On the Origins of Modern Biology and the Fantastic: Part 8 — Isaac Asimov and Messenger RNA

“To succeed, planning alone is insufficient. One must improvise as well.” —Salvor Hardin, Foundation by Isaac Asimov

Isaac Asimov loved a cozy mystery, the kind involving few suspects that are solved by the logical deductions of a brilliant mind. In his two most famous series, logic was a prevailing theme. In the Robot series, Asimov used logic on a small scale to extrapolate and examine the impact of his Three Law of Robotics and in his Foundation series, psychohistory applied logic and a scientific approach to mass psychology to avert a dark age after the collapse of the Galactic Empire. Furthermore, near the end of his life, Asimov used logic to tie the two series together, rooting psychohistory in an extrapolation of the three laws, thus tying the fate of humanity to a singular partnership between a robophobic detective, Elijah Baley, and a humaniform robot, R. Daneel Olivaw, in solving a mystery.

The elucidation of the structure of DNA by Watson and Crick in 1953 was a similarly singular event in biology, but it presented scientists with another mystery. That year, Watson said, “A genetic material must duplicate itself, and it must exert a highly specific influence on the cell. Our model suggests a simpler mechanism for the first process, but at the moment we cannot see how it carries out the second one.” George Beadle and Edward Tatum’s 1941 one-gene-one-enzyme hypothesis offered a place to start, but how one gene became one protein was an utter black box. And so biology’s own cozy mystery was afoot, and it took a handful of brilliant minds to solve it.

Asimov always considered himself to be a prodigy. Born in Russia in 1920, his family emigrated to Brooklyn when he was three. He was a precocious kid, but his know-it-all attitude isolated him from his peers and he spent much of his childhood reading and working in the family candy store. From a young age, Asimov loved the pulps, but followed John W. Campbell’s Astounding in particular, writing regular letters to the editor. His ubiquitous name in the magazine resulted in his first (lifelong) friendships with the Futurians, a New York-based fan club, which included Frederik Pohl, Cyril Kornbluth, and Donald Wollheim among others. Despite his involvement in the community he didn’t become serious about writing until 1937, when he began to slowly tinker with a time travel story, and when the regular shipment of Astounding failed to arrive on time, his panic over the prospect of the magazine folding spurred him to complete and hand-deliver the manuscript to Campbell. Campbell, amused, rejected it encouragingly. Asimov kept writing for (and was rejected by) Campbell, but he made his first sales in 1939, first to Amazing, then another to Pohl for Astonishing. Convinced of his own brilliance, he kept at it and his fourth sale (“Trends”) was made to Astounding.

That same year, early clues to a mechanism of protein synthesis came to light. Two independent research groups (one Swedish, one Belgian) found that cells synthesizing proteins were rich in RNA, and that process was localized to the cytoplasm. It wasn’t until 1952 that dense particles containing RNA and protein were described in bacterial cytoplasm by Arthur Pardee at Berkeley, and Paul Zamecnik at Massachusetts General Hospital isolated said “microsomes” from rat liver and demonstrated they were the sites of protein synthesis. That same year, Pardee attended a talk by a French biochemist, Jacques Monod, on changes in bacterial enzymes after phage infection, a subject of significant interest to Pardee. He would closely follow Monod’s work thereafter and in 1954, when a Monod paper footnote mentioned that uracil (a base specific to RNA) was required to make an enzyme for lactose metabolism, Pardee conducted an experiment to show production of the enzyme stopped when RNA synthesis was interrupted. Unfortunately, the evidence was circumstantial; Pardee could only conclude, “Continuous formation of RNA is essential to protein formation.”

As Pardee admired Monod, so Asimov admired Campbell. Campbell, already the most powerful man in science fiction, aspired to build an author from the ground up whose work would reflect Campbell’s own style and interests, and Asimov flourished under the attention. In 1940, Asimov wrote one of his personal favorite stories, “Robbie,” about a lost robot, which he sold to Pohl after a Campbell rejection, but he knew Campbell had an affinity for religious themes and proposed a story about a robot who refuses to believe it was made by humans (“Reason”), which Campbell bought. When he proposed another about a mind-reading robot, Campbell stopped him, saying the robots should follow three rules: no hurting humans, obeying orders without doing harm, and protecting themselves without disobeying or harming, marking a shift from the mindless destructive robots of older fiction to something more humane. The “Three Laws of robotics” would inspire 36 short stories, as well as four Elijah Baley novels, which largely used a cozy mystery backdrop to explore what it meant to be human. Between 1939 and 1958, 39 of Asimov’s 131 short story sales went to Campbell and Astounding, and from 1943-1949, he sold to no one else.

A pairing in biology between Monod and François Jacob would produce similarly dazzling results. Born in 1910, Monod was a gifted youth, so much so that his family debated whether he would be the next Beethoven or the next Pasteur. During World War II, he fought for the French Resistance and, while in hiding, he worked in André Lwoff’s lab at the Institut Pasteur. Before the war, he described the phenomenon of diauxie, where bacteria grown on a mix of glucose and lactose would preferentially consume glucose, followed by a short pause, then would resume growth using lactose. Monod hypothesized that the change was due to enzyme adaptation (a popular hypothesis at the time) and in Lwoff’s lab, he used mutants for lactose (lac) metabolism to describe β-galactosidase (the enzyme that breaks down lactose) and show it wasn’t produced in cells without lactose present. He also discovered a constitutive (always on) mutant (lacI-) that made β-gal regardless of lactose. Monod hypothesized the lacI- mutant made a dominant “internal inducer” protein to constantly activate the production of β-gal, but lacked the biological tools to test it.

Born in 1920, Jacob had a gift for physics and math, but his time at the prestigious (and apparently hellish) Lycée Carnot inspired him to turn to medicine. During the war, he joined the medical company of the French 2nd Armored Division and won several awards for valor. In 1950, his interest in genetics led him to approach Lwoff to oversee a PhD. There, he worked with Élie Wollman using a mutant strain of E. coli that, following bacterial conjugation (where genetic material is exchanged), resulted in a high frequency of genetic recombination (Hfr). They used the Hfr strain to do Mendelian-like crosses in order to map traits on the bacterial chromosome (which Jacob and Wollman determined to be circular). Furthermore, they identified mutants in the lac pathway—one that never produced β-gal (lacZ-), and one that could not transport lactose into the cell (lacY-). They published their paper in 1957, and Monod (who ate lunch with Jacob most days) realized that Jacob had just the tools needed to test his internal inducer hypothesis. With Jacob’s knack for experimental design and Monod’s talent for theory, they soon found the lacZ-, lacY– and lacI– mutations were so closely linked that they sat beside each other on the chromosome, dubbing it the “lac operon.”

Back on the literary front, Asimov’s gift for logical extrapolation and Campbell’s ability to come up with story ideas resulted in the wildly popular Foundation series. In 1941 Asimov wanted to write a future history inspired by Edward Gibbon’s The History of the Decline and Fall of the Roman Empire. Campbell’s interest in turning the study of human behavior and psychology into hard sciences led him to propose the concept of a foundation of psychohistorians who predict the future using knowledge of large group behavior in order to save the galaxy from 30,000 years of darkness. The trilogy appeared in Astounding between 1942 and 1950. During this time, Asimov’s popularity made him one of science fiction’s “Big Three,” along with Heinlein and Arthur C. Clarke. Despite his relative fame, the money he made was a pittance, and in 1949, when Doubleday began publishing their line of science fiction novels, Pohl convinced Asimov to send them a trunked novella. Novel royalties would provide a solution to his financial woes, and Pebble in the Sky was published in 1950, marking the beginning of a new lifelong partnership between Asimov and Doubleday.

At this point, Jacob and Monod required one more piece to definitively discern the method of regulation of the lac operon. In 1957, Pardee developed a technique to destroy bacterial DNA with radioactive phosphorus, and he came to Paris to work with Monod and Jacob to see if DNA or just the internal inducer was required for β-gal synthesis. Their logic indicated that if a donor (Hfr) strain lacking the internal inducer (lacI+) with a functional β-gal (lacZ+) was crossed with a recipient strain with the internal inducer (lacI-) but no β-gal (lacZ-), the recipient should make β-gal right away (since the dominant inducer would already be present, waiting for a functional enzyme to make). Conversely, if they crossed a donor inducible strain (lacI-) with no β-gal (lacZ-) to a recipient strain lacking the internal inducer (lacI+) but making β-gal (lacZ+), no β-gal would be made until the cell had time to make the internal inducer, regardless of lactose presence. The first experiment went according to plan, but in the second, no β-gal was made until lactose was added: Monod was wrong. Furthermore, in the first experiment, 90 minutes after conjugation, synthesis of β-gal stopped completely, while in the second, synthesis continued indefinitely after lactose was added. After much head-scratching, Jacob drew from parallels in phage work to come up with the missing piece—instead of an inducer being made, perhaps the lacI- mutation inhibited a repressor that, based on the cessation, acted on some unstable “cytoplasmic messenger” intermediate  . The resulting paper, published in 1958, was affectionately dubbed the PaJaMo paper, a mashup of its authors names.

By 1958, Asimov had hit a similar wall. Campbell’s fascination with L. Ron Hubbard’s Dianetics was alienating many in the science fiction community, including Asimov. While new markets picked up Campbell’s slack (including Galaxy and The Magazine of Fantasy and Science Fiction), Asimov had stopped producing fiction to a large degree. He noted that the launch of Sputnik had given many Americans a sense of being lost in the Soviet wake, and recognized an immediate need for greater science literacy, turning from fiction to popular science writing as a result. Asimov had gotten a Bachelor of Science degree in Chemistry from Columbia in 1939, but had bad hands (i.e. was bad at designing and carrying out successful experiments) for research (side note: he was also a serial groper, prompting women at his publishing houses to leave when he was coming in ), and he limped through the requirements to get a doctorate in biochemistry in 1948. He lucked into an instructor position at Boston University, thanks to a fan (William C. Boyd) on the teaching staff, and in 1949 he moved to Boston. Asimov would write fiction at home, and nonfiction articles about science at work between lectures, which immediately sold. So encouraged, he found that he enjoyed writing nonfiction more than fiction, and in 1954, when Boyd handed him a request to write a nonfiction book for teenagers about biochemistry, he dove in. 1954’s The Chemicals of Life marked the start of a thirty-year career as a science popularizer.

The last piece of the messenger mystery emerged from an informal meeting at Cambridge. In 1957, Crick gave a talk at University College in London on “The Biological Replication of Macromolecules,” where he espoused the what’s become known as the central dogma, citing RNA as intermediate between DNA and protein, with microsomes as the location. If genes were the template, any RNA messenger should be of similar base composition, but RNA extracted from ribosomes was uniform in base composition across species and didn’t match its host’s DNA composition. Furthermore, these ribosomal RNAs were stable and comprised 90% of the RNA fraction, with only an elusive 10% existing as a short-lived fraction. Thus was born the suspicion that there was a subset of specialized microsomes responsible for protein production. After the PaJaMo paper was published, Pardee returned to California, and in 1958 he and his student, Margot Riley, discovered that if they destroyed DNA with radioactive phosphorus, protein production stopped, inconsistent with an stable specialized microsome intermediate. It wasn’t until 1960, however, when an informal chat between Monod, Jacob, Crick, and Sydney Brenner, a South African biologist newly arrived to Cambridge, gave way to an epiphany. Jacob described the PaJaMo findings and Pardee’s unstable messenger experiment, which led Crick and Brenner to realize that the unstable messenger could, in fact, be that short-lived fraction of RNA. If that was indeed the case, then it should have the same base composition as the DNA template—and they knew just who could help get an answer.

In 1957, Asimov was dismissed from his teaching job at Boston University, due to his refusal to do research and generally rubbing the senior administration officials the wrong way, but during his time there he’d found that he loved public speaking, and by this point his writing income had outpaced his academic salary. He convinced the university to let him keep his title and settled into full-time writing. On top of becoming a sought-after public speaker, he would remain continuously in print for the rest of his life, curating anthologies and writing essays, joke books, annotated texts, reference texts, and educational material, winning a special Hugo for “adding science to science fiction” in 1963. But Asimov couldn’t stay completely away from science fiction (mostly at the behest of his publisher), and he would win Hugo, Nebula, and Locus awards for The Gods Themselves in 1973, and the Hugos would keep coming for shorter works and new installments in his Foundation series during the ’80s. He would also be asked to attach his name to all kinds of projects, and in 1977, Isaac Asimov’s Science Fiction Magazine was first printed, and while he shied away from editorial oversight, he contributed essays each month (in addition to his monthly essay for the Magazine of Fantasy and Science Fiction) for the rest of his life. He would also go on to publish the Black Widowers stories—his own cozy mysteries.

The scientific mystery of the messenger was finally cracked in 1961 by Crick and Brenner. They flew to Caltech to work with Meselson’s ultracentrifuge in order to test if specific ribosomes or the short-lived RNA was the culprit using phage infection as a model. They could distinguish if RNA made after infection went to newly made or existing ribosomes using radio-labeling methods. After a frantic month of work, they had their answer: microsomes (aka ribosomes) were universal, and RNA was the intermediate. Brenner and Crick’s paper appeared in a 1961 issue of Nature, and a long review article by Jacob and Monod to illustrate the roles of “messenger RNA” was published in the same month in Journal of Molecular Biology. Jacob, Monod, and Lwoff won the Nobel prize in 1965.

In 1977, Asimov suffered a heart attack; in 1983, he underwent a triple bypass during which he contracted HIV from tainted blood. Because of the climate of paranoia surrounding the AIDS crisis, he and his second wife Janet, kept the news of his diagnosis quiet, and after years of declining health, Asimov died at home in 1992. He published over 500 books, and nearly 400 short stories during his life, making him one of the most prolific writers of all time. A generation of scientists were inspired by his work, from biologists to computer scientists to engineers—not to mention the indelible mark Asimov left on science fiction. He was named the 8th SFWA Grand Master in 1986.

While the mystery of the messenger was being solved, parallel work done by Crick and Brenner would tie up the the “central dogma” of the flow of genetic information from DNA to RNA to protein with a neat bow, as we’ll soon see. Plus, we’ll look at the work of the third of the “Big Three” science fiction icons: Arthur C. Clarke.

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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