The Story of Western Science

by Susan Wise Bauer

As biochemists dug deeper into the chemical makeup of life, biologists continued to puzzle over Mendel’s genes.

  A swirl of information surrounded them, but no one had yet snatched the relevant bits from the air and pieced them together. In the early 1880s, Walther Flemming had seen chromosomes, tiny threadlike structures in dividing cells; in 1890 the biologist Hermann Henking had noticed that, while some chromosomes paired off evenly during cell division, like square-dance partners meeting up to sashay down the line, others (apparently identical) made it into only half of the newly produced cells. He had no idea why this was so, but he gave the sometimes-tardy chromosome a name: the X chromosome, a mystery.8

  After the German biologist Theodor Boveri confirmed, in 1902, that chromosomes were somehow responsible for ferrying Mendel’s “genes” from generation to generation, the next step was to relate this bit of information to the existence of two different kinds of chromosomes. Three different biologists, all American, added their observations: Clarence McClung, working on grasshoppers, was the first to suggest that perhaps the presence or absence of the X chromosome was responsible for determining the sex of offspring; Edmund Beecher Wilson, studying hemipterans (aphids, cicadas, sweet-potato bugs) theorized that the X chromosome had to be present in female offspring; and Nettie Stevens, working with higher-quality cells from fruit flies, confirmed Wilson’s theory through observation.9

  After Stevens published her fruit fly results, the zoologist Thomas Hunt Morgan led a seven-year research project at Columbia University that was able to track generation after generation after generation of fruit flies. Fruit flies reproduce so quickly that seven years is practically deep time; with so much information to chart, Morgan and his colleagues were able to show that the genetic information determining eye color was carried on the X chromosome.10

  This was the first direct association of a particular phenotype (an observable quality, such as height, weight, nose shape, hair color) with a specific genotype (arrangement of chromosomes). And it provided a biological explanation for something that had been observed for centuries: that some physical qualities cannot be passed directly from father to son.†

  The members of one family may bleed profusely, while those of another family may bleed little. So says the Babylonian Talmud, compiled around the third century; it is one of the oldest references we have to hemophilia, the disorder that prevents blood from clotting. In the centuries after, physicians grappled with this strange condition. The tenth-century Cordoban surgeon Albucasis observed that healthy mothers could give birth to hemophiliac sons; at the beginning of the nineteenth century, the Philadelphia doctor John Otto wrote that the disorder seemed to appear only in males; and the royal families of Germany, Spain, and Russia were tormented by the disease’s irregular appearance in their princes.11

  Charles Darwin himself had charted the pattern of inheritance, which looked something like this:

  Morgan’s fruit fly experiments now made it possible to explain the oddness of the pattern. If the genetic information for hemophilia is carried only on the X chromosome, the disease itself will show up only if all copies of the X chromosome are affected. And since male children have only one X chromosome, they are far more likely to be afflicted. (Dr. Otto was misled by statistics; it is uncommon, but not impossible, for women to suffer from hemophilia.)

  Morgan’s work made it possible to uncover the invisible lines of transmission: an apparently healthy daughter is actually a silent carrier of the disease, with a 50/50 chance of passing it on to an infant son.

  But all this still had nothing to do with the mechanism of inheritance. How the genetic information was carried on the chromosome, and how it went about shaping and forming the recipient (the relationship between genotype and phenotype, in other words), remained a mystery. Biologists working with chromosomes and genes were still doing little more than keeping statistics: observing which chromosomes went where, and what the result might be.

  Light began to dawn when chemistry, biology, and physics formed a brief three-way intersection.

  In 1927 the biologist Hermann Muller, a coworker of Morgan’s in the fruit fly project, announced that bombarding fruit flies with X-rays changed their genetic information. His irradiated flies had produced offspring with a whole array of new phenotypes; Muller himself lists “splotched wing,” “white eye,” “miniature wing,” “forked bristles,” and more. The work of Roentgen, the Curies, and Rutherford had already shown that radiation produced changes in the structure of atoms and molecules;‡ Muller’s results suggested that the still-mysterious genes were, in fact, molecules—structures that were vulnerable to the changes that X-rays produced. And since radiation didn’t produce the same changes over and over again, genes were likely to be a whole array of different molecules, rather than a sack of similar particles, “merely repetitions of one another.”12

  So: genes were molecules, conveyed by chromosomes from parent to child. That was an answer to the first part of the puzzle. The second remained: How did a molecule produce a certain shape of earlobe, a long second toe, freckles: phenotypes?

  The answer came by way of bread mold.

  In the 1940s, two Stanford biochemists, named George Beadle and Edward Tatum, carried out a series of experiments on Neurospora, a fungus that grows on bread (and also turns soybean scraps and coconut remnants into the Indonesian staple dish known as oncom). Their work showed that when genes were altered, the production of certain enzymes ceased—making the cells of an organism unable to carry out certain chemical reactions.

  Those chemical reactions were what gave the organism its identity. A century before, Anselme Payen and Jean-François Persoz had identified the first enzyme, and Jöns Berzelius had put his finger on the importance of “catalytic processes” for living creatures. Over the decades that followed, biochemists refined and built on this knowledge, so that Beadle and Tatum were now able to define a living thing—its entire makeup, its metabolism and its phenotype, the way it functioned and the way it looked—as the totality of its chemical reactions. Enzymes were the catalysts of those chemical reactions. An altered gene resulted in an altered enzyme; an altered enzyme resulted in an altered phenotype; an altered phenotype produced a mold cell that needed different nutrients than its parent, a splotch on a fruit fly’s wing, a long second toe or cleft chin. Mess with the enzymes, and you change the organism.

  Here at last was the connection between genotype and phenotype. Beadle and Tatum worked for the next few years making maps of which enzymes, carried by which chromosomes, produced different sorts of phenotypes. Their work became known as the “one gene, one enzyme” hypothesis: genes (human, bacterial, or otherwise) affected the production of enzymes, and enzymes affected the characteristics of the living creature.13

  But the gene itself was still a mystery. There was no familiar molecule, no recognized organic substance, no already-identified chemical compound that had such power over enzymes.

  Simultaneously, a biologist named Oswald Avery (working, as Levene had, at the Rockefeller Institute in New York) was studying pneumococcal viruses. One particular pneumococcal strain had a unique quality: the viral cells could form capsules around themselves, made out of a complex molecule called a polysaccharide. These capsules strengthened the virus and made it more potent.

  Avery realized that if a solution of DNA (the acidic substance identified, by Levene, as an element of Miescher’s “nuclein”) was taken from a pneumococcal strain capable of forming polysaccharide capsules and introduced into other pneumococcal strains, the recipient strains were transformed. Suddenly, they too were able to form polysaccharide capsules.

  This could have been a eureka moment.

  In fact, Oswald Avery (a cautious, responsible man) mused in a private letter to his brother that this DNA solution appeared to be acting, unexpectedly, like one might expect a “gene” to act. But he and his colleagues were too skeptical of their results to make any great claims. They published their results in the Journal
of Experimental Medicine, where the paper attracted little interest. The study of cells and their properties had been so spread out across disciplines, fragmented into subfields and minidiscoveries, that few biologists (or biochemists) could claim full knowledge of all the relevant discoveries.14

  Only a small fraction of those biologists knew anything about a third, parallel but separate investigation: biologists Max Delbrück and Salvador Edward Luria and bacteriologist Alfred Hershey were working together at a Long Island lab, attempting to pull apart the exact structure of viruses that had the ability to infect bacteria. These viruses (“bacteriophages”) invaded bacterial cells, reproduced inside them, and then destroyed the host cells and set themselves free.

  It became increasingly clear that these viruses had the ability to replicate themselves exactly. And in 1947, another biochemist, Seymour Cohen, noticed that when a certain strain of bacteriophage invaded bacterial cells, the synthesis of DNA within the infected cell abruptly stopped—and then began again, a few minutes later, at a multiplied pace. This was a strong hint that DNA had something to do with that exact replication.

  Other researchers theorized that perhaps DNA was the agent that allowed cells to reproduce themselves. But the proteins in nuclein were generally thought to be a much stronger contender for that role. In neither case could scientists explain exactly how the genetic information was coded by the parent cell, or decoded by the child.15

  A very young James Watson, still pursuing his PhD and not quite sure what he wanted to study, began to work with the Long Island “phage group” in 1948. At first he had little interest in the study of nucleic acids, a field where “ideas could not be easily disproved”: “Much of the talk about the three-dimensional structure of proteins and nucleic acids was hot air,” he later observed. Theories abounded, none of them susceptible to tests.

  But in 1951, in Europe on a postdoctoral fellowship, Watson attended a talk given by the British physicist and biologist Maurice Wilkins, who had been working on DNA at Kings College in London. Wilkins’s talk was illustrated by X-ray pictures of DNA that showed clear structural patterns, and suddenly Watson found himself gripped. Surely, such a clear pattern could be the key to finding the “regular structure” of DNA, and perhaps that structure would demonstrate that DNA was responsible for carrying that elusive genetic information.16

  Defying the terms of his fellowship, Watson wangled himself a position in England, working at Cambridge’s Cavendish Laboratory with the biophysicist Francis Crick. Crick, twelve years his senior, had been interested in DNA for some years, but Watson discovered—to his surprise—that the conventions of English society had prevented Crick from pursuing further study. “At this time,” Watson wrote in The Double Helix, “molecular work on DNA in England was, for all practical purposes, the personal property of Maurice Wilkins.”

  It would have looked very bad if Francis had jumped in on a problem that Maurice had worked over for several years. . . . It would have been much easier if they had been living in different countries. The combination of England’s coziness—all the important people, if not related by marriage, seemed to know one another—plus the English sense of fair play would not allow Francis to move in on Maurice’s problem. In France, where fair play obviously did not exist, these problems would not have arisen. The States also would not have permitted such a situation to develop. One would not expect someone at Berkeley to ignore a first-rate problem merely because someone at Cal Tech had started first.17

  The Chicago-born Watson managed to push Crick into poaching on Wilkins’s territory, and together the two men arranged to get hold of the most recent high-quality X-ray portraits of DNA—painstakingly difficult work done by Wilkins’s assistant Rosalind Franklin, a skilled scientist in her own right who was consistently dismissed by the old boys at Cambridge as no more than a troublemaking “bluestocking.” (“The best home for a feminist,” Watson remarked, in one of his less charming moments, “was in another person’s lab.”)

  Meanwhile, the almost mythically famous American biochemist Linus Pauling had also turned his attention to DNA. Determined to one-up Wilkins and to “beat [Pauling] at his own game,” Crick and Watson submerged themselves in DNA research. This was, as Watson writes, a question of asking “which atoms like to sit next to each other” and then building hypothetical structures, using “a set of molecular models superficially resembling the toys of preschool children.” Their goal was to come up with a model that was consistent both with the X-ray pictures taken by Franklin and with all known chemical properties of the molecules involved.18

  Early in 1953, Pauling proposed a possible solution: DNA was a “three-chain helix” with a sugar-phosphate “backbone” on the inside. Watson immediately realized that the model wouldn’t work; the phosphate molecules would repel each other (or, as he put it, “Linus’ chemistry was screwy”). But Pauling was clearly closing in on a workable model.

  Watson threw himself into devising new models with even more energy (“I was racing [him] for the Nobel prize”). Obsessively doodling possible structures on reams of paper, building models from stiff cardboard, Watson finally settled on a new structure for DNA: a double helix, with the “backbone” on the outside. He and Crick calculated the chemical properties of this model, compared the existing X-ray data with the patterns that their model would produce, and decided that the hypothesis was sound. In April of 1953, they proposed this model in a short article published in the journal Nature; it concluded with a brief sentence (composed by Crick) suggesting that the double helix would allow nucleic acids to form hydrogen bonds—which meant DNA could be replicated. “It has not escaped our notice,” Crick wrote, “that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”19

  The copying mechanism involved both double-stranded DNA and single-stranded ribonucleic acid (RNA); as biologist Colin Tudge explains, Crick and Watson envisaged the double strands of DNA splitting into

  two single strands, followed by the replication of each one. . . . A strand of DNA, once separated from its partner, can either begin to make a complementary copy of itself, and so replicate, or can begin to make a complementary strand of RNA, which then leaves the nucleus and supervises the manufacture of appropriate protein in the cytoplasm.20

  RNA served as the intermediary between the DNA and the newly manufactured proteins, but the exact way in which this happened (later researchers would eventually identify three different kinds of RNA with three different functions) was still unclear.

  Even in its broader outline, though, the model was convincing: chemically sound, consistent with observed properties of nucleic acids. It was tested worldwide, elaborated upon by such biochemical luminaries as Frederick Sanger, George Gamow, Marshall Nirenberg, and J. Heinrich Matthaei. By the time James Watson published The Double Helix: A Personal Account of the Discovery of the Structure of DNA in 1968, the double-helical structure of DNA and its role in reproducing genetic material was accepted as gospel.

  Francis Crick would later refer to the flow of information, from DNA to DNA, from DNA to RNA to protein, as the “central dogma” of modern biology, a label still widely used. Despite his use of the word “dogma,” Crick knew that the theory was still speculative: “a grand hypothesis,” he himself wrote, “that, however plausible, had little direct experimental support.” In fact, the experimental support would not come along for another two decades. Not until the late 1970s would scientists have the technical tools to produce a truly detailed map of DNA, and protein-DNA interactions were not glimpsed until 1984. Watson’s energetic and entertaining account is snappily titled, but neither he nor Crick had “discovered” DNA. Like Copernicus, they had instead built a convincing theory that accounted, very neatly, for decades of observable phenomena.21

  JAMES D. WATSON

  The Double Helix: A Personal Account of the Discovery of the Structure of DNA

  (1968)

  Watson’s origina
l text is available as both a paperback reprint and an e-book. A more elaborate edition, containing editorial annotations, historical background, excerpts from personal letters, and additional illustrations, is available in hardcover and as an e-book from Simon & Schuster.

  James D. Watson, The Double Helix: A Personal Account of the Discovery of the Structure of DNA, Touchstone (paperback and e-book, 2001, ISBN 978-0743216302).

  James D. Watson, The Annotated and Illustrated Double Helix, ed. Alexander Gann and Jan Witkowski, Simon & Schuster (hardcover and e-book, 2012, ISBN 978-1476715490).

  * * *

  * In this context, an “acid” is simply a substance that, when added to water, increases the concentration of protons, or hydrogen ions (H+), in the water.

  † It should be noted that sex determination works very differently in fruit flies and in mammals, but the fruit fly research provided a theoretical framework for understanding sex-linked characteristics.

  ‡ See Chapter 16.

  TWENTY-FOUR

  Biology and Destiny

  The rise of neo-Darwinist reductionism, and the resistance to it

  We are survival machines—robot vehicles blindly programmed

  to preserve the selfish molecules known as genes.

  —Richard Dawkins, The Selfish Gene, 1976

  We are biological and our souls cannot fly free.

  —E. O. Wilson, On Human Nature, 1978

  We are inextricably part of nature, but human uniqueness is

  not negated thereby.

  —Stephen Jay Gould, The Mismeasure of Man, 1981

  Watson and Crick’s model carried all before it.

  Continuing elaborations of the double helix only strengthened the assumption that this was the missing piece of Darwin’s puzzle: the mechanism of inheritance, the location and engine of Mendel’s gene, the cornerstone of life. Much remained to be studied, but by the 1960s the greatest mysteries of life seemed to have been solved. “In the coiled structure of the DNA molecule and the complex arrangement of its atoms lie the final secrets of heredity,” marveled Life magazine in October of 1965. “Scientists have begun to be able to read the genetic code. . . . Once we can read, we may then learn to ‘write’—i.e., to give genetic instructions—in the DNA code. When that time comes, man’s powers will be truly godlike.” Godlike, that is, in the ability to create: “creatures never before seen or imagined in the universe,” or “new forms of humanity . . . better adapted to survive on the surface of Jupiter, or on the bottom of the Atlantic Ocean.” Or even, more simply, ideal human beings: through the manipulation of DNA, “emphasizing man’s good qualities and eliminating the bad ones.”1