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May 09 2013

Additional Thoughts On Open Peer Review Of Ethan Perlstein’s Yeast Studies Of Sertraline

Scientists don’t respond to peer review critiques that propose alternative hypotheses to the ones they favor by whining like a college freshman whose heartfelt poetry assignment just got trashed that the professor “just doesn’t understand, maaan”. You put on your big-boy or big-girl scientist pants and address those alternative hypotheses by making arguments based on actual experiments–either already performed or proposed to be performed–that are capable of ruling them out.

In relation to the yeast studies of sertraline, an on-point critique of the proposed alternative hypotheses would involve well-established pharmacological controls. In particular, how does the dose-response curve of yeast to sertraline compare to the does-response curve to chemically similar compounds whose does-response curves for neural effects in mammals are greatly shifted?

For example, are there enantiomeric forms of sertraline that have well-separated dose-response curves for neural effects in mammals? I don’t know if there are, but if so, how do yeast respond to these enantiomeric forms? If not, are there other amphiphilic cations with similar detergent-like properties to sertraline, but with very different neural effects in mammals? How do yeast respond to these compounds?

How do yeast respond to basic laboratory detergents? Are the mutants isolated in the screen as resistant to 45 uM sertraline also resistant to other detergents?

And the fact that these yeast mutants in genes that regulate membrane cellular biochemistry and trafficking also affect cellular uptake of low concentrations of sertraline means nothing on its own. Nor does the fact that there is a cytoprotective effect at lower concentrations that is genotype-specific. The key question is whether these effects also occur for other chemically similar compounds whose does-response curves for neural effects in mammals are greatly shifted.

That is how you respond to a peer-review critique that proposes alternative hypotheses, not with generalized philosophical complaints, appeals to authority, and semantic whining about “what does ‘non-specific’ mean anyway, maaan?”

Here is the substantive bottom line: If the effects of sertraline on yeast are relevant to its effects on neurons because there are mechanistic similarities in how it influences cellular function in both cell types, then there will be parallels in the effects of chemical variants of sertraline on dose-response in these two systems. Compounds that exhibit altered effects in neurons should exhibit similarly altered effects on yeast, and compounds that exhibit relatively unaltered effects neurons should exhibit relatively unaltered effects on yeast.

And if these experiments–or other appropriate pharmacological controls–have been done, and the results rule out my alternative hypotheses, then great! I am happy to admit I am wrong and to consider my critique overcome. This is how big-boy/big-girl peer review works.

9 comments

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  1. 1
    Kevin

    @1. go away.

    @OP: I”m sorry, I’m missing something. Why yeast? Why not neurons? There are plenty of studies that use single neurons in culture.

  2. 2
    DrugMonkey

    You answered your own question Kevin. They guy needs to distinguish himself as different. In the broader sense this is great! Atypical approaches can lead to new insight. The key is to get as many people as possible on board with the potential awesomeness of your cunning plan. Understanding common objections and figuring out a good response is key to improving your chances of making people believers.

  3. 3
    sciliz

    I will leave it to someone who loves devouring yeast corpses (in the form of bread and beer) less than I to discuss ethical implications of yeast work.
    However, I do not think any person who is NOT ethically bankrupt can fail to see at least ONE advantage of using non-neuroned lifeforms.

  4. 4
    Trebuchet

    Comradde: Thank you for making TWO actual blog posts. The topic is, of course, over my head, but I’m gratified to see you making the effort. More, please.

  5. 5
    Kevin

    @3: With all due respect, calling people who do research on animals as “ethically bankrupt” is not going to win you any friends in this neck of the woods.

    Yeast is not neuronal tissue. Demonstrating toxicity of a substance in yeast in no way demonstrates its toxicity in neuronal tissue. If the FDA were to approve a drug based only on studies in yeast, a fuckload of dead people would demonstrate what a fucking stupid idea that is.

    Please be so kind as to fuck off.

  6. 6
    Dr Becca

    Kevin, I don’t think that sciliz was calling animal researchers “ethically bankrupt”– in fact quite the opposite (I tried counting, and there are 3 or 4 negatives in her sentence, so it may have gotten a little confusing)!

    If I may, I believe the subtext of her point is that animal researchers DO recognize the ethical issues involved in doing animal research. We do it despite these issues because the gain from animal research is worth it, but as you know, we do it as humanely as possible, and with as few animals as possible. If we didn’t recognize the ethical issues (i.e. were ethically bankrupt), we wouldn’t take these measures. But we do.

  7. 7
    lylebot

    I think Perlstein’s tone in his response is intentional—he’s neither debating nor writing a response to you; he’s writing to the people that might be dissuaded from donating based on your critique. He’s calculating that those people distrust pseudonymity and is playing to that distrust. It’s just another kind of salesmanship.

  8. 8
    DonDueed

    Getting a significant does-response is obviously going to require some big bucks.

  9. 9
    Takver

    I find it strange the E.O.P. is all pro-open source and crowd-funding but then gets hyper-sensitive to open-source criticism. #7 has is spot-on, he’s calculated his tone as a salesmanship tactic.

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