to work, there had to be something natural to select. A population of organisms in the wild must have enough natural variation such that winners and losers can be picked. A flock of finches on an island, for instance, needs to possess enough intrinsic diversity in beak sizes such that a season of drought might be able to select birds with the toughest or longest beaks. Take that diversity away—force all finches to have the same beak—and selection comes up empty-handed. All the birds go extinct in a fell swoop. Evolution grinds to a halt.
But what is the engine that generates natural variation in the wild? Hugo de Vries had proposed that mutations were responsible for variation: changes in genes created changes in forms that could be selected by natural forces. But de Vries’s conjecture predated the molecular definition of the gene. Was there experimental proof that identifiable mutations in real genes were responsible for variation? Were mutations sudden and spontaneous, or were abundant natural genetic variations already present in wild populations? And what happened to genes upon natural selection?
In the 1930s, Theodosius Dobzhansky, a Ukrainian biologist who had emigrated to the United States, set out to describe the extent of genetic variation in wild populations. Dobzhansky had trained with Thomas Morgan in the Fly Room at Columbia. But to describe genes in the wild, he knew that he would have to go wild himself. Armed with nets, fly cages, and rotting fruit, he began to collect wild flies, first near the laboratory at Caltech, then on Mount San Jacinto and along the Sierra Nevada in California, and then in forests and mountains all over the United States. His colleagues, confined to their lab benches, thought that he had gone fully mad. He might as well have left for the Galápagos.
The decision to hunt for variation in wild flies proved critical. In a wild fly species named Drosophila pseudoobscura, for instance, Dobzhansky found multiple gene variants that influenced complex traits, such as life span, eye structure, bristle morphology, and wing size. The most striking examples of variation involved flies collected from the same region that possessed two radically different configurations of the same genes. Dobzhansky called these genetic variants “races.” Using Morgan’s technique of mapping genes by virtue of their placement along a chromosome, Dobzhansky made a map of three genes—A, B, and C. In some flies, the three genes were strung along the fifth chromosome in one configuration: A-B-C. In other flies, Dobzhansky found that configuration had been fully inverted to C-B-A. The distinction between the two “races” of flies by virtue of a single chromosomal inversion was the most dramatic example of genetic variation that any geneticist had ever seen in a natural population.
But there was more. In September 1943, Dobzhansky launched an attempt to demonstrate variation, selection, and evolution in a single experiment—to re-create the Galápagos in a carton. He inoculated two sealed, aerated cartons with a mixture of two fly strains—ABC and CBA—in a one-to-one ratio. One carton was exposed to a cold temperature. The other, inoculated with the same mixture of strains, was left at room temperature. The flies were fed, cleaned, and watered in that enclosed space for generation upon generation. The populations grew and fell. New larvae were born, matured into flies, and died in that carton. Lineages and families—kingdoms of flies—were established and extinguished. When Dobzhansky harvested the two cages after four months, he found that the populations had changed dramatically. In the “cold carton,” the ABC strain had nearly doubled, while the CBA had dwindled. In the carton kept at room temperature, the two strains had acquired the opposite ratio.
He had captured all the critical ingredients of evolution. Starting with a population with natural variation in gene configurations, he had added a force of natural selection: temperature. The “fittest” organisms—those best adapted to low or high temperatures—had survived. As new flies had been born, selected, and bred, the gene frequencies had changed, resulting in populations with new genetic compositions.
To explain the intersection of genetics, natural selection, and evolution in formal terms, Dobzhansky resurrected two important words—genotype and phenotype. A genotype is an organism’s genetic composition. It can refer to one gene, a configuration of genes, or even an entire genome. A phenotype, in contrast, refers to an organism’s physical or biological attributes and characteristics—the color of an eye, the shape of a wing, or resistance to hot or cold temperatures.
Dobzhansky could now restate the essential truth of Mendel’s discovery—a gene determines a physical feature—by generalizing that idea across multiple genes and multiple features:
a genotype determines a phenotype
But two important modifications to this rule were necessary to complete the scheme. First, Dobzhansky noted, genotypes were not the sole determinants of phenotypes. Obviously, the environment or the milieu that surrounds an organism contributes to its physical attributes. The shape of a boxer’s nose is not just the consequence of his genetic heritage; it is determined by the nature of his chosen profession, and the number of physical assaults on its cartilage. If Dobzhansky had capriciously trimmed the wings of all the flies in one box, he would have affected their phenotypes—the shape of their wings—without ever touching their genes. In other words:
genotype + environment = phenotype
And second, some genes are activated by external triggers or by random chance. In flies, for instance, a gene that determines the size of a vestigial wing depends on temperature:
you cannot predict the shape of the wing based on the fly’s genes or on the environment alone; you need to combine the two pieces of information. For such genes, neither the genotype nor the environment is the sole predictor of outcome: it is the intersection of genes, environment, and chance.
In humans, a mutant BRCA1 gene increases the risk for breast cancer—but not all women carrying the BRCA1 mutation develop cancer. Such trigger-dependent or chance-dependent genes are described as having partial or incomplete “penetrance”—i.e., even if the gene is inherited, its capacity to penetrate into an actual attribute is not absolute. Or a gene may have variable “expressivity”—i.e., even if the gene is inherited, its capacity to become expressed as an actual attribute varies from one individual to another. One woman with the BRCA1 mutation might develop an aggressive, metastatic variant of breast cancer at age thirty. Another woman with the same mutation might develop an indolent variant; and yet another might not develop breast cancer at all.
We still do not know what causes the difference of outcomes between these three women—but it is some combination of age, exposures, other genes, and bad luck. You cannot use just the genotype—BRCA1 mutation—to predict the final outcome with certainty.
So the final modification might be read as:
genotype + environment + triggers + chance = phenotype
Succinct, yet magisterial, this formula captured the essence of the interactions between heredity, chance, environment, variation, and evolution in determining the form and fate of an organism. In the natural world, variations in genotype exist in wild populations. These variations intersect with different environments, triggers, and chance to determine the attributes of an organism (a fly with greater or lesser resistance to temperature). When a severe selection pressure is applied—a rise in temperature or a sharp restriction of nutrients—organisms with the “fittest” phenotype are selected. The selective survival of such a fly results in its ability to produce more larvae, which inherit part of the genotype of the parent fly, resulting in a fly that is more adapted to that selective pressure. The process of selection, notably, acts on a physical or biological attribute—and the underlying genes are selected passively as a result. A misshapen nose might be the result of a particularly bad day in the ring—i.e., it may have nothing to do with genes—but if a mating contest is judged only by the symmetry of noses, then the bearer of the wrong kind of nose will be eliminated. Even if that bearer possesses multiple other genes that are salubrious in the long run—a gene for tenacity or for withstanding excruciating pain—the entire gamut of these genes will be damned to extinction during the mating contest, all because of that damned nose.
Phenotype, in short, drags genotypes behind it, like a cart pulling a horse. It is the perennial conundrum of natural selection that it seeks one thing (fitness) and accidentally finds another (genes that produce fitness). Genes that produce fitness become gradually overrepresented in populations through the selection of phenotypes, thereby allowing organisms to become more and more adapted to their environments. There is no such thing as perfection, only the relentless, thirsty matching of an organism to its environment. That is the engine that drives evolution.
Dobzhansky’s final flourish was to solve the “mystery of mysteries” that had preoccupied Darwin: the origin of species. The Galápagos-in-a-carton experiment had demonstrated how a population of interbreeding organisms—flies, say—evolves over time. But if wild populations with variations in genotype keep interbreeding, Dobzhansky knew, a new species would never be formed: a species, after all, is fundamentally defined by its inability to interbreed with another.
For a new species to arise, then, some factor must arise that makes interbreeding impossible. Dobzhansky wondered if the missing factor was geographic isolation. Imagine a population of organisms with gene variants that are capable of interbreeding. The population is suddenly split into two by some sort of geographical rift. A flock of birds from one island is storm-blown to a distant island and cannot fly back to its island of origin. The two populations now evolve independently, à la Darwin—until particular gene variants are selected in the two sites that become biologically incompatible. Even if the new birds can return to their original island—on ships, say—they cannot breed with their long-lost cousins of cousins: the offspring produced by the two birds possess genetic incompatibilities—garbled messages—that do not allow them to survive or be fertile. Geographic isolation leads to genetic isolation, and to eventual reproductive isolation.
This mechanism of speciation was not just conjecture; Dobzhansky could demonstrate it experimentally. He mixed two flies from distant parts of the world into the same cage. The flies mated, gave rise to progeny—but the larvae grew into infertile adults. Using linkage analysis, geneticists could even trace an actual configuration of genes that evolved to make the progeny infertile. This was the missing link in Darwin’s logic: reproductive incompatibility, ultimately derived from genetic incompatibility, drove the origin of novel species.
By the late 1930s, Dobzhansky began to realize that his understanding of genes, variation, and natural selection had ramifications far beyond biology. The bloody revolution of 1917 that had swept through Russia attempted to erase all individual distinctions to prioritize a collective good. In contrast, a monstrous form of racism that was rising in Europe exaggerated and demonized individual distinctions. In both cases, Dobzhansky noted, the fundamental questions at stake were biological. What defines an individual? How does variation contribute to individuality? What is “good” for a species?
In the 1940s, Dobzhansky would attack these questions directly: he would eventually become one of the most strident scientific critics of Nazi eugenics, Soviet collectivization, and European racism. But his studies on wild populations, variation, and natural selection had already provided crucial insights to these questions.
First, it was evident that genetic variation was the norm, not the exception, in nature. American and European eugenicists insisted on artificial selection to promote human “good”—but in nature there was no single “good.” Different populations had widely divergent genotypes, and these diverse genetic types coexisted and even overlapped in the wild. Nature was not as hungry to homogenize genetic variation as human eugenicists had presumed. Indeed, Dobzhansky recognized that natural variation was a vital reservoir for an organism—an asset that far outweighed its liabilities. Without this variation—without deep genetic diversity—an organism might ultimately lose its capacity to evolve.
Second, a mutation is just a variation by another name. In wild fly populations, Dobzhansky noted, no genotype was inherently superior: whether the ABC or CBA strain survived depended on the environment, and on gene-environment interactions. One man’s “mutant” was another man’s “genetic variant.” A winter’s night might choose one fly. A summer’s day might choose quite another. Neither variant was morally or biologically superior; each was just more or less adapted to a particular environment.
And finally, the relationship between an organism’s physical or mental attributes and heredity was much more complex than anticipated. Eugenicists such as Galton had hoped to select complex phenotypes—intelligence, height, beauty, and moral rectitude—as a biological shortcut to enrich genes for intelligence, height, beauty, and morality. But a phenotype was not determined by one gene in a one-to-one manner. Selecting phenotypes was going to be a flawed mechanism to guarantee genetic selection. If genes, environments, triggers, and chance were responsible for the ultimate characteristics of an organism, then eugenicists would be inherently thwarted in their capacity to enrich intelligence or beauty across generations without deconvoluting the relative effects of each of these contributions.
Each of Dobzhansky’s insights was a powerful plea against the misuse of genetics and human eugenics. Genes, phenotypes, selection, and evolution were bound together by cords of relatively basic laws—but it was easy to imagine that these laws could be misunderstood and distorted. “Seek
simplicity, but distrust it,” Alfred North Whitehead, the mathematician and philosopher, once advised his students. Dobzhansky had sought simplicity—but he had also issued a strident moral warning against the oversimplification of the logic of genetics. Buried in textbooks and scientific papers, these insights would be ignored by powerful political forces that would soon embark on the most perverse forms of human genetic manipulations.
Transformation
If you prefer an “academic life” as a retreat from reality, do not go into biology. This field is for a man or woman who wishes to get even closer to life.
—Hermann Muller
We do deny that . . . geneticists will see genes under the microscope. . . . The hereditary basis does not lie in some special self-reproducing substance.
—Trofim Lysenko
The reconciliation between genetics and evolution was termed the Modern Synthesis or, grandly, the Grand Synthesis. But even as geneticists celebrated the synthesis of heredity, evolution, and natural selection, the material nature of the gene remained an unsolved puzzle. Genes had been described as “particles of heredity,” but that description carried no information about what that “particle” was in a chemical or physical sense. Morgan had visualized genes as “beads on a string,” but even Morgan had no idea what his description meant in material form. What were the “beads” made of? And what was the nature of the “string”?