Nature Chemistry | The Sceptical Chymist

Chemiotics: Chemists — masters of the Cartesian dualism

Posted on behalf of Retread

People speak of information pretty glibly. Claude Shannon defined it as various combinations of bits (binary digits which can be ones and zeros) for electronics 61 years ago in a paper written about his classified work during World War II. Neuroscientists speak of information processing by the brain as the way it manipulates its input (a series of action potentials in nerve fibers which are about as close to Shannon’s ones as you can get).

So that’s what information is. But we really don’t understand the entities (electronics, the brain) which actually do the processing terribly well. Consider first solid-state electronics, which catches Shannon’s ones and zeroes. Just how well do we understand the solid state? Not very well according to Robert Laughlin, Nobel physicist, in his book “A Different Universe: Reinventing Physics from the Bottom Down”. Quantum mechanics is now introduced to chemists in college, and I assume a course is obligatory in graduate school these days. Laughlin says it doesn’t really matter in understanding the solid state, in the same way that the underlying chemical structure of the zillions of organic compounds which have been crystallized does not in any sense matter in explaining the crystalline state. All that matters, is that each molecule adopts the same shape regardless of what that shape is (this is why proteins are hard to crystallize). The book will make your head swim.

How about the brain? Do we understand it? Ask your friendly neighborhood neuroscientist why we need sleep, or better, exactly how and where in the brain memories are stored. You may hear a few mumbles about reverberating circuits or long term potentiation, but we really don’t know. Although the brain has 10^10 neurons and probably 10^13 synapses (which is how neurons talk to each other), we can’t use statistical mechanics to understand it. Amazingly, even in the case of the monatomic ideal gas, the atoms are assumed not to interact with each other (other than collide), and their energies are sufficiently low that electronic excitation isn’t possible. Just as a list of the 10^23 positions and the 10^23 momenta do not explain the pressure of a gas, the list of what the 10^13 synapses are doing every millisecond, in addition to being incomprehensible, would not explain in any sense how and where memories are stored.

Where does chemistry come in? Consider the chemiotics posts of 9 Feb and 20 Jan. They say something profound about information, and not just in the cell. The information in DNA depends on how it’s read (one way by the ribosome reading mRNA to make a protein, another by the splicing machinery to determine what mRNA is made, and a third way by microRNAs to determine how long the mRNA hangs around). Only through chemistry can the reader of the information be understood, and I think chemists understand the readers fairly well. I’m not sure if Shannon’s concept of information entropy could even be applied to a DNA sequence being read 3 ways at once by different molecular machines. All discussions of information I’ve seen, pretty much ignore what’s actually doing the reading.

Galileo famously said, “The universe cannot be read until we have learnt the language and become familiar with the characters in which it is written. It is written in mathematical language”. Well, the information we have the best chance of understanding (because we understand the reader) is written in the language of chemistry. Thus do chemists stand astride the Cartesian dualism of materiality and the nonphysicality of information.


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    JZ said:

    In fact proteins are not HARD to crystallize – the hard part is obtaining a good difraction pattern, which comes from proteins all crystallizing in the same conformation. The proteins that are hard to crystallize usually are this way because they have regions that do not form good crystal packing contacts, either through inherent instability or electrostatics. In fact, there are cases in which more than one different conformations are seen in the same crystal.


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    Retread said:

    JZ — sorrry for the delay in responding, but I can’t find my copy of “Crystallography made Crystal Clear” which made crystallizing anything sound quite difficult — using robots to find the best conditions etc. etc. If crystallizing proteins was so easy we’d know the exact structure of the Abeta peptide as it aggregates to form (most of) the senile plaque of Alzheimer’s disease. There must be hundreds of papers trying to figure out just what’s going on, but crystals are not to be found apparently and the papers approach this very important problem obliquely.

    Similarly, the first paper describing a G protein coupled receptor (GPCR) in a mammalian system appeared in 2007, despite enormous interest in this protein class by pharmacologists and drug developers. Even granted that the GPCR is membrane embedded, a huge amount of work went into getting the protein in some kind of shape to determine its structure.

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    Yggdrasil said:

    Atomic resolution structues of amyloid-forming peptides (including the peptide from the infamous Alzheimer’s amyloid-beta protein) were somewhat recently solved by David Eisenberg’s group (Sawaya et al. Nature 2007, doi:10.1038/nature05695). Furthermore, the first mamalian GPCR structure was not the beta-adrenergic receptor structure solved in 2007. It was the structure of bovine rhodopsin solved in 2000 (Palczewski et al. Science 2000, doi: 10.1126/science.289.5480.739).

    In regard to crystallizing proteins, it is true that structural biology projects often stall because the protein fails to crystallize. However, structural biology projects can often fail before or after the crystallization phase. For example, many proteins, especially many GPCRs, are very difficult to express and purify recombinantly. Also, even if one has crystals of the protein, it can be difficult to get these crystals to diffract to sufficiently high resolution. It can also be difficult to obtain the phases for the reflections in the diffraction pattern, which are important for interpreting the diffraction pattern and building a structural model. Indeed, although the ribosome had been crystallized in the 1980s, the structure of the ribosome was solved at atomic resolution almost two decades later primarily because of difficulties solving the phase problem (the methodology for phasing has improved dramatically since then, but phasing can still be a stumbling block for crystallographers).

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    Retread said:

    Yggdrasil — thanks for the comments. A few quibbles.

    (1) In the amyloid paper [ Nature vol. 447 pp. 453 – 457 ‘09 ] the structure representative of the Alzheimer amyloid-beta peptide is of a 6 amino acid fragment of the parent (which contains 40 to 42 amino acids). The authors themselves note “Although the 13 segment structures are known with high accuracy (resolutions between 0.85 and 2.0 A ̊ and R-factors between 0.07 and 0.24), there is lingering uncertainty as to how reflective these structures are of amyloid fibrils.” I’d call this paper yet another oblique approach to the full structure — but an important and fascinating one.

    (2) Bacteriorhodopsin and bovine rhodopsin are indeed G protein coupled receptors (GPCRs) and do have precedence, but they weren’t the GPCRs human biologists, drug developers and pharmacologists were hungering for — e.g. the type that the body throws small molecules (such as neurotransmitters) at from outside the cell. The beta1 adrenergic receptor was the first of this latter class to be determined, and the structure contained significant surprises relative to rhodopsin