Balance, Fairness and Accuracy – a CRISPR Primer

Harvard University’s search for a new president, just now entering its final stages, is a great story.  The stakes could scarcely be higher – not just for the university but for Boston as a global center of learning.

After two troubled presidencies, those of Neil Rudenstine and Lawrence Summers, and a third devoted mostly to restoring civility and calm. The university needs a leadership of a different sort. Historian Drew Faust, who replaced Summers in 2007, notified Harvard’s governing board last year that she wishes to retire this summer.

Harvard’s undergraduate newspaper, The Crimson, has done a wonderful job of keeping readers abreast of the search. In December the Crimson reported the list had been narrowed to fewer than twenty names.

Next, Medical School Dean Gregory Daley, venturing a widely-shared opinion that the university should be led by a scientist, mentioned four life scientists he “expects” are on the list. He named Broad Institute President Eric Lander, a geneticist; physician and University of Michigan President Mark Schissel; World Bank President and former Dartmouth College President Jim Yong Kim; and Harvard Provost Alan Garber, a physician and economist. Ten days later, citing “prominent donors and professors,” The Crimson added three internal candidates to its list, Harvard Business School Dean Nitin Nohiria; Dean of Arts and Sciences Michael Smith; and Government professor Danielle Allen.

The newspaper established a pattern based on the search ten years ago:  the search committee – all twelve members of the corporation and three representatives of the alumni Board of Overseers – spend July and August gathering information about candidates and forming opinions about the state of the university. They travel widely in the autumn, mostly calling on top administrators of other universities. A shortlist is prepared, and in January and February the committee interviews a handful of candidates before making a final decision.  Members of the committee convened amid great secrecy two weeks ago at the home of a committee member in suburban Belmont, The Crimson reported.

Meanwhile, a cultural plot line is playing out behind the scenes: Puritan probity vs. Silicon Valley hustle and TED talk hype.

In ordinary circumstances, Lander, 60, would be the hands-down favorite for the Harvard job.  His career has been spectacular – and difficult to summarize. A Princeton undergraduate (who took John McPhee’s celebrated writing course) and Rhodes Scholar, he earned a D. Phil in mathematics at Oxford University in 1981.  While teaching managerial economics at Harvard Business School in the 1980s, Lander taught himself molecular biology in the evenings and began collaborating with David Botstein, a professor of genetics at the Massachusetts Institute of Technology. In 1986 he became a fellow of MIT’s start-up Whitehead Institute, then a controversial experiment with making non-faculty appointments (several other universities, including Harvard and Duke, had turned it down). Four years later MIT’s Department of Biology made him a professor.

Since then, his short biography states, “Lander has played a pioneering role in all major aspects of the reading, understanding, and medical application of the human genome—including being one of the principal leaders of the international Human Genome Project from 1990 to 2003. Lander has also played an active role in public policy, including serving as co-chair of the President’s Council of Advisors on Science and Technology from 2009 to 2017.” As the Human Genome project wrapped up, he founded in 2004 the Broad Institute, an MIT/Harvard collaboration, today involving some 4,000 persons, including 300 faculty. Along the way, he was involved in founding several biotech firms, including Millennium Pharmaceuticals and Foundation Medicine.

Lander was among those on the shortlist in Harvard’s last search, according to The Crimson, but under the circumstances it would have been awkward to replace one wunderkind with another. This time it would have been easy – except for the row that erupted two years ago after Lander published an article, The Heroes of CRISPR (that term being an acronym for clustered interspaced short palindromic repeats) in the journal Cell. Its summary begins:

Three years ago, scientists reported that CRISPR technology can enable precise and efficient genome editing in living eukaryotic cells. Since then, the method has taken the scientific community by storm, with thousands of labs using it for applications from biomedicine to agriculture. Yet the preceding 20-year journey – the discovery of a strange microbial repeat sequence; its recognition as an adaptive immune system; and its repurposing for genetic engineering – remains little known. This Perspective aims to fill in this backstory – the history of ideas and the stories of pioneers – and draw lessons about the remarkable ecosystem underlying scientific discover.

Thereupon Lander launches into a tale of “serendipity and planning, of pure curiosity and practical application,” that reads like high-grade magazine journalism while simultaneously serving as well as insider’s guide to various priority claims for having arrived at the current state of affairs — never mind the gigantic patent fight over CRISPR methods that has developed. For readers who are curious about the origins of a tool that seems to offer the power to tinker with human evolution, there can’t be a better primer – never mind who wins the patent fight.  There is a timeline summary of Lander’s narrative on the Broad site for experts who want to cut to the chase.

The reception?  An Internet firestorm, from those who accused Lander of interfering with a patent fight from which his Broad Institute stands to gain. See STAT’s Why Eric Lander morphed from science god to punching bag for a recap. For those who don’t know it, STAT is a web-based John Henry startup, edited by former New York Times assistant managing editor and Politico executive editor Rick Berke. Its lively stories about health, medicine, and the life sciences often appear in The Boston Globe, which Henry also owns.

“Science can be a blood sport,” Duke University science historian and policy expert Robert Cook-Deegan told STAT’s Sharon Begley. “This seems to be one of those times.” The greatest anger, Begley wrote, was to be found among “critics [who] charged that rather than writing an objective history he downplayed the role of two key CRISPR scientists who happened to be women.” The Crimson’s take at the time: Geneticist Embroiled in Conflict of Interest Controversy.

Since then Science, the authoritative magazine of the American Association for the Advancement of Science, has described  The Birth of CRISPR Inc. (subscription required), zeroing in on the role of the two scientists who felt most slighted by Lander’s version of things.  The article began,

In early 2012, Emmanuelle Charpentier, a little-known French microbiologist who would soon meet worldwide fame, contacted her old friend Rodger Novak to tell him about her recent studies at Umeå University in Sweden of the mechanisms behind a novel bacterial immune system. “She said, ‘Hey, what do you think about CRISPR?’” recalls Novak, a biotech executive who more than a decade earlier had worked with Charpentier in academic labs studying antibiotic resistance. “I had no clue what she was talking about.”

It was only later that Novak learned that Charpentier, in collaboration with a prominent structural biologist, Jennifer Doudna of the University of California at Berkeley, had transformed the CRISPR immune system into a tool that could edit genomes with great ease. As they and colleagues noted in what has become a landmark Science paper, published online 28 June 2012, this tool had “considerable potential.”

Novak enlisted an old friend, Shaun Foy, a venture capitalist in Vancouver.  With Charpentier and Doudna,” they began speaking with others working on the CRISPR research frontier about starting a company. “We were, as far as I know, the first ones to really think of that and really try to put something together,” says Charpentier, who is now at the Max Planck Institute for Infection Biology in Berlin. They approached Harvard’s George Church and his former postdoc, Feng Zhang, by then of the Broad Institute. “We thought in the beginning it would be very important to bring everyone together,” Charpentier told Science reporter Jon Cohen. “One of the goals was to simplify the process of intellectual property,” she said.

Instead, Cohen wrote, “the attempt at unity collapsed—with a good deal of noise and dust.” Zhang, other researchers in Church’s lab, and, for that matter, Virginjus Siksnys, of Vilnius University, Lithuania, considered that they had prior claims. Three rival companies formed and promptly sued one another. Cohen summed up: “The community fractured as the tool became a business.”

Having read the various accounts, I decided to take a look at the issue in Cell in which Lander’s Perspective article appeared.  I knew that Doudna, a Berkeley professor and member of the National Academy of Sciences, had an article there as well.  It appeared just after Lander’s essay, and was described as a “review.”  Biology and Applications of CRISPR Systems: Harnessing Nature’s Toolbox for Genome Engineering contained none of the backstory on which Lander had dwelt. Instead it was a straightforward technical account of the powerful tools that had emerged in the previous three years from “the arms race between bacteria and bacteriophage [internalized viruses that disable bacteria]” through which adaptive immune systems had evolved. No layman could hope to understand the article, much less whatever overtones there were.

From the online record, I wasn’t able to tell what set the two articles in motion. Was Doudna’s a response to Lander’s submission, which zeroed in on the contributions of  Zhang, Church, and Siksnys, as well as her own?  The two scientists were in communication throughout, though Doudna has said that Lander failed to show her key passages his article. Joseph Caputo, a spokesman for Cell, whose editors have themselves been accused of favoritism by some, issued a statement at the time of the controversy’s firestorm phase.

We are well aware of the ongoing discussions regarding CRISPR patents and credit for different scientific contributions.

Attention to balance, fairness and accuracy were front and center for both the editors and the author throughout the consideration process.  The peer reviewers were specifically asked to comment on balance and fairness and any comments they provided back were addressed in revision. In addition the author [of “Heroes”] engaged in substantial fact checking directly with relevant individuals.

The other thing I found was a TED talk by Doudna in London in September 2015 – a veteran scientist in an unfamiliar setting, asserting that she, with her colleague Charpentier, had “invented a new technology… called CRISPR Cas9” a few years before;  calling attention to the extensive commercial possibilities in the offing; warning of the ethical  social issues involved;  urging a moratorium on the use  of tools on humans to create heritable traits – a not-so-subtle act of grandstanding, I thought, compared to the even-handed inquiry of the Lander article that appeared four months later. In other words, it seemed to me that the bitter controversy surrounding Lander’s attempt to tell the CRISPR story was a collective version what in sports they call a flop – an exaggerated if not downright feigned reaction to a supposed injury, designed to get the referee’s attention.

Let’s hope the Harvard search committee takes a broad view of the matter.  The controversy is not irrelevant to the search; it is in many ways the proof of the pudding.  In expressing an informed opinion on the patent tangle, Lander demonstrated the sort of civic leadership that Harvard seeks in its larger sphere. He’s done the same many times before. It would be a tragedy to lose him because he wrote a primer on the origins of the CRISPR tools.

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