2 Quotations

Quote #1: “I would’ve either blacked out or thrown up.”
Quote #2: “When I first heard this result in a public seminar, my mind literally began to reel, leaving me dizzy and slightly nauseated.”

Gracious, the things that go on in academia.

Here’s the completion of the second quote “as all hope of understanding how sequence encodes structure seemed to suddenly vanish”  You can read all about it in [ Proc. Natl. Acad. Sci. vol. 106 pp. 21011 – 21012, 21149 – 21154 ’09 ].  It’s a bit dated but I wanted to get the Linear Algebra Survival Guide for Quantum Mechanics out of the way first.   The editorial and paper concern an interesting mutation in a protein fragment (leucine at position changed to tyrosine) which completely changes its secondary and tertiary structure from a 3 helix bundle to a 4 stranded beta sheet.  I’ve talked about CASP (thanks Matthias) before in which people are given an amino acid sequence and are asked to predict the 3 dimensional configuration of the protein (which is being determined concurrently).

There is another side of the coin. It is possible to substitute 50% or more of the amino acids in a stably folded protein using a mutagenized library, without changing the protein fold or greatly lowering the stability.  Most of the ‘tolerant’ sites are on the protein surface.   In addition, segments of 8 amino acids have been found which have different secondary structures in different tertiary structures [Proteins vol. 30 pp. 228 – 231 ’09].   They are called chameleon sequences.   and ‘usually’ consist of both strong helix-forming and strong beta strand forming amino acids. [ Curr. Opin. Struct. Biol. vol. 16 pp. 525 – 530 ’06 ].  One more example.  [ Proc. Natl. Acad. Sci. vol. 99 pp. 1280 – 1285 ’02 ] The Arc repressor secondary structure is quite sensitive to mutation, a simple interchange of amino acids #11 and #12 leads to a new structure in which each beta-strand is replaced by an alpha helix.
Way back when (1956) Noam Chomsky classified various types of formal grammars, which were of great interest to people who were just beginning to develop computer languages (as opposed to programming in machine code or assembly language).  The least general type was the context free grammar, and most computer languages are like this, in which a symbol means exactly one thing regardless of the context in which it is found.  Why?  Because such languages are easily translated into machine instructions using a program called a compiler which literally marches through the program file letter by letter.  

The above works show that the protein language is highly context dependent. So is human language, and the power of our language is its ambuiguity, not its clarity.  This may be why programming is so difficult– we think in many levels and contexts at once using metaphor and simile.  Computer languages are not this way at all. 

This was really brought home earlier this week when my wife and I went crosscountry skiing, on some beautiful trails snaking through the woods in the Berkshires.  It brought Frost’s poem “Stopping by Woods on a Snowy Evening” to mind.  But of course, the poem has almost nothing to do with snowy woods.  That’s language for you, and it may be proteins for you as well. 

Here’s Quote #1 again: ”I would’ve either blacked out or thrown up.” (if I hadn’t left the talk). It was uttered, not by a proper Victorian Lady suffering the vapors, but by Nancy Hopkins, the Amgen Inc. Professor of Biology at MIT, as quoted by the Boston Globe.  The occasion: Larry Summers’ talk about why women weren’t doing that well in the higher reaches of the scientific establishment.  Well, you all know what happened.  He lost the presidency of Harvard and was sent to a re-education camp in North Vietnam.  The story does have a happy ending of sorts.  Larry has learned to love Big Brother, in fact he’s presently at work for Big Brother himself.  Stay tuned.  
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  • Matthias Winkelmann  On February 26, 2010 at 5:53 am

    It’s CASP not CAST. Good post anyway (no Idea about the formatting, change the editor view to html if possible and remove all html-tags).

    I think the language metaphor works very well when using i. e. HMMs for secondary structure prediction which is generally quite accurate. I don’t see an easy way to use it for tertiary structure prediction, as there are then hundreds of “words” (aas) which could interact and change their meaning depending on the context. It’s just like language, except that sentences have 400 words in no apparent order.

  • Wavefunction  On February 26, 2010 at 9:54 am

    With protein structure as with real estate, it’s all about location, location, location…

    Steven Pinker had a slightly different take on Summers (link here) with which I partly agree. No subject should be so taboo that scientists are simply scared to ask even neutral, serious questions about it (examples include race and gender-specific traits). I especially like the following exchange with Pinker:

    (HARVARD) CRIMSON: Were President Summers’ remarks within the pale of legitimate academic discourse?

    PINKER: Good grief, shouldn’t everything be within the pale of legitimate academic discourse, as long as it is presented with some degree of rigor? That’s the difference between a university and a madrassa.

    CRIMSON: Would it be normal to hear a similar set of hypotheses presented and considered at a conference of psychologists?

    PINKER: Some psychologists are still offended by such hypotheses, but yes, they could certainly be considered at most major conferences in scientific psychology.

    CRIMSON: Finally, did you personally find President Summers’ remarks (or what you’ve heard/read of them) to be offensive?

    PINKER: Look, the truth cannot be offensive. Perhaps the hypothesis is wrong, but how would we ever find out whether it is wrong if it is “offensive” even to consider it? People who storm out of a meeting at the mention of a hypothesis, or declare it taboo or offensive without providing arguments or evidence, don’t get the concept of a university or free inquiry.

  • luysii  On February 26, 2010 at 5:04 pm

    Matthias — thanks for the comment. You might be interested in a previous post here concerning CASP — here’s the link –https://luysii.wordpress.com/2009/11/29/time-for-the-glass-eye-test-to-be-inserted-into-casp/.

  • luysii  On February 26, 2010 at 5:52 pm

    Wavefunction — For some reason, when I read quote #2, I remembered quote #1, even though it was uttered 5 years earlier. Memory is a strange thing. The last paragraph was fun. You can’t be serious all the time.

    I don’t want to start a debate on all this, but “Some psychologists are still offended by such hypotheses” certainly rings true. That’s why it isn’t the science it could be. How many psychologists do you suppose are currently investigating the incidence of mental disturbance in the children raised by same sex couples?

  • Wavefunction  On February 28, 2010 at 12:22 am

    You are quite right; if they are not investigating that they should!

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