There’s a thread running on the LabLit forums inspired by a recent news article in Nature about two young scientists who have been facing an uphill battle to get their unconventional work published. Have a look at Erika Check’s piece for the details, but briefly, two youngish researchers have been compiling evidence that miRNAs can occasionally activate genes instead of knocking them down. After a lot of experiments and numerous rejections, they finally managed to get some of the findings published in PNAS. But despite a few additional supporting papers from independent labs, apparently most of the RNA interference community still doesn’t believe them. (Interestingly, one of the researchers says he’s been scanning through archives of biology message forums and found that “other scientists – often graduate students – have also seen evidence of RNA activation. But they have been encouraged to discount it”.)
Now, I haven’t had a chance to read the PNAS paper yet, but clearly, if the work is true, it’s an important piece of information for researchers to know about. Not just those who study the biology of small RNAs, either, but the even larger proportion of folks, like me, who use siRNA as crucial knock-down tools. The big journals say they can’t publish without a ‘mechanism’, but I suspect that if an RNAi luminary like Greg Hannon, Craig Mello or Thomas Tuschl had submitted this work to a top-tier journal, the referees and editors might have been a bit more receptive. In short, the inexperience of the authors was probably one of the main sticking point.
In some ways, I suspect it’s healthy to have your skepticism dial turned up to eleven when faced with inexperienced researchers. Not only are they more error-prone but, let’s face it, they are also packed full of youthful excitability. I can still recall in vivid detail during my first year of graduate school, on several occasions, racing from the darkroom to my boss’s office, so flushed with a good result that I didn’t even bother to check the precise order in which I’d loaded my samples onto the gel. And Julie would give me that look, frogmarch me back to my notebook – and I’d belatedly realize the whopping dark band I was celebrating was actually just the positive control.
How times have changed. These days, I’m treating cells with siRNAs targeted to novel genes and looking for phenotypes. I’ve had a beautiful phenotype staring me in the face for weeks; I’ve repeated it five times using different conditions, made cautious scribbles and sketches in my notebook about how there “appears” to be an effect – the images are annotated with circles and arrows and everything. I’m camped out by the microscope. But somehow, I just haven’t been able to truly believe it. And here’s the crux: I think it’s also about age, but this time the other side. We might be hyper-gullible about our results when we first start, but as we get wiser and more cynical, it gets harder to convince ourselves that our own data is real, let alone that of some green newbie fresh out of grad school. (Disclaimer: I am speaking generally. Some of my best friends are green newbies fresh out of grad school.)
Of course, thanks to hearing about this weird new activation role of small RNAs, my scepticism feels entirely justified. Just as I was feeling comfortable with my phenotype, I suppose I am now obliged to suspect that it was an artefact all along.
But no, it’s too late – I’ve already given it a name!
(See, I knew reading Nature was dangerous. Cheers, Erika.)
Oh no! My own siRNA experiments (and exon microarray analysis) are doing something odd. One of three, my target gene goes down. Two of three, it goes UP up uppity up. The third one is down a little bit.
It’s all rather confusing, really.
That’s just the antipodes, dear. They go to your head.
Hmmm. The funniest thing about this whole thing is how weird everyone thought the whole RNAi thing was at the beginning – you’d think they could handle dogma-shattering weirdness in turn. Yet instead, they’ve gone all mainstream and skeptical on the next generation of rebels. Maybe they secretly don’t want to be out-weirded?
The PNAS paper is an outstanding piece of work because the authors show a number of well-designed experiments against the classical dogmatic RNA interference mechanism.
I’m glad to hear it, ARV ARV. (Can I call you ARV for short?) In that case, I am glad that PNAS published it, mechanism or no mechanism. The purpose of my blog was not to wonder whether the phenomenon was true, but to explore the issues of lab skepticism, and how that links in with the age of the person trying to change peoples’ minds.
You wrote: “I suspect that if an RNAi luminary like [Names Deleted Because They Make No Nevermind] had submitted this work to a top-tier journal, the referees and editors might have been a bit more receptive.”
Jenny, and with the greatest respect, this is complete and utter nonsense. As an editor at Nature I regularly reject substandard papers from luminaries, and nothing pleases me more than being able to publish a fabulous (and well supported) finding from someone of whom I have never heard. Perhaps that’s because I handle real science (evolutionary biology) rather than alchemical stamp collecting … 🙂
I have no doubt that most editors have this ethos (having been one myself, I know), but I am not so sure about the referees. In fact, there is a lot of evidence that peer reviewers routinely take the authors’ reputation into account, which is why there have been calls to make the entire process double-blind. The decision that the editor makes is clearly influenced by the enthusiasm, or lack thereof, of the referee reports. Therefore, luminary status and experience can influence skepticism, which can in turn influence whether a paper is accepted in a journal. Sorry if this wasn’t clear in my blog wording.
Sorry, Jenny, I don’t buy any of this. First, where is the evidence that peer reviewers routinely take the author’s reputation into account? If they do, it works both ways – in my experience referees demand more, not less, of authors with reputations to maintain, than of authors just starting out. Second – the double-blind process doesn’t work, because it is easy to guess the author from style and citation listing. Third, yes, editorial decisions are indeed influenced by referee enthusiasm. But we also get to know our referees well, so that enthusiasm can be carefully gauged. And yes, we actually read the reports, too.
I never said double-blind refereeing would work – I merely pointed out that people have been lobbying for it (not fully understanding how this process is impossible) because they believe some bias is occurring. And as a former handling editor, I’m the last person you need to convince that editors make independent decisions and know how to ‘read’ their regular referees.
My ‘evidence’ about reviewers taking the authors’ reputation into account comes from my experience as a handling editor, reading the actual reports – they can make statements such as ‘The experiments seem on the face of it to be done well, but I don’t trust it because they’ve only been in the field for X years’ — it doesn’t get more explicit than that. (And of course these are only the referees that admit it on paper – most won’t mention such misgivings. Indeed, a lot of the ‘blinding’ that comes from seeing a famous name, or lack thereof, may take place on the subconscious level.) My evidence also comes from the other end, chatting to my peers who are in the process of peer reviewing a manuscript – people who say they are going to recommend rejection because the lab doesn’t have a track record in a field. I have also been privy to the anecdotes of my editorial colleges across a broader range of journals.
I think you have to take into account that in many ways Nature is probably different from a lot of other journals. Most journals don’t have a personal relationship with their referees – I’ve worked on a journal that does, but on the last set I worked with, we had a referee database of 10,000 names which were chosen solely on the basis of keywords; because of the turnover, the referee reports carried much more weight because there simply wasn’t time to coddle each manuscript.
Also, the fields which you are used to dealing with, and the pools of referees you habitually use, might be a bit different from those of molecular biology. I could tell many stories to back up my point, but discretion forbids it – maybe over a beer sometime off the record. In the meantime, I think it’s naive insist that peer review is lily-white instead of a spectrum of grayscale, especially when you consider that’s it’s carried out by human beings. The idea that bias couldn’t possibly occur – or occur on a fairly regular basis – is ludicrous.
Well, I’m recommending Rohn’s manuscript for acceptance. And it’s not because I know her, oh dear no.
Jenny – you wrote “… people who say they are going to recommend rejection because the lab doesn’t have a track record in a field”. If so, that’s truly horrible! My experience is just the opposite – people tend to make allowances for junior colleagues. But it could be that we work in different fields. The world of evolutionary biology is far less competitive than molecular biology, so people can afford to be more generous. I know which one I prefer…
I’m sure it’s a field thing, Henry. Things have gotten really remarkably cut-throat in biomedical research – I guess where floods of money comes, nastiness follows.
Personally, I would have loved to have been a gentleman (metaphorically speaking) armchair naturalist from the 18th or 19th century…nobody had to wonder what the impact factor of their fossil might be.
Hmm… “an armchair naturalist from the 18th or 19th century”. Something of a caricature, don’t you think?
As are the best fantasies.
Yes, but we are talking real life, here. Evolutionary biology has advanced well beyond the 19th-century caricature people outside seem to think, in that somewhat patronizing way they do. It is a vital, mature discipline that’s solving really important, fundamental questions. Somehow it suits other scientists – those with all the money and none of the manners – to belittle it at every turn.
Henry, you misunderstood me completely. I was not trying to belittle your field as it stands today. I was feeling nostalgic for the day when the process of science was a bit slower and less competitive, that’s all. As molecular biology didn’t exist a few hundred years ago, I often wonder what it would be like to have done science in olden times, necessarily in other fields: to have been a naturalist, a botanist, an early microscopist, seeing the first microorganisms. It must have been tremendously exciting.