CHAPTER FOUR
The Finger of the Angel
I study myself more than any other subject. That is my metaphysics; that is my physics.
—MICHEL DE MONTAIGNE,
“Of Experience”
BENZER KEPT HIS BASE in the physics department at Purdue, but he began living like a gypsy. In the late 1940s and early 1950s he spent a year at Oak Ridge National Laboratories in Tennessee; two years in Delbrücks laboratory at Caltech; a summer at the laboratory of Cornelius van Niel at Pacific Grove; and a year in André Lwoff’s laboratory at the Institut Pasteur in Paris. In all these places Benzer helped establish the style of the phage group by doing simple and elegant experiments (“pretty and witty,” in the words of Horace Freeland Judson, the historian of molecular biology). Like Arrowsmith’s mentor Max Gottlieb, Benzer, from the beginning, was a scientist’s scientist. He kept a low profile, and he worked mostly in the middle of the night.
It was Delbrück who set the tone for the phage group. Even in that crowd, Delbrück was intimidatingly intelligent. He was also young, quick, fit, and mordantly funny, with a young and beautiful wife. Those who followed Delbrück found him so charismatic that they let him treat them the way a Zen master treats his disciples; he threw them into the mud again and again to help them achieve enlightenment. Delbrück always chose a front-center seat at seminars. That way when he sprang up in the middle of a talk he would block the slide projector and force half his row to let him pass as he struggled toward the door, denouncing the lecture as he went. Everyone who visited Delbrück’s group at Caltech was obliged to give one of these seminars, and Delbrück always pronounced the same verdict: “This was the worst seminar I ever heard.”
The great breakthrough in the gene problem arrived unannounced one morning in April 1953, in a tower room of the Cavendish Laboratory in Cambridge—already a legendary place in physics, where J. J. Thomson had discovered the electron and Ernest Lord Rutherford had split the atom. When James Watson and Francis Crick put together their model of the double helix, they accomplished in a few minutes what Morgan’s Raiders had been trying to do for decades. Physics, chemistry, and biology came together in one beautiful spiraling molecule, the staircase of DNA, now an icon of twentieth-century science together with the fly bottle and the mushroom cloud. Crick was still in his thirties, and Watson was one month away from his twenty-fifth birthday. In snapshots from that time he looks like a boy, though he has a lean and hungry look. Watson used to run around Cold Spring Harbor in short pants and with each sneaker trailing the double strands of its laces. Long hair, shorts, and unlaced sneakers were his signature, Benzer remembers, his way of shocking the bourgeois. (“He used to really infuriate André Lwoff by showing up in meetings in France with his shoelaces deliberately untied.”)
Watson and Crick saw at a glance that they had not only solved the physical structure of the gene; they had found the way it carries the secret code. The spiral staircase of DNA holds the secret in the treads, the small molecular crosspieces that are known as bases or nucleotides, and these bases come in four chemical varieties. Schrödinger’s What Is Life? had pointed out that even a small number of signs can make an alphabet. In Morse code there are just two different signs, dot and dash. Schrödinger had predicted that the code of life might turn out to have only a few signs as well. In fact it has four, the four treads of the twisted stair: adenine, cytosine, thymine, and guanine, or A, C, T, and C. The spiral staircase can hold any sequence of bases, any permutation of letters, A, C, T, G, A, G, C, A, and so on, millions of letters in a single strand of DNA, three billion letters coiled and supercoiled in the nucleus of every human cell.
CRICK SAYS THAT WHILE they were writing a report for Nature, “A Structure for Deoxyribose Nucleic Acid,” Watson “suffered from periodic fears that the structure might be wrong and that he had made an ass of himself.” And for some years afterward neither Watson nor Crick could rest easy. It was one thing to say that they had found the code of life, another to prove it. On the maps of classical geneticists, white, yellow, and miniature were dots, abstractions. They did not look like long twisted-chain molecules; they looked the way planets had looked to astronomers before telescopes or the way atoms had looked to physicists at the turn of the century, indivisible and indestructible points.
Cold Spring Harbor Laboratory, early 1950s: revolution on five dollars a day. Max Delbrück and many of the first molecular biologists who gathered around him were young and poor, and they created their new science in bohemian high spirits. “Max had a tradition of trading haircuts with people,” Seymour Benzer says (he’s doing the cutting here). “He made a deal with me on this occasion that each of us would cut the other’s hair, but the one who was cut first was not allowed to look in the mirror beforehand.” (Illustrations credit 4.1)
A center of the revolution: Max Delbrück’s phage laboratory at Caltech. Delbruck sits by the window, Gunther Stent in the middle of the huddle. The two men would later be among the first to turn from the study of the gene to the study of genes and behavior. (Illustrations credit 4.2)
So after the eureka of Watson and Crick, one of the challenges for the new science (which did not yet call itself molecular biology) was to connect these classical maps of the gene with the new model of the double helix. It was Benzer who thought of a way to do it. Not long after Watson and Crick announced their discovery, Benzer hit on a plan that might unite the old revolution and the new revolution: classical genetics and molecular biology.
Benzer’s starting point was, as usual, “pretty and witty.” He decided to go back to the event that had opened the science of genetics, Sturtevant’s big night. When two chromosomes line up and exchange bits of genetic material, Benzer reasoned, many genes must cross over together en masse. Since each gene on the map looks like an indivisible point, classical geneticists had always assumed that during crossing-over the chromosome always breaks between genes, just as when the blades of a scissors cut through paper they always pass between atoms. But Benzer knew that if Watson and Crick were right about the double helix, then each gene is not a mathematical point with open space around it. Instead, a gene must be a long, continuous, twisted thread, a string of rungs or nucleotides. If it is a molecular construction consisting of millions upon millions of atoms linked together, there is no particular reason why a break should not fall within a gene as well as between two genes, just as if one rips a piece of newspaper at random the tear will go through words as easily as it goes between them.
Benzer (right), in the summer of 1953 at Cold Spring Harbor, planning the rII experiment. (Illustrations credit 4.3)
A few of Morgan’s Raiders had speculated the same way and tried to explore the idea. One of Morgan’s students’ students, Guido Pontecorvo, had written a brilliant paper on the subject; a few others had managed to rip a fly gene once or twice, in heroically laborious experiments. Now, in the light of the double-helix model, in which a gene is made of the rungs in a long, twisted ladder, these speculations and experiments seemed more compelling. Any spaces between the genes must be made of rungs of the same material as the genes themselves. In this model, there is no obvious reason why during crossing-over a thread of DNA should not sometimes break right in the middle of a gene. If genes do sometimes break in the middle, and if Benzer could find one of those breaks, he thought he could join the old science of the gene with the new science that he and his friends were creating and lift them both to a dizzying new level.
By chance, two particles of virus (at top) have attached themselves to a single E. coli bacterium and injected their long strands of DNA. In 1953, the year of the discovery of the double helix, Benzer invented a way to use this mingling of viral DNA to map the interior of a gene. This illustration comes from one of the historic papers in which Benzer reported the results of the experiment. Benzer’s caption: “The artist, Martha Jane Benzer, who graciously signed the drawing, was five years old at the time.” (Illustrations credit 4.4)
Benzer�
��s plan required him to arrange matings between strains of virus, just as Mendel had crossed peas and Morgan had crossed flies. Viruses do not have sex. But Benzer could get around that problem by infecting a plate of bacteria with two strains of phage at once. Here and there on the plate, two virus particles, one from each of the two strains, might come together in attacking a single bacterium. This event would later come to assume so much importance for Benzer that his younger daughter, Martha, at the age of five, would be moved to draw a picture of that rare event, the double infection.
Each virus has only a single chromosome. But inside a hapless twice-bit bacterium, the chromosome from one virus particle would twine together with the chromosome of the other. Then the two chromosomes would twist like copulating coral snakes, just like pairs of chromosomes in peas, flies, and human beings, and some of their genes would cross over.
By 1953, phage workers had already mapped much of the phage chromosome. On their maps, a mutation called r appeared as a mathematical point in a chromosome region called rII. The r stood for “rapid”: r mutants devour bacteria fast. Benzer arrived at the idea for his now legendary experiment when he stumbled across a strain of defective r mutants—a strain of mutants that was, so to speak, off its feed—and he decided to focus on the rII region.
He would cross two separate strains of defective r mutants in a petri dish. In the classical view of genes and mutations, the two strains of mutants would have identical rII regions and would produce nothing but defective children. But if the Watson-Crick view was right, then the damage in each of two strains of r mutants might lie at two different points inside that region. By crossing two defective r mutants, he might be able to prove that. Suppose, for example, one parent carried genetic damage at one end of its rII region. Suppose the other parent carried damage at the opposite end of its rII region. And suppose that when the two chromosomes twined together, they happened to trade bits of the rII region. Then the mosaic chromosome they put together inside the bacterium might contain a healthy chunk of the rII gene from one parent and a healthy chunk of the gene from the other parent. Their children would be healthy.
So if Benzer crossed two defective r mutants and got one or more healthy r children, their arrival would prove that crossing-over can sometimes cut right through a gene, not just between genes. That would mean that genes, like atoms, are not indivisible points but solid objects that can be cut and dissected. If Benzer could in fact dissect a gene, he foresaw that he and his friends would soon be able to take his experiment much, much further.
Benzer realized all this one fine day in the fall of 1953 in his laboratory on the third floor of the physics building at Purdue University, where he was still (nominally) a professor of physics. The year before, in the course of a routine experiment with r mutants at the Institut Pasteur in Paris, he had stumbled across a defective r strain. Benzer remembers shrugging and throwing them out: “As Pasteur would say, ‘My mind was not prepared.’ ” Now, at Purdue, while arranging a bacteriophage experiment for a classroom demonstration, he came across another defective r mutant. At first he thought he had made a mistake. “Dummkopf, do it again.” He prepared a fresh carpet of bacteria and added more r mutants. But when he came back a little later, he saw that the r mutant still did not behave like a normal r mutant. Now his mind was prepared.
After much thought and a few summer-long conversations in Cold Spring Harbor with phage friends, Benzer wrote out a sketch of his plans for rII. Toward the end of the summer of 1954 he ran into Delbrück at a meeting in Amsterdam and showed him the sketch. By now Delbrück was the elder statesman of their revolution, just as Morgan had been the elder statesman of the old revolution, and Delbrück thought Benzer’s rII manuscript was outrageous. The very idea that a gene might be split into pieces seemed to irritate Delbrück, Benzer says. “One of his typically succinct comments was ‘Delusions of grandeur.’ ” Benzer still cherishes the comments that Delbrück scribbled on his manuscript: “You must have drunk a triple highball before writing this. This is going to be offensive to a lot of people that I respect.”
Even assuming that Benzer’s reasoning was correct, the chance of crossing two defective r parents and producing normal r children was astronomically low, on the order of one in a billion. At least, that was what his calculations suggested: he would have to breed enough virus to detect one-in-a-billion events reliably. But there would be more than enough particles of virus to do an experiment like that in a petri dish. “One can therefore perform in a test tube in twenty minutes,” Benzer later wrote, “an experiment yielding a quantity of genetic data that would require if humans were used virtually the entire population of the earth.” And Benzer saw all this and more in that first instant in his physics lab at Purdue, when he looked at the defective r mutant with a prepared mind. As Judson writes in The Eighth Day of Creation, “There was no way to see it except instantly.”
In essence it was a very simple experiment, like all of Benzer’s experiments, and almost from the moment he began he was splitting genes into pieces. He plunged into a whirlwind, like the young Martin Arrowsmith when he discovers phage: “Then his research wiped out everything else, made him forget Gottlieb and Leora … and confounded night and day in one insane flaming blur as he realized that he had something not unworthy of a Gottlieb, something at the mysterious source of life.” In his petri dishes, genes and mutations finally ceased to be abstractions. The splitting of atoms by Rutherford had led to the atomic bomb, and the splitting of genes by Benzer would lead to the explosions of genetic mapping and genetic engineering that now dominate biology. For a few years his research made him forget everything else (except Dotty—they were uncommonly close). The excitement was particularly intense for lapsed physicists like Benzer and Crick, who had jumped from the flagship of the sciences for a small open boat in a wide sea. Crick asked Benzer to speak at the Kapitza Club in Cambridge, an exclusive club of physicists. (The discovery of the neutron was first announced there.) In the audience was Paul Dirac, one of the most powerful theoretical physicists of the century and also one of the quietest—much quieter than Benzer. Physicists visiting him at Cambridge were satisfied if they heard him say a single yes or no. “At least,” they would tell one another, “I got a word out of Dirac.”
Benzer opened his talk at the Kapitza Club by writing on a blackboard the date 1808, when John Dalton had published A New System of Chemical Philosophy. Next Benzer wrote the date 1913, when Bohr had published “On the Constitution of Atoms and Molecules.” One hundred five years had passed between the first clear description of atoms as a possibility and the first clear description of atoms as a physical reality.
Then Benzer wrote on the board the date 1866, when Mendel had published his paper about peas, and the date 1953, when Watson and Crick had published their paper about the structure of the gene, the double helix of DNA. Only eighty-seven years had passed between the first clear description of genes as a possibility and the first clear description of genes as a physical reality.
Dirac looked at the blackboard and said four words: “Biology is catching up.”
AFTER HE SPLIT the rII gene, Benzer spent a few manic years doing nothing but collecting r mutants and crossing them two by two. A friend and mentor of his in the phage world, Alfred Hershey, had once offered this definition of heaven: “To find one really good experiment and keep doing it over and over.” Benzer felt he had found Hershey Heaven. In each mutant the rII region of the chromosome carried an error somewhere in the string of rungs of its DNA. He could use each error exactly the way Sturtevant had used his half-dozen mutations when he invented gene mapping. If two letters inside a gene are close together, their chance of being parted by crossing-over is small. If two letters are farther apart, their chance of being parted by crossing-over is correspondingly large. So whenever Benzer found a new mutant strain of rII in his petri dishes (these r mutants arise spontaneously and with some frequency in petri dishes, just as white-eyed flies arise spontaneously in
fly bottles) Benzer could determine precisely where that particular copy of the rII gene was damaged. In other words, he could use the same method that Morgan’s Raiders had used to map the locations of genes on chromosomes to map the relative positions of mutations inside the rII region. He was making the first detailed map of the interior of a gene. In the novel, when Arrowsmith discovers bacteriophage, he leaves his laboratory dawn after dawn, “eyes blood-glaring and set,” and after a few weeks goes slightly mad with tension and exhaustion, “obsessed by the desire to spell backward all the words which snatched at him from signs.” Benzer, driving home from his laboratory dawn after dawn on the long flat roads of Indiana, noticed his mind playing the same tricks: POTS. DEEPS TIMIL. TIMIL DEEPS. TIXE.
By the summer of 1956, he had mapped hundreds and hundreds of bits of the rII gene. He recorded them all on a mural that stretched farther and farther across his laboratory wall in the physics building. It was the world’s first version of what would come to be called the sacred text, the code of codes. Biologists of a certain age can still remember the impression that Benzer made with his gene map at conferences, bearing it up on stage and unrolling it like a Torah scroll. If the single chromosome of a phage were stretched out in a straight line and magnified 150,000 times, it would be about ten meters long. At that magnification, the rII region would be about half a meter long. Benzer’s scroll mapped the fine structure of that half-meter, with hundreds of different damage points inside.
To this day his old phage cronies from Cold Spring Harbor talk about Benzer and rII with awe:
“This is the atom breaker of biology.”
“What he did in fine structure was epochal.”
“He spent all summer at Cold Spring Harbor talking about the rII idea. I could have stolen it. I could have gone into my lab and done it myself. We didn’t do that in those days.”
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