A Whig History of CRISPR

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“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 errors. I’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]

New stuff, recent and future

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Two upcoming gigs, one online, one live:

Finally, I took a little holiday down-time to update the Scribblings page to include some of my recent articles, in Aeon, The Nation, Nature, and elsewhere. Links to html articles and/or pdfs included whenever possible. Enjoy!

 

The history of designer babies

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I have a new article up over at Aeon magazine. It’s called “Better Babies: The long and peculiar history of the designer human, from Plato’s citizen breeders to Nobel sperm banks and beyond.”

courtesy Aeon Magazine (www.aeon.co)

After touching upon some of the earliest methods of designing babies, I move through Francis Galton and some of the history of eugenics that should be familiar to Genotopia readers by now. But I take the story up through CRISPR, arguing first that attempts to design our children are all but certain; and second, that they are almost certain to fail. What both the cheerleaders and the hand-wringers fail to take into account is the complexity of the genomics in a species as complex and modulated by culture as ours. Any trait that’s very interesting socially—criminality, sexuality, drug addiction, aggression, etc.—is going to be extraordinarily complex and won’t be reducible to single genes, or even a few.

By all means, new techniques such as CRISPR can and should be applied where they can bring genuine medical benefit. But I caution that high-tech medical benefit comes with social costs—and that high-tech biomedical hype always overreaches real clinical reality.

DNA as Commodity

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Here’s a riddle: In the morning I was in the soup. At noon I was in a dish. In the afternoon I was in your gas tank. And at night I am in the bank. What am I?

The answer is DNA. From a natural object emerging, some say, from a primordial soup, to a laboratory object, to a cultural object, it has become data, a special string of computer code endowed with the power to foretell disease, identify criminals, and be leveraged, like software, as a product.

from venturebeat.com

Robert Resta, a genetic counselor and always a reliable source of depressing, ironic, frightening, and amusing stories about heredity and DNA, forwards this piece, by @alexlash, from Xconomy.com on how your DNA is becoming commodified. What’s happening is interesting not for how new it is, but for the way in which the exotic is becoming commonplace. Featuring the San Francisco biotech company Invitae, the piece shows how this small but highly capitalized company is taking on giants such as Illumina, 23andMe, and Myriad in a bid to monetize your sequence—and give you a small cut.

The troubling thing is how commonplace this is all becoming. Nothing Invitae is doing is really new. They want to persuade you to donate your genome to their database, where it can be analyzed to inform you about your health, contribute to research, and be sold to other companies who might use it for anything from curing cancer to targeted advertising. Invitae CEO Randy Scott he is not bringing in new tests–only offering existing ones all in one place, an approach he calls “generic genetics.” (“Generic genomics” would be more accurate–this is about as far from Gregor Mendel as you can get with a double helix.) And he wants to include users in the process, so that if their sequence is bundled into some DNA-based product, you get a tiny royalty. Sort of like allowing ads on your blog.

For some time, historians and sociologists of science have been writing about “biological citizenship,” the idea that we’re coming to base our identity on our biological status rather than our labor. Many people today identify more as a cancer survivor, as living with depression, or as gluten-intolerant than as a carpenter, secretary, or professor.

DNA has been a big part of that shift to biological citizenship. It’s not the only thing, of course, but it’s a big one. DNA, a hypothetical Marxist historian (there are still a few!) might say, came to have “use value.” We hear every day suggestions that our genes make us who we are. Leaving aside for the moment whether they actually do—a challenge for me, as regular readers know—we believe our DNA to be the secret of life. And so, in a sense, it is.

What’s happening now is that use value is being converted into exchange value. DNA is becoming a currency. An investment account we’re all born with. What are you going to do with yours? Hide it under a mattress? Or make it work for you?

One could imagine a day when there’s a new kind of hereditary aristocracy. A group of nouveau riche whose wealth nevertheless was inherited. Those who, through no effort of their own, received a legacy of valuable SNPs (single-nucleotide polymorphisms). But it will take a go-getter to capitalize on that legacy. You’ll have to have ambition, street smarts, and at least a bit of lab smarts.

Marx also said that history was determined by the material reality of the individual. One might now say the molecular reality of the individual. But total self-awareness at the molecular level won’t lead to the end of exploitation of man by man. Indeed, it is only the beginning.

Drug pushers beware

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Love this piece from the Onion.

“A lot of teens just don’t know how to say no when drugs are constantly pushed on them,” quoth their fictitious expert. “These kids see their friends and classmates using drugs in middle school, or even elementary school, and they start to think it’s normal. We have to break that cycle. These kids need to know that just because the person pressuring them to use drugs is older than they are and uses forceful language, that does not mean using drugs is a good idea.”

The catch: the drug pushers are mental health professionals. As the best satire does, this brilliantly skewers its topic–in this case by showing that, under a certain light, professional medicine can be condemned in the exact same language that we’d use for the illegal drug trade.

NB to the Gotcha Squad: This is neither to condone the culture of illegal drugs in this country nor to roundly condemn mental health medicine, so shut up already. But the piece, as good humor does, makes ya think a bit, no?

 

Poor Richard Dawkins’ Almanack

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September:

Fine fall weather may tempt you to harvest your memories in a Booke, but beware an early frost. Avoid fatuous pontification before the Squash blooms wither. One who failed to heed this commonsense warning was “greeted with critical sneering so intense it was almost audible,” If only he’d followed Poor Richard’s advice!

On the 20th, don’t forget to turn your clock back. Into a clock. A Muslim boy may bring you a timepiece that seems like a bomb. We know this sounds like one of our Homely allegories, but seriously. It may indeed prove to be a time bomb—but only if you will it so. Question not the boy’s motives, for once you walk down that road you may not ever walk it back. Even your Guardian cannot protect you then, no matter how much you Huff and Puff. Remember: Tweet not, want not!

The autumnal equinox is on the 23rd, but for you, Fall may already have begun. Early to bed…and maybe just stay there for the winter.

Plant seeds of next book during the full moon: sowing animus and xenophobia can be back-breaking labor. Early to bed and early to rise brings wealth to all men telling fortunes and lies!

 

Exclusive: Interview with Dick Dorkins

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GENOTOPIA: Welcome to Sideline, where we towel off the washed up and try to make them look presentable. Dr. Dick Dorkins is President and CEO of the Society for the Prevention of Intelligent design, Theology, Transcendentalism Or Other Nonsense (SPITTOON). His new meme-oir, haha, is called Me, Me: Portrait of a Selfish Geneticist. It’s a 900-page tell-all about Dorkins’s contributions to science, culture, and life. It also features lots of nice things people have said about him and many other nice things he has said, and continues to say, about himself. We just couldn’t resist inviting him to come and tell us about it. Dr. Dick, welcome to the program.

DICK DORKINS: It’s nice to have me here, isn’t it?

GT: Why, yes, of course. It seems like only yesterday that you made some geniune—

DD: I mean, you were right just then: you are fortunate. I just think it’s so important for us to recognize life’s gifts, the random generosities of the cosmos, as it were.

My book is another one. I truly believe—scratch that: I know it is the best thing I’ve ever written—which of course is saying something. Some of my closest friends agree with me. My dear friend Harold Hairnet, for example, said…pardon me, let me get my glasses… [intones]:

Bravissima! Encore, encore! Dick Dorkins’s Me, Me is the finest example of memoir since anatomically modern man last mated with a Neanderthal. Its sparkling prose and flashing wit are a perfect mirror of the towering intellect that produced it.

That’s a nice bit just there, isn’t it? There’s more:

Being a book, it is highly readable, and in addition to having pages it has even more pages, which is a most excellent and fortuitous happenstance, for they are, every man Jack of them, examples of their kind.

GT: Impressive.

DD: Well I was impressed. He adores me, and I love that quality in people. And that’s just one tiny fraction of the good things—glowing, radiant, heart-warming things—my very best friends say about me, my book, and my theories. In fact, I wrote a computer simulation to model how much my book would sell if wise, thoughtful opinions such as this spread throughout the population. It could be done with a kind of hypnosis I’ve developed in which my minions—sorry, readers—echo my ideas, thereby persuading everyone around them. I call it “lognosis,” from logos and gnosis.

Here’s how it works. Imagine that praise is a real, physical thing, like general intelligence (with which, obviously, it is correlated). Now, when I read that passage to you, you listened raptly, absorbing every word.

GT: Every word.

DD: Just so. It’s as if I transferred a gene for loving my book into your brain. It’s just like mating in bacteria: when two cells conjugate, one transfers some of its genes into the other. When it happens with ideas, I call it “thought-sex.”

GT: Thought-sex?

DD: Yes, but without the question mark—that’s a deleterious mutation you’ve made there. It does not faithfully transfer admiration of me into your nucleus Dorkins.

GT: Nucleus Dorkins?

DD: Again with the question mark! You must absorb my words exactly as your hear them, otherwise I am simply wasting my time.

GT: I am simply wasting my time.

DD: Good! Much better. By the way, if you’ll allow me a little digression (and you will), the nucleus Dorkins, a small but exceedingly important region of the brain, was described by my brilliant and—I damn it, it’s my interview, so I’ll say it—drop-dead gorgeous friend, the stunningly attractive and successful neuroscientist Andromeda Telekinesis. Anyone who says that women don’t belong in science doesn’t know Andromeda. She really pops off my pipette tip, as we used to say in the damp, dear labs at Oxbridge. Anyway, while having dinner with me one night, she discovered a nucleus in the brain that recognizes talent, wit, good looks, and achievement. And she decided then and there to name it after me. I protested, of course, but she would hear none of it. I was deeply humbled, and I say so every chance I get.

At any rate, I described my simulation in my book Unweaving the Basket. The original simply cannot be improved upon, so I shall quote. Eh-im!

I found that if I produced a memoir of staggering significance and touching sentimentality, and then had thought-sex with twenty beautiful, intelligent, influential women a day, conservatively assuming an intellectual fertility rate of fifty percent and a generation time of 24 hours, I should be able to buy that sweet little eight-person jet I’ve been eyeing in just nine months!

And do you know what? I flew here today in that very jet! That, my little friend, is the power of science.

GT: [sotto voce, sarcastically] Power of science. Pooh! [Aloud] About that…we received a call from the highway patrol and they are rather upset about the traffic jam your plane has caused on I-95. The interstates really aren’t meant to be used as runways.

DD: This is America, right? Let’s just call it a little experiment in the efficacy of prayer.

GT: With the establishment of SPITTOON, you have become one of the world’s most notorious atheists. Now, you are English by birth…

DD: —By right, damn it!

GT: Damn it! [regains composure] So my question is, why did you relocate to the United States when you founded SPITTOON?

DD: Death to America! Haha, that’s one of my wittle litticisms. But in all seriousness, I did so in order to infiltrate one of the most powerful fundamentalist states in the world. Through my ceaseless efforts of self-promotion, I have accumulated lit’rally thousands of followers who hang on my every word. My every word!

GT: Your every word?

DD: [eyes us suspiciously] Yyess. [brightens] So. I liken what I do to a kind of genetic engineering of the mind. By having thought-sex with my followers, I am indoctrinating them into the doctrine of de-indoctrination, if you will. Then they go out and explode others’ mistaken beliefs. I call them “suicide bombers of the soul.”

GT: [incredulously] Suicide bombers of the soul?

DD: [narrows eyes] Are you…?

GT: No.

DD: Good. Because if you are…

Off mike: Boss? Ever’tin’ OK? [sound of knuckles cracking]

DD: For the moment, Vinny, yes, thank you.

GT: I assure you, I would never. It’s just…isn’t that a little…inflammatory?

DD: You can’t start a forest fire without burning a few trees, what!

GT: How is that working out for you?

DD: Funnily enough, a recent independent survey by one of my graduate students found that religious fervor and hate crimes have tended to increase in towns with SPITTOON chapters compared to the general population.

GT: That ought to make you think, I imagine.

DD: Absolutely right, old sod! It makes me think, “What a wonderful confirmation of our wisdom in targeting the most populations with the most entrenched religious problems.” We are right where they need us!

GT: What about in East Carolina, where the young man blew himself up, killing two young Muslims, and citing your influence in his suicide note?

DD: Mm, unfortunate, that. Wasn’t meant to be taken quite so lit’rally. But my followers are passionate people! They believe in disbelief!

GT: Unbelievable. I’d like to go back a bit now, to a different crusade: the so-called sociobiology wars of the 1980s. What exactly was your beef with scientists such as Popinjay Gould?

DD: As I wrote in what I consider my least-appreciated book, The Gould Delusion, they made one of the classic errors of science: they let their ideology color their work. They believed things and then did science, instead of doing science and then knowing things, as I do.

GT: So you bring no beliefs, no values, no opinions whatsoever to your science?

DD: Positively not! I have no beliefs—only certainties.

GT: Have you ever changed your mind on anything?

DD: Nope. Wait a minute—yes. I do remember once back when I was an undergraduate. My philosophy professor was introducing us to Einstein’s concept of gedankenexperimenten—that’s “thought experiments,” for the philistines in the audience—and mine was to try to change my mind. I halfway succeeded for a moment, but then my mind snapped back again, like the steel trap that it metaphorically is. I was just too strong for myself, haha!

GT: [sound of hand slamming table] Right. That’s enough. This conversation is repetitive, pointless, and vacuous. You’re just smugly self-indulgent and vain, and you keep bashing away at the one or two really original things you’ve ever said, thirty years ago.

[Enter VINNY SMALLCHANGE, a 350-lb. bouncer, in black suit, dark glasses, and with suspicious bulge in his pants.]

VS: Just too strong for myself. Hey-uh, Dr. Dick. Dis guy botherin’ ya? I can take his microphone from his mout’ and insert it in another orifice, if y’ get my drift.

DD: What a brilliant analysis, Vinny! Bravo! But I’m afraid I cannot stand by and watch violence carried out, especially on my behalf. So I’ll just turn around and inspect this utterly fascinating fly on the wall there…

GT: Ha. Ha. Well! Look at the time. I’m afraid we’re going to have to wrap up. Dr. Dick, I’d like to thank you for being on Sideline. G’bye!

DD: It’s been a pleasure having me.

VS: […]

The preceding is for entertainment purposes only. Any resemblance to vertebrates living or fossilized is completely coincidental.

Top 10 Things I Learned From Reviewing Richard Dawkins

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10) Links between genetic determinism and white supremacy remain strong.

9) The staunchest Dawkins followers got nothin’.

8) Wasps are brainless but extremely aggressive.

7) Opinions on Dawkins split down party lines as neatly as a Congressional vote.

6) Saying, “So, chill” is defensive.

5) When they like you, it’s good writing. When they don’t, it’s “rhetoric.”

4) Fundamentalist atheists HATE being called that. So do it early and often.

3) Incredibly, even an atheist with postgraduate work in ecology and evolution can still be a church-kissing, climate-change-denying reactionary one step to the left of Mike Huckabee.

2) Lay back and let your friends and your enemies duke it out.

1) It is important to log off Twitter with the same number of fucks you logged in with.

Through a candle, darkly

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Dull, dull, dull, my God it’s dull! It’s so desperately dull and tedious and stuffy and boring and des-per-ate-ly DULL! —Michael Palin

Nature has posted my review of Brief Candle in the Dark, the bloated second volume of memoir by  Richard Dawkins, everyone’s favorite genetic determinist. Nature is very genteel–and they have very strict lawyers–so my temper is muted.

Still, the gist should come across. It reads, frankly, like he contracted for two books but, incomprehensibly, just got bored with writing about himself.

Perhaps the review may provoke a smile–or a scowl, if you’re of that genotype.

Enjoy!