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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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October 11, 2007

Let Us Now Turn To the Example of Yo' Mama

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Posted by Derek

Now we open the sedate, learned pages of Nature Methods, a fine journal that specializes in new techniques in molecular and chemical biology. In the August issue, the correspondence section features. . .well, a testy response to a paper that appeared last year in Nature Methods.

“Experimental challenge to a ‘rigorous’ BRET analysis of GPCR oligimerization” is the title. If you don’t know the acronyms, never mind – journals like this have acronyms like leopards have spots. The people doing the complaining, Ali Salahpour and Bernard Masri of Duke, are taking issue with a paper from Oxford by John James, Simon Davis, and co-workers. The original paper described a bioluminescence energy transfer (BRET) method to see if G-protein coupled receptors (GPCRs) were associating with each other on cell surfaces. (GPCRs are hugely important signaling systems and drug targets – think serotonin, dopamine, opiates, adrenaline – and it’s become clear in recent years that they can possibly hook up in various unsuspected combinations on the surfaces of cells in vivo).

Salahpour and Masri take strong exception to the Oxford paper’s self-characterization:

“Although the development of new approaches for BRET analysis is commendable, part of the authors’ methodological approach falls short of being ‘rigorous’. . .Some of the pitfalls of their type-1 and type-2 experiments have already been discussed elsewhere (footnote to another complaint about the same work, which also appeared earlier this year in the same journal - DBL). Here we focus on the type-2 experiments and report experimental data to refute some of the results and conclusions presented by James et al.”

That’s about an 8 out of 10 on the scale of nasty scientific language, translating as “You mean well but are lamentably incompetent.” The only way to ratchet things up further is to accuse someone of bad faith or fraud. I won’t go into the technical details of Salahpour and Masri’s complaints; they have to do with the mechanism of BRET, the effect on it of how much GPCR protein is expressed in the cells being studied, and the way James et al. interpreted their results versus standards. The language of these complaints, though, is openly exasperated, full of wording like “unfortunately”, “It seems unlikely”, “we can assume, at best” “(does) not permit rigorous conclusions to be drawn”, “might be erroneous”, “inappropriate and a misinterpretation”, “This could explain why”, “careful examination also (raises) some concerns”, and so on. After the bandilleros and picadors have done their work in the preceding paragraphs, the communication finishes up with another flash of the sword:

In summary, we agree with James and colleagues that type-2 experiments are useful and informative. . .Unfortunately, the experimental design proposed in James et al. to perform type-2 experiments seems incorrect and cannot be interpreted. . .”

James and Davis don’t take this with a smile, naturally. The journal gave them a space to reply to the criticisms, as is standard practice, and as they did for the earlier criticism. (At least the editors know that people are reading the papers they accept. . .) They take on many of the Salahpour/Masri points, claiming that their refutations were done under completely inappropriate conditions, among other things. And they finish up with a flourish, too:

"As we have emphasized, we were not the first to attempt quantitative analysis of BRET data. Previously, however, resonance energy transfer theory was misinterpreted (for example, ref. 4) or applied incorrectly (for example, ref. 5). (Note - reference 4 is to a paper by the first people to question their paper earlier this year, and reference 5 is to the work of Salahpour himself, a nice touch - DBL). The only truly novel aspect of our experiments is that we verified our particular implementation of the theory by analyzing a set of very well-characterized. . .control proteins. (Note - "as opposed to you people" - DBL). . . .In this context, the technical concerns of Salahpour and Masri do not seem relevant."

It's probably safe to say that the air has not yet been cleared. I'm not enough of a BRET hand to say who's right here, but it looks like we're all going to have some more chances to make up our minds (and to appreciate the invective along the way).

Comments (21) + TrackBacks (0) | Category: Biological News | Drug Assays | The Scientific Literature


COMMENTS

1. Anonymous on October 11, 2007 9:16 AM writes...

For a nice example of how complicated these kinds of exchanges can get, I would take a look at this exchange in Nature Chemical Biology...

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2. Analytical Chemist on October 11, 2007 10:05 AM writes...

LOL. Good title.

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3. Paul Dietz on October 11, 2007 1:51 PM writes...

My favorite scientific smackdown word is 'putative', as in: "Yo' Momma and Yo' Putative Fatha."

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4. paiute on October 11, 2007 2:09 PM writes...

My favorite series of refutations was by Cornforth in the late 70's/early 80's commenting on work done by a Samir Chatterjee (as I recall). Reading between the lines you could tell that people in Cornforth's lab had wasted a lot of time and had done a lot of bitching trying to replicate the original work without any success. One detail I remember was his comment that a particular dione allegedly characterized in the work reported IR data of two carbonyls. Cornforth observed that such a structure would actually be in the form of an enol and give the IR of same. If you were reading the journal in a really quiet place, you could actually hear Cornforth muttering, "Take that, you dry-labbing cad!"

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5. paiute on October 11, 2007 2:13 PM writes...

Found it:

In Tetrahedron Letters (1982), 23(21), 2213-16, Cornforth reports his failure to replicate the results published by one Samir Chaterjee:
"Attempts were made to verify the 1st 3 stages of a claimed synthesis of the aconitine skeleton (S. Chatterjee, 1979). Chatterjee reported [details snipped]. The authors were unable to reproduce these reports in any single particular, whether of yield, chem. nature of products, or phys. properties of the substances claimed; it is concluded that Chatterjee did not obtain the reported products of these 3 stages or any later stage. [Cornforth's results snipped.]"

Burn!

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6. Hap on October 11, 2007 2:45 PM writes...

When I took a graduate seminar, the professor referred to implementations of imaginary chemistry as "Chaterjee methylations/demethylations", because I think those were implemented in the above paper.

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7. jose on October 11, 2007 2:48 PM writes...

And then we have Scott Denmark, Angew. Chem. Int. Ed. 2001, 40, No. 12, 2255-56.

[Discussion of prior work in Denmark's labs]...We were therefore surprised to read the recent report by Buono et al. [...] Although there was no reason a priori to question the results, we were particularly struck by the remarkable facility and selectivity reported [...] However, the claims were so contrary to our own experience that we felt compelled to repeat the experiments as described by Buono et al. We describe herein the details of that exercise. Despite multiple repetitions with different experimentalists we have been unable to authenticate the results published by those authors.

[The article then end with] ... until the questions raised herein are appropriately addressed, all the results described by Buono et al. should be viewed with skepticism.

Also some juicy footnotes on papers published while in press.

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8. Wavefunction on October 11, 2007 3:19 PM writes...

The Cornforth reference seems to be:
Tetrahedron Letters, Volume 21, Issue 8, 1980, Pages 709-710

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9. Wavefunction on October 11, 2007 3:21 PM writes...

My bad; the above reference is correct. This is an additional previous one.

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10. Hap on October 11, 2007 3:54 PM writes...

The responses to LaClair's synthesis of (hexacyclinol/whatever he called it afterwards) by Rychnofsky and Porco might fit into this category as well.

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11. mevans on October 11, 2007 9:51 PM writes...

Ooh! This is exciting because I just learned about BRET...it's kind of a shame that this kind of bickering takes up space in journals, if you ask me.

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12. anonymous on October 12, 2007 1:23 AM writes...

Scott Denmark wasn’t surprised to read the report by Buono. Buono had originally submitted it to JACS, who sent it to Scott for review, and it didn’t make the cut (to put it mildly). It later appeared in Angewandte, unchanged.

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13. JSinger on October 12, 2007 8:12 AM writes...

My favorite at the opposite end of the spectrum was over a paper a few years ago on "A Solution to Statistical Problem X". A few months later, the journal published a response from someone claiming "This work completely ignores statistical problem X!"

The authors' reply explaining that addressing statistical problem X was the entire point of the paper somehow avoided using the words "you idiot" anywhere, which is more than I could have managed.

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14. TX in JP on October 12, 2007 8:25 AM writes...

I think this type of point/counterpoint is very refreshing and healthy from a scientific standpoint. In particular, when considering the amount of handwaiving arguments that I am used to hearing daily in my pharmaceutical company that get accepted without any comments due to political reasons.
And, for each one of the examples of potential scientific misconduct, there are thousands of excellent scientific level. Let's look at the glass 99% full.

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15. S on October 12, 2007 11:18 AM writes...

# 1:

Hergenrother gave a seminar this week in our dept. He spent a LOT of time emphasizing his results especially wrt the issue of tracking back cell death to actual procaspase-3 inhibition. The data seemed all right to all of us here.

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16. rcyran on October 12, 2007 12:17 PM writes...

Reminds me of my favourite putdown-

'That's not right. It's not even wrong'

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17. pharmachem on October 13, 2007 3:12 PM writes...

recently a paper from baldwin labs(?) regarding synthesis in goverdhan mehtas lab in iisc bangalore, india..wonder what happened to it..

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18. alex on October 15, 2007 4:08 AM writes...

Here is another interesting example:
G. W. J. Fleet, N. G. Ramsden, N. M. Carpenter, S. Petursson and R. T. Aplin, Some Comments on an Allegedly "Facile Synthesis of Nojirimycin," Tetrahedron Lett., 1990, 31, 405.

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19. the truth has a liberal bias on October 15, 2007 8:26 AM writes...

And here's another classic- subtle, ain't it? I strongly object to the use of the generic phrase "Indian authors" in the title and am surprised that the editors let it stand...but the rest of the manuscript speaks for itself.
-----------------

How to use major parts of a paper previously published by others to write a new one. An allegation of plagiarism by Indian authors. Levai, Albert; Toth, Gabor. Department of Organic Chemistry, University of Debrecen, Debrecen, Hung. Synthetic Communications (2002), 32(10), 1625-1631. Publisher: Marcel Dekker, Inc., CODEN: SYNCAV ISSN: 0039-7911. Journal; Miscellaneous written in English. AN 2002:449324 CAPLUS

Abstract

In our present communication we prove the allegation that Indian authors plagiarized the major parts and conclusions of our paper published in 1997 and used them in their paper published in this journal in 2000.

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20. anon@anon.com on October 15, 2007 9:41 AM writes...

There are interesting examples in the patent literature.

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21. Anonymous BMS Researcher on October 15, 2007 9:05 PM writes...


My major professor once got the same manuscript to review from the editors of six different journals. His review for journal number six read something like "I have reviewed this manuscript for six different journals and categorically recommended rejection each time. I do not wish to see it again." That was the last he heard of this paper.

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