The Read/Write Metaphor Is a Flawed Way to Talk About DNA

In 2014, chemist Floyd Romesberg, of the Scripps Research Institute, synthesized a new pair of artificial nucleotides and got a cell to accept them as part of its genetic code. In metaphorical terms, he extended the alphabet of life.

To review, the DNA molecule is built from four nucleotides, or “letters”: adenine (A), thymine (T), guanine (G) and cytosine (C). Each letter is one half of a pair—A always goes with T, and G with C—and each pair forms a single rung of the molecule’s twisted ladder. Romesberg’s team, after years of work, synthesized a third pair—X and Y—and inserted it successfully into the code of a bacterium, which then reproduced, maintaining its synthetic code. Life on Earth depends on a four-letter code; Romesberg had invented a life-form with six. In 2017, he updated the accomplishment, optimizing and stabilizing the cell. More important, he showed that the cell could express a novel protein. “We stored information, and now we retrieved it,” Romesberg told The MIT Technology Review. “The next thing is to use it. We are going to do things no one else can.”

Discussing his project with The New York Times in 2014, Romesberg used a metaphor: “If you have a language that has a certain number of letters,” he said, “you want to add letters so you can write more words and tell more stories.” In his TED Talk, he extended this metaphor, asking the audience to imagine a typewriter with only four keys. Wouldn’t six keys be better? Couldn’t you say more? The metaphor seems flawed to me. It may be that new nucleotides = new amino acids = new organisms, but it does not follow that new letters = new words = new stories. I know lots of writers, but none of us have been thinking, “If only there were 30 letters in the alphabet, then I could finish my novel, The Story of Jimβθ!”

George Estreich is the author of The Shape of the Eye: A Memoir. His writing has appeared in Tin House, The New York Times, Salon, and other publications.

The MIT Press

Romesberg is careful to separate himself from wings-and-ultraviolet-vision transhumanism. His declared goals are squarely, soberly medical: a six-letter alphabet could code for a larger complement of possible amino acids, which could be assembled into proteins not found in nature, which might be useful as medicines, which Synthorx, the company Romesberg cofounded, hopes to develop for profit. And yet Romesberg’s metaphor points to a tension between expansive and restrictive views of technology. On the one hand, to “tell more stories” can be glossed as “creating as many novel life-forms as possible.” On the other hand, Romesberg defined those “stories” in familiar, clinical terms—curing disease, including cancer—and the cells, Romesberg noted, would remain obediently in the lab, dependent on a diet of artificial nucleotides to stay alive. Their meaning would be circumscribed, contained, their lives kept safely in vitro. Romesberg’s rhetoric walks a familiar line between old and new, “natural” and “synthetic.” In this, it mimics the application it serves, which splices old and new nucleotides, natural and artificial, together. But more significant is the fact that Romesberg uses metaphor at all: that he uses literary techniques to persuade and does so self-consciously, reflecting on the materials of meaning. He behaves as, is, a writer.

For high-profile scientists, the ones who speak to lay audiences, write popular books, and deliver TED Talks, metaphor is a key persuasive tool. The right metaphor can soothe fears, explain the recondite, and familiarize the unfamiliar. It is scary to say, “We want to create, not only new life, but a new kind of life, one fundamentally different from every single organism that has ever lived.” It’s less scary if creating new life-forms is just like telling stories. We associate stories with entertainment, meaning, and self-expression. Like the vaguely positive keywords anchoring ads for noninvasive prenatal testing (health, choice, empowerment) or de-extinction (revive, restore), story shines a rosy, apolitical light on a technological development, familiarizing the new.

Beneath the metaphor of a story is another, one so ubiquitous as to go unnoticed: that DNA is a language, one which we “read,” “write,” and “edit.” This is closely related to other information metaphors: that DNA is a code, or software. As Hallam Stevens explains in Biotechnology and Society: An Introduction, “[h]istorians have documented how ‘information’ and ‘code’ came to be powerful metaphors in molecular biology in the 1950s and 1960s.” Stevens notes the pervasiveness of the metaphor—“It is hard to imagine it any other way”—but notes that it is not inevitable: “After all, the As, Gs, Ts, and Cs are not like English and Japanese. They are not really a language. Nor are they really a code … it is important to remember that information and code are metaphors rather than literal descriptions of how biology works on a molecular level.” Historian of biology Lily Kay, writing in 1998, noted both the use and limits of the metaphor:

There is no way of avoiding metaphors and analogies as heuristics in the production of knowledge, biological or otherwise, and the information discourse has been particularly powerful and productive. But metaphors have their limits, and analogies should not be confused with ontologies.

A first step toward clarity, toward disentangling the categories of life, language, and code, is to not take metaphors literally: to recognize when metaphor is being used, to explore its implications, and to recognize its limits. One limit of the DNA = story metaphor has to do with the way reading works. Reading is linear and one-dimensional. When we read a novel or poem or essay, we read one word at a time, in order, and even when we reread books, we understand them in terms of the sequence of the whole. It matters that chapter 1 comes first and chapter 23 comes last. But in the Book of Life, the linear paradigm doesn’t hold. Nathaniel Comfort writes, “The old metaphor is not wrong; it is incomplete. In the new genome, lines of static code have become a three-dimensional tangle of vital string, constantly folding and rearranging itself, responsive to outside input.”

If DNA is three-dimensional, in constant interaction with its cell, if it is constantly being “read” in different locations simultaneously, and some of the “reading” affects other “reading” in a dynamic, at-present-incalculably-complex set of interconnected feedback loops, then the “reading” looks very different from human “reading.” So the metaphor has explanatory value, but its value is limited. (In a short article on genes and metaphor, John C. Avise acknowledges the practical use of seeing genomes as information. He also offers other metaphors—ecosystem, community, city—and argues that “metaphors can and should evolve to accommodate new findings.”)

There are other differences. In books, the definition of every word is known; we do not know the function of every gene. Further, we expect books to be densely coherent. Even when they stretch and sprawl and wander, they still make sense—however “sense” is defined—at every level of form, from word to sentence to paragraph to chapter. They don’t typically contain long, random character strings. But as Comfort writes, the book of life is a mess—“[I]f a genome is text, it is badly edited. Most DNA is gibberish.” Lily Kay notes that the parts that aren’t gibberish remain difficult to interpret:

Once the complexities of DNA’s context-dependence—genetic, cellular, organismic, and environmental contexts—are taken into account, pure genetic upward causation is an insufficient explanation … And when epigenetic networks are included in the dynamic processes linking genotype to phenotype (e.g., post-translation modifications, cell-cell communication, differentiation, and development), genetic messages might read more like poetry in all their exquisite biological nuances and rich polysemy.

Every metaphor breaks down somewhere. To have a story, and to be one, are not the same. George W. Bush can have a story, and so can Lassie, or a tapeworm. But none of these creatures is a story, something designed deliberately and in molecular detail by a single creator, written into existence, letter by letter, word by word. So when Romesberg says, “[Y]ou can write more words and tell more stories,” his metaphor assumes (and normalizes) the idea that it is acceptable to design new creatures in the first place. It lessens the difference between the evolved and the designed: all are “stories.” And it subtly shapes the hearer’s sense of the technology in question, making it seem more powerful and more certain. The scientist, at his “typewriter,” taps out a new “story.” The metaphor emphasizes human intention and interpretive certainty, a message with a clear meaning, reliably reproduced.

Turning Romesberg’s rhetorical you to a literal one, I would ask, If a new story is a new creature, then what stories do you want to tell? We have no cultural limit on stories, on their complexity or intricacy: will there be any limits on the stories told with the new letters, or on their ability to replicate, or on the ability of the designed creatures to interact with the evolved? Who will be our storytellers, and what will they believe?

In Romesberg’s formulation, new organisms are new stories, a conceit made possible by the root metaphor that DNA is a language. But a project completed around the same time by the J. Craig Venter Institute took the metaphor a step further. In his book Life at the Speed of Light, Craig Venter himself—the brash, iconoclastic scientist and entrepreneur, and the institute’s founder—described his project as the first “synthetic cell”; it was named Mycoplasma mycoides JCVI-syn1.0, but it acquired the nickname “Synthia.”

You can tell a lot about a biotech application about the way it’s named (“noninvasive,” “de-extinction”), and Venter’s new cell is no different: its formal name highlights the merging of the biological and digital. By hybridizing Linnaean and digital terminology, Venter indicates his view that we are at “the dawn of digital life,” when life, because it can be translated into digital code, can “move at the speed of light.” The name also denotes authorship and intellectual property: Venter’s initials are inscribed in the organism’s taxonomical name (JCVI, for J. Craig Venter Institute).

As many have pointed out, Venter did not synthesize an entire cell. Instead, his team began with the genome sequence of one bacterial species (M. mycoides), altered the sequence on computer, built it from scratch, and implanted it in the cells of a different bacterial species; the assembled genome then took over the new cells. The synthetic genome, over a million base pairs long, was assembled from pieces ordered from a DNA synthesis company, which took Venter’s digitally composed sequence—the string of bases, or “letters”—and then chemically synthesized it and delivered it in short, overlapping stretches called oligonucleotides. Venter’s lab painstakingly stitched these together into larger pieces, which were themselves stitched together into a full genome: a synthetic chromosome, which was then transplanted into a cell. The project took 15 years. Venter emphasizes the precision required in the experiment: the transplantation failed repeatedly because of a single typo, a single misplaced letter in a key gene. When the transplantation finally succeeded, the DNA at the cell’s heart had been human designed and human assembled, but the cell divided and reproduced as if it were natural. As The Guardian reported, the cell “paves the way for designer organisms that are built rather than evolved.”

Announcing the cell’s completion, Venter demonstrated an instinct for publicity, as The New York Times reported:

At a press conference Thursday, Dr. Venter described the converted cell as “the first self-replicating species we’ve had on the planet whose parent is a computer.”

“This is a philosophical advance as much as a technical advance,” he said, suggesting that the “synthetic cell” raised new questions about the nature of life.

In the same article, Nicholas Wade reported the misgivings of leading scientists who found Venter’s technical achievement remarkable, his hype distasteful. Leroy Hood used the word “glitzy.” Nobel laureate David Baltimore granted the technical achievement, but added, “To my mind Craig has somewhat overplayed the importance of this … He has not created life, only mimicked it.” Gerald Joyce similarly noted the “power” of designing a genome letter by letter, but rejected the idea that the cell was “a new life form”: “Of course that’s not right—its ancestor is a biological life form.” The public rivalries of scientific frenemies are a popcorn-worthy combination of Mean Girls and Pacific Rim, but beyond the gossip, the arguments are as rhetorical as they are scientific: how should scientists represent their work to the public? To my mind Craig has somewhat overplayed the importance of this.

In the Science paper unveiling the project, Venter is relatively restrained, but in his press conferences and in his book, his claims lie somewhere between science, philosophy, literature, and guru-like prophecy. Depending on the audience, the same synthetic cell is communicated in radically different ways. This rhetorical divide is characteristic of new biotechnologies—think, for example, of the difference between an ad for NIPT and a consent form signed by a patient—but is also traditional. Like many of his scientific forebears, James Watson in particular, Venter is understated in scientific publications and hyperbolic before the press.

In Venter’s case, the hyperbole takes the form of metaphor. In Life at the Speed of Light, Venter’s description of his synthetic organism is exuberantly synthetic, splicing together elements of life, writing, publication, software, and the Internet: “We were ecstatic when the cells booted up … It’s a living species now, part of our planet’s inventory of life.” Throughout the book, Venter treats metaphor like an engineer stress-testing a metal, pushing it to the point of failure. His point is that the metaphor is not metaphorical:

[DNA] is in fact used to program every organism on the planet with the help of molecular robots. [Emphasis mine.] …

All living cells run on DNA software, which directs hundreds to thousands of protein robots …

Digital computers designed by DNA machines (humans) are now used to read the coded instructions in DNA, to analyze them and to write them in such a way as to create new kinds of DNA machines (synthetic life).

To drive his point home, Venter encoded messages in Synthia’s genome. These, described as “watermarks,” distinguished the creature as synthetic. Venter used a code, with triplets of DNA letters equivalent to letters of the alphabet, to spell out messages, including the names of contributors to the Science paper announcing Synthia’s existence. Also included were three quotations, in all caps (the code didn’t include lowercase): one from James Joyce’s Portrait of the Artist as a Young Man (TO LIVE, TO ERR, TO FALL, TO TRIUMPH, TO RECREATE LIFE OUT OF LIFE); a saying attributed to J. Robert Oppenheimer’s teacher, SEE THINGS NOT AS THEY ARE, BUT AS THEY MIGHT BE; and WHAT I CANNOT BUILD, I CANNOT UNDERSTAND, a misquote from the physicist Richard Feynman. (The original: “What I cannot create, I do not understand.”) These were initially presented as a puzzle to solve: also encoded in the genome was an email address, so the DNA machines (human) who’d figured out what the DNA machine (Synthia) was saying could contact the DNA machines at the J. Craig Venter Institute and let them know. Like Romesberg’s “stories” written in six-letter DNA, Synthia is conceived as a kind of message, but it takes that vision to a literal extreme.

To me, Synthia is an elaborate, clever instance of biological wordplay—more sudoku than poetry, but suggestive nonetheless, a puzzle that remains mysterious even on decoding. But according to Venter, Synthia’s meaning is clear. It—she?—has two lessons to impart. First, it disproves “vitalism,” the idea that something nonmaterial—spirit, a “life force”—is necessary for life to exist. Life is material. And second, Synthia proves that life is information. Venter stresses the point, saying that “[t]hese experiments left no doubt that life is an information system.” His work offers “the proof … that DNA is the software of life.”

Mycoplasma mycoides JCVI-syn1.0 is a quasi-literary text, inscribed in a cell. For that reason alone, it seems to me that its potential interpretations are more varied, more uncertain, and more interesting than the ones advanced by its author. Among Synthia’s all-caps proverbs is the declaration WHAT I CANNOT BUILD, I CANNOT UNDERSTAND, which implies that its builders best understand its meaning; however, if the history of literature teaches us anything, it’s that the author is the last person you should turn to when seeking the meaning of a work. What an inventor wants something to mean matters less than what the world chooses to make of it.

If Synthia were just a really short book, no one would bother with it. It’s a cereal box version of Bartlett’s Familiar Quotations: three quotes, a list of names, and an email address. It wasn’t written by the author whose initials enclose the whole, and one of the quotes is incorrectly transcribed. Worse, it performs the remarkable feat of making James Joyce sound like a bad motivational speaker: TO LIVE, TO ERR, TO FALL, TO TRIUMPH, TO RECREATE LIFE OUT OF LIFE! And yet a closer look is rewarding, because the more you look, the more the cell’s meanings splinter into uncertainty, beginning with its name.

Synthia, I’d thought at first, was a clever bit of wordplay on Venter’s part, the cell’s name expressing its nature: syn for synthetic biology; the letter S substituted for C, suggesting the editing process by which words were encoded in its sequence. It turns out that the name was coined back in 2007 by the ETC Group, a Canadian civil society group fiercely opposed to the project. The name was intended as mocking, like “Obamacare,” but the effort backfired: it was catchy, so it stuck, and soon it became a handy generic name, if only because “Mycoplasma mycoides JCVI-syn1.0” does not exactly roll off the tongue.

If the mockery misfired, it may be because Synthia fits easily into the rhetoric of invented life, the specific kind of whimsy of those who, playing God or not, enjoy playing with words: Dolly, the cloned sheep (named after Dolly Parton, because the sheep was cloned from a mammary cell); cc, the cloned cat; Hercules, the genetically engineered, supermuscular beagle; “Eau d’E. coli,” a variant of E. coli engineered to smell good. In books like Venter’s Life at the Speed of Light and George Church’s Regenesis, the lighthearted, catchy names sit oddly beside the grand claims about life, science, and the future. It is as if someone had stuck a limerick into the Odyssey.

This dissonance points less to science than to a saturated media environment, in which extremity and novelty are rewarded. The two rhetorical registers of biotech futures—stentorian announcements of a New Epoch and catchy names for new animals—are simply two forms of novelty, two ways to distract an audience from distraction. You can do that with entertainment or wisdom, a joke or a truth, a witty slogan or a sonorous prophecy. To delight and instruct, in the age of social media: our new pitches map onto an old poetic goal, made more urgent by the sheer quantity of information we have to sort through.

What is the best way to read a cell? Synthia’s declarations tend more toward prophecy than wit, but even ignoring the substance of its all-caps wisdom, the very fact of quotation is suggestive. Plucking sentences from context mirrors the project itself, which tears genes from previous contexts and installs them in new ones, both digital and biological. And who is quoted matters as much as what is said: pointing to Oppenheimer, Feynman, and Joyce elevates the idea of the iconoclastic genius, clearly implying that Venter belongs in their company. By implication, it is Venter who has TRIUMPH[ED] by RECREAT[ING] LIFE OUT OF LIFE, who SEE[S] THINGS NOT AS THEY ARE, BUT AS THEY MIGHT BE. And with the quotation WHAT I CANNOT BUILD, I CANNOT UNDERSTAND, Venter lays claim to a superior understanding of life—and causes the built object, the living cell, to ventriloquize the claim.

It is an odd thing for a cell to say I, odder still when that cell’s existence is a team effort. But Synthia hovers between individual and group achievement. Venter’s initials occupy the taxonomic name, but as part of an institute; the names of his coauthors are inscribed in the “watermarks”; the cell, with Joyce, elevates an individual ideal of achievement, but at the same time distributes credit, albeit less prominently, to the group. As a digital creature, its uncertainties reflect a digital age when the author is in decline; when old ideas of intellectual property battle with new ones; when everyone on social media is writer, reader, and publisher at once; and when so much of what we share is curated, appropriated, and snipped from one context and repurposed for another. The quotations illustrate this tendency, but their real function is to identify the cell as synthetic and not natural. The quotes are claims that stake a claim. Of course, there’s no end of irony in using appropriated text to establish intellectual property rights, especially when one sentence is a misquote. A string of random characters would have been simpler.

To me, the altered quotation from Feynman is endlessly suggestive. WHAT I CANNOT BUILD, I CANNOT UNDERSTAND can be read at face value, as a declaration of the synthetic biology principle that life must be constructed to be understood, and yet, as a misquote, it reads as a flaw in construction. Human achievement is undercut by human error. Given Venter’s insistence on the precision of his genome editing, the proofreading error is especially ironic. At the same time, it reveals which kinds of precision matter. DNA may be, in Venter’s accounting, an information system, but some forms of information are clearly more important than others. Bacterial genomes are proofread down to the base pair; human sentences—eh, close enough.

Implied in Synthia’s text, and made explicit by Life at the Speed of Light, is an idea about which kinds of knowledge matter most. There’s a paradox in books like these: scientists take on the role of artists, but the arts are distinctly secondary. Even as the scientist is portrayed as a storyteller with an automated sequencer, a painter with a palette of nucleotides, the arts come off as a sort of third wheel of civilization. They aren’t ways of understanding the world, loci of transcendent shared loneliness across time, the set of practices every culture has, and without which life would have no point; they’re just a source of iconic explanatory examples. Whatever is cited tends to be famous and big. Venter notes Joyce; George Church, in Regenesis, explains that he wants to make new genomes synthetically, not simply copy old ones, because “[p]hotographing the Mona Lisa is not as impressive as creating it in the first place.” In this figure, art is more decorative than structural. It is the trim in the house of science, the false columns in front, substantial looking but not load bearing.

In both Regenesis and Life at the Speed of Light, this attitude to art is rooted in an engineer’s approach to the world. What matters is doing something, making something useful. This idea resonates with me, but not when it’s used to demote other human endeavors that are necessary and useful in their own ways. George Church, for example, defines synthetic biology in opposition to something “self-indulgent”:

Synthetic biology is mostly about developing and applying basic engineering principles—the practical matters that help transform something academic, ivory-towerish, pure, and sometimes self-indulgent or abstract into something that has an impact on society and possibly even transforms it.

Venter, too, defines himself as a problem solver, setting himself in opposition to a fictional ivory tower:

Richard Feynman issued a famous warning about the dangers of attempting to define anything with total precision: “We get into that paralysis of thought that comes to philosophers … one saying to the other: ‘You don’t know what you are talking about!’ The second one says: ‘What do you mean by “talking”? What do you mean by “you”? What do you mean by “know”?’”

Like Church, Venter—though he touted Synthia as “a philosophical advance as much as a technical advance”—implies a clear contrast between practical doers and philosophical yappers. And yet: isn’t disproving vitalism, the point of Synthia, kind of … philosophical? Doesn’t transcribing a message in a cell raise questions about language? And don’t Venter’s own metaphors, like saying that people are DNA machines or saying the cells booted up, raise questions about what it means to talk, to know, to be a “you”— about, in other words, language, knowledge, and people? These questions are raised by transformative biotechnologies. That they can be pursued to dead ends is no reflection on the questions themselves: any line of inquiry, in any field, can be sterile and pointless. The key is to consider the questions in a fruitful way. That begins with questions of power: who gets to speak, who is considered authoritative, and who is spoken about.

These are ancient questions, but the digital age renews them. The existence of a “programmable cell” blurs life and nonlife, organisms and messages. Language like the dawn of digital life or E. Cryptor or H. sapiens 2.0 celebrates the blur, playing with it in words, but beneath the play is a message of control, the ability to build a cell to order, to make it serve a task. Both meanings, it seems to me, are evident in the word watermark, which embodies the durable and ephemeral: it could stand for life (its code enduring, its forms changing) or the internet, where the folk belief that data live forever is belied by the fact that data tend to disappear, either drowned by the sheer wash of new data or simply lost. But watermark is a printer’s word, not a poet’s. A sign of ownership. A mark of intellectual property, inscribed in fluid life.

It took a scientist to point out another irony to me: the very fact that cells change as they evolve means that the watermarks will change. Left to their own devices, Synthia’s descendants will evolve. Since the “watermarks” are embedded in noncoding regions, the cell has no need to preserve them. Therefore the list of authors, the quotations, and the email address to contact will begin to degrade. They will be no more permanent than marks in stone; they will weather from the inside out, the author’s intentions fading, letter by letter. As an organic book, one that can reproduce independently, Synthia is self-publishing, but it is self-revising too.

As a living creature, Synthia is a chimera, an engineered blend of two species. But as a living book, it is a chimera of minor forms, a vanity-press amalgam of title, aphorisms, contributors’ notes, and copyright page. These, Russian-doll style, are all enclosed in the “watermarks,” which are in turn enclosed in a brainteaser: the entirety of Synthia’s legible text was presented as a puzzle for smart, science-oriented people to solve. It is, in other words, an intelligence test, but it emphasizes one kind of intelligence, selecting for those who—like Synthia’s inventors—have a problem-solving mind-set and a brain for code, and who are digitally savvy and connected enough to contact the J. Craig Venter Institute with their solution. This does not describe most of the humans in the world. It is technology that divides, not technology that embraces. I prefer a different view of technology and a different voice. A voice that is open and questioning, and that begins and ends with people and thinks about how tools might fit, rather than beginning with the tool and assuming that people will find a place.

Adapted excerpt from Fables and Futures: Biotechnology, Disability, and the Stories We Tell Ourselves by George Estreich, © 2019 George Estreich.


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