Authors retract striking circadian clock finding after failing to replicate

Screen Shot 2016-03-02 at 9.29.28 AMThe authors of a paper showing a “striking and unanticipated” relationship between light and temperature in regulating circadian rhythms are retracting it when the results couldn’t be replicated.

After being contacted by another group who couldn’t reproduce the data, the authors failed to, as well. They “have absolutely no explanation for the discrepancies with the original results,” according to the note in PLOS Biology.

It’s an unfortunate turn of events, but failing to replicate is an an all-too-common event in research; authors who are so honest and transparent are clearly “doing the right thing” in our book. When it comes to non-reproducible research, it’s a tough call over whether it should be retracted or not; many scientists in the same position would not have made the same decision.

The researchers were led by Michael Rosbash, a chronobiologist based at Brandeis University and an investigator at the Howard Hughes Medical Institute, who has been studying circadian rhythms for some 30 years.

The retraction note explains how the authors learned of  the replication issues:

Our original paper strongly implicated the photoreceptor cryptochrome (CRY) in the response of the Drosophila circadian system to temperature. The claim was based on three findings:

  1. CRY formed a complex with the two key clock proteins Period (PER) and Timeless (TIM) not only in response to a light pulse but also in response to a 37°C heat pulse.
  2. A mutant strain missing wild-type CRY did not phase shift in response to a heat pulse, implicating CRY in heat-mediated phase shifts in addition to its well-known importance for light-mediated phase shifts. This mutant phenotype was rescued by expressing wild-type CRY within clock neurons.
  3. The absence of CRY inhibited the perL effect on another temperature-centric feature of rhythms, temperature compensation of circadian period. The period of perL becomes longer at elevated temperatures, whereas it is essentially unaffected in wild-type flies. We reported that a double mutant strain, expressing PERL and also missing wild-type CRY, recovered normal temperature compensation. In other words, CRY was necessary for PERL to affect temperature compensation, consistent with a PER-CRY interaction.

We were contacted some months ago by Mike Young and colleagues at The Rockefeller University, who could not repeat the second finding. We subsequently repeated this experiment ourselves and also observed what Young and colleagues told us, i.e., we could not replicate the original observation that implicated CRY in heat-mediated phase shifts. As we no longer had the double mutant strain necessary to repeat the third finding (restoration of proper temperature compensation in a double mutant strain containing the mutant perL chromosome and missing wild-type CRY), we constructed a very similar strain and assayed these perL; cry0 flies for temperature compensation. It was aberrant, essentially indistinguishable from single mutantperL flies. We have therefore failed to reproduce two of the three findings in the original paper.

Although we have absolutely no explanation for the discrepancies with the original results and despite the lack of an attempt to reproduce the first finding (the heat-mediated formation of a CRY-PER-TIM interaction), the failure to reproduce two of the three findings in the original paper compels us to retract the paper. We deeply regret any inconvenience that this has caused the scientific community.

PER-TIM Interactions with the Photoreceptor Cryptochrome Mediate Circadian Temperature Responses in Drosophila,” published in 2007, has been cited 44 times, according to Thomson Reuters Web of Science.

An author summary of the retracted paper explains the significance of the findings:

The molecular mechanisms underlying light synchronization are reasonably well understood, but an understanding of how temperature affects the circadian clock is lacking. This study demonstrates a striking and unanticipated relationship between light and temperature resetting mechanisms in Drosophila.

The summary continues:

Moreover, the data not only indicate that light and temperature reset the clock through similar mechanisms but also that these two inputs can act synergistically. An interaction between light and temperature may fine-tune the dawn and dusk response of the clock and even contribute to seasonal adaptation of clock function, an emerging area of research in circadian biology.

Mike Young, who had tried to repeat the finding, has also done seminal work in understanding the circadian clocks of fruit flies. Interestingly, Young and Rosbash share multiple awards, including the 2009 Peter and Patricia Gruber Foundation Neuroscience Prize and the 2011 Louisa Gross Horwitz Prize. In a news release for the latter, Young said,

“I’m very grateful to be recognized in this way, and I am especially pleased to share the Horwitz Prize with my colleagues Jeff Hall and Michael Rosbash,” said Young. “The three of us set out on this project when not a thing was known about circadian clocks at the molecular level, and our efforts have been tightly interconnected for nearly 30 years.”

We reached out to Rosbash and Young, and will update this post with anything else we learn.

Hat tip: Gaetan Burgio

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2 thoughts on “Authors retract striking circadian clock finding after failing to replicate”

    1. and how do you want it to be “repeated”? what exactly do you mean by this? There is a difference between “repeated” and “reproduced”…

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