Recently, a kerfuffle in the world of CRISPR illustrated just how easily money -- and our perception of it -- can impact science.
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In late May, a paper came out questioning how effective the gene-editing technology really is. Working with mice, researchers found that edits made with CRISPR can also result in thousands of unintended changes to a genome. The study cast serious doubt on whether CRISPR is ready for prime time.
The fallout was swift. Stock prices of three CRISPR companies -- Editas Medicine, Intellia Therapeutics and CRISPR Therapeutics -- tumbled. Scientists affiliated with those companies fired back, questioning the study's methodology. Stocks bounced back. The scientific world was set atwitter, questioning not only the validity of the initial study, but how to trust a rebuttal against that study when it came from those who stood to lose the most from its publication.
— Sebastian Wellford (@WellfordBiology) June 23, 2017
"You want a crime story? Look into who shorted CRISPR stocks before that awful paper came out. How about that." -- guy I met at #BIO2017
— Damian Garde (@damiangarde) June 20, 2017
Conflicts of interest aren't a new problem in science. One frequently-cited example is the role that tobacco industry-funded scientists played in distorting the health consequences of smoking. There is a significant body of evidence suggesting financial interests can correlate with favourable results. But conflicts of interest aren't always all bad. Research funding from sources with a vested interest in a topic can sometimes help advance science that otherwise might not get funded at all -- think the patient advocacy groups funding cures for little-known diseases.
What's undoubtedly true is that money plays a significant role in science. And rarely has there been as much money at stake as with CRISPR, the nascent gene-editing technique that promises to cure everything from genetic disease to global famine by allowing researchers to easily cut and paste particular genes. When scientists whose fortune and reputation hinges on a particular technology speak out against a paper questioning that technology, it's hard not to wonder how that bias might factor in.
"There is this unspoken assumption the people in academia are driven primarily by the quest for knowledge and the science," Josephine Johnston, a bioethicist at The Hastings Institute, told Gizmodo. But in recent history, controversies over things such as tobacco and GMOs have begun to erode that perception. "When it became clear that more and more scientists have a specific financial stake, it caused a lot of concern," Johnston said.
When it comes to CRISPR, the financial stakes are certainly complicated. Two separate groups of scientists have long been embroiled in a battle over the patent for the technology, with one headquartered at The Broad Institute of MIT and Harvard, and the other at UC Berkeley (so far, the US has awarded the patent to Broad but Europe and China have sided with Berkeley). The patent gives the scientists the ability to licence the technology. In this case, Broad has licensed the technology to Editas, a company founded by scientists at both Berkeley and Broad. Berkeley licensed its patents Intellia, which Berkeley's Jennifer Doudna is also a founder of, as well as to CRISPR Therapeutics.
Most of the headline-grabbing scientists associated with CRISPR have major financial stakes in publicly traded CRISPR companies, creating a strong incentive across the industry for CRISPR to succeed. The concern is that a CRISPR-favouring bias could potentially cause researchers to misinterpret or skew study results, or forge ahead with human clinical trials before CRISPR is really ready.
That isn't say that there's necessarily anything wrong with the points industry-affiliated CRISPR scientists raised in their rebuttal to the paper questioning their science. In fact, several other scientists raised similar concerns.
"Finances certainly can influence science. Not just companies, but also the premises supporting government grant finances," George Church, an author of the rebuttal paper and founder of Editas, told Gizmodo via email. "We were basically raising issues that the original authors can address. This, fortunately, doesn't require perfect unbiased authors. Anyone can point out a potential problem."
Michael Kalichman, director of UC San Diego's research ethics program, pointed out that financial interest isn't the only bias that scientists have to be wary of.
"We've talked about conflicts of interest for many years in science and for many reasons much of that focus has been on financial conflicts. For one, it's easy to see," he told Gizmodo. "What I find astonishing is that even scientists forget that there are other conflicts that can influence work, like tenure, your reputation or just being excited about an idea."
Kalichman said his biggest concern is less that scientists are actually doing anything unethical, and more that financial conflicts of interest create the perception that they are. The paper that sparked the CRISPR controversy received press in most major news outlets, and the blowback against it has received significant attention, too.
"Part of me is worried about the way [this CRISPR fight] is playing out because of the picture it paints of science," he said. "We have this battle going on in the pages of scientific journals that creates this perception that this is what science is about when most of science is not about this."
Johnston echoed those concerns.
"The introduction of these financial interests muddies the water enough that people don't know who to trust," she said. "Whether or not we can see anything wrong with either study, or anyone else can, there's still this suspicion that the financial stakes must have played some role here. That's a very corrosive thing across science."
In the initial Nature Methods paper, scientists from Stanford and University of Iowa working to cure blindness in mice found that while CRISPR did successfully edit the gene for blindness, it also caused mutations in more than a thousand unrelated genes. The consequences of those off-target effects, far more extensive than previously realised, are largely unknown. "This finding warns that CRISPR technology must be further tailored, particularly before it is used for human gene therapy," the researchers wrote.
As mentioned, scientists associated with CRISPR companies were not the only ones, or even the first, to criticise the study's design. Many scientists raised red flags about basic mistakes, such as misidentifying genes, mislabelling genetic defects, and the small number of animals the researchers had included in their research. But other scientists found the reaction against the paper, which was written as a brief letter to the editor intended mainly to point to an area where more study might be needed, to be overwrought. Some, such as UC Davis professor Paul Knoepfler, suggested the real problem was that the results had been over-interpreted and blown up in the press, setting in motion an out-sized blowback.
Scientists from Intellia and Editas both sent separate letters to Nature Methods, forcing it to eventually add a note to the study about the controversy surrounding the letter. What's more, in publishing their own study taking down the initial work's methodology, scientists associated with Editas opted to publish a pre-print online before it was peer-reviewed, though the initial paper did go through a peer review process. And while the response paper mentions the institutions and companies each author is affiliated with, there is no clear conflict of interest section. (Church said conflicts of interest will be included with journal publication.)
This week, a pre-print of a second paper was published by scientists at Intellia that reanalysed the original paper's data and found far fewer off-target edits also appeared online.
In a statement, the Broad Institute said that the peer review process should weed out the impact of any conflict.
"Scientific papers -- whether making a new claim, or analysing an existing scientific claim -- should always be subject to rigorous evaluation by the scientific community to establish whether the scientific evidence actually supports the argument in the paper," the Broad Institute told Gizmodo. "Such review by the community provides protection against incorrect arguments, whether due to a scientific error, financial or reputational interest, or something else."
Most journals and research institutions have a comprehensive conflict of interest policy. In 2010, UNESCO called for journals to adopt a common standard of dealing with "the complex and growing financial arrangements that have developed in recent years between vested interests and independent scientists". Even so, sometimes those ties wind up omitted.
Kalichman said more might be needed to address conflicts of interest in the realm of basic science.
"In clinical research, you do everything you can to separate financial interests from the people doing the work," Kalichman said. "We don't really talk about that in basic research, but maybe we need to do something like that. Maybe if you have a financial interest, you're not the one that looks at the raw data."
It's next to impossible to fully weed out conflict in science -- be it financial or otherwise. Besides, it makes sense that scientists should be able to make money off of their own work. But it's also impossible not to acknowledge that those interests can influence the science. How could they not?