Golden opportunity

The fabled Karolinska Institutet (KI). To anyone involved with science in the last century or so, that name springs to the mind’s eye plated with the gold of the Nobel Prize. It conjures images of elegant, wealthy Stockholm, a supermodel of a city: cold to the touch, remote, yet gifted with such stunning beauty, elegance, and wealth that it almost seems unfair, hoarded. Is has the glamor and pomp of royalty, the self-confidence (and cost of living) of New York, yet the cozy social democracy that provides reliable, clean public transportation and schools.

The KI is Stockholm’s crown jewel. Every December, Nobel week transforms almost the entire city into an opulent, charming celebration of science. Historians of science know that the curtain before the prize archives moves slowly forward, revealing the nominations and evaluations of individual laureates fifty years after the prize is awarded. The Chemistry and Physics prize archives are maintained at and administered by the Royal Swedish Academy of Sciences. The Physiology or Medicine archives and prize, however, are administered by and housed at the Nobel Forum, a separate entity on the Karolinska campus. Alfred Nobel constructed an administrative architecture designed to maintain the integrity of his prizes, but the result is Byzantine.

Like the Rockefeller University or the PhD program at Cold Spring Harbor Laboratory, the Karolinska is all science. Almost. They do have a small staff of trained, credentialed historians, who work at the Hagströmer Medico-Historical Library, a medium-sized yet rich collection—larger than Johns Hopkins now, yet much smaller than London’s Wellcome Library)—yet rich collection that focuses on works from the sixteenth through the early nineteenth centuries. Located in a nineteenth century building that was, until recently, a courthouse. The facilities are solid with stone, warmed with wood, and softened by thick rugs.

In May, I had the great fortune to both work in the Nobel Forum archive and to be a guest at the Hagströmer Library. Both were thanks to the effort, persistence, and generosity of Eva Åhren a historian of science and medicine and now the head of the Unit for Medical History and Heritage, which includes the library and also houses a number of scholars in medical history,

Hagströmer

The old courtroom at the Hagströmer Library

I first gave the Hagströmer Lecture, a public talk, sponsored by the Friends of the Hagströmer Library, to showcase the value of historical studies of science and demonstrate their relationship to both current science and current events. My lecture, based on my last book, was titled “From medical genetics to genomic medicine.” The main argument is that a medical-eugenic thread runs through Progressive-era eugenics all the way through the birth of medical genetics and the emergence of modern personalized genomic medicine. Thus, the “old, bad eugenics” was less hostile to medicine than scholars have thought—and contemporary medical genetics and genomics have a stronger connection to human population improvement than most of us are comfortable acknowledging. I’ve never seen much intellectual value in making people comfortable.

The lecture took place in what is certainly the most beautiful venue in which I have ever given a talk. It was in the former main courtroom, built on a circular plan, now lined with old books, and lit by a vast picture window that admitted the long Swedish evening throughout the lecture and the following reception.

Judging from the audience and the questions, we got the attention of the Karolinska scientists and some of the intellectual public of Stockholm. After the lecture, we had a luxuriously long question-and-answer period, in which scientists and laypeople alike peppered me with thoughtful questions on everything from the history of European eugenics to CRISPR and the possibility of designer babies. Near the end, Eva and I had a fun one-on-one conversation—a sort of scholarly stand-up routine—about the value and the need for historical studies of science. My argument, as regular readers will know, is that the more dominant science becomes in our culture, the more we need historians to help interpret it. The sciences and the humanities are not—or should not be—in competition. It’s more like human evolution: the better your fine motor skills become, the more valuable it is to have a well-developed prefrontal cortex to aid in planning, strategizing, choosing future options.

Dumanski and me

Ms Dumanski and me, at the podium where they announce the prize. You see? She’s actually very nice!

Having sung, I then had my scholar’s supper: Eva was pivotal in arranging for me to work in the Nobel Forum archives. The entire Physiology or Medicine prize, from sending out the nomination forms to organizing and hosting the meetings of the Nobel Committee, to arranging the banquet is done by three full-time staff. There is no trained archivist, even part-time. The administrator Ann-Marie Dumanski is gatekeeper to the archive and the Nobel Forum. By necessity, one of her principal jobs is to keep out the kooks and riff-raff. Not even my Johns Hopkins and Library of Congress affiliations satisfied her. For me to gain access, we had to persuade her that I was not a loony.

 

The fierce Ms Dumanski was in a good mood. Indeed, she was warm, welcoming, even chatty. Before handing over the documents I had requested, she regaled us with stories from her years there. The Nobel Prize is not the richest prize in science, but, thanks in large measure to Marie Curie, who won it twice (in 1903 and 1911) it is the most famous and the most prestigious. Some people will do almost anything to get one. They forge nominations. They show up at the front door with their inventions, saying, “I can haz Nobel Prize?” One man mailed them a generic silver trophy, on which he had had engraved:

Nobel Peace Prize

Nature             Science

Awarded to [his name]

The cover letter simply asked that they return the cup to his address, registered mail. That way, he could say, truthfully, that he had received a Nobel prize from the Karolinska Institute! Ms Dumanski said, “That cup will never leave this building!” I began to understand why she needs to be so protective.

Nobel table

Where the Knights of the Nobel (in Physiology or Medicine) congregate

The documents themselves were rich and fascinating. I was looking at the prize for the double helix, to James Watson, Francis Crick, and Maurice Wilkins in 1962. I received every nomination they received (which spanned 1960, 1961, and 1962), as well as some of the evaluations conducted by members of the Nobel committee. You will have to wait for the book for all the details, but the story behind this prize is a good deal more complicated than the histories thus far have told. Maurice Wilkins has a much more interesting role than has been acknowledged, as does Laurence Bragg, the director of the Cavendish Institute, where Watson and Crick (but not Wilkins) worked. This in turn has implications for the social history of DNA, such as Watson’s treatment of Wilkins and Rosalind Franklin in his best-selling book, The Double Helix. Looking at the nominations, one would have expected Watson and Crick to win the prize in Chemistry, not Physiology or Medicine. Nearly all their nominations were in Chemistry—and most did not include Wilkins. But Wilkins had a strong partisan on the Nobel committee, and Bragg and Arne Tiselius (the head of the committee) played a good deal of politics. It is not a coincidence that the Chemistry prize went to two other Cavendish scientists who worked with X-ray crystallography: Max Perutz and John Kendrew. It was a red-letter day for X-ray work, for the Cavendish, and for Bragg.In all, it was an exhilarating trip.

Linnaeus

Linnaeus’s house

I haven’t even mentioned the jaunt up to Uppsala before Stockholm, in which I stayed next to Linnaeus’s garden, gave another talk, on DNA, to the history of science colloquium, and saw some of the sights of this charming old university town. These events were organized by another good friend and colleague, Maria Björkman. Maria also did me the indispensable favor of arranging for a graduate student, Felicia Edvardsson, to assist me by translating the Swedish evaluations.
I’ll admit, there was a bit of glamor to the trip. At the Hagströmer, I felt a slightly embarrassing surge of pride as I came onstage via the small back door through which the judge once entered the courtroom from his chambers. At the Nobel Forum, Ms Dumanski allowed me to sit at the seven-meter-diameter table, carved from a single piece of wood, where the Nobel committee deliberates the prizes, and let me stand at the podium where the prize is announced every October. We took a ferry that entered Stockholm harbor—for centuries, the primary way one arrived in Stockholm—with its grandly imposing buildings on full display. These moments are folded now into my life’s narrative, among the colorful stories with which one can bore one’s grandchildren.

UppsalaCathedral

Uppsala cathedral makes you believe in *something.*

Most important and valuable, though, were the opportunities to be a real historian: tracking down and poring over difficult-to-obtain documents; discussing both history and the value of history with scientists and the public; and spending time with generous and intelligent colleagues who are also friends.

This was not “collegiality,” the canned concept, often paired with “interdisciplinarity,” that is rife in university mission plans and which largely stands for not pissing anyone off. My experience in Sweden, however, was collegiality without quotation marks. It was the real deal: the genuine mutual affection, the shared joy of working with ideas, books, manuscripts, and past actors, the dedication to humanistic values that is eroding so quickly in today’s neoliberal university.

One can still find pockets of true collegiality. When we do find it, we need to enjoy every second.

The Whig interpretation of the gene

I have an essay in the June issue of The Atlantic, out online now and at your favorite magazine dealer or airport in a week or so.

It’s an essay review centered around Siddhartha Mukherjee’s newest book, The Gene. The book is part history of genetics and part discussion of current genetic science and medicine. Scientists don’t seem to like the latter too well. An article, based on the book, that appeared in the New Yorker earlier this spring, is receiving a great deal of criticism from the scientific community. They say that the piece badly misrepresents the mechanisms of epigenetics.

I take him to task on his history. I use the book as the base for a discussion of “Whig history” and why it is so dangerous when writing about science. Whig history, crudely, is writing about the past from the perspective of history’s winners; it is history as a justification of the present.

Good, critical history of science is vital to doing good science on a community scale. Only when we understand that “the” gene is a human concept that describes a bit of biology in a particularly productive way, can we harness the full power of genetic knowledge for good.

Take a look!

 

For once, I didn’t wince

Did an interview on CRISPR and eugenics with Amanda Smith of The BodySphere, a radio program from ABC Australia. It’s probably the first interview I’ve done that didn’t make me wince when I listened to it!

http://www.abc.net.au/radionational/programs/bodysphere/new-eugenics:-designer-bodies/7274992

Assessing the ethics of CRISPR

The Nuffield Council on Bioethics has issued an open call for evidence to inform its examination of ethical issues arising in relation to genome editing. “Submission of evidence” is defined broadly, and includes opinions, reflections, and suggestions. No flames or trolls though, obviously.

The deadline to respond is Monday, 2/1, it’s recommended that it’s roughly 2000 words if submitted in writing, and it needs to be accompanied by this form: http://nuffieldbioethics.org/wp-content/uploads/NCOB_GenomeEditing_response-form.docx.

The Council has posed a number of questions pertaining to human biomedical applications. The Center for Genetics and Society is composing a response and has shared with me this distilled guide to the Council’s questions. If any of you are inclined to make your voice heard on one of the most prominent biotechnical issues today, I encourage you to use this guide in drafting your own submission.

General Questions:

  • Information: references, especially recent or unpublished information & current or planned research or applications; other sources of information that we should consult?
  • Opinion: What are the rates and direction of travel, likely applications and timescales? What is on the scientific horizon and what is (currently) science fiction?
  • Insight:
    • What are the relevant perspectives and the issues they foreground?
    • Are any perspectives unfairly marginalised?
    • How are different actions and outcomes valued, and on what basis?
    • Using what frames of reference and systems of values might we understand and respond to genome editing?
  • Evaluation:
    • What are the potential benefits and to whom do those benefits accrue?
    • What are the potential risks and adverse effects, and how are those risks and effects likely to be distributed?
    • How are we to identify and evaluate the scale and significance of those benefits and risks in relation to each other?

Specific Questions:

CRISPR & the Genome: the BioTechnological Continuum

  • Is CRISPR transformative or disruptive of the field of genetic engineering? Is it continuous? Should it be treated separately? What is its distinctive significance?
  • Is the Human Genome categorically different or special in ways that make intervening into it different from other ways of manipulating nature (e.g. selective breeding of plants, animals)?

Duties Owed & Rights

  • What obligations do scientists developing genome editing technologies owe to society?
  • What freedoms does/should society owe/allow to scientists?
  • What obligations do governments owe to society to ensure “safe” science or shape R+D?

Morality

  • What conventional moral principles does genome editing challenge?
  • What moral or legal frameworks are necessary or desirable to ensure adherence to moral principles?
  • What are the issues of greatest moral concern raised by genome editing?

Justice & Access

  • What is the proper context in which to evaluate the pursuit of high tech strategies and high ambition clinical objectives in relation to possible alternatives and opportunity costs?
  • Are the benefits and costs of treatment likely to be distributed equitably? How would genome editing differentially affect vulnerable or marginalised groups?

Evaluation Frameworks

  • Biomedical Apps at Issue: Germline Intervention, Gene Therapy & Xenotransplantation
  • In translating research into treatment, does genome editing raise any special considerations (such as: assessment, risk management, who should assess safety and accessibility)?
  • In setting policy for research and applications, who should lead and who should be involved? Different than other experimental or reproductive biomedicines?
  • What are the significant decisions that need to be taken before therapeutic use of (somatic or germline) genome editing may be contemplated and who should have the responsibility for those decisions?
  • Who is framing the global debate and what is the importance attached to global consensus?

 

 

 

 

Criticism of Lander reaches mainstream media

Sometimes the Whigs get called on the carpet. Carolyn Johnson summarized the kerfluffle over Lander’s history of CRISPR in today’s Washington Post. “The tweetstorm erupted,” she writes,

when the leader of an institution vying for control of the technology published a lengthy historical account of CRISPR in a top scientific journal, an account that one critic (who happens to work at the opposing institution) described as erroneous “propaganda.”

To critics, the big problem is that “Heroes of CRISPR” is a history told by a person with a dog in the fight over who created it. The author, Eric Lander, is head of the Broad Institute, a Harvard- and MIT-affiliated research institution that is now in an all-out patent battle against the University of California, Berkeley, with hundreds of millions of dollars on the line.

To put this in perspective for non-scientists, Lander is a powerful voice in the field — a former leader of the human genome project, a co-chair of the committee that advises President Obama on science and technology matters, and a charismatic communicator who has turned his institution from a start-up to a massive research heavyweight over a decade. In other words, he is influential and people read his work, including this paper.

Whig history is all about who gets to control a historical narrative. For to some extent, it is to the one who controls the history to whom go the spoils—in this case, potentially a winner-take-all patent that could be worth billions, as well as lucrative and glorious prizes, awards, and honors. Nominators for those prizes will write their nominations with a narrative in their minds. Whatever becomes crystallized as “the” history will invariably shape how credit is attributed. I have watched people “campaign” for Nobels and then win them.

I find it impossible to avoid reading Lander’s seemingly generous history of CRISPR as a canny attempt to strip credit from the Broad Institute’s principal competitors, Jennifer Doudna and Emmanuelle Charpentier. It seems inconceivable that the fact that it ran in Cell just days before a judge filed an interference (conflict between two patents) between the Broad’s Feng Zhang and Doudna/Charpentier is mere coincidence.

It would be nice to think that those of us who howled at Lander’s history ran a little interference of our own. Once again, credit is due to Michael Eisen for bringing my attention to the matter, and thanks to everyone else who also cried “Foul!”

Landergate: a link list

Lander’s article has spawned further commentary, as well as raising afresh the general issue of the CRISPR patents. I’ll try to keep a running list. I’ll include links from yesterday’s post for completeness. If I miss any posts or articles, post it in a comment and I’ll add it.

  • Here’s an article from Nature, Jan. 12, on the heating up of the CRISPR patent battle.
  • …and one from The Scientist.
  • …and one from Antonio Regalado over at MIT Tech News.
  • Interesting how Lander’s history in Cell coincided with a clutch of articles in other journals, hm?
  • Storify of (some of) Michael Eisen’s tweets about Lander’s article.
  • Included in yesterday’s post, there has been vigorous discussion at PubPeer.
  • As noted at the end of yesterday’s post, here’s Dominic Berry on the intellectual-property issues involved.
  • Derek Lowe, over at Science Translational Medicine, asks “Why this CRISPR article now?
  • KQED in the Bay Area has a useful article on some of the legal brambles in the CRISPR story.
  • In “‘Heroes of CRISPR’ disputed,” The Scientist notes that not only Jennifer Doudna but even George Church have cited factual errors in Lander’s account. While Doudna says she wasn’t consulted, Church says he was, that he responded, and that none of the errors he pointed out were corrected.
  • A longread from Yarden Katz asks, “Who owns molecular biology?” Nice setting of the patent dispute in historical context, going back to Bayh-Dole.
  • And by the by, here’s the Broad’s official statement on the patent interference process.
  • Michael Eisen is collecting “evidence that Eric Lander serially rewrites scientific history”  under the delightful hashtag #LandersWhigHistory.
  • Nice post mortem over at MIT Technology Review.
  • 1/19: Emmanuelle Charpentier added her own brief rebuttal on PubMed Commons.
  • 1/20: Jennifer Oullette, over at Jezebel, accuses Lander of “writing women out” of the history of CRISPR. I agree that’s the effect, but there’s no reason to believe it was his motivation. Doudna and Charpentier are his major competitors. He’d have done the same if his rivals were named John and Emanuel.

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—now often lower-cased to distance itself from the particularities of British politics—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 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:

Screen Shot 2016-01-18 at 10.38.28 AM

Screen Shot 2016-01-18 at 10.40.57 AM

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.

Screen Shot 2016-01-18 at 10.38.53 AM

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:

Screen Shot 2016-01-18 at 10.45.59 AM

Doudna and Charpentier go neck and neck with Siksnys through the next sections, but Doudna and Charpentier’s contributions are repeatedly diminished. “Sisnysys submitted his paper,” begins one paragraph. At the end of the paragraph Doudna and Charpentier’s paper receives mention. “Both groups clearly recognized the potential for biotechnology,” Lander writes.

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. 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.

I think Eisen has a point, therefore, 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.

Update 1/19: Both Doudna and Church have said the 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? Zhang, Church, and Doudna? Zhang, Church, and Mojica? 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 matters.

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/