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.