A Whig History of CRISPR

“Shitstorm” would be one term of art for the reaction in the genome community to a commentary in Cell by Eric Lander, published on January 14. It presents as a definitive account of the discovery of CRISPR, the “gene editing” technique invented in 2013 and which blasted onto the science pages this year. CRISPR is likely to go down as the most important biotechnological invention since Kary Mullis invented the polymerase chain reaction (PCR).

But I prefer another phrase to describe Lander’s account: “Whig history.” The term comes from the Europeanist Herbert Butterfield. In a classic 1931 essay, Butterfield wrote that Whig history was “the tendency in many historians to write [English history] on the side of Protestants and Whigs, to praise revolutions provided they have been successful, to emphasize certain principles of progress in the past and to produce a story which is the ratification if not the glorification of the present.”

The term has become historical shorthand for one way to use history as a political tool. It rationalizes the status quo, wins the allegiance of the establishment, justifies the dominance of those in power. One immediate tip-off to a Whiggish historical account is the use of triumphalist or melodramatic terms such as “heroes” in the title.

Lander’s piece is called “The heroes of CRISPR.”

In April 2014, the Broad Institute at Harvard and MIT—of which Lander is the director— was awarded the first patent for CRISPR technology. The team of Jennifer Doudna (UC Berkeley) and Emmanuelle Charpentier (Umeå University, Sweden) filed their own application seven months earlier, but Zhang obtained fast-track approval. Much remains at stake over CRISPR: fat scientific prizes, almost certainly including a Nobel, as well as further patents. Who claims them will be decided in part by what version of history becomes accepted as “the truth.”

When Michael Eisen, the UC Berkeley/Howard Hughes Medical Institute biologist and astute commentator on genomics read Lander’s article, he went ballistic. In a tweet-blast of righteous indignation, Eisen howled that Lander’s piece minimizes Doudna’s contributions to CRISPR and thus (I’m paraphrasing here) serves as a propaganda organ on behalf of the Broad’s claim to the patent rights. “The whole thing is about trying to establish Zhang paper as pinnacle of CRISPR work,” tweeted Eisen. He continued, “it’s a deliberate effort to undermine Doudna and Charpentier patent claims and prizeworthiness.” It is, he believes, “science propaganda at its most repellent.” “Eric Lander and @broadinstitute should be ashamed of themselves.”

Others have joined in to express their dismay. At the least, many in the community think, some sort of conflict-of-interest statement should have accompanied Lander’s article. A long thread at PubPeer is devoted to the kerfluffle.

Is Eisen right? I’ll leave analysis of the technical arguments over the relative merits of each group’s contributions to the biologists. What I can do is look at the paper itself. Good writers know how rhetoric can be used to persuade. Does Lander use writing techniques to advance a self-interested version of history?

On first read, Lander’s piece seems eminently fair, even generous. It “aims to fill in [the] backstory” of CRISPR, Lander writes; “the history of ideas and the stories of pioneers—and draw lessons about the remarkable ecosystem underlying scientific discovery.” He traces CRISPR’s origins all the way back to Francisco Mojica, a doctoral student at the University of Alicante, in Spain, in 1989. Mojica discovered a new class of repeating sequence that was present in diverse organisms, suggesting widespread taxonomic importance. These, of course, were the first CRISPR sites—clustered regularly-interspaced short palindromic repeats. By 2000, Mojica had found CRISPR loci in 20 different organisms.

By turning his lens on such unsung heroes, laboring away at universities well beyond the anointed labs of Harvard, MIT, UCSF, Johns Hopkins, and the like, Lander creates the impression of inclusiveness, of the sharing of credit among all the “heroes” of CRISPR.

But when he reaches Doudna and Charpentier’s chapter in the story, the generosity becomes curiously muted. Though Lander maintains his warm, avuncular tone, Doudna and Charpentier enter the story as brave soldiers, working shoulder to shoulder with others on the long journey to practical application of CRISPR. Some subtle techniques create a very definite impression.

For example, Lander narrates Charpentier’s story alongside that of the Lithuanian scientist Virginijus Siksnys. But Siksnys receives top billing. His name appears in the first line of two sections of the paper:

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Charpentier’s name, on the other hand, appears at the bottom of a paragraph devoted to a component of the CRISPR-cas9 system called tracrRNA.

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Jennifer Doudna is graciously given the epithet “world-renowned,” which may distract our attention from the fact that her first mention is buried in the middle of a paragraph, in the second half of a long sentence, the direct object rather than the subject of the sentence:

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Doudna and Charpentier go neck and neck with Siksnys through the next sections, but Doudna and Charpentier’s contributions are repeatedly diminished. “Sisknys submitted his paper to Cell on April 6, 2012,” begins one paragraph.  It gets rejected without review. He revises and resubmits, to PNAS and appeared online on Sept. 4. The Doudna-Charpentier paper, he writes, “fared better.” He takes care to note that Doudna and Charpentier’s paper was “submitted to Science 2 months after Siksnys’s on June 8.” It “sailed through review,” he writes, and appeared online on June 28. His point: Although Doudna and Charpentier published first, Siksnys submitted his paper weeks before them. Equating the two papers, Lander writes, “both groups clearly recognized the potential for biotechnology.” This clearly undermines Doudna and Charpentier’s claim to invention of the CRISPR-cas9 technology and hence weakens their case for a patent.

Now, enter Feng Zhang and George Church of the Broad Institute. They receive the longest treatment of any actor in the story—a solid page out of nine pages of text. Zhang’s biographical sketch alone receives a long paragraph. Lander is enough of a writer to know that you indicate a character’s importance with the amount of space you devote to them; the longer the bio, the more important the person.

Then Doudna submits a key paper “with assistance from Church.” This and three other “short [ie., minor] papers,” Lander makes sure to note, “were accepted soon after Zhang and Church’s papers were published in early January, 2013.

Lander concludes his saga with words of benevolent wisdom, extolling the “ecology” of science that produces profound discoveries. History provides optimistic lessons about the idealistic world of pure science, carried out purely for the sake of furthering knowledge. One can almost see Lander dabbing away tears of joy as he writes,

The human stories behind scientific advances can teach us a lot about the miraculous ecosystem that drives biomedical progress—about the roles of serendipity and planning, of pure curiosity and practical application, of hypothesis-free and hypothesis-driven science, of individuals and teams, and of fresh perspectives and deep expertise.

So I think Eisen has a point in reading the paper as a crafty effort to establish Zhang and Church as the scientists who brought the relay race to the finish line—and to portray their principal competitors for patents and prizes, Doudna and Charpentier, as merely two in a long string of runners.

I’m glad to see other scientists, such as Mojica, receive credit in a major CRISPR narrative. Too often the early players and the scientists at lesser-known universities become lost to history altogether. But we should also recognize how Lander uses those actors to create a crowd in which to bury Doudna and Charpentier. It would have been possible to mention Mojica, Gilles Vergnaud, and others while still giving Doudna and Charpentier their due.

Why did he do it? The most obvious reason is the patents over the CRISPR technology. The Broad Institute, which Lander directs, is in a heated patent battle with U.C. Berkeley, Doudna’s home. Lander craftily undermines Doudna and Charpentier’s claim to both priority and originality, as well as to the recognition of CRISPR’s commercial potential. Whig history is written by the winners—and sometimes by the competitors.

Update 1/19: Both Doudna and Church have said Lander’s article contains factual errorsI’ll leave it to the experts to debate the technical details of the science. My argument—stimulated and shaped by Eisen’s tweets—is about the tone and style of the piece. Lander is a public-relations master. He’s a compelling speaker and a sophisticated writer. He’s a giant in the field: he has been a leader in the genome community since early days of the human genome project. He knows exactly what he’s doing.

A Nobel can be split at most three ways, and there are four principal actors. How will the prize be partitioned? Doudna, Charpentier, and Zhang? Doudna, Charpentier, and Mojica? Zhang, Church, and Lander? I have witnessed the steady PR campaigns of scientists who went on to win Nobels. The Prize is supposed to be wholly merit-based, but, we being humans, reputation and economics matter.

Update: One should also note the gender dynamics of the story. However conscious or unconscious it may be, efforts such as this underscore the often-subtle ways in which “history by the winners” still tends to end up being “history by the men.” Only way that stops is by saying it out loud. Tip o’ the pin to Anne Fausto-Sterling and Alondra Nelson for nudging me on this.

At its best, science is a model of human interaction: cooperative, open, focused on evidence and reason, unbiased by prejudice of ethnicity, gender, sexuality, or disability. But science is no longer done in monasteries. Competition, pride, ego, greed, and politics play all too great a role in determining who gets credit, who wins the prizes, and who gets into the textbooks. As Butterfield recognized, controlling the history is both a perk of coming out on top and, while the battle still rages, a way to cement your team’s role in the crystallizing master narrative.

When a scientific history promises an account of “heroes,” when it is filled with sentimental language “miraculous ecosystem” of “pure curiosity and practical application,” and when that history is written by an individual who has much to gain by the acceptance of his own account, the piece should come with a conflict-of-interest statement—or at least a road-sign reading, “Danger! Whig history ahead.”

PS: See also Dominic Berry’s take on the Lander article, also drawing on the history of science but framing it in terms of intellectual property, here: http://blogs.sps.ed.ac.uk/engineering-life/2016/01/18/crispr-in-the-history-of-science-and-intellectual-property/

[2017-12-06: Minor edits, mainly typos and style]

“Fascist Park” Recreates Thrills of Tyranny’s Golden Age

Imagine going “on safari” across Europe in 1939. Out of a nearby bunker steps none other than Adolf Hitler. He goose-steps in your direction, glowering. His little mustache twitches. Now you must choose: Siegheil! Or run!

In the latest of a new breed of extreme entertainment such as “Tough Mudder,” the biotech company Tyro-Scene has announced that it plans to recreate the twentieth century’s most vile tyrants and let them compete for resources in a naturalistic setting, while paying customers experience an afternoon of terror, repression, and the threat of genocide. Riffing on the iconic dinosaur-cloning movie series, they are calling it “Fascist Park.”

Inspired by current research into the recreation of extinct species such as the Woolly Mammoth, a company spokesman says Tyro-Scene will create scenarios that will enable customers to truly live the worst horrors of the twentieth century, including Nazism, Stalinism, apartheid, and Maoist communism. No one under 18 is permitted, and the experience is not advised for adults with heart conditions or psychological “triggers.”

idi aminFor those up to the challenge, the park promises to get your pulse racing. At any moment, Benito Mussolini, Josef Stalin, Idi Amin, Pol Pot, or even Hitler himself may pop out from behind a tree and attempt to oppress or even exterminate you.

Fascist Park will be located on nearly 10,000 desolate acres in southeastern Utah. Efforts are underway to terraform the landscape into regions resembling various tyrannical eco-systems, including central Europe, North Korea, Uganda, Libya, and Siberia. Customers will ride through the region in armored light patrol vehicles equipped with an add-on landmine protection kit and driven by a former Navy SEAL. Further protection will include issuing all customers an AK-47 rifle and requiring them to watch a fifteen-minute safety video before setting out.

The courageous will have opportunities to leave the vehicle and get “up close and personal” with some of history’s most vile human beings. Guests may be interrogated, waterboarded, or shot at. And because they may drive over land mines, pass through mists of chemical or biological weapons, or give chase, they are urged to wear loose, washable clothing and sturdy shoes.

Reanimating the twentieth century’s most fearsome tyrants may seem like mindless entertainment, but it has both scientific and historical value, the company insists.

“By recreating these dictators in a controlled but naturalistic environment, we can study the biological basis of an array of important human traits, from systematic violence to megalomania to a taste for large, dark sunglasses,” the spokesman said. “Understanding how these genes are shaped by the environment is a crucial step toward preventing genocide going forward.”

Indeed, the park will also be available to research teams who wish to study the dictators in their natural habitat. The Canadian anthropologist Woot Derbyshire, often referred to as “the Jane Goodall of messianic assholes,” plans to be first in line. “So far, I’ve had to rely on computer simulations for my work,” he said. “There’s still so much we don’t know about these sons of bitches, from their mating rituals to their grooming habits.”

Behind the scenes, Fascist Park will be an industrial research park. More than one hundred scientists will labor to maintain stocks of fresh dictators; in the wild, they inevitably impinge on one another’s plans for world domination. This leads to thrilling battles, coups, and sabotage—but it also requires regular replacements.

The park plans to open in November, 2018, with a gala opening featuring a simulated Kristallnacht. Tyro-Scene is already thinking about expanding the franchise. Action figures and plush toys are in the works, as well as customized genealogical DNA kits that will allow customers to find out which dictator they are related to. Also planned is a movie tentatively starring Ellen DeGenerate and George Cloney.

Physiognomy Encore!

A while ago, we reprinted a set of brilliant pictures of “composite photography”, a more high-tech version of a technique Francis Galton invented in the late 19th century. Here’s a different approach, less sophisticated but still interesting. The artist, Ulric Collette (who has 3 eyes, 2 noses, and 2 mouths) has digitally stitched together the faces of family members. Many are comic grotesques, but quite a few just seem to have the normal asymmetries we all have. As the artist suggests, cover first one side of a face and then the other to see how different the originals were, and then reblend them in your mind. The show’s title? Genetic Portraits.

Here are just a couple teasers. Click the link and go see them all. 

I’m pretty sure I saw this person in the East Village about 5 years ago.


H/t to Richard Nash and to fullym.com.


The Arsehole Gene

There is a tragic epidemic plaguing us–particularly in the U.S. and in France. Assholes, or, as the Brits say, arseholes. The philosopher Aaron James, in his breakthrough work, Assholes: A Theory, has defined an asshole as a person with an entrenched sense of entitlement who is immune to criticism of his behavior.

Until now, these people have been blamed for their behavior, but genetic science has uncovered a mutation in a gene, dubbed the “arsehole gene,” that leads to the creation of an asshole. Here is a link to a touching new documentary by Eric Romero that chronicles the discovery. Please watch it and pass on the link.

Against turgidity as a quality measure in academia

It happened again last night.

I was at dinner with a group of smart, honest colleagues–a small table-ful of the people in my field I respect most. The conversation turned to another colleague, one who everyone at the table admires, not just as a scholar but as a force of nature. He is enormously productive, a serious scholar–and, damn him, he sometimes reaches a broad audience. In discussing this man’s recent work, one of my table-mates said, “I must confess: he writes so beautifully that sometimes I don’t trust what he’s saying!”

It was meant as a quip, but there was a serious point to it. I have heard this line for nearly 30 years. I’ve heard it in the sciences and I’ve heard it in the humanities. Among some academics, style is a demerit. Attention to rhythm or sonority or, Twain-help-you, wordplay, marks you as unserious, a mere Sophist rather than a Philosophe. Serious researchers are too invested in their ideas to pay attention to communicating them. They have been in the lab or the archive generating data, or in the stacks reviewing the historiography, or at their desktop spinning cotton candy out of the latest theoretical buzzwords. Attention to audience is mere marketing, a sell-out. Turgidity is the mark of a true scholar.

The fallacy involved in this slight on stylists is the confusion of pleasing with slick. Somehow they think that if your prose is graceful you must be doing something slippery that they don’t understand. You must not be revealing all your evidence, or your argument is merely clever instead of well-substantiated. The conflation, frankly, can only be made by someone so grossly unattuned to style that they can’t distinguish wit from reasoning–or persuasion from persuasiveness. But there are a lot of such people in academia, and some of them are distinguished scholars and scientists.

In a way, these crass critics are right. Style can be used to make a point. Scholars who I consider stylists (Hisa Kuriyama’s Expressiveness of the Body is a good example) use word choice, rhythm, sonority, image, and structure to help convey a point. It’s an idea journalists and English majors take in with their first undergraduate lattés: style operates on the aesthetic level, where argument operates on the rational level. A persuasive argument is layered, using evidence, argumentation, and aesthetic elements to make the case.

Pulling that off makes a piece more rigorous, not less. Whether it counts as good academic writing is another story.

Horace Judson: a eulogy

On May 6, at the age of 80, the writer Horace Freeland Judson died. He didn’t pass away; he would have insisted that he simply die. We worked together for five years, from 1997 to 2002, at The Center for History of Recent Science, George Washington University. Here is my appreciation.*

He was six feet in his stockings, which were certainly silk. He dressed impeccably. His leather shoes were glossy, his slacks pressed, even on writing days. His collar was crisp, his cufflinks shone. His houndstooth jacket might be a little worn at the seams, as if from catching too many brambles, but it was always clean. He wore a pocketwatch, and spoke with a vaguely “U” (upper-class, to the English) accent. He was raised in Chicago. A black, broad-brimmed hat, molded just so and rakishly tilted, cravat, and even a cape were not unknown on special occasions. I once saw him open a bottle of New Year’s champagne with a sword. Horace Judson was more than a little vain. But judgment should be tempered by the knowledge of two facts: his preening both reflected and masked enormous effort; and he had terrific taste. He seemed to put thought into every stitch of clothing on his body, every stick of furniture in his house, every book in his library, every word in his books.

His meticulous appearance was, like a peacock’s tail, a display of vigor, for he zipped his pants, buttoned his shirt, oiled his hair, and tied his shoelaces with only one good hand. The left. Childhood polio had withered the other, leaving it floppy and florid. The handicap slowed him down a little—he reconfigured that slowness into a magisterial pace—but prevented him from doing nothing. He shook hands cross-handed (I soon learned to shake left-to-left with him). He opened wine, canned tomatoes, and drove a stick-shift, flamboyantly flouting his disability. He never asked for help. His pride was his strength.

Of course, he typed the quarter million or so words of The Eighth Day of Creation, and everything else he wrote, with one hand. The deliberation this required contributed to the precision and elegance of his prose. Though a journalist by training, he wrote not like a reporter but like an essayist or a novelist. His style was always formal, never slangy (though he was not averse to the occasional earthy vulgarity), and occasionally pompous. He used every rhetorical trick in Aristotle, and had a flair for the dramatic. But his prose was always muscular, and he regularly knocked off passages of such clarity, insight, and grace as to leave the attentive reader breathless.

Consider his definition of X-ray crystallography, an arcane science if ever there was one, from chapter 2 of The Eighth Day. He begins with an analogy simultaneously quantitative and yet immediately apprehensible: “The X-rays used in crystallography are shorter than visible light by some four thousand times.” That does what good writing must, especially when it is on a technical subject: it connects the unknown to the known. Any educated person has a rough idea about visible light, and a sense of how big four thousand times is. Judson then explains the one thing everyone wants to know about X-rays. “Their wavelength is 1.5 Angstroms, which is the same order of size as the spacing between atoms in many solids, and that is why X-rays go through substances that are opaque to the eye.” Did you know that? “Penetrated by a thin beam”—thin beam is nice, both as explanation and in sonority—“the orderly array of atoms in a crystal, layer upon layer, scatters the X-rays in an orderly way, causing a repeating series of overlapping circles of waves.” Note the repetition of orderlyorderly, prefiguring the repeating series of the following clause. Powerful rhetoric illustrates the underlying concept. “At intersection with the flat sheet of film”—note the alliteration, intercalated by the contrasting long vowel sound—“the troughs and peaks of these waves reinforce each other at some points and cancel each other out elsewhere.” The image recalls every child’s game of dropping two stones into a pond and watching the ripples crash. Here is the crucial insight: “The interference pattern that results is characteristic of the structure that produced it,” he writes, and he abruptly ends the lesson by waving a hand at the Nobel-winning mathematics behind it, which would confuse and bore his audience: “…though to figure back to the structure takes mathematics and experience.” That’s all you need to know, really, and not a word more than it takes to describe it.

He never matched that book. How many of us get even one book of that magnitude? Judson is by far the non-PhD most quoted by historians and philosophers of twentieth-century biology, and scholars hate the fact. “Molecular biology is a discipline, a level of analysis, a kit of tools,” he wrote at the beginning of chapter 4. “Which is to say, it is unified by style as much as by content.” There’s a dissertation in that casual observation. He had hundreds like it. At the same time, the book is notoriously difficult to teach, and so few do. (I like to assign chapter 3. Students love it, but find it challenging.) Teachable books show their scaffolding and leave their beams exposed, so that students can skim for argument and get on to their orgo problem sets. Not so Judson. He draws you in, makes you read slowly. The paragraphs are meticulously constructed, but the themes are buried a sentence or two deep, and the arguments build incrementally. You end up highlighting every line.

That quality, combined with his pomp and occasional arrogance, alienated many historians of science. He could be difficult. Yet three things saved him for me. First, his intelligence and his skill as a writer and editor. Many times he annoyed me by ignoring my requests to comment on my green prose, only to read through it once and mark it up on the fly, effortlessly extracting the voice and meaning that I had buried in murk and flab and cliché. He still sits on my shoulder as I write, insisting that I justify the sequence of items in a list, put a twist on every cliché, and, unless I have a specific reason to do otherwise, narrate my story in strict chronological order. Second, his generosity. He often went far out of his way for people, with no expectation of recognition. Behind the formality was a genuinely warm person who loved sentiment but hated sentimentality. And third, his tragedy. He wanted to be accepted as a historian, and never quite was. I think he idealized the university as only someone can who doesn’t have the professorial press pass. Which is too bad, because he was better—gave more insight and more pleasure—than many credentialed scholars. His obituary in the Times listed him as a historian of science, which would have pleased him but which underestimated him. He was a writer.

*Thomas Soderqvist has also posted a piece on Judson. Highly recommended.

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