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.”
Throughout the 1950s Benzer’s scroll map got longer and longer. The gene was no longer a dot, a distant planet seen with the naked eye. The gene was the new territory of molecular biology. In 1959, when a geneticist put together a retrospective volume called Classic Papers in Genetics, he began his anthology with Mendel’s peas, as a point of origin, and ended with Benzer’s rII, as the point of origin for whatever would come next. So it proved. By the last years of the century, gene mapping would have grown into a project costing billions of dollars, the Human Genome Project, often called the Manhattan Project of biology. International teams of molecular geneticists would be racing one another to map every fly gene, every worm gene, and every last human gene at a cost of billions of dollars and at rates of more than one hundred million letters per year.
“The atom-breaker of biology.” From late 1953 through the early 1960s, Benzer worked on his map of the interior of a gene. He kept the map on a lengthening scroll. Here he poses wearily for a Purdue publicity picture with the scroll unrolled on his laboratory bench. (Illustrations credit 4.5)
But in the 1950s all this work was still obscure. It was remote from the shapes, colors, and visible wilderness that attracts most biologists to study life in the first place. Even in 1959, most biologists did not understand Benzer, any more than most biologists had understood Morgan back in 1911. He was mapping continents the rest of the world knew nothing about. In the summer of 1959, giving himself a break from his scroll, his years of “hard rII,” as he put it, Benzer took a course in embryology at the Marine Biological Laboratory in Woods Hole, Massachusetts. During one evening lecture he was startled when the professor happened to mention the word “gene.” Suddenly Benzer realized that he hadn’t heard that word all summer, or the word “mutation.”
“Yes, but what is a mutation?” one of the students asked.
“Oh, that’s a very deep problem,” said the professor. “We don’t know anything about that.”
“My God, what am I doing here?” Benzer thought to himself. “I’ll go back to my genes and my mutations.”
Eventually, to give people a better idea of what he was mapping, Benzer began collecting typographical errors from newspapers (which were now full of stories of the Cold War). Typos come in different categories. There are substitutions, places where one letter replaces another:
… already the doomsday warnings are arriving, the foreboding accounts of a Russian horde that will come sweeping out of the East like Attila and his Nuns.
—Boston Globe
And deletions:
“I can speak just as good nglish as you,” Gorbulove corrected in a merry voice.
—Seattle Times
Insertions:
“I have no fears that Mr. Khrushchev can contaminate the American people,” he said. “We can take in stride the best brain-washington he can offer.”
—Hartford Courant
Inversions:
He charged the bus door opened into a snowbank, causing him to slip as he stepped out and ran which bus, the beneath fall over him.
—St. Paul Pioneer Press
And nonsense:
Tomorrow: “Give Baby Time to Learn to Swallow Solid Food.” etaoin-oshrdlucmfwypvbgkq
—Youngstown (Ohio) Vindicator
Benzer was finding and mapping many of these sorts of mistakes in the rII gene: insertions, deletions, and nonsense. Mutations come down to nothing more than typos. The single chromosome of the phage virus contains about 200,000 letters of genetic code, about as many letters as there are in several pages of newspaper, so even in a single virus there is plenty of room for typos. And mutations that affect a fly, a mouse, or a human being in their repertoires of fundamental behavior will come down to typos too. In a sense, rII itself is a behavior gene, since damage there affects the behavior of the virus. Damage at any one of the thousand points in Benzer’s map produced an identical change in the behavior of the virus. That is, a typo at any one of those thousand points in the map would wreck the rII gene. There is an old saying, “Each finger can suffer.” In the genome, each gene can suffer, and each letter in a gene can suffer too.
In the summer of 1960, in the basement of Caltech’s Church Hall, the physicist Richard Feynman took up what was known in those days as “Benzer mapping.” Feynman loved Benzer’s tricks for finding the single rare phage particle he was looking for in a dish of bacteria. He told friends it was like “finding one man in China with elephant ears, purple spots, and no left leg.” And soon afterward in the Cavendish Laboratory, where Watson and Crick had put together the double helix, Crick and Sydney Brenner used rII mutants and Benzer mapping to help crack the genetic code. Crick and Brenner knew that they were looking at a four-letter code, A, T, C, and G. In an ingenious series of rII experiments, they proved that the code is a triplet. That is, the words are written in groups of three letters: CAT, TGA, ACT. Not long afterward, Benzer went to a meeting in India. Wandering in the street markets looking for exotica—he had acquired a taste for strange foods as well as strange hours—Benzer saw a soothsayer with a bird. Passersby would ask the soothsayer a question. Then the man would ask the bird. The bird would go into the cage, peck among the scraps of paper on the floor, and bring out an answer. Benzer asked, “Is the genetic code universal?” The bird gave the answer “The news from home is good.”
In Paris, in the attic of the Institut Pasteur, Jacques Monod and François Jacob explored some of the implications of the new view of the gene. Each of us starts out as a single cell, and each of us ends up a collection of cells of many different kinds. Yet each of our cells still contains the same set of genes as the first. In a sense each of our cells knows everything but expresses only a small part of what it knows.
There is a story in Jewish legend that each baby arrives knowing everything, which accounts for the infinite wisdom we see in the faces of newborns. As the baby comes out into the world an angel places a finger just above its mouth to keep it from expressing all this wisdom, which accounts for the philtrum, the crease above the upper lip. Somehow something like the finger of the angel must touch our DNA and keep most of it from being expressed in each of our cells. Some genes turn on only in a liver cell and others only in a brain cell. Much later, in the 1990s, when molecular biologists began mapping all of the genes in the human body, they would discover several thousand genes that switch on only in the neurons of the brain—twice as many genes are expressed in the brain than are expressed anywhere else in the body. But no cell ever reads all of the words on the scroll. So every living thing and every last cell in our own bodies can say, with the preacher of Ecclesiastes, “When I travelled, I saw many things; and I understand more than I can express.”
In their rabbit warren of laboratories at the Institut Pasteur, Jacob and Monod discovered the finger of the angel. They identified what they called “repressors” that float through the cell’s nucleus and, by touching the double helix here and there—attaching themselves to strategic places all along its coils—silence most of the genes in most of our cells most of the time, so that only a small part of each double helix is expressed at any moment. The few genes that the cell does need are expressed; the rest only stand and wait. Today molecular biologists can actually watch this happen. Using an instrument called an atomic force microscope, they can watch enzymes sliding down strands of DNA and they can see the strands of DNA unrolling, very much like Torah scrolls, to begin reading or cease reading the portion of the scroll that is appropriate for that moment.
Jacob and Monod knew that these angelic floating proteins were a first glimpse of the connection between genes and behavior. They were looking at the beginnings of the senses, the tools with which a living thing picks up changes in the environment around it and uses the information to shape its behavior. Everything depends on such small felicitous moments of recognition: on compound meeting compound, shape meeting shape, profile recognizing profile. The shapes of these floating proteins allow a cell to recognize new chemicals entering the cell and to read just the portion of DNA that it needs at each moment in order to respond to each small event in its vicinity. Ezra Pound wrote a poem after spotting friends in the Paris Métro:
The apparition of these faces in the crowd
Petals on a wet black bough.
The fingers of the angels in every one of our cells are engaged in these small moments and shocks of recognition, not just when we are born but every moment of every day in every one of our cells.
Toward the end of the century a molecular geneticist working with a flock of sheep in Scotland would discover a way to give a cell a little shock of electricity and make the angels, just for a moment, snatch back their fingertips. His work would suggest that any cell—even a cell scraped from the inside of a ewe’s udder or from a human cheek—can be made to express every bit it knows and grow into a lamb or a human baby, philtrum and all.
Even in the 1950s, the first molecular geneticists knew they were moving into strange new territory, and Benzer’s taste for strange food and strange hours seemed of a piece with it. Benzer worked with Crick in his tower room at the Cavendish, with Jacob and Monod in their mansard rooms at the Institut Pasteur, with Delbrück in a basement at Caltech, and everywhere he went they told stories about his behavior. When Benzer was at the Pasteur, he shared a laboratory with Jacob. Jacob remembers Benzer in his memoirs: “Every day, at lunch, he brought some unusual dish—cow’s udder, bull’s testicles, crocodile tail, filet of snake—which he had unearthed on the other side of Paris and which he simmered on his Bunsen burner.”
Benzer ate like that at home too: caterpillars, duck’s feet, horsemeat, live snails. His little girl Barbie woke up one morning in Paris with her eyes swollen shut, and he took her to a doctor, who asked, “Has she eaten anything unusual lately?” Benzer was too mortified to be truthful.
“During the first months, there were few exchanges between us,” Jacob writes, describing his labmate in his memoirs. “We did not keep the same hours. I arrived at nine in the morning; he, around one in the afternoon. As he came in, he would throw out a resounding ‘Hi!’ and then, after lunch, immerse himself in the inspection of his cultures. During the afternoon, he would belch once or twice. Around seven o’clock in the evening, I would bid him good-night and leave him to his nocturnal experiments.”