The Gene: An Intimate History - Siddhartha Mukherjee Page 0,47

thing that will eventually acquire its particular form?

In two transformative decades between 1920 and 1940, the first two of these questions—i.e., variation and evolution—would be solved by unique alliances between geneticists, anatomists, cell biologists, statisticians, and mathematicians. The third question—embryological development—would require a much more concerted effort to solve. Ironically, even though embryology had launched the discipline of modern genetics, the reconciliation between genes and genesis would be a vastly more engaging scientific problem.

In 1909, a young mathematician named Ronald Fisher entered Caius College in Cambridge. Born with a hereditary condition that caused a progressive loss of vision, Fisher had become nearly blind by his early teens. He had learned mathematics largely without paper or pen and thus acquired the ability to visualize problems in his mind’s eye before writing equations on paper. Fisher excelled at math as a secondary school student, but his poor eyesight became a liability at Cambridge. Humiliated by his tutors, who were disappointed in his abilities to read and write mathematics, he switched to medicine, but failed his exams (like Darwin, like Mendel, and like Galton—the failure to achieve conventional milestones of success seems to be a running theme in this story). In 1914, as war broke out in Europe, he began working as a statistical analyst in the City of London.

By day, Fisher examined statistical information for insurance companies. By night, with the world almost fully extinguished to his vision, he turned to theoretical aspects of biology. The scientific problem that engrossed Fisher also involved reconciling biology’s “mind” with its “eye.” By 1910, the greatest minds in biology had accepted that discrete particles of information carried on chromosomes were the carriers of hereditary information. But everything visible about the biological world suggested near-perfect continuity: nineteenth-century biometricians such as Quetelet and Galton had demonstrated that human traits, such as height, weight, and even intelligence, were distributed in smooth, continuous, bell-shaped curves. Even the development of an organism—the most obviously inherited chain of information—seemed to progress through smooth, continuous stages, and not in discrete bursts. A caterpillar does not become a butterfly in stuttering steps. If you plot the beak sizes of finches, the points fit on a continuous curve. How could “particles of information”—pixels of heredity—give rise to the observed smoothness of the living world?

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