Original link: https://www.tor.com/2019/03/07/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
