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- March 2014: Portrait of a Novel: Henry James and the Making of an American Masterpiece
- February 2014: Forged: Why Fakes are the Great Art of Our Age
- January 2014: Full Upright and Locked Position by Mark Gerchick '73, P'13
- December 2013: This Indian Country by Fred Hoxie '69
- November 2013: The Partner Track by Helen Wan '95
- October 2013: The Forage House by Tess Taylor '99
- September 2013: Inferno by Dan Brown '86
- August 2013: Six Years by Harlan Coben '84, P'16
- July 2013: The Gods of Heavenly Punishment by Jennifer Cody Epstein '88
- June 2013 - Brothers Emanuel by Ezekiel Emanuel '79
- May 2013 - Cadaver by Jonah Ansell '03
- April 2013 - Masters of Disaster by Chris Lehane '90
- March 2013 - Schroder by Amity Gaige
- February 2013: El Iluminado by Ilan Stavans
- January 2013: Everything Under the Sun by David Suzuki '58
- December 2012: Arcadia by Lauren Groff
- November 2012: The Hidden Europe by Francis Tapon '92
- October 2012: The Price of Inequality by Joseph Stiglitz '64
- September 2012: Tubes: A Journey to the Center of the Internet by Andrew Blum '99
- August 2012: Hitlerland by Andrew Nagorski '69
- July 2012: Dinner: A Love Story by Jenny Rosenstrach '93
- June 2012: Vineyard at the End of the World by Ian Mount '92
- May 2012: God's Jury by Cullen Murphy '74
- April 2012: Big Birthday by Kate Hosford '88
- March 2012: EyeMinded by Kellie Jones '81
- February 2012: 1493 by Charles Mann '76
- December 2011: The Vices by Lawrence Douglas
- November 2011: Don't Cross Your Eyes by Aaron Carroll '94
- October 2011: Come On All You Ghosts by Matthew Zapruder '89
- September 2011: The Pale King by David Foster Wallace '85
- August 2011: Scoundrels in Law by Cait Murphy '83
- July 2011: Terror and Wonder by Blair Kamin '79
- June 2011: What Should I Do? by Professor Alex George
- May 2011: Model Nazi by Professor Catherine Epstein
- April 2011: A Thread of Sky by Deanna Fei '99
- March 2011: Unlikely Allies by Joel Paul '77
- February 2011: Secret Historian by Justin Spring '84
- December 2010: The Best of Foxtrot by Bill Amend '84
- November 2010: Higher Education? by Andrew Hacker '51
- October 2010: Routes of Man by Ted Conover '80
- September 2010: The Facebook Effect by David Kirkpatrick '75
- August 2010: Innocent by Scott Turow '70
- July 2010: Simple Fresh Southern by Matt and Ted Lee '93
- June 2010: Ballet's Magic Kingdom by Professor Stanely Rabinowitz
- May 2010: Ecological Intelligence by Daniel Goleman '68
- April 2010: Andean Express by Adrian Althoff '04
- March 2010: Freefall by Joseph Stiglitz '64
- February 2010: Beautiful Creatures by Margaret Stohl '89
- December 2009: What to Read When by Pam Allyn '84
- November 2009: On Poets and Poetry by William H. Pritchard '53
- October 2009: Julie & Julia by Julie Powell '95
- September 2009: Rules for Old Men Waiting by Peter Pouncey
- August 2009: The End of Overeating by David Kessler '73
- July 2009: The Mirror Effect by Dr. Drew Pinsky '80
- June 2009: Art and Politics of Science by Harold Varmus '61
- May 2009: Hold Tight by Harlan Coben '84
- April 2009: Passing Strange by Marni Sandweiss
- March 2009: Skeletons at the Feast by Chris Bohjalian '82
- February 2009: Loneliness as a Way of Life by Tom Dumm
- January 2009: Painter from Shanghai by Jennifer Cody Epstein '88
- December 2008: The Monsters of Templeton by Lauren Groff '01
- November 2008: The Most Famous Man in America by Debby Applegate '89
- October 2008: The Thing Itself by Dick Todd '62
- September 2008: Are We Rome by Cullen Murphy '74
The Art and Politics of Science by Harold Varmus '61
Origins and Beginnings
I generally think of my childhood as unexceptional. Certainly it lacked the drama of familial unhappiness or divorce, the trials of poverty or discomfort, or the exhilaration of exotic travel or adventure. Still, my family represented an extraordinary and uniquely American phenomenon.
Less than fifty years before my birth, all of my grandparents were struggling to make a living in Europe—my father’s parents in an unknown town in Poland, my mother’s parents on farms near Linz in Austria. The computerized files at the Ellis Island Foundation have recently provided me with specific information about my grandfathers, although nothing to corroborate the little I know about the histories of my grandmothers. My mother’s father, Hersch Barasch, later called Harry, arrived in New York on the Edam on August 5, 1898 at the age of seventeen, after sailing from Rotterdam; my father’s father, Jakob Warmus, aged twenty-five, landed on October 26, 1904, on the Neckar, which had departed from Bremen. Although family legend claims that he had lived in a now exterminated suburb of Warsaw, the record shows that he called Lopuszna, a pretty farming village near Cracow, his most recent place of residence in Poland. Lopuszna is now a tour destination for cyclists and trout fishermen.
Like so many European Jews of their social class, my grandparents found their way to Ellis Island, then on to jobs in the environs of New York City. The change in class status between their generation and the next was electrifying. By 1932, at a time when the affluent country that had attracted my grandparents was in the depths of its Great Depression, my father, Frank, had attended Harvard College and graduated from Tufts Medical School, and my mother, Beatrice Barasch, had graduated from Wellesley College and was headed for the New York School of Social Work—achievements reasonable enough for people whose family had been in the country for a couple of centuries, but astonishing for the children of recent immigrants.
Still, I grew up thinking such accomplishments were ordinary and, of course, they were not uncommon. I knew there had been hard times in my father’s past. His mother, Esther, had died in the influenza epidemic of 1918 when he was eleven, leaving him with a lifelong aversion to religion. Mostly, this aversion was expressed as a lack of interest in social events linked to the synagogue or good-humored mockery of rabbinical sermons. But as we followed my mother’s hearse to the cemetery in 1971, he told me that he had never been able to believe in a God who would allow the mother of an eleven-year-old boy to die. His father, Jacob (an Americanization of Jakob), had never learned to speak much English and never earned more than what was possible for a small farmer near Newburgh or a hat factory worker in Newark. But, despite what must have been a relatively bleak home life, Frank was an academic star at Newark High (a culture that I have learned more about from the novels of Philip Roth than from my father’s own accounts). Harvard offered a scholarship that was good enough to keep him at the college for two years, where he played lacrosse, mingled with aristocratic classmates (one, at least, was a Saltonstall), and must have felt very far from Newark. After that, he worked for a year as a waiter in Boston to stash away the funds necessary to pay for medical school.
My mother took an easier path—one that I can more readily picture, since I lived for most of my youth in the town, Freeport, New York, in which she, too, had grown up. Her parents, Harry and Regina, had come to America with access to relatives who had already established successful small businesses along the South Shore of Long Island. So my mother grew up, as did I, in a large house in a suburban community, in a family of some means and with conventional signs of respectability. Her father, Harry (for whom I was named), was among the founders of the first conservative synagogue in town, and the owner of Barasch’s, a popular children’s clothing store that held the Girls Scouts’ franchise and provided employment for virtually everyone in the family, including my mother’s two brothers and, much later, during school vacations, me. When the smart, popular Bea left for Wellesley in 1928 to study psychology and learn the traditions of a formidable New England college, she got no Horatio Alger send-offs. And when she returned home after graduation to train as a psychiatric social worker, her family seems to have greeted her choice as another sensible and quite ordinary step for a young woman of talent.
By this time, my father was a member of the house staff at Kings County Hospital in Brooklyn. A fellow trainee introduced him to my mother, initiating the sequence of events required for my own existence a few years later: a courtship, a honeymoon in the summer of 1936 at Lake George, and the settling down—living in a pleasant gray house, building a family practice of medicine, and having a first child (me, at the end of 1939)—in Freeport.
The entry of the United States into a world war just two years later occasioned the most exotic segment of my childhood, life in a semitropical Florida suburb, Winter Park, not far from my father’s post as a physician and officer at the Orlando Air Base, a situation that allowed evenings of fishing in a nearby lake with alligators. But by the start of 1946, we were back in Freeport, accompanied by a new family member, my younger sister, Ellen, in a larger, somewhat eccentric Victorian house, with a barn and an acre of land for vegetables and flowers, at short walking distances from three important influences: my maternal grandmother, my schools, and the public library.
How unremarkable all this history of comfortable living seemed to me during my childhood! It seemed entirely natural to belong to a family that in two generations had advanced from persecution and poverty in one part of the world to a contented existence in the professional class in another. Rarely did anyone in our family discuss the obligatory trials of this transformation or the alternative outcomes (the Holocaust being only the most obvious). Ellen and I took the benefits of our pleasant existence more or less for granted, growing up with a sense of entitlement and a confidence about the future that were probably unwarranted, however useful they proved to be.
In a small middle-class town like Freeport in the 1940s and 1950s, expectations about the future of its young were high, and closely tied to parental status. (Things seem to be different there now: Freeport’s recent appearances in the New York Times have been triggered by a wave of drive-by shootings.) For me then, a bright and earnest Jewish son of a general practitioner whose friends were mostly physicians and dentists and businessmen, a career in medicine seemed preordained. Everything I can remember or document from browsing in my high school yearbook suggests that I did not resist that prescribed destiny.
Yet a number of signs implied that I might be an unlikely prospect for an education in science or for a professional alliance with my father. I did not have the kind of youthful romance with chemistry that Oliver Sacks describes in his recent book Uncle Tungsten.1 If any of my relatives provided a similar sort of inspiration, it was Harvey Rattner, a second cousin in a nearby South Shore village, who introduced me in my teens to Kafka, other European writers, and existentialism. The sciences were never my favorite subjects in high school, and I did not aspire to enter, let alone win, any science fairs.
If I felt distinctive as a student in high school, it was because my family had packed me off, following my sophomore year, to summer work camp at the Putney School in Vermont, after many years of misadventures at a Boy Scout camp called Wauwepex, near Lake Ronkon-koma, on Long Island. I returned from Putney trying to write short stories and eager to spend weekends with my new and more sophisticated friends from Manhattan or the North Shore of Long Island. But I felt too insecure about my abilities and too loyal to my Freeport pals to transfer to Putney for the last two years of high school, as my parents thought I should. To try to imitate the high-mindedness of Putney in the more pedestrian two summers that followed, I managed to persuade William Hull, a young professor at nearby Hofstra University, to teach the novels of James Joyce to a group of my high school friends one evening a week. Hull proved to be a lively teacher and a serious scholar; I still treasure my copy of Ulysses, annotated with marginalia from his classes.
When I had to make a choice regarding college in my senior year, I did not think much about the scientific training I might receive at the schools under consideration, although I did pay attention to their success with medical school admissions. I sought a place where I would be certain to get a broad introduction to both arts and sciences, a school small enough to provide a reasonable chance of knowing members of the faculty. Largely on these grounds, I chose Amherst over Harvard. I perceived my father’s enthusiasm for this choice as a measure of both his dissatisfaction with his own Harvard experiences, and his uncertainty about my abilities to thrive in what he portrayed as the more competitive and self-reliant atmosphere in Cambridge. I hope I was wrong about the latter perception, but I never asked.
In the 1950s, Amherst was distinctive among leading American colleges for its adherence to what was called the New Curriculum. Its 250 freshmen, all males, formed firm bonds from the common experience of taking the same set of courses, which included calculus, physics, European history, readings of the classics, and a justifiably famous course in expository writing called English 1-2, in which we all struggled with the same essay assignments. Memorably, the first assignments in the fall of 1957 asked us to describe our convictions, why we had them, and how they could be changed by our teachers, or “frisked,” as Robert Frost had put it. Most of us found—and as I am still finding—that we didn’t really know what we thought, what our principles were, until we tried to write them down. What we thought we believed was hard to put into ordinary sentences—so did we have any convictions at all? We discovered that we were more complicated than we knew, as we tried to define our opinions in words that others could comprehend.
Science classes also confronted us with the potential ambiguities of knowledge. I remember especially a cartoon shown by our first-year physics professor, Dudley Towne. A scientist sits on one side of a wall trying to make measurements of—and deductions about—the sounds produced by the antics of bizarre individuals on the other side of the wall. The implication was obvious. Science is limited by the tools we possess for measuring natural phenomena and by the imagination we exercise to interpret those measurements. Not so far from the lessons of English 1-2.
Exposure to many fields of inquiry, as then required by the Amherst curriculum, can be both invigorating and distracting to a curious student. In my first years at college, I toyed with the possibilities of majoring in philosophy (ultimately too abstract), physics (ultimately too hard), and English literature (ultimately selected). I remained loyal to my original intention of fulfilling premed requirements, but I never seriously considered majoring in biology. I couldn’t understand how some of my close friends (among them, some now distinguished scientists) could spend long afternoons and evenings incarcerated in a laboratory, when they could be reading books in a soft library chair or reciting poetry on Amherst’s green hills. I was once urged by a professor of organic chemistry, Robert Whitney, whose required premed course I was failing, to consider dropping the course and jettisoning my medical school aspirations, since I was so plainly headed for a career in literature. Because I doubted that Whitney knew much about me or what I should do, I moved out of my pleasantly boisterous fraternity house into a solitary dorm room and pulled myself up to a gentlemanly C. It later proved to be enough for at least one medical school.
My extracurricular obsession was the school newspaper, the Amherst Student. Serving as the chairman—the editor in chief—for a year was the headiest experience of my college career. The other members of the staff were among the most interesting students I knew at Amherst, and many later became academics, artists, journalists, and editors. We ran long reviews of books, lectures, readings, concerts, and movies; some issues had the appearance of a literary magazine. In addition, our editorials took on many controversial topics of the times, including student political activism (mostly to support racial equity in the South), college spending on athletics (our efforts to augment intramural at the expense of intercollegiate sports were very unpopular with some segments of the student body), the influence of philanthropic foundations on educational policy (equally unpopular with administration officials), and the presidential election of 1960 (favoring Kennedy over Nixon). These views were so often unpopular that a group of undergraduates attempted to recall some of us with a referendum, which we managed to survive. A few of the controversies made me uncomfortable, but I also found them exhilarating. A career in journalism seemed worth considering, too.
But English literature was the most powerful attraction. The Amherst English department had grown prominent, especially under the influence of Reuben Brower, who had departed Amherst for a Harvard professorship shortly before I arrived. Brower was a famously strong advocate for the literary movement known as the New Criticism, which argued that the interpretation of literature had become too heavily influenced by history and biography, and needed to return to the raw experience of directly confronting and analyzing the words on the page.
I remember particularly well my first exposure to the writings of I. A. Richards, one of the earliest prophets of the New Criticism.2 Richards insisted on careful, close reading of primary texts and a clear exposition of what a writer is trying to say, before the reader seeks help from biographies of the author, scholarly or critical writings of others, or the historical context. I now see my enthusiasm for this approach to texts as not unlike the love I later developed for primary scientific data. Just as the data allow scientists to decipher natural systems, the texts allow literary critics to approach an author’s state of mind. My devotion to the principles of the New Criticism probably delayed my appreciation of the ways texts and lives both shape and are shaped by cultures, aspects of the reading experience that I now find both instructive and enjoyable—and endorsed by new literary movements such as the New Historicism.*
I also fell under the spell of some extraordinary teachers at Amherst—Benjamin DeMott, a prolific essayist, with a national reputation, who lectured on Milton and eighteenth- and nineteenth-century novels; Theodore Baird, a rarely published, self-consciously eccentric teacher and an originator of the famous English 1-2 course, who taught Shakespeare; Roger Sale, an ebullient conversationalist and games player, who loved Spenser; Carter Revard, a young and imaginative scholar, who spoke on Chaucer.
Planning to write a senior thesis, I approached DeMott, who flattered me by saying that I should undertake the study of a major writer, such as Shaw or Dickens or Shakespeare, but then disappointed me by saying that he was already oversubscribed as a thesis adviser. Instead, I ended up working with William Pritchard, a recent Amherst graduate, newly arrived from Harvard, where he had studied for his Ph.D. with Reuben Brower. I didn’t know much about Pritchard when we found ourselves assigned to each other. He then seemed very young and slightly insecure, but being the first thesis student of such a bright and lively man proved to be an enormous benefit. Certainly, by being his first, I received his attention and, I’d like to think, some special affection. We have enjoyed watching each other develop over the subsequent nearly five decades.*
I was intent on devoting the summer of 1960 to the choice of a thesis topic. In an act of pure nepotism, my father got me a featherbedded job at Jones Beach State Park, where he served part-time as the park physician for over thirty years. Jones Beach, an extraordinary expanse of sand, ocean, and recreation facilities, built by Robert Moses in the 1920s and 1930s, was only a few miles from Freeport. In the job-free summers of my boyhood, I would often spend the afternoon bobbing in the surf or reading on the beach, while my father removed fishhooks from the hands of careless fishermen or splinters from the feet of those who went shoeless on the wooden boardwalks. But the job I was given was not much more onerous than no job at all, and gave me plenty of time to contemplate thesis topics. I was responsible for keeping barnacles from forming on the motors that propelled floats through the lagoon that separated the audience from the stage at Guy Lombardo’s Jones Beach Marine Theater. This meant swimming briefly in Zach’s Bay once a week to wipe off the propellers, and keeping out of the sight of supervisors or beachgoers the rest of the week.
I settled into a comfortable position in a shed protecting the motors at one end of a float and launched an attack on the major bodies of work that DeMott had advised me to read—especially plays by Shaw and Ibsen, any Shakespeare I hadn’t read, and a few novels by Dickens. I had persuaded a small group of Freeport High School students to allow me to teach them a short literature course—featuring overly ambitious novels, like The Wings of the Dove, which I had only recently read in one of my courses at Amherst. So, lounging next to my motors, I also prepared those evening classes.
Back at Amherst in the fall, Bill Pritchard and I quickly settled on Dickens as the “major author” to tackle. This choice meant struggling to find something original to say about his lengthy, well-known novels. By reading several biographies of Dickens as well, I began to see a pattern. It seemed plausible to link Dickens’s paternalistic attitude toward his family and friends with events in the novels that allow the pallid good characters, finally and mysteriously, to get the upper hand over the colorful and fully rendered evil ones. In the thesis that emerged, I argued that Dickens, as a narrator, was as protective of his weak, kind characters as he tried to be, in life, to his invalided sister-in-law and other relatives and friends. In his letters and his life, he seemed conscious of the enormous power of his personality and his anger at injustice; in his novels, he used that power and anger as a narrator to confront social ills and destroy wicked people. I called this narrative ploy “the murder of evil.”
I knew that I wasn’t starting a revolution in critical writings about Dickens. Still, I felt I had forged a coherent and creative statement about a major writer and his life. And, of course, I had moved away from the purity of the New Criticism, because my interpretation of the texts was strongly affected by my knowledge of the author’s life and times. Weighing the evidence for my thesis, in the novels and the life of the writer, proved to be more consuming and satisfying than I had imagined. Encouraged by Pritchard and others in the English department, I began to think that I should consider literature as a career, not simply as an undergraduate adventure on the way to medical school.
But my mind was far from made up. My confusion was represented physically by a “career decision mobile” that I built in my dormitory room. From a ceiling fixture I had hung copies of my applications for admission to several graduate schools in English and to three medical schools; for a Fulbright Fellowship to study Ibsen and Shaw in Norway; for a visiting fellowship to a Japanese university; and for a couple of jobs in journalism.
My success rate with these options was not high, but there was good mail as well as bad. I was pleased to receive letters saying that I had been admitted to the Harvard graduate program in English and awarded a Woodrow Wilson Fellowship to pay my expenses in the program. On the other hand, a rejection letter from Harvard Medical School, which I now consider a small badge of honor, then seemed a stern judgment on my suitability for medicine. And my applications for various fellowships and jobs were rebuffed. So I readied myself for Harvard’s Ph.D. program in English, to start a few months after college graduation, in the fall of 1961.
The Summer of 1961:
A Glimpse of the New Science
My preparation for graduate school began that summer, immediately after the Amherst commencement, with my first adventure in Europe. I was eager to see places where the great English writers had lived, walked, and worked, and I was not intimidated by the distances or difficulties of travel. I was excited by the London street signs with names from Dickens’s novels, but also by the haunts of Keats and Shelly in Rome and of Lord Byron on the Bosphorus.
One significant departure from my literary itinerary, a detour through the Soviet Union, starting in Stockholm and ending in Istanbul, provided an unexpected window on new developments in science. One of my classmates, Arthur Landy, now a well-known molecular biologist at Brown University, had won an Amherst biology prize that allowed him to attend that year’s international biochemistry meeting, located in Moscow, and he invited me to join him.
I learned the enormous political significance of this meeting only years later. During Stalin’s reign, the science of heredity and evolution, as conceived in the West by Charles Darwin, Gregor Mendel, Thomas Hunt Morgan, and others, was derided as bourgeois. Soviet scientific programs were dominated by T. D. Lysenko, a politically well-connected advocate of the theory of acquired characteristics. This now debunked theory is usually attributed to the late eighteenth-century biologist Jean-Baptiste Lamarck, who popularized the idea that traits imposed or learned during an organism’s lifetime could be transmitted to offspring. As later described by the enlightened Soviet historian Zhores Medvedev,3 Lysenko was nearly single-handedly responsible for keeping Soviet science from applying modern genetics to agricultural and medical sciences until at least the early 1960s. The invitation to hold an international biochemistry meeting in Moscow was perhaps the first public sign that Lysenko’s destructive domination of biological science in the Soviet Union was coming to an end, as the more moderate Nikita Khrushchev began to soften his government’s stance toward the outside world in the wake of Stalin’s death in 1953.
The biochemistry meeting in Moscow is also remembered for another and ultimately more significant event. Marshall Nirenberg, a young American scientist at the NIH, announced his success in deciphering the genetic code. That was a pivotal moment in the history of molecular biology. Even though I did not understand its meaning or its importance at the time, I was not oblivious to the excitement around me. Eventually, Nirenberg’s discovery influenced everyone’s thinking about biology and informed the work that all other biologists have done since then.4
What did it mean to decipher the genetic code? And why was its unveiling so significant? I could not have begun to answer these questions on my trip in 1961, but it will help with the story I aim to tell if I use the occasion of the Moscow meeting to introduce a few basic features of the revolution in molecular biology and genetics that was occurring at that time.
Eight years earlier, Jim Watson and Francis Crick had announced the structure of the DNA double helix—probably the pivotal discovery in twentieth-century biology.5 Previous studies at the Rockefeller Institute and Cold Spring Harbor Laboratory strongly suggested that DNA, an enormous molecule discovered almost a century earlier, was the chemical form of genes.6 If so, DNA had to contain the inherited instructions that were responsible for the contents, appearance, and functions of cells and organisms.
The notion that DNA was the repository of genetic information was accepted only reluctantly, since no one knew how an apparently simple molecule, composed of long chains of just four kinds of chemical building blocks, called nucleotides, could possibly encode so much information. Furthermore, it was not understood how DNA could transmit genetic information accurately to daughter cells during cell division or how it could direct a cell to make components, like proteins, that the information was supposed to specify. It was as though someone had claimed that a piece of paper contained information for making dining room tables, but could not explain three critical things: how the marks on the paper (letters) formed words with meaning, how the paper could be copied for others to use (e.g., by using a Xerox machine), or how the instructions would be carried out (with wood, nails, and tools) to build actual tables.
Within a period of about ten years, a golden age in molecular biology, all this uncertainty evaporated.* When Watson and Crick unveiled their aesthetically pleasing and now fabled double helix, some things were immediately apparent. First, the two strands of the DNA helix are held together in a highly provocative way. The double helix resembles a spiral staircase, with two very long interwound strands, each composed of thousands of the four types of nucleotides. Within the staircase, the “steps” holding the chains together are the parts of the nucleotides that differentiate the four types. These parts, called bases, hold the chains together by regular matches or pairings. Of the four types of bases—denoted by their abbreviated names, A, C, G, and T—A pairs only with T, and vice versa; likewise, C pairs only with G, and vice versa.
If it is assumed that the order of the bases somehow conveys information, then base-pairing provides the clue to perpetuating that information when DNA is duplicated to make two daughter cells. When the strands of DNA are copied, the order of the bases is transmitted, because each strand serves as a template to make a new and opposite strand. The components of the new strands are paired, base for base, with the template, thereby preserving the order. In other words, each new strand would be “complementary” to its template. In the concluding sentence of their paper in 1953, Watson and Crick famously recognized this possibility by saying, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”
This may explain how the order of nucleotides is preserved when DNA is duplicated. But how does the order denote genetic information? And how does the cell use the information to build components like proteins? The first question poses the problem of deciphering the genetic code—of knowing what DNA says. The second question addresses the related problem of expressing genes to make proteins—of knowing how to use the information. To understand how these questions were tackled in that golden age, it is easiest to begin by saying a few things about the way in which cells convert information embedded in DNA to make proteins. (This is like finding out what tools are available for making a table before learning how to read the paper with lettered instructions.)
In its simplest form, anointed the Central Dogma of Molecular Biology by Francis Crick, gene expression consists of two steps, often summarized telegraphically: DNA makes RNA makes protein. More explicitly, cells are equipped with two sets of important tools. First, cells have enzymes that can copy the information in DNA to make chains of a closely related nucleic acid called RNA. This event, called transcription, resembles transcribing one text into another that is more easily read, like rewriting a cursive text into block letters. Because the chemical properties of RNA and DNA are so similar, this can be done, like the copying of DNA strands to make more DNA, by base-pairing—preserving the order of the bases and hence the information. In concrete terms, each G in DNA becomes a C in RNA, each T in DNA an A in RNA, and so forth. In this way, the information in DNA is accurately conveyed to the more readable RNA.
Second, a small intracellular machine, called a ribosome, can “translate” the RNA chain into a chain of protein, like turning a French text to an English one. This happens when the machine reads the information in the RNA and adds the appropriate amino acid, one out of the twenty possible ones, to a growing protein chain.*
By 1961, the Central Dogma and the idea that information in DNA was inherent in the order of the bases had begun to gain wide acceptance. But the rules for reading DNA were far from obvious. Just as a language based on written letters would be impossible to understand if we didn’t know the lengths of words and their meanings, it was equally hard to understand what DNA said or how a cell interpreted it, unless the analogous rules for genetic information were explained. For DNA to encode proteins—the long chains of amino acids that are among the most important and most various of the ingredients in cells—the order of the bases in DNA would presumably have to dictate the order of the twenty amino acids found in proteins. But how? Since four kinds of bases were available, sixty-four combinations of triplets were possible, more than enough to denote all of the amino acids. But which sequences of the four available bases signified which amino acids?
It was this question that Nirenberg (and also Severo Ochoa and his colleagues at NYU) had begun to answer in the experiments he described in Moscow, by means of a very clever approach.9 By the early 1960s, it was possible to make RNA, the “readable” nucleic acid, in a test tube and then ask whether it can direct the protein-making machines to incorporate certain amino acids. In the simplest case, if RNA were made from a single type of nucleotide (e.g., only A’s), it would contain only one kind of three-letter word (e.g., AAA). By identifying the amino acid added to proteins in response to RNA containing only that word, one of the sixty-four code words would be deciphered (in this case, as lysine). It was exactly that kind of experiment and discovery—AAA is the genetic word for the amino acid lysine—that excited the crowd of biochemists meeting in Moscow in 1961.*
Over the ensuing decade, the structure of DNA, the Central Dogma, and the genetic code were determined to be essentially universal—used in all plants, animals, and bacteria—with only minor deviations in a few species. These fundamental aspects are now so ingrained in our understanding of biology—and so strongly supportive of the idea that all life on earth evolved from a single constellation of fortuitous events—that it is hard to imagine the history of the last five decades of biology without them.
As an eighth-grader in 1953, I was understandably unaware of the discovery by Watson and Crick, and remained so for nearly a decade. When the first words of the genetic code were revealed at the biochemistry conference, I was a college graduate, but oblivious to science, riding Moscow’s fabled ornate subways and roaming Russian art galleries, not sitting in the audience. In any case, it is unlikely I would have appreciated the force of Nirenberg’s experiments. If I had been more knowledgeable, able to recognize that the challenge was learning to read and interpret genetic instructions, the questions might have been quite enticing to a student of language and literature! Still, listening to Art Landy’s excited report at the end of the day in our rooms at Moscow State University, I began to understand that something of fundamental significance had occurred, and I felt that a seed of professional envy had been planted. Scientists seemed likely to discover new, deep, and useful things about the world, and other scientists would be excited about these discoveries and eager to build on them. Would this be true of literary critics and teachers?
* My familiarity with these views of literature is among the happy by-products of my membership, many years later, in a group of academic bicyclists, including Stephen Greenblatt and Tom Laqueur, at the University of California at Berkeley.
* Pritchard has become one of America’s best-known biographers and critics. A devoted and greatly admired teacher, he continues to carry a full course load in his mid-seventies without any loss of energy or enthusiasm.
* This era is beautifully portrayed in Horace Freeland Judson’s Eighth Day of Creation.7
* One of the important features of gene expression is its capacity to be regulated. That is, in different cells or under different conditions, each gene may be “read out” (expressed) at different rates or not at all, as determined, for example, by whether and how efficiently it is transcribed into RNA. Efforts to study gene regulation will resurface repeatedly in several subsequent chapters.
* Nirenberg, Ochoa, and Robert Holley (who helped to determine how cells read the genetic code to make proteins) received the Nobel Prize in Physiology or Medicine in 1968.