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Chemical Biology

A Quick Retraction

The open-source program that I use for literature management (Zotero) set off a feature not long ago that I didn’t realize it had. A red banner appeared across the top with a notice that a paper that I had in one of my collections had been retracted. That’s pretty handy: a red X now appears next to the paper, and it’s also part of a new folder that the program created (“Retracted Items”) I was naturally curious to see what paper it was that I’d found interesting that was now being pulled, and was surprised to find that it was a high-profile publication from the Crews lab at Yale on protein degradation.

They had reported a powerful variation on the technique last year: instead of targeting proteins in the cytosol with bifunctional molecules that cause them to be ubiquitinated, they had a system that caused extracellular proteins to be actively taken up and degraded. That would be quite interesting and useful – there are a lot of circulating proteins that one could imagine being therapeutically cleared in this way, across several major disease classes. The Crews group’s so-called ENDTAC molecules were said to hijack the endosome/lysosome pathway, and this was demonstrated with uptake and removal of a GFP-fused target protein.

Well, apparently not. The retraction notice says that they cannot reproduce these findings and are thus pulling the paper. That’s a good thing, and exactly what should happen. But it says something about the state of the literature that it’s notable when it does. There are any number of un-retracted papers out there, some of them from pretty prominent labs, whose reported results are partly or even completely non-reproducible. Most active researchers will have encountered some; this is not a phenomenon that’s peculiar to any one branch of chemistry (or any one branch of science in general).

Like all retractions, there is surely a story behind this one. It’s interesting that there had been (as far as I can see) no publications so far calling the original paper into question. It only appeared last May, so the overall turnaround time was pretty quick by scientific literature standards. The usual way that such hot results fall apart is for other people to jump on the new method and fail to get it to work, but that can happen inside the original research group, too. There have been a number of painful cases over the years where it turned out that the amazing results only seemed to happen when one particular grad student or post-doc was doing the experiment, and not because they had such good experimental technique, either. When you isolate the variables, sometimes you isolate ones that you weren’t counting on (!)

There are honest mistakes too, of course, but the process of discovering and writing up some new and interesting result is supposed to shake those out before a paper gets published. At some point deliberate fraud actually becomes a better explanation than the level of sloppiness needed otherwise, but of course one would rather avoid having to reach for either one. I’m sure this was a painful experience for Prof. Crews and his lab. But I’m glad that they took this action, and whatever it was that happened, I would assume that steps have been taken to keep it from ever happening again.

28 comments on “A Quick Retraction”

  1. John Wayne says:

    FWIW, the timing of this feels honest. From what I’m told, deliberate fraud takes longer than you’d think to fully discover and communicate. Congratulations to the Crews lab for doing the right thing; I wish you all the good karma you deserve (grants, jobs, papers, etc.)

  2. NMH says:

    I dont wish them good Karma. Someone was not minding the store, and hopefully this lab and the PI will pay the price. Plenty of other labs deserve the money they got to support this crappy research.

    1. anon says:

      Other labs aren’t that different.

    2. Anonymous says:

      Some scientists are trained to “measure twice, cut once.” When you forgo the 2nd or 3rd measurement that might call the first results into question in order to quickly publish the singleton, that is bad science. Many groups take the time and effort to check results, especially new results, very carefully. They avoid publishing papers that would otherwise have to be retracted. They also pay the price of having fewer papers.

      On the other hand, I inherited and exposed many (more than 7) irreproducible papers in groups I have worked with (beginning in grad school). Not one of those papers was ever acknowledged, corrected or retracted by the originating group. Two of those papers were exposed by other research groups papers as being totally unreliable, years after I called them into question. External researchers brought problems with some of the other papers to the attention of the PIs who continued to ignore the warnings and left the papers to fester (and be cited) the literature.

      Correcting or retracting an unreliable claim may be a good thing but it is something that should be avoided altogether by better research methods. Many other groups do just that.

      1. Charles H. says:

        It’s much better to avoid mistakes as often as possible. But you can’t always avoid them. Even the most careful approaches will occasionally fail. And it is best if you are willing to acknowledge the errors.

    3. Ian Malone says:

      An attitude that leads to funding going to places not willing to admit their mistakes.

      Don’t make a habit of it, try to fix whatever led to it, but if you find you were wrong then it should be better to own up than cover up.

      And when you do that killer experiment that perfectly confirms your favourite hypothesis, do us all a favour and check it twice. At least twice.

  3. Ru baby says:

    Good thing I already got my funding to start my photo-catalyzed endtac program

  4. Colm says:

    I really love Zotero and recommend it to all our undergrads, this feature is such a great addition.

    1. Zotero-curious says:

      Do you recommend the browser or desktop version?

      1. Derek Lowe says:

        I have the desktop version with a browser extension, just so I have access to my library even if I don’t have connectivity.

        1. Colm says:

          Same, desktop version.

          1. Ian Malone says:

            I thought the browser-only version had been discontinued? I use desktop with a browser extension now.

  5. Eugene R Fisher says:

    Mistakes happen, even when the work is reviewed by multiple, experienced Engineers and Scientists. When the device or process hits the real world things can fall apart on the smallest detail.

  6. li zhi says:

    I don’t agree that 11 months is “quick”. I don’t argue that publishing, circa 1970, would view this as blazingly fast, but for the year 2020? Not so much. I also think it delusional to expect “steps … taken to keep it from ever happening again.” Any system can be hacked – given sufficient motivation and time. The fact that honest, objective (i.e. disciplined) work is so common is what is astonishing to me. It is, imho, contrary to some of the core drives of human nature. Isn’t is too bad that there seems to be no middle-ground? Either a paper is “true” (replicable) or is to be consigned to the trash-bin of history. I wonder if my impression is accurate that generally little to no effort is made to salvage any of it, by authors/publishers. With a bald retraction, I’m left wondering where did they go wrong?

  7. Talented Postdoctor says:

    Crews and Arnold must be collaborting a novel ligase enabled by directed evolution

  8. Jacob says:

    +1 for Zotero.

    Should a paper be retracted just because it couldn’t be replicated? Doing so implies any non-retracted paper *did* replicate, which is very much *not* the case. IMHO another publication stating the results didn’t replicate would make sense, though in practice I guess a retraction notice like this is functionally very similar.

    1. paperclip says:

      It should not necessarily be a retraction if a second lab cannot replicate the results. Who’s to say that the second lab wasn’t the one who made a mistake? Or, in some fields more than others, but probably in all fields, a *tiny* difference can yield a big influence. The strain of bacteria isn’t quite the same, or the purchased chemical has a small impurity.

      It gets really worrying when a lab can’t replicate its own results, in the same environment and using the same material.

  9. Lazy guy says:

    That acronym they came up with sums up the whole story.

  10. Try LyTACs instead says:

    From what i’ve been told, Crews rushed to put this out when they caught wind Bertozzi’s LyTACs were being put out. As I understand it, the Crews method is totally irreproducible. Bertozzi’s method on the other hand has been widely reproducible (and not even published yet, officially).

    1. anon says:

      Kind of ironic it was published in Bertozzi’s journal.

  11. RB Woodward says:

    Wake up call: This retraction is indicative of a much larger problem in the ‘protein degradation’ space. Reproducibility will not be the only pitfall. The ‘protein degraders’ are large (MW about 1000) and often reactive electrophiles such as acrylamides. Such compounds would cause havoc in any biochemical assay or whole cell functional assay. It is far from clear that these project teams, particularly the academics, know the difference between protein degradation and protein denaturation. Cringeworthy. RB

    1. Me says:

      Reproducibility is not a problem at least for PROTACs. Also, I have seen over 300 compounds (degraders) from the literature and none of them have an acrylamide moiety (I am curious where your statement come from?). In your last sentence, you are clearly underestimating academic biologists.

      1. Curt F. says:

        I think the source of the problem that many industrial folks have with academia is that in industry, you don’t hear much about all the bad work that people do. It doesn’t get published, and it doesn’t get discussed at conferences, and unless you can somehow convince someone to pay billions for your bad work, no one ever really hears about it at all. In contrast, in academia, just about everything, bad and good, gets published.

        So if you’re just paying attention to what you hear about, your signal for how good academia is relative to industry is pretty biased.

    2. MrCovalent says:

      If you were trying to channel Woodward’s intellect for your post, let me tell you, it ain’t working.

  12. db says:

    Perhaps there should be institutions or departments within institutions soley devoted to testing reproducibility. Not a new topic around here. Or perhaps grants should be tailored to require a certain amount of reproducibility checking of others’ work as a condition for receiving resources for new research?

    A concept beloved in libertarian political circles is a proposed fourth branch of government, or a third house of Congress, devoted to repealing laws and regulations that have not proven effective at their original stated purpose, but for political reasons, have become impossible to repeal due to entrenched interests favored by them. Perhaps something like this in academia?

  13. Thoryke says:

    Derek reminds us periodically that ‘you get more of whatever you reward’.

    So, another way to improve the likelihood of research being done thoroughly ‘the first time’ rather than rushed through with increased risk of retractions is to change the reward structure for publications.

    You want novelty? We’ll give you all kinds of novelty….but maybe not reproducibility or utility.

    So this effort to switch away from Journal Impact Factors [JIF] to Transparency and Openness Promotion (TOP) Guidelines might be very helpful — link to article in today’s Scholarly Kitchen in the website slot.

  14. Femto says:

    The feature

  15. Femto says:

    The feature is really nice. Thanks to it I learned about this terse retraction https://pubs.acs.org/doi/10.1021/jacs.9b03677 I asked my friends from the concerned Czech institution what those “inaccuracies” are. Well, someone just deleted peaks of a impurity that inhibits the presented reaction. The authors retracted the paper only after the investigation and pressure from the university president. It seems to me that sometimes the journal allows/facilitates whitewashing of outright fraud. I would not be surprised if it was some Bail’s list journal, but JACS? Are there other similar cases?

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