The Villain of CRISPR

There is something mesmerizing about an evil genius at the height of their craft, and Eric Lander is an evil genius at the height of his craft.

Lander’s recent essay in Cell entitled “The Heroes of CRISPR” is his masterwork, at once so evil and yet so brilliant that I find it hard not to stand in awe even as I picture him cackling loudly in his Kendall Square lair, giant laser weapon behind him poised to destroy Berkeley if we don’t hand over our patents.

This paper is the latest entry in Lander’s decades long assault on the truth. During his rise from math prodigy to economist to the de facto head of the public human genome project to member of Obama’s council of science advisors to director of the powerful Broad Institute, he has shown an unfortunate tendency to treat the truth as an obstacle that must be overcome on his way to global scientific domination. And when one of the world’s most influential scientists treats science’s most elemental and valuable commodity with such disdain the damage is incalculable.

CRISPR, for those of you who do not know, is an anti-viral immune system found in archaea and bacteria, that until a few years ago, was all but unknown outside the small group of scientists, mostly microbiologists, who had been studying it since its discovery a quarter century ago. Interest in CRISPR spiked in 2012 when a paper from colleagues of mine at Berkeley and their collaborators in Europe described a simple way to repurpose components of the CRISPR system of the bacterium Streptococcus pyogenes to cut DNA in a easily programmable manner.

Such capability had been long sought by biologists, as targeted DNA cleavage is the first step in gene editing – the ability to replace one piece of DNA in an organism’s genome with DNA engineered in the lab. This 2012 paper from Martin Jinek and colleagues was quickly joined by a raft of others applying the method in vivo, modifying and improving it in myriad ways, and utilizing its components for other purposes. Among the earliest was a paper from Le Cong and Fei Ann Ran working at Lander’s Broad Institute which described CRISPR-based gene editing in human and mouse cells.

Now, less than four years after breaking onto the gene-editing scene, virtually all molecular biology labs are either using, or planning to use, CRISPR in their research. And amidst this explosion of interest, fights have erupted over who deserves the accolades that usually follow such scientific advances, and who owns the patents on the use of CRISPR in gene editing.

The most high-profile of these battles pit Berkeley against the Broad Institute, although researchers from many other institutions made important contributions. Jinek’s work was carried out in the lab of Berkeley’s Jennifer Doudna, and in close collaboration with Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin; while Cong and Ran were working under the auspices of the Broad’s Feng Zhang. Interestingly, the prizes for CRISPR have largely gone to Doudna and Charpentier, while, for now at least, the important patents are held by Zhang and the Broad. But this could all soon change.

There has been extensive speculation that CRISPR gene editing will earn Doudna and Charpentier a Nobel Prize, but there has been considerable lobbying for Zhang to join them (Nobel Prizes are, unfortunately, doled out to a maximum of three people). On the flip side, the Broad’s claim to the patent is under dispute, and is the subject a legal battle that could turn into one of the biggest and most important in biotechnology history.

I am, of course, not a disinterested party. I know Jennifer well and an thrilled that her work is getting such positive attention. I also stand to benefit professionally if the patents are awarded to Berkeley, as my department will get a portion of what are likely to be significant proceeds (I have no personal stake in any CRISPR-related patents or companies).

But I if I had my way, there would be no winner in either of these fights. The way prizes like the Nobel give disproportionate credit to a handful of individuals is an injustice to the way science really works. When accolades are given exclusively to only a few of the people who participated in an important discovery, it by necessity denies credit to countless other people who also deserve it. We should celebrate the long series of discoveries and inventions that brought CRISPR to the forefront of science, and all the people who participated in them, rather than trying to decide which three were the most important.

And, as I have long argued, I believe that neither Berkeley nor MIT should have patents on CRISPR, since it is a disservice to science and the public for academic scientists to ever claim intellectual property in their work.

Nonetheless, these fights are underway. Which beings us back to Dr. Lander. Although he had nothing to do with Zhang’s CRISPR work, as Director of the Broad Institute, he has taken a prominent role in promoting Zhang’s case for both prizes and patent. But rather than simply go head-to-head with Doudna and Charpentier, Lander has crafted an ingenious strategy that is as clever as it is dishonest (see Nathaniel Comfort’s fantastic “A Whig History of CRISPR” for more on this). Let’s look at the way Lander’s argument is crafted.

To start, Lander cleaves history into two parts – Before Zhang and After Zhang – defining the crucial event in the history of CRISPR to be the demonstration that CRISPR could be used for gene editing in human cells. This dividing line is made explicit in Figure 2 of his “Heroes” piece, which maps the history of CRISPR with circles representing key discoveries. The map is centered on a single blue dot in Cambridge, marking Zhang as the sole member of the group that carried out the “final step of biological engineering to enable genome editing”, while everyone who preceded him gets labeled as a green natural historian or red biochemist.

(Note also how he distorted the map of the world so that the Broad lies almost perfectly in the center. What happened to Iceland and Greenland? How did Europe get so far south and so close to North America? And what happened to the rest of the world? Where’s Asia, for example? Shouldn’t there be a big blue circle in Seoul?)

While some lawyer might find this argument appealing, it is a scientifically absurd point of view. For the past decade, researchers, including Zhang, have been using proteins – zinc finger nucleases and TALENs – engineered to cut DNA in specific places to carry out genome editing in a variety of different systems. If there was a key step in bringing CRISPR to the gene editing party, it was the demonstration that its components could be used as a programmable nuclease, something that arose from a decade’s worth of investigation into how CRISPR systems work at the molecular level. Once you have that, the application to human cells, while not trivial, is obvious and straightforward.

The best analogy for me is the polymerase chain reaction (PCR) another vital technique in molecular biology that emerged from the convergence of several disparate lines of work over decades, and which gained prominence with the work of Kary Mullis, who demonstrated an efficient method for amplifying DNA sequences in vitro. Arguing that Zhang deserves singular credit for CRISPR gene editing is akin to arguing that whomever was the first to amplify human DNA using PCR should get full credit for its invention. (And I’ll note that the claim that Zhang was unambiguously the first to do this is questionable – see this and this for example).

I want to be clear that in arguing against giving exclusive credit to Zhang, I am not arguing for singular credit to go to any other single group, as I think this does not do justice to the way science works. But if you are going to engage in this kind of silliness, one should at least endeavor to do it honestly. The only reason one would ever argue that CRISPR credit should be awarded to the person who first deployed it in human cells is if you decided in advance that full credit should go to Zhang and you searched post facto for a reason to make this claim.

Even Lander seems to have sensed that he had to do more than just make a tenuous case for Zhang – he had to also tear down the case for Doudna and Charpentier. And this wasn’t going to be easy, since their paper preceded Zhang’s, and they were already receiving widespread credit in the biomedical community for being its inventors. Here is where his evil genius kicks in. Instead of taking Doudna and Charpentier on directly, he did something much more clever: he wrote a piece celebrating the people whose work had preceded and paralleled theirs.

This was an evil genius move for several reasons:

First, the people whose work Lander writes about really are deserving of credit for pioneered the study of CRISPR, and they really have been unfairly written out of the history in most stories in the popular and even scientific press. This established Lander as the good guy, standing up to defend the forgotten scientists, toiling in off-the-beaten-path places. And even though, in my experience, Doudna and Charpentier go out of their way to highlight this early work in their talks, Lander’s gambit makes them look complicit in the exclusion.

Second, by going into depth about the contributions of early CRISPR pioneers, Lander is able to almost literally write Doudna and Charpentier (and, for that matter, the groups of genome-editing pioneer George Church and Korean scientist Jin-Soo Kim, whose CRISPR work has also been largely ignored) out of this history. They are mentioned, of course, but everything about the way they are mentioned seems designed to minimize their contributions. They are given abbreviated biographies compared to the other scientists he discusses. And instead of highlighting the important advances in the Jinek paper, which were instrumental to Zhang’s work, Lander focuses instead on the work of Giedrius Gasiunas working in the lab of Virginijus Siksnys in Lithuania. Lander relates in detail how they had similar findings to Jinek and submitted their paper first, but struggled to get it published, suggesting later in the essay that it was Doudna and Charpentier’s savvy about the journal system, and not their science, that earned them credit for CRISPR.

The example of Gasuinas and Siksnys is a good one for showing how unfair the system we have for doling out credit, accolades and intellectual property in science can be. While Gasuinas did not combine the two RNA components of the CRISPR-Cas9 system into a single “guide RNA” as was done by Jinek – a trick used in most CRISPR applications – they demonstrated the ability to reprogram CRISPR-Cas9, and were clearly on the path to gene editing. And neither Jinek or Gasuinas’s work would have been possible without the whole body of CRISPR work that preceded them.

But the point of Lander’s essay is not to elevate Siksnys, it is, as is made clear by the single blue circle on the map, to enshrine Zhang. His history of CRISPR, while entertaining and informative, is a cynical ploy, meant to establish Lander’s bonafides as a defender of the little person, so that his duplicity in throwing Siksyns under the bus when he didn’t need him anymore wouldn’t be so transparent.

What is particularly galling about this whole thing, is that Lander has a long history of attempting to rewrite scientific history so that credit goes not to the forgotten little people, but to him and those in his inner circle. The most prominent example of this is the pitched battle for credit for sequencing the human genome, in which Lander time and time again tried to rewrite history to paint the public genome project, and his role in it, in the most favorable light. 

Indeed, far from being regarded as a defending of lesser known scientists, Lander is widely regarded as someone who plays loose with scientific history in the name of promoting himself and those around him. And “Heroes of CRISPR” is the apotheosis of this endeavor. The piece is an elaborate lie that organizes and twists history with no other purpose than to achieve Lander’s goals – to win Zhang a Nobel Prize and the Broad an insanely lucrative patent. It is, in its crucial moments, so disconnected from reality that it is hard to fathom how someone so brilliant could have written it.

It’s all too easy to brush this kind of thing aside. After all Lander is hardly the first scientist to twist the truth in the name of glory and riches. But what makes this such a tragedy for me is that, in so many ways, Lander represents the best of science. He is a mathematician turned biologist who has turned his attention to some of the most pressing problems in modern biomedicine. He has published smart and important things. As a mathematician turned biologist myself, it’s hard for me not to be more than a little proud that a math whiz has become the most powerful figure in modern biology. And while I don’t like his scientific style of throwing millions of dollars at every problem, he has built an impressive empire and empowered the careers of many smart and talented people whose work I greatly value and respect.

But science has a simple prime directive: to tell the truth. Nobody, no matter how powerful and brilliant they are is above it. And when the most powerful scientist on Earth treats the truth with such disdain, they become the greatest scientific villain of them all.