In September 2019 Nicola Smith, a molecular pharmacologist in Australia, faced a brutal decision. She’d realized that she’d made a mistake — or rather, failed to catch a mistake in her group’s research before the crippling error was published — in two academic articles which were the culmination of years of work. And she could either tell the world, or pretend it never happened.
Her students had been having trouble reproducing lab data. Once she looked into it and she figured out why, she told them, “Guys, you’re not going to believe this.” A cloning error had ensured the experiments were doomed to fail from the start.
If she came clean, she knew that at least one of the articles would most likely be retracted and she’d have to live with a lasting mark on her and her team’s record. “What can I do to minimize the impact” on her two students? Smith thought at the time.
In particular, Tony Ngo,who was first author on both papers and had recently finished a PhD in her lab, was looking forward to a future in academia. Smith was terrified of tarnishing his prospects.
What was to stop her from just keeping quiet about it?
Smith, then at the Victor Chang Cardiac Research Institute in Sydney, studied G protein-coupled receptors – which are the largest class of receptors, are often targeted by drugs, and allow many hormones to interact with cells in the body.
She specialized in “orphan” G protein-coupled receptors, those activated by unknown molecular partners. At that time, she was looking into one labeled GPR37L1, which exists in humans and affects the cerebral development of mice. The research community studying the receptor is small and scientists are still trying to decipher its activity. “There is a lot of mystery around this receptor,” says Irina Kufareva of the University of California, San Diego, who collaborated with Smith and was co-senior author on one of the studies.
In Smith’s area of study, researchers can’t observe a receptor directly. Instead, they use a genetic vector to carry it inside cells, then pay close attention to the resulting activity – looking for telltale chemical indicators of what the receptor might be doing.
In 2016, her group published a paper in Science Signaling in which they reported what happened when they cut off the head of the protein in question: the receptor’s activity dropped – effectively switching activity on and off. They were able to show that the G protein-coupled receptor could be active without being triggered and could be controlled by severing that first chunk.
An indicator which helped them monitor this activity had also been present in their previous tests using yeast cells. Which was encouraging — now with human cells they were seeing similar results.
Then in 2019 an honors student (a post-undergraduate researcher) in Smith’s lab was trying to make genetic constructs with mutated receptors to compare how they behave in cells with the natural ones. The constructs required for the experiments were comprised of a vector embedded with the genes of interest.
When he couldn’t, they figured the failure was simply because the process was “fiddly,” as James Coleman, then a post-doc in Smith’s lab and co-first author on the paper with Ngo, puts it. The trouble persisted until August 2019, when they gave up and decided to order ready-made versions of the constructs instead.
But when the constructs arrived, and the lab tried to recreate the past experiments, the new construct “was behaving completely unlike the one that we had been working with previously – the one that we had published with,” Coleman says.
In September they sequenced the troublesome genes and found they had been using the wrong vector to carry them.
That wasn’t all. Not only was the gene put in the wrong vector, the receptor gene itself — a string of genetic information — was inserted into the vector backwards so it couldn’t be read correctly. Even one of those catastrophic errors would have almost certainly invalidated her findings, but both together killed all chances of a meaningful result.
The reason it was so hard to catch the snafu sooner was that normally when one makes a mistake like this, Smith says, the experiment simply wouldn’t work. Remarkably, not only had the experiment worked, it had produced results that were in line with what the researchers had seen in related experiments. Now that the team had arrived at the root of the problem, their hearts sank as it became clear that their once-promising results were a fluke.
After realizing her group’s mistake, Smith turned to a trusted colleague for advice. She says the colleague told her that “despite the fact that you really care about this receptor, no one else in the world really gives a toss about it.”
In essence, the sentiment was: Weigh the damage done by letting an error affect a few niche publications against the potential fallout and long-term career damage it would do to her and her team. And for that day Smith was almost convinced that keeping quiet to protect her team was the best option.
After hours of turmoil, Smith realized that her colleague’s line of reasoning – that she could ignore her error and just move on – was “utter bullshit,” she says. It didn’t matter whether or not anyone else cared about the receptor; feigning ignorance was wrong.
You just have to do the right thing, Smith says, “even though it’s the most painful thing you’ll ever do.” She couldn’t spend the rest of her career wondering how much damage her error would cause. She alerted her institutes about the error (both Victor Chang and the University of New South Wales, with which it’s affiliated) and, shortly after, the journals involved. She decided that total transparency was the best path.
After making that choice, “The weight just lifted off my shoulders; it was the right decision,” Smith says. She was committed to doing the right thing, but knew she’d have to face consequences.
Months after Smith’s realization of the error, she found herself in the heart of a storm. She was immensely stressed, getting regular phone calls from the investigators at her institute, whose funding body required them to launch a preliminary investigation to see if there were signs of misconduct, Smith says.
She was organizing experiments for her students to contextualize the error. One of those students was Brendan Wilkins, a research assistant who often worked until midnight.
Smith did all of this while taking care of her two boys, one age three, the other not yet one. The ordeal had pulled her away from her family and began not long after she returned from maternity leave. “[M]y three-year-old started mimicking me at the computer, saying: ‘Sorry, Mummy, I’m doing work,’” because it was so all consuming, Smith says.
But at the worst of it, she got an email from another researcher which strengthened her resolve. The researcher had a question about the Science Signaling paper, which she and her co-authors had asked the journal to retract. It would be, but at the time the forward facing text was unchanged. That moment drove home to her the importance of correcting the record. Scientists spend so much time and energy struggling to reproduce genuine data, Smith says, there isn’t room in the literature for known errors.
Smith explained what had happened and asked the researcher to be discreet while the retraction was being worked out.
Shortly after, on Dec. 17, 2019, the Science Signaling paper was retracted. In the retraction notice, the authors wrote, “After publication of the work, we discovered a cloning error in the GPR37L1 construct …” and that, ”when experiments were repeated with the correct construct, they failed to confirm” the kind of signaling they’d previously seen.
It was Smith’s younger son’s first birthday.
The process of retracting the Science Signaling paper was “relatively pain-free,” Ngo says. But the problems with the other work, an article published in Nature Chemical Biology, were more nuanced. The error invalidated their experimental results, but the paper was built around a methodology which remained unaffected, Smith says. What do you do when part of your article collapses in a heap while the rest is still sound?
Smith has found scant guidance for these grey areas, but she says she’s striven to be transparent with the journals. The work hasn’t been retracted yet. She and her colleagues was able to publish an explanation of the error on BioRxiv, though the original online publication doesn’t link to it nor include an editor’s note that the work is pending retraction. The editor of Nature Chemical Biology didn’t respond to multiple requests for comment.
The authors also wrote a book chapter and a review which referenced the invalidated results and required correcting.
The experience took a toll on the lab, including Ngo, who, having finished his doctorate in May 2017, had already moved on to a post-doc position at Kufareva’s lab when he got the news.
“I think everyone’s been through quite a major trauma,” Smith says.“[I]t’s been horrific for me, obviously, and for my staff,” she says, but adds that it’s important for people to consider: what happens when the scientific literature needs to change due to an honest mistake?
The idea that someone could look her up, see that one of her papers was retracted without knowing the backstory, and jump to the conclusion that she was responsible for data falsification “still makes me feel sick,” Smith says. Beyond the stress, the experience took an emotional toll on her. She said it made her fall “out of love with science.”
Her husband, an engineer, wondered why she bothered with a community that would put her through such a trial on top of all the funding competition and other challenges scientists put up with. “My husband, I think, hated science,” she says.
Coleman, the co-first author of the Science Signaling paper, says he “didn’t have grand ambitions of being a professor someday.” He was stressed but didn’t worry about the retraction ruining his career. He is now working for the Australian government and says he is perfectly happy being out of academia.
Ngo was much more concerned. Unlike Coleman, he was determined to pursue a career in academia, and the mark of a retraction could, theoretically at least, be much more of a hindrance.
At first, he said, he blamed Smith for not supervising the research more closely, then he blamed himself for not being careful and checking others’ work. But after some time, Ngo reflected on his history with Smith as a “mentor and friend” to him and realized that the support he had received from her over the years outweighed any anger he might feel about the incident.
Still, for some time, he says, he struggled to trust again. “[S]cience is really built on trust and sometimes when the trust is broken, it’s really hard to build that back,” Ngo says.
Ngo has been trying to figure out how prominently to show his retraction and corrections. On the one hand, he says he wants to be completely transparent and take any chance to explain the honest mistake to a potential supervisor up front. On the other hand, he says he doesn’t necessarily want the retraction to be the first thing someone knows about him. Should he put it in his CV or cover letters?
Mentors have told him “It’s better to put these questions up front” rather than have a committee member down the line ask you “why were you hiding it?” Ngo says, and this reinforced his gut decision.
At the time of the investigation, “I felt my career was over,” Smith said when reflecting on the episode last year. But the events no longer overshadow everything she does and she says thanks to support from her community, she feels her love of science again.
Those 24 hours, in which her resolve wavered after speaking with her group about the error, have been Smith’s only real regret throughout the process, she says. After telling her community about the retraction and writing about it on Twitter, Smith says she has felt some catharsis in getting it out there and receiving positive support.
Smith says, she has even referred to the retraction in conversation with a friend, only to have them respond: What retraction? “Sometimes I laugh and I think, ‘What kind of ego did you have to think that they would have noticed in the first place?’”
Smith was eventually able to salvage part of the retracted Science Signaling paper, which has been published in Nature’s Scientific Reports. But she has had her fill of the GPR37L1 receptor. Barring one more project, she says she’s moving away from it “mainly because of the trauma,” and has now settled at the University of New South Wales, where she studies other G protein-coupled receptors.
At one point, she advised graduate students not to join her lab because she was concerned about the stigma of the retraction damaging their prospects. But she found that her current students stood by her and new ones were still interested, so she took several on, including Wilkins, the research assistant who worked late during the investigation and who continued on to do his PhD with the group.
Ngo transitioned from Kufareva’s lab to a post-doc at the Sanford Burnham Prebys Medical Discovery Institute, in La Jolla, Calif., for funding reasons, he says, but so far, he’s been unaffected by the retraction.
Now Smith and her lab members can joke about the experience, though she has also added much stricter policies around keeping lab records – to the extent that new students may be intimidated by them.
She still worries that she may have let down her team.
“She hasn’t let anyone down,” Coleman, the former post-doc, says. “I think she would have let people down if she had decided to pretend this whole thing never happened that not speak up about it.”
Updated 1/12/21 to correct some typographical errors, clarify Wilkins’ title and specify Kufareva’s role as a co-senior author.
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What a hero!
I’m sorry, but to me this could have been prevented with a simple diagnostic restriction digest of the plasmid that was created, along with sequencing. That is what I do with all of my plasmids that I make. If this was not done, then this was pretty gross negligence on somebody’s part and the PI should have insured that this did not happen. The reprucussions could be deserved; I know Ive gotten in a heck of a lot of trouble when I make errors, why not them?
It’s astonishing how low and how high your ego can be at the same time. You should be focusing on your career or a hobby instead of complaining in every single retraction how unfair academia is for you and bad scientists are stealing your job.
Its astonishing to me that someone either received or created a plasmid(s) without doing simple three hour tests (restriction digests, visualization on agarose gels, sequencing which can be sent out for a few dollars) to make sure that the insert is correct and the vector is correct. This is extremely negligent behavior not to do this simple test, as about 1/2 the plasmids I either get from other labs or make on my own are wrong. If, in particular, this group was cutting corners to “get ahead” (speed up time to get publications), then, yes, the price to be paid needs to be a high one by everybody involved, in particular the PI. Just my opinion. I’m sure there are plenty other labs that will spend grant money more carefully.
I am neither a scientist nor an academic nerd yet even I know that “diagnostic restriction digest of the plasmid that was created, along with sequencing” is just a bunch of gobbledegook and hardly as simple and obvious as you apparently think.
You also misspelled ‘repercussions’ which shows that perhaps you should have paused and checked your comment for errors before publishing it in Retraction Watch.
Let him without errors cast stones.
Dr Nicola is to be praised for doing what is right.
Goobledegook? No, those are words often used in molecular biology, and are pretty simple ones at that for the field at that. And yes, its that simple and obvious.
What happened was negligence. Full stop.
Yeah those things would take a maximum of 2 days to complete (1 afternoon for the restriction digest maybe 2 days for the sequencing to come back). It’s super easy even for a lab with not much funding. Also amazing that they didn’t do a western blot (or RT-PCR) for the transgene when they transfect the cells. How do they know how much (or if any) of the transgene gets expressed? This is pretty basic stuff. Sloppy IMO.
“I am neither a scientist nor an academic nerd”; well then that’s why you think it’s “gobbledegook”!
These are literally standard things for validating plasmids and cloning schemes in molecular biology. I do this once a week…
The point is – to err is human. Errors are inevitable. Given that – what is our response to the error? The only appropriate response is to correct them as quickly as possible. Any action that disincentivizes the researcher to correct their error is seriously counter productive.
So, berating the reseacher is not productive. Instead, I admire her and congratulate her for having a clear ethical compass, when we ALL know that many do not.
Not a bio-science guy – come for the other end of the science business. The end with the very nasty math. But one thing I have got very good at in the last 40 odd years in the business is spotting someone spouting word-salad BS and claiming it is “science”. Absolutely nothing you wrote sounds like it was written by someone with superior relevant domain expertise or any serious research background. Its sounds more like something written by a failed lab tech at best.
Now a real scientist, someone who understands and has worked in serious research science, would think – There but for the Grace of God goes I. And whose only reaction to this story could be, what a fantastic person. For doing the right thing rather than what was easy and expedient.
She should be lauded as a great example to others. Not lambasted by an obviously very bitter, very petty and in so many way, a very small person.
There are so many stories of people bringing science into disrepute it is great for once to read such a positive and uplifting story.
Well, I take that as a reference to me *chuckle*.
Anyway, here’s where you wrong, jmc: “plasmid”, “agarose gel” “sequencing” are all pretty basic techniques that require an even more basic understanding in my field. Additionally, I check all of my plasmids before I use them, and so my work (I’ve probably have published using 20 different plasmids in my career) is correct; every single one I used I know was what it was. Why? I have this (apparently) great flaw, which has, in part, rendered me a failed scientist (not enough pubs to impress anybody):
I’m careful.
These people were not, IMO, and they deserve any repercussions they get. Scientific research is unbelievably competitive, and if you are either going to commit fraud, or not do careful work, then you need to get out and let others take your place.
Correction: that actually is about 100 plasmids, 75 that I have created myself and about 25 I got from other labs. Each and every one checked to be in the correct vector with restriction digests and agarose gels, and sequenced in the region where I amplified with PCR to check for mutations, and to confirm the sequence was in the correct direction . Every single one of those 75 plasmids I made. It was time consuming, but at least it wasn’t costly.
With plasmids from other labs, you have to be extremely careful, as about 1/2 of those I have ever gotten were wrong in some fashion.
Im not a molecular bio but a chem guy. Any chem paper requires a huge load of experiments (for synthesis folks that’s really just nmr. I do peptides so that’s analytical hplc and maldi-tof ms) to confirm what you use is what you think it is. It’s not uncommon to see a synthesis thesis with half of its pages as labeled nmr Spectra, it’s boring as heck and difficult to read but it is necessary. I found molecular bio peers don’t check their inserts beforehand baffling if thats ever true.
Now Dr Smith did the right thing despite her peer called a science and a nature paper “some trivial project nobody cares” by working up the courage to retract them, don’t get me wrong on that. However that doesn’t deny the fact this molecular bio group didn’t check their vectors and caused this whole shenanigan to begin with.
uh, maybe look for protein next time?
Retractions due to scientific errors, as in this case, should not be penalized – in fact, it should be rewarded. At the end of the day, Science should win.
I agree. I would not, prima facie, see a retraction as a reason not to trust the researcher or her group. Rather, i would find out the reason for the retraction. In thus case, it’s a badge of scientific honour!
I disagree. Failing to punish people for negligent errors that end up contaminating the literature means that there’s a strong selective advantage for lab groups that do not do careful science but can publish more rapidly. If you want to make sure responsible, methodical, and reproducible scientists exit science I can’t think of a a more efficient way.
Academic science needs more incentive to be careful, not less.
Yes. I really believe doing careful science with a lot of replicates and other signs of reproducibility puts you at a severe disadvantage in academic research. AR selects for number and impact of publications, not reproducibility.
We had two “highly productive” labs in the school I’m at (the two PI’s brought in 5 RO1’s) closed for apparent fraud because nobody in the lab was keeping their primary data, and so it was assume they were committing fraud. There were other signms of fraud as a lot of the papers were appearing on pubpeer. So, here, “highly productive” means here producing a lot of crappy irreproducible papers.
That AR selects for money which does not necessarily lead to good science is one of the reasons I’m leaving it. Furthermore, because my publication is weak (but with reproducible stuff), I’m seen as a “failed scientist (!)”, hence my delightful self-imposed title. More cynically, I think the post-docs who lost their jobs in the fradulent labs have a better chance at a job than I do because of the number of papers they were putting out–albeit crappy ones.
I predict AR will only produce more and more crap as schools reinforce the business model (select for well funded labs, producing a lot of possibly crappy papers). I could not advise anybody to pursue the natural sciences as a career, because you have to suffer through AR at some point in your training.
Clearly this “obvious check” is not known to all. Why is that? Perhaps a LTTE is in order.
To err is human; to correct the scientific record, rather than allow an error to persist, divine.
Honesty is very important in science. It is very admirable that Dr. Nicola Smith went through so much trouble in correcting a mistake.
In contrast some people deliberately make up and / or plagiarize data and publish. If one looks up PUBPEER there are so many examples of fraud. Dr. Elizabeth Bik has pointed out many of these. Even when errors are pointed out in PUBPEER, they are ignored by some authors.
If correcting your own honest mistake “is the most painful thing you’ll ever do” (which undoubtedly is) there is something very wrong with how science works…
Legends. All of them.
May they have long and successful careers! And bright futures for the kids too – they have an excellent role model!
Great article. I could really feel Dr. Smith’s pain and the toll this took on her, both personally and professionally. While the scar will never fully heal, I’m glad that she and her team has been able to move on from this. And there is no doubt that she is a better scientist for it.
I faced a similar issue (completely different research topic), except I discovered the error when the paper was in press but not yet published (days before early view was available online). The editor was understanding, though they had to reorganize the upcoming issue. Pretty sure no one would have ever figured it out to this day, but I can’t imagine publishing a data set I know to be in error.
>Any action that disincentivizes the researcher to correct their error is seriously counter productive.
I totally agree with Phillip Shaffer’s comment, above.
My expertise? I took Biology II with Dr Bengt Liljeroot in 9th grade.
I would like to speak up on behalf of the poster who labels himself as “Failed Scientist”. What he says is EXACTLY correct. It is most certainly not “gobbledygook”. Any molecular biologist can confirm veracity. This was an experimental oversight & poor practice. A restriction digest or simple sequencing would have revealed the error. Such tests are de rigueur for plasmid construction. Having said that, ‘to err is human’, indeed. It is laudable that the PI came clean and did the right thing.
Agree with “Failed Scientist”, this was definitely sloppy science. A good analogy for this retraction case would be running someone over with your car and NOT fleeing the scene of the accident. Yeah, you did the right thing, but you also messed up pretty bad.
It is like I always told my kids when they were younger, you will always make mistakes, always screw up somehow. What is important is what you do after that – the true test of character and dignity. Here the researcher did the correct thing.
I don’t get the trouble with retraction. What if someone thought it was about data falsification? But such an assumption is thoroughly unscientific and strange, especially if made by top scientists who would potentially hire her or her assistants.
Too bad the global warming hoaxsters aren’t as ethical.
Science is about finding out about things. As such errors are part-and-parcel.
Science is not about anyone’s career.
Compliment for Nicola, but another action would have been wrong, although to many scolars would have done just that.
By the way; is it common to use a concept like ‘post-undergraduate”?
I agree. I have not done much of this type of work, but have done some transient expression experiments that have been published in a couple of articles. The one piece of advice I was given was ALWAYS sequence every construct…… This fiasco would not have happened had this been done.
What I can’t understand in this story is this: Any genetic construct I have ever made I have checked first by restriction digest, then by sequencing. Performing a restriction digest of a mini prepped bacterial vector will tell you immediately if your construct has a chance of being the correct one. And the amount of work it takes to do this test is 24hrs as a little side. (Any construct no matter in what form or where it is finally used passes through the stage of a bacterial vector. Subsequent sub cloning steps retain the orientation of the construct. So how were these guys doing their lab work? Even (or especially) if the construct was given to me with the assurance that it was the correct construct I would still run the very simple restriction digest. Furthermore, if this construct was expressed in cells they must have had an antibody (either against the protein or a tag) to detect its expression. I would never start functional experiments without having first ascertained that the truncated or otherwise modified protein was actually expressed by the transformed cell. This story casts a bad light on the management of the lab in question.