Posted on behalf of Retread

A few chemists who were both literary and literal recently looked fairly silly on the pages of the New York Times and in the blogosphere. You can read all about it on Michelle’s Francl’s blog “”https://cultureofchemistry.blogspot.com/“>Culture of Chemistry”. See her post of 1 May ‘08 — “”https://cultureofchemistry.blogspot.com/2008/05/you-pronounce-unionized-as-un-ionized.html">How to tell if you’re really a chemist." To make a long story short, 3 chemically impossible organic molecules (5 bonds to carbon etc., etc…) spelled out the word SEX in a review of a book about (what else?) sex. The chemists missed the semantic forest while closely inspecting the chemical trees.

Is there anything inside the cell being read chemically two different ways? Yes there is, and it has implications for how we determine what in the genome is being worked on by natural selection and what is being left alone. If intron, exon, neutral selection and synonymous and nonsynonymous codons aren’t old friends, have a look at the first comment which will give you all the background you need (which is quite a bit).

People attempt to measure the rate of natural selection acting on proteins using synonymous and nonsynonymous codons in the same protein in different organisms (say hemoglobin for example). Positive selection is measured as the rate of nonsynonymous nucleotide substitution (Ka) per nonsynonymous site, relative to the underlying ‘neutral mutation rate’, which is given by the rate of synonymous substitution per synonymous site (Ks). Usually Ka is much less than Ks (as most new mutations aren’t helpful or are actually harmful — this is negative selection). Positive selection is implied by Ka/Ks greater than 1. However, strictly by chance, the ratio of nonsynonymous (Ka) to synonymous (Ks) amino acid substitutions is 2:1.

All very nice, but ESSs and ESEs are found in exons, and mutations of them will change alternate splicing (something a functioning cell has a great interest in). It’s easy to see how changing one nucleotide in an ESS or an ESE could render it more or less effective, while leaving the amino acid sequence of the underlying protein unchanged. In short, the ‘neutral mutation rate’ may in fact not be neutral at all (if it is in an ESE or an ESS). Or possibly switching one amino acid for another has nothing whatever to with the protein and everything to do with controlling alternate splicing.

Now, chemists are adept at doing all sorts of different things with the same structure. Think what organic chemists can do with a carbonyl group. But whatever they do is over and done with. In protein-coding genes, the same sequence can mean two different things without being chemically changed at all.

We are far from understanding all the things DNA can do in a cell. Less than 2% of our 3.2 gigabases of DNA codes for exons. Calling the 98% of the genome not doing so ‘junk’ is a vestige of the protein-centric era of molecular biology, just as calling changing one synonymous codon for another neutral. Both assume that the only thing that DNA does is code for protein.

The expressive power of language lies in its ambiguity not its precision. DNA may be similar as we uncover the languages it speaks. My guess is that there are more to be found.

Posted on behalf of Sugar Daddy

There seems to be this mindset among scientists, particularly chemists, that what we do is noble and somehow above the fray. Perhaps it comes from our training as graduate students. We live lives often completely removed from the world around us. We have friends who go home at 5 pm, cook dinner every night, watch TV programs, write books, do crossword puzzles, or other “normal” things. These people don’t “take” the whole weekend off; it is naturally given to them, an unalienable right of living in the “real world”. We are in a research lab and when we leave for brief periods, we don’t leave our work behind. Now that’s not necessarily a bad thing, but every now and then — going to get your driver’s license renewed, or “taking” a day off to go to some tourist site because a family member or friend is in town — we cross paths with the real world around us.

Bubble, meet daylight.

Long hours and an physico-emotional connection to our work are probably two of the most hackneyed topics amongst graduate students in science. But why is it that way? The obvious answer is ambition, a state of mind that isn’t unique to aspiring young scientists but can be applied to aspiring people in any walk of life — lawyers, politicians, chefs, artists, sports players, etc. But there is something unique about science. Many of us have a sense of elitism, that what we do really is that important, so noble, and there’s this sense of urgency that we can never put it down for fear of being overtaken. And that feeling, I think, contributes to a sense that we really shouldn’t be doing much else at all with our time. Do you think that? I know some graduate students do, and I’m curious as to where this feeling comes from: ourselves, our advisors, who are typically the ones who have risen to the top (one particularly cynical comment to a previous post comes to mind), our work environment, or other influences entirely?

Posted on behalf of Retread

In the early days of quantum mechanics Einstein and Bohr threw thought experiments (gedanken experiments) at each other like teenagers throwing firecrackers. None were thought possible at the time, although thanks to Bell and Aspect, quantum nonlocality and entanglement now have a solid experimental basis.

Two Chemiotics posts ago there appeared the following: “I doubt that most strings of amino acids have a dominant shape (e.g., biological meaning), and even if they did, they couldn’t find it quickly enough (the Levinthal paradox again).”

How would you prove me wrong? The same way you’d prove a pair of dice was loaded. Just make (using solid-phase protein synthesis) a bunch of random strings of amino acids (say 41 amino acids long) and see how many have a dominant shape. If one crystallizes it does, if not, use NMR to look at them in solution. You can’t make all of them, because the earth doesn’t have enough mass to do so (see “How many proteins can we make?” a few posts back). That’s why this is a gedanken experiment — it can’t possibly be performed in toto.

Even so, the experiment is over (and I’m wrong) if even 1% of the proteins you make have a dominant shape.

However, choosing a random string of amino acids is far from trivial. Some amino acids appear more frequently than others depending on the protein. Proteins are definitely not a random collection of amino acids. Consider collagen. In its various forms (there are over 20, coded for by at least 30 distinct genes) collagen accounts for 25% of body protein. Statistically, each of the 20 amino acids should account for 5% of the protein, yet one amino acid (glycine) accounts for 30% and proline another 15%. Even knowing this, the statistical chance of producing 300 copies in a row of glycine–any amino acid–any amino acid by random distribution of the glycines are less than zilch. But one type of bovine collagen protein has >300 such copies in its 1042 amino acids.

One further example. If you were picking out a series of letters randomly hoping to form a word, you would not expect a series of 10 ‘a’s to show up. But we normally contain many such proteins, and for some reason too many copies of the repeated amino acid produce some of the neurological diseases I (ineffectually) battled as a physician. Normal people have 11 to 34 glutamines in a row in a huge (molecular mass 384 kiloDaltons — that’s over 3000 amino acids) protein known as huntingtin. In those unfortunate individuals with Huntington’s chorea, the number of repeats expands to over 40. One of Max Perutz’s last papers [Proc. Natl. Acad. Sci. USA 99, 5591–5595 (2002)] tried to figure out why this was so harmful.

On to the actual experiment. Suppose you had made 1,000,000 distinct random sequence proteins containing 41 amino acids and none of them had a dominant shape. This proves/disproves nothing. 10^6 is fewer than the possibilities inherent in a string of 5 amino acids, and you’ve only explored 10^6/(20^41) of the possibilities.

Would Karl Popper, philosopher of science, even allow the question of how commonly proteins have a dominant shape to be called scientific? Much of what I know about Popper comes from a fascinating book “Wittgenstein’s Poker” and it isn’t pleasant. Questions not resolvable by experiment fall outside Popper’s canon of questions scientific. The gedanken experiment described can resolve the question one way, but not the other. In this respect it’s like the halting problem in computer science (there is no general rule to tell if a program will terminate).

Would Ludwig Wittgenstein, uberphilosopher, think the question philosophical? Probably not. His major work “Tractatus Logico-Philosophicus” concludes with “What we cannot speak of we must pass over in silence”. While he’s the uberphilosopher he’s also the antiscientist. It’s exactly what we don’t know which leads to the juiciest speculation and most creative experiments in any field of science. That’s what I loved about organic chemistry years ago (and now). It is nearly always possible to design a molecule from scratch to test an idea. There was no reason to make ⁷paracyclophane, other than to get up close and personal with the ring current.

If the probability or improbability of our existence, to which the gedanken experiment speaks, isn’t a philosophical question, what is?