Sensitive CRISPR diagnostics using RNA targeting CRISPR enzyme

0000-0002-8715-28960000-0003-0319-5416 I was recently involved in a collaboration between the Zhang and Collins labs at MIT to use the RNA-targeting CRISPR protein Cas13a/C2c2 to detect either DNA or RNA from pathogens. By combining the use of Cas13a/C2c2

Patents are destroying the soul of academic science

The soul of academic science is being destroyed, one patent at a time.

Nowhere is this more evident than in the acrimonious battle between the University of California and The Broad Institute of Harvard and MIT over who owns the rights to commercialize gene and genome editing systems based on the CRISPR  immune system of bacteria. There are a dizzying number of patents involved in this dispute, and many more players staking claims to what has the potential to be billions of dollars in royalties down the road. But the heart of the matter is rather simple.

UC claims it should own broad rights to CRISPR-based gene editing because UC Berkeley’s Jennifer Doudna and colleagues were the first to show how a protein (Cas9) from the bacterium Streptococcus pyogenes could be weaponized to permit the easy editing of DNA. (Full disclosure: I am a professor in Doudna’s department). The Broad counters that they should get the rights to the application of CRISPR-based gene editing in humans and other eukaryotes (which include all animals, fungi and plants – i.e. most of the organisms where there is money to be made) because, they assert, The Broad’s Feng Zhang was the first to demonstrate the use of Cas9 in eukaryotic cells.

Last week a panel of judges of the U.S. Patent Trial and Appeal Board sided with The Broad, finding that the application of CRISPR-based gene editing to humans and other eukaryotes was not an obvious extension of demonstrating the basic utility of the system, and hence constitutes a separate patentable invention.

I encourage you to read the judges’ decision. Far from being a descent into an arcane warren of patent law, as most people seem to expect, this case is very straightforward, resting on the simple question of whether the extension of CRISPR from bacteria and a test tube to human cells would have been expected to work by someone or ordinary skill and experience in the field. I don’t agree with the ruling, but the judges offer a lucid and very accessible account of what was presented to them and how they arrived at their decision.

While on the surface this case seems like a fairly mundane “I invented it first! No I did!” dispute, albeit with unusually large financial stakes, to me it represents something far more important: a battle for the very soul of academic science and the principles upon which it is based.

When I first heard, in 2012, that scientists in the Doudna lab had discovered that the Cas9 protein cuts DNA at a specific point based on instructions in a small piece of RNA, and that they had invented a way to simplify its application, I didn’t give a moment’s thought to patents. Instead I marveled that evolution, through the never ending fight between organisms and the viruses that plague them, had created a protein whose key properties were just what was needed to allow molecular biologist to easily edit the DNA of their favorite organism.

If academic science worked like it should we all would have spent the subsequent five years focused only on figuring out all the cool things we could do with this new toy – and there are a lot of cool things. But where we should have seen nothing but scientific opportunity, many saw dollar signs, and the flurry of CRISPR activity beginning in 2012 has become as much a patent gold rush as a journal of discovery.

The academic quest for patents is no longer the side story. Where once technology licensing staff rushed to secure intellectual property before scientists blab about their work, patents now, in many quarters, dominate the game. Experiments are done to stake out claims, new discoveries are held in secrecy and talks and publication are delayed so as not to interfere with patent claims. This is bad enough. But the most worrying trend has been the willingness of some researchers and research institutions to distort history, demean their colleagues and misrepresent the scientific process to support these efforts.

And while all of academia is complicit, The Broad Institute has taken the game to a new level. In 2015, as the patent fight was heating up, The Broad published a “CRISPR timeline” which defined history as ending with Feng Zhang’s demonstration of CRISPR gene editing in human cells. It also demoted the work from Berkeley to playing second fiddle to the work of Virginijus Siksnys’s group who, conveniently, did not have a competing patent claim.

The Broad set up a website describing their patent claims, which includes the following statement:

In April, 2014, the USPTO granted Patent No. 8,697,359 to Broad Institute, MIT and Dr. Feng Zhang. This Patent (which draws priority from a provisional patent application filed in December 2012) contained successful experiments.

Implying, absurdly, that the Berkeley application did not.

Then there was The Broad Institute Director Eric Lander’s widely derided “Heroes of CRISPR” essay in Cell which further rewrote history. Written under the conceit of giving credit to forgotten scientists, Lander wove a sweeping story of scientists toiling in obscurity until The Broad stepped in an made their work important. Doudna and her close collaborator Emmanuelle Charpentier were once again reduced to bit players in this narrative.

This was all clearly done as part of a public relations strategy to support their patent case, in which the assault on reality continued.

We can agree or disagree whether or not it was obvious that Cas9 would ultimately work in eukaryotic cells. The expert testimony shows that cogent arguments can be made on either side. But The Broad chose not to rely on cogent arguments. They had a trick up their sleeves. They scoured Jennifer Doudna’s public statements about the process of getting CRISPR to work in human cells, and found some where she appeared to be making The Broad’s case for them, which they submitted as evidence for their case and trumpet on their website.

For example, The Broad highlighted Doudna saying she experienced “many frustrations” in getting CRISPR to work in eukaryotic cells. But one can believe that it was obvious that CRISPR would work in eukaryotic cells, and still not expect that it would work the first time someone tried it or that the process would be free or frustration. Because that’s how science works! It is often difficult and frustrating – indeed it almost always is – even when you’re working on something that is obvious. Lander knows this. He was once a scientist. And yet he and The Broad are perfectly happy to misrepresent the scientific process to bolster their legal case.

A second quote featured by The Broad has Doudna saying “it was not known whether such a bacterial system would function in eukaryotic cells.” But this is an absolutely true statement that any good scientist would say even if they believed CRISPR would work in eukaryotic cells. In science something is not known until you demonstrate it. This is what any good scientist should say when they have yet to prove that something is true. By pretending that this is a statement about the patentability of CRISPR in eukaryotic cells, The Broad is once again misrepresenting the scientific process and condemning Doudna for little more than being a careful scientist and speaking honestly about it.

Is this the lesson we really want to learn from CRISPR? That scientists working in fields with commercial potential should never speak honestly about their work and the scientific process? That if they do they will get screwed over by someone unscrupulous who prioritizes winning patents and trains their scientists to behave like clandestine operatives rather than the public servants they really are?

By making the scientific process itself party to their legal case, Lander and The Broad are doing more than just securing victory in court; they are willfully undermining science for personal and institutional gain. If academics – including one of the most prominent academic scientists in the world – are willing to lie to promote their own and their institution’s financial interests, why should anyone believe anything they say? If there’s one thing that’s more dangerous than fake news, it’s fake science.

And it’s not just The Broad. While in this case UC’s defense of their CRISPR intellectual property could rely on a truthful account of its discovery, I have no doubt that they would be willing to resort to unsavory tactics and falsehood to secure victory (see their history of trying to coverup cases of sexual misconduct).

Sadly, there will always be venal and weak people in science – it is, after all, a human endeavor. But we do not need to feed them. As we decry The Broad’s behavior, we have to recognize its source – the transformation of academic science from an engine of discovery into a source of institutional and personal riches. And there is a simple way to reverse this trend: deny academic institutions intellectual property in their research and inventions.

Academic science is, after all, largely funded by the public. By all rights discoveries made on with public funds should belong to the public. And not too long ago they did. But legislation passed in 1980 – the Bayh-Dole Act – gave universities the right to claim patents on inventions made by their researchers on the public dime. Prior to 1980 these patents belonged to the federal government and many languished unused. The logic of Bayh-Dole was that, if they owned patents in their work, universities and other grantees would be incentivized to have their inventions turned into products, thereby benefiting the public.

But this is not how things worked out. Encouraged by a small number of patents that made huge sums, universities developed massive infrastructure to profit from their researchers. Not only do they spend millions on patents, they’ve turned every interaction scientists have with each other into an intellectual property transaction. Everything I get from or send to a colleague at another academic institution involves a complex legal agreement whose purpose is not to promote science but to protect the university’s ability to profit from hypothetical inventions that might arise from scientists doing what we’re supposed to do – share our work with each other.

And the idea that this system promotes the transformation of inventions made with public funding into products is laughable. CRISPR is a perfect case in point. The patent battle between UC and The Broad is likely to last for years. Meanwhile companies interested in actually developing CRISPR into new products are stymied by a combination of a lack of clarity about with whom to negotiate, and universities being difficult negotiating partners.

It would be so much easier if the US government simply placed all work arising from federal dollars into the public domain. We have a robust science and technology industry ready to exploit new ideas, and entrepreneurs and venture capitalists eager to fill in where existing companies are uninterested. Taxpayers would benefit by allowing the market, and not university licensing offices, to decide whose ideas and products make the best use of publicly funded inventions.

And most importantly we all would benefit returning academic science to its roots in basic discovery oriented research. We see with CRISPR the toxic effects of turning academic institutions into money hungry hawkers of intellectual property. Pursuit of patent riches has transformed The Broad Institute, which houses some of the most talented scientists working today, into a prominent purveyor of calumny.

We have to fix this problem now or there will be countless other Jennifer Doudnas slimed by colleagues, their contributions to science attacked not for their validity or importance, but for their impact on some other institutions patent portfolio. The soul of academic science is at stake.

CRISPR Clarifies Split-Hand/Foot

20150429-gene_editing-techWhile James R. Clapper, Director of National Intelligence, calls genome editing a “national security threat”, bioethicists warn of CRISPR-created superbabies, and prominent researchers argue whether patents trump papers, I prefer to quietly look at applications of the technology that aren’t

Is Lander’s revisionist CRISPR history sexist?

Explosive disagreements over the origins of CRISPR, the leading methodology for editing genes, were inevitable. CRISPR has given scientists (and journalists) dizzying dreams of a near-unlimited ability to manipulate the genomes of animals and plants,

Researchers identify potential alternative to CRISPR-Cas genome editing tools

An international team of CRISPR-Cas researchers has identified three new naturally-occurring systems that show potential for genome editing. The discovery and characterization of these systems is expected to further expand the genome editing toolbox, opening new avenues for biomedical research. … Continue reading

Research Reading Roundup: Research Parasites, CRISPR patent dispute and more

Here is your weekly roundup of research news: Have you seen the #ResearchParasites hashtag on Twitter? It’s in response to a New England Journal of Medicine editorial about data sharing. There are two rebuttal articles found

The Villain of CRISPR

Eric LanderThere 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.

Screen Shot 2016-01-24 at 7.49.00 PM

(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.

The cancer moonshot and other future science fantasies

Last Friday, On Science Blogs was given over to the many “best of science” lists of 2015. This week’s post is about what bloggers foresee for 2016–and beyond. THE CANCER MOONSHOT: WELCOME TO 2016 Vice-President

The Gene Editing Tsunami and the 10 SynBio Highlights of 2015

When we decided to crowdsource a review of the year from the synthetic biology community we weren’t sure what the response would be – but it has been fantastic! So good in fact, that we

More on gene editing rules, CRISPR in humans and dogs, bioethics & breakthroughs

THE HUMAN GENE EDITING SUMMIT, CONT’D Citizens seeking to understand what was decided at last week’s Human Gene Editing Summit might be understandably confused by the contradictions in these headlines: Scientific community approves human gene