On the Origins of Modern Biology and the Fantastic: Part 9—Arthur C. Clarke and the Genetic Code

“Unlike the animals, who knew only the present, Man had acquired a past; and he was beginning to grope toward a future.” —Arthur C. Clarke in 2001: A Space Odyssey

2001: A Space Odyssey was science fiction’s Big Bang. Written as a collaboration between two giants of their fields, Arthur C. Clarke and Stanley Kubrick, it has taken its rightful place among the best movies of all time since its release in 1968. Its visuals are iconic—the featureless black monolith, HAL’s cyclopean eye, Frank Poole’s chilling exit ad astra, and Dave Bowman’s evolution into the star child—and its timing is prescient, preceding the moon landing by fifteen months, released at a time when many of science fiction’s dreams were becoming reality. Clarke was, above all, an optimist, confident in mankind’s ability to escape the demoralizing gravity well of the atomic bomb by journeying into the stars.

Biology, too, was on the verge of its own Big Bang. Two tenets of Crick’s central dogma theory had become reality: DNA, as the hereditary material, both replicated itself and was shown to have an intermediary RNA messenger. But the question remained: How did that message encode the proteins? After all, it was the central problem of biology itself—just how did DNA determine the shape and function of a cell, an organ, and ultimately an organism? The problem was one of information, and while Pardee, Jacob, and Monod were working towards their own understanding of the nature of the messenger, simultaneous effort was bent towards what Crick referred to as the “coding problem”… and like the monolith in 2001, his inspiration would come from a unexpectedly cosmic source.

Born in 1917, Arthur C. Clarke found his lifelong loves early: in the stars over his family’s farm in Somerset, the alien life in the tidepools by his aunt’s house by the sea, and in the possibilities offered by communications technology. Clarke, a bright and driven child, won a scholarship to the prestigious Huish prep school, where his teachers encouraged his penchant for invention. He would make rockets with homemade fuel, light beam transmitters, and telescopes with whatever money he made delivering papers, but it wasn’t until he found an issue of Astounding in 1930 that he began to write. Immediately hooked, he collected whatever issues of the magazine he could find—putting him in contact with the larger English fan community, since mostly remaindered issues would arrive as ship ballast, afterthoughts from the booming American publishers. But Clarke’s discovery of two books on the library shelves soon changed everything: Olaf Stapledon’s Last and First Men changed his perspective of time, space, and humanity’s place in the universe, while David Lasser’s The Conquest of Space got him thinking about the practical problems of interplanetary flight—two themes that would dominate the rest of his life.

Like space flight, the coding problem also required practical and theoretical approaches, and the protein bit was astonishingly complex. DNA had been called a stupid molecule for a reason: It had only four bases and a regular structure, whereas proteins were as varied as they were complex. Work since the turn of the century had shown enzymes were proteins made of 20 different amino acids linked by peptide bonds, but even when Watson and Crick’s paper was published in 1953, doubt remained whether proteins even had regular structures. It was a biochemical problem to be tackled by a famously practical scientist, Fred Sanger. Sanger was interested in the amino acid composition of insulin, a cheap protein with a small size and simple composition which, most importantly, could easily be purchased in pure form at the pharmacy. Sanger used two digestion steps to separate smaller and smaller fragments using chromatography, which allowed him to identify the amino acids based on migration patterns. Sanger published the full sequence of insulin in 1955 (the first sequence ever), and demonstrated proteins were regular. In doing so, Sanger gave biology a powerful new tool to sequence any protein, and he won the Nobel Prize for it in 1958.

Clarke’s earliest fiction strongly indicated the trajectory his life and interests would take, featuring engineering solutions to the problems of space travel and communication. In 1936, he enrolled in the civil service in order to move to London, to meet other fans and get involved with the nascent British Interplanetary Society, dedicated to convincing the public of the possibility of space travel. Clarke threw himself into writing, making his first fiction sale in 1937, while writing about space travel for BIS newsletters and editing for one of the first British SF magazines, Novae Terrae (later New Worlds). During WWII, Clarke enlisted in the RAF to learn celestial navigation, but instead developed radar technology, all the while becoming a regular name in the pulps. But it was one of his articles for the BIS in 1946, proposing the idea of geostationary satellites for global communications, which got him recognized by the scientific community, and in 1951 his first two novels were published by Ballantine: Prelude to Space and The Sands of Mars. Both were perfect marriages of hard science and science fiction, depicting space flight and Mars with an unprecedented degree of scientific accuracy. Prelude sold for $50,000, enabling Clarke to finance his first trip to the United States, where he met Heinlein, Asimov, and Ray Bradbury. While his first novels sold well, it was Childhood’s End (1953), a powerfully philosophical story about an alien race guiding humanity through its evolutionary next step, which proved to be his breakthrough, selling two hundred thousand copies in less than two weeks.

Back in the world of biochemistry, while Sanger’s breakthrough gave proteins definite structure, how they were made was still an open question. Two theories prevailed in 1955: multi-enzyme theory, which held that proteins were made from smaller peptides into larger complexes by enzymes, and template theory, which argued full proteins were built on a template. Enter George Gamow, a Russian theoretical physicist and cosmologist, notable for his work in the development of the Big Bang theory in 1946. Upon discovering Watson and Crick’s and Sanger’s work on DNA and insulin, he excitedly penned a theory in which DNA acted as a direct template for protein synthesis and developed a coding scheme, stating “any living organism can be characterized by a long number… written in a four-digital system [i.e. the four nucleotides], and containing many thousands of digits… If one assigns a letter of the alphabet to each amino acid, each protein can be considered as a long word based on an alphabet with 20 different letters [the amino acids].” He thought base permutations formed holes of different shapes along the wide groove into which amino acids fit, and after some intellectual contorting, posited that this meant there were restrictions on amino acid order. But his understanding was incomplete, and when he sent the theory to Crick, Crick immediately saw the errors. Protein synthesis happened in the cytoplasm, not the nucleus, and the chemistry of it was impossible. Furthermore, restrictions on amino acid orders gave too many permutations to experimentally test… but Gamow’s crucial contribution was to get Crick thinking about the coding problem in a new way.

Following the financial success of Childhood’s End, meanwhile, Clarke was able to indulge in another childhood love: the ocean. His friendship with an aspiring filmmaker, Mike Wilson, introduced him to skin diving, and a commission to write a book about the Great Barrier Reef gave Clarke the opportunity to escape from an impulsive marriage. Clarke was gay, and it has been suggested that he married out of fear of being discovered in the wake of Alan Turing’s suicide in 1952. While en route to Australia he fell in love with the country of Ceylon (now Sri Lanka), saying of it, “Six thousand miles from where I was born, I had come home.” In 1956, the year he won his first Hugo award for “The Star,” he relocated permanently. Clarke was more in demand for lecture tours and appearances than ever, and though the launch of Sputnik in 1957 was disheartening, Clarke’s optimistic predictions about spaceflight and telecommunications as a unifying force for humanity were becoming a reality.

Meantime in 1951, Crick sent a letter to the RNA Tie Club (started by Gamow to bring together top minds on the problem), called “On Degenerate Templates and the Adaptor Hypothesis,” where he refuted Gamow’s theory and hypothesized that amino acids were transported to forming protein chains on the microsomes by specific adapter molecules. These adaptors would hold the amino acid against an RNA template that matched a sequence likely 3 bases long (based on the number of possible combinations of four nucleotides to code for 20 amino acids—4^3 gives 64 possible combinations), including two to tell the protein where to start and stop assembling. Since there were more “codons” than amino acids, Crick theorized the code was degenerate, with different combinations encoding for the same amino acid. Crick knew the experimental proof needed to demonstrate a change in the bases of a gene equaled a change in an amino acid in a protein. Proof, at least, of the adaptor hypothesis, would come that same year from Paul Zamecnik and Mahlon Hoagland’s work with the cell free system, identifying RNA in the cellular fraction that carried amino acids to the microsomes, calling it “transfer RNA.” Hoagland said, “Here was one of those rare and exciting moments when theory and experiment snapped into soul-satisfying harmony.” Still, proof for the stickier parts of Crick’s theory remained elusive.

In 1964, Stanley Kubrick, fresh off of his success with Doctor Strangelove, decided to make a science fiction film. Prior to 2001, science fiction movies were primarily of the “B” variety and Kubrick felt, “Cinema has let science fiction down.” True to form, Kubrick threw himself into reading and the same name kept popping up: Arthur C. Clarke. Clarke had been wanting to get into movies (and had actually created an underwater production company in Sri Lanka with Wilson), so when he and Kubrick met in 1964, there was immediate rapport. Over a series of meetings in New York, they agreed to use Clarke’s 1948 story, “The Sentinel,” about an alien artifact found on the moon, as their premise. The novel was written collaboratively, and once the plot was pinned down, five years of production began. So accurate was the set design that the head of the Apollo program called the set “NASA East.” The result was a pioneering achievement in visual effects, from the 35 foot centrifuge set, to the film treatments done for the star gate sequence. An immediate hit, the film was a largely wordless affair, and moviegoers flocked to Clarke’s novel for explanation and enlightenment—making the book a bestseller, and turning Clarke into a financially solvent household name.

In 1956, Crick sought the evidence of the connection between gene and protein codes with Vernon Ingram, a researcher at the Cavendish Laboratory characterizing hemoglobin proteins from people with sickle cell anemia. It was known that sickle cell disease was due to a gene mutation, so together they used Sanger’s technique to compare the amino acid fingerprint of the hemoglobin protein between normal and sickle cell samples and found a single amino acid change. They published their results in 1957 in Nature, and, proof in hand, Crick gave a symposium paper, “On Protein Synthesis” at University College in London that the historian Horace Judson said, “permanently altered the logic of biology.” In it, Crick laid out his sequence hypothesis, and formalized the central dogma, stating genetic information was transcribed to RNA, then to protein, but not back again, implying that acquired changes in a protein could not be inherited, and that DNA contained all the information necessary for making a protein. Furthermore, he asserted the code was universal to all higher forms of life. It was a stunning work of theoretical genius, while the code remained elusive.

In 1969, Apollo 11 landed on the moon, and to cover the event, Clarke convinced CBS to enlist the help of Doug Trumbull, the lead effects man from 2001. Clarke, being a longtime popularizer of space travel, had become a staple in Apollo coverage and commentary alongside Walter Cronkite on CBS (save for the abortive Apollo 13 mission, the capsule of which was named “Odyssey” in Clarke’s honor ). Of the moon landing Clarke said, “I’m looking forward to the next few years, when I absorb all this, to do my best science fiction.” And he was right. He would go on to publish eleven more books, including Rendezvous with Rama (1973), an adventure story aboard an alien spaceship passing through the solar system, and Fountains of Paradise (1979), about the history of Sri Lanka and the construction of a space elevator, both of which won Hugo awards.

The cracking of the code would eventually come from Marshall Nirenberg, a biologist studying how information transferred from DNA to protein. Nirenberg wanted to make a protein in vitro and so joined Leon Heppel’s lab at the NIH. Heppel had spent the 1950s working at Cambridge on polynucleotide phosphorylase, where he created a number of synthetic RNAs as an experimental byproduct. Nirenberg used a variation on the cell free system made from bacteria, adding different synthetic homopolymer RNAs, reasoning if the RNA contained only one nucleotide, resulting proteins would only have one amino acid, which is what he found. Nirenberg presented the paper to a mostly empty room in Moscow in 1961, where a startled Crick was in attendance. Crick made him present again to the general session and the race to the code was on. The meticulous work of Har Gobind Khorana at the University of Wisconsin would provide the final pieces of the puzzle, using different permutations of synthetic RNAs until the three letter codons for each amino acid (as well as for stop and start) were found. The code was degenerate and universal, just as Crick predicted, and in 1968, Nirenberg and Khorana would win a Nobel prize for their work.

On top of being named a SFWA Grand Master in 1985 and winning numerous Hugo and Nebula awards, Clarke was also awarded the UNESCO Kalinga prize for popularizing science (alongside the likes of Julian Huxley and Gamow), the Commander of the Order of the British Empire for his work in bringing communications technology and education to Sri Lanka, as well as being awarded Sri Lanka’s highest civil honor, and was knighted in 1998. In addition, numerous awards, foundations, institutes, and astral bodies would be named for him, and he served (and continues to serve) as an inspiration to countless engineers, scientists, astronauts, and science fiction writers. Clarke died in 2008 at the age of 90 in Sri Lanka.

Clarke once said, “For it may be that the old astrologers had the truth exactly reversed, when they believed that the stars controlled the destinies of men. The time may come when men control the destinies of stars.” The ever-expanding discoveries in biology since Darwin first published his theory of evolution had turned the tables in a similar way: The universe was beginning to know itself, and new frontiers were opening before it. Next time, we’ll see how biology would undertake its first act of creation, and look at a writer who would bring science fiction to whole new audiences: Ray Bradbury.

Kelly Lagor is a scientist by day and a science fiction writer by night. Her work has appeared at Tor.com and other places, and you can find her tweeting about all kinds of nonsense @klagor

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