The DSM again

The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-V) is in the news. The press has not been favorable, nor have two new books concerning it. Here are some links

l. A review of a book on it from today’s Nature (2 May ’13)–http://www.nature.com/nature/journal/v497/n7447/full/497036a.html
2. An article in the New York Times today concerning the Nature book and one other — neither favorable –http://www.nytimes.com/2013/05/02/books/greenbergs-book-of-woe-and-francess-saving-normal.html?ref=todayspaper&_r=0

Added 8 May ’13 The US National Institute of Mental Health (NIMH) will no longer use the Diagnostic and Statistical Manual of Mental Disorders (DSM) to guide psychiatric research, NIMH director Thomas Insel announced on 30 April. The manual has long been used as a gold standard for defining mental disorders. Insel described the DSM as ill-suited to scientific studies, and said the NIMH will now support studies that cut across DSM-defined disease categories.

But, as Ernst Mayr once said — nothing in biology makes sense except in the light of evolution. Keeping that thought in mind, what I wrote a few years ago is relevant today. Here’s the post. Although it starts off in Mathematics, it gives some history which helps explain why the DSM is the way it is.

Even so, psychiatric wisdom should be taken with a good deal of salt. A psychiatrist in my medical school class (1966) knew people who were thrown out of their psychiatric residencies because they were gay, and back then homosexuality was a psychiatric disease.

Here’s the post of 3 years ago

Reification in mathematics and medicine

Can you bring an object into existence just by naming and describing it? Well, no one has created a unicorn yet, but mathematicians and docs do it all the time. Let’s start with mathematicians, most of whom are Platonists. They don’t think they’re inventing anything, they’re just describing an external reality that is ‘out there’ but isn’t physical. So is any language an external reality, but when the last person who knows that language dies, so does the language. It will never reappear as people invent new languages, and invent them they do as the experience with deaf Nicaraguan children has shown [ Science vol. 293 pp. 1758 - 1759 '01 ]. Mathematics has been developed independently multiple times all over the world, and it’s always the same. The subject matter is out there, and not just a social construct as some say.

A fascinating book, “Naming Infinity” describes a Russian school of mathematicians who extended set theory beyond the work of the French and Germans. They literally believed that describing a mathematical object and its properties implied that the object existed (assuming the properties were consistent). The mathematicians involved were also very devout mystical Christians, who were called “Name Worshippers”. They thought that repeatedly invoking the name of Jesus would allow them to reach an ecstatic state. The rather contentious theory of the book is that their religious stance allowed them to imbue all names with powerful properties which could bring what they named into existence and this led to their extensions of set theory. Naturally the Communists hated them, and exterminated many (see p. 126). People possessed of all absolute truths dislike those possessed of a different set.

Docs bring diseases into existence all the time simply by naming them. This is why the new DSM-V (Diagnostic and Statistical Manual of Mental Disorders) of the American Psychiatric Association (APA) is so important. Is homosexuality a disease? Years ago the APA thought it was. If your teenager won’t do what you want, is this “Adolescent Defiant Disorder”? Is it a disease? It will be if the DSM-V says it is.

There are a lot of things wrong with what the DSM has become (297 disorders in 886 pages in DSM-IV), but the original impetus for the major shift that occurred with DSM-III in the 70s was excellent. So it’s time for a bit of history. Prior to that time, it was quite possible for the same individual to go to 3 psychiatric teaching hospitals in New York City and get 3 different diagnoses. Why? Because diagnosis was based on the reconstruction of the psychodynamics of the case. Just as there is no single way to interpret “Stopping by Woods on a Snowy Evening” (see the previous post), there isn’t one for a case history. Freud’s case studies are great literature, but someone else would write up the case differently.

The authors of the DSM-III decided to be more like medical docs than shrinks. In our usual state of ignorance, we docs define diseases by how they act — the symptoms, the physical signs, the clinical course. So the DSM-III abandoned the literary approach of psychodynamics and started asking what psychiatric patients looked like — were they hallucinating, did they take no pleasure in things, was there sleep disturbance, were they delusional etc. etc. As you can imagine, there was a huge uproar from the psychoanalysts.

Now no individual fits any disease exactly. There are always parts missing, and there are always additional symptoms and signs present to confuse matters. The net result was that psychiatric diagnosis became like choosing from a menu in a Chinese restaurant, so many symptoms and findings from column A, so many from column B. (Update 2013 — Having been to China for 3 weeks this year, restaurant menus over there aren’t like that).

This led to a rather atheoretical approach, but psychiatric diagnoses became far more consistent. Docs have always been doing this sort of thing and still do (look at the multiple confusing initial manifestations of what turned out to AIDS back in the 80s). Different infections were classified by how they acted, long before Pasteur proved that they were caused by micro-organisms. Back when I was running a muscular dystrophy clinic, we saw something called limb girdle muscular dystrophy , in which the patients were weak primarily in muscles about the shoulders and hips. Now we know that there are at least 13 different genetic causes of the disorder. So there are many distinct causes of the same clinical picture. This is similar to the many different genetic causes of Parkinson’s disease I talked about 2 and 3 posts earlier. At least with limb girdle muscular dystrophy it is much easier to see how the genetic defects cause muscle weakness — all of the known genetic causes involve proteins found in muscle.

Where DSM-IV (and probably DSM-V — it’s coming out later this month) went off the rails, IMHO, is the multiplicity of diagnoses they have reified. Do you really think there are 297 psychiatric disorders? Not only that, many of them are treated the same way — with an SSRI (Selective Serotonin Reuptake Inhibitor). You don’t treat all infections with the same antibiotic. This makes me wonder just how ‘real’ these diagnoses are. However in defense of them, you do treat classic Parkinsonism pretty much the same way regardless of the genetic defect causing it (and at this point we know of genetic causes of less than 10% of cases).

There is a fascinating series of articles in Science starting 12 Feb ’10 about the new DSM-V. The first is on pp. 770 – 771. One of the most interesting points is that 40% of academic inpatients receive a diagnosis of NOS (Not Otherwise Specified — e.g. not in the DSM-IV — clearly even 297 diagnoses are missing quite a bit).

But insurance companies and the government treat this stuff as holy writ. Would you really like your frisky adolescent labeled with “prepsychotic risk syndrome” which is proposed for DSM-V. Also, casting doubt on the whole enterprise, are the radical changes the DSM has undergone since it’s inception nearly 60 years ago. We’ve learned a lot about all sorts of medical diseases since then, but strokes and heart attacks back then are still strokes and heart attacks today and TB is still TB. Do these guys really know what they’re talking about, and should we allow them to reify things?

That being said, cut psychiatry some slack. Regardless of theory, there are plenty of mentally ill people out there who need help. They aren’t going to go away (or get better) any time soon. Psychiatrists (like all docs) are doing the best they can with what they know.

That’s why it’s nice to be retired and reading stuff that it is at least possible to understand — like math, physics, organic chemistry and molecular biology. But never forget that it is trivial compared to human suffering. That’s why the carnage in the drug discovery industry is so sad — there goes our only hope making things better (written in 2010, but still true in 2013).

Retinal physiology and the demise of the pure percept

Rooming with 2 philosophy majors warps the mind even if it was 50 years ago.  Conundrums raised back then still hang around.  It was the heyday of Bertrand Russell before he became a crank.  One idea being bandied about back then was the ‘pure percept’ — a sensation produced by the periphery  before the brain got to mucking about with it.   My memory about the concept was a bit foggy so who better to ask than two philosophers I knew.

The first was my nephew, a Rhodes in philosophy, now an attorney with a Yale degree.  I got this back when I asked –

I would be delighted to be able to tell you that my two bachelors’ degrees in philosophy — from the leading faculties on either side of the Atlantic — leave me more than prepared to answer your question. Unfortunately, it would appear I wasn’t that diligent. I focused on moral and political philosophy, and although the idea of a “pure precept” rings a bell, I can’t claim to have a concrete grasp on what that phrase means, much less a commanding one.

 Just shows what a Yale degree does to the mind.

So I asked a classmate, now an emeritus prof. of philosophy and got this back

This pp nonsense was concocted because Empiricists [Es]–inc. Russell, in his more empiricistic moods–believed that the existence of pp was a necessary condition for empirical knowledge. /Why? –>
1. From Plato to Descartes, philosophers often held that genuine Knowledge [K] requires beliefs that are “indubitable” [=beyond any possible doubt]; that is, a belief counts as K only if it [or at least its ultimate source] is beyond doubt. If there were no such indubitable source for belief, skepticism would win: no genuine K, because no beliefs are beyond doubt. “Pure percepts” were supposed to provide the indubitable source for empirical K.
2. Empirical K must originate in sensory data [=percepts] that can’t be wrong, because they simply copy external reality w/o any cognitive “shopping” [as in Photoshop]. In order to avoid any possible ‘error’, percepts must be pure in that they involve no interpretation [= error-prone cognitive manipulation].
{Those Es who contend  that all K derives from our senses tend to ignore mathematical and other allegedly a priori K, which does not “copy” the sensible world.} In sum, pp are sensory data prior to [=unmediated by] any cognitive processing.

So it seems as though the concept is no longer taken seriously.  To drive a stake through its heart it’s time to talk about the retina.

It lies in the back of our eyes, and is organized rather counter-intuitively.  The photoreceptors (the pixels of the camera if you wish) are the last retinal elements to be hit by light, which must pass through the many other layers of the retina to get to them.

We have a lot of them — at least 100,000,000 of one type (rods).  The nerve cells sending impulses back to the brain, are called ganglion cells, and there are about 1,000,000 in each eye.  Between the them are bipolar cells and amacrine cells which organize the information falling on the photoreceptors.

All this happens in something only .2 milliMeters thick.

The organization of information results in retinal ganglion cells responding to different types of stimuli.  How do we know?  Impale the ganglion cell with an electrode while still in the retina, and try out various visual stimuli to see what it responds to.

Various authorities put the number of retinal ganglion cell types in the mouse at 11, 12, 14, 19 and 22.  Each responds to a given type of stimulus. Here are a few examples:

The X-type ganglion cell responds linearly to brightness

Y cells respond to movement in a particular direction,

Blue-ON transmits the mean spectral luminance (color distribution) along the spectrum from blue to green.

From an evolutionary point of view, it would be very useful to detect motion.  Some retinal ganglion cells being responding before they should. How do we know this?  It’s easy (but tedious) to map the area of visual space a ganglion cell responds to — this is called its receptive field.  The responses of some anticipate the incursion of a moving stimulus — clearly this must be the way they are hooked to photoreceptors via the intermediate cells.

Just think about the way photoreceptors at the back of the spherical eye are excited by something moving in a straight line in visual space.  It certainly isn’t a straight line on the retinal surfaced.  Somehow the elements of the retina are performing this calculation and predicting where something moving in a straight line will be next.  Why  couldn’t the brain bedoing this?  Because it can be seen in isolated retinas with no brain attached.

Now for something even more amazing.  Each type of ganglion cell (and I’ve just discussed a few) tiles the retina. This means that every patch of the retina has a ganglion cell responding to each type of visual stimulus.  So everything hitting every area of the retina is being analyzed 11, 12, 14, 19 or 22 different ways simultaneously.

So much for the pure percept: it works for a digital camera, but not the retina.  There is an immense amount of computation of the visual input going right there, before anything gets back to the brain.

If you wish to read more about this — an excellent review is available, but it’s quite technical and not for someone coming to neuroanatomy and neurophysiology for the first time.  [ Neuron vol. 76 pp. 266 - 280 '12 ]

The New Clayden pp. 931 – 969

p. 935 — I don’t understand why neighboring group participation is less common using 4 membered rings than it is using  3 and 5 membered rings.  It may be entropy and the enthalpy of strain balancing out.  I think they’ve said this elsewhere (or in the previous edition).   Actually — looking at the side bar, they did say exactly that in Ch. 31.  

As we used to say, when scooped in the literature — at least we were thinking well.

p. 935 — “During the 1950′s and 1960′s, this sort of question provoked a prolonged and acrimonious debate”  – you better believe it.  Schleyer worked on norbornane, but I don’t think he got into the dust up.  Sol Winstein (who Schleyer called solvolysis Sol) was one of the participants along with H. C. Brown (HydroBoration Brown).

p. 936 — The elegance of Cram’s work.  Reading math has changed the way I’m reading organic chemistry.  What you want in math is an understanding of what is being said, and subsequently an ability to reconstruct a given proof.  You don’t have to have the proof at the tip of your tongue ready to spew out, but you should be able to reconstruct it given a bit of time.   The hard thing is remembering the definitions of the elements of a proof precisely, because precise they are and quite arbitrary in order to make things work properly.  It’s why I always leave a blank page next to my notes on a proof — to contain the definitions I’ve usually forgotten (or not remembered precisely).

I also find it much easier to remember mathematical definitions if I write them out (as opposed to reading them as sentences) as logical statements.  This means using ==> for implies | for such that, upside down A for ‘for all’, backwards E for ‘there exists, etc. etc. There’s too much linguistic fog in my mind when I read them as English sentences.

       So just knowing some general principles will be enough to reconstruct Cram’s elegant work described here.  There’s no point in trying to remember it exactly (although there used to be for me).   It think this is where beginning students get trapped — at first it seems that you can remember it all.  But then the inundation starts.  What should save them, is understanding and applying the principles, which are relatively few.  Again, this is similar to what happens in medicine — and why passing organic chemistry sets up the premed for this style of thinking. 

p. 938 – In the example of the Payne rearrangement, why doesn’t OH attack the epoxide rather than deprotonating the primary alcohol (which is much less acidic than OH itself).

p. 955 – Although the orbitals in the explanation of why stereochemistry is retained in 1,2 migrations are called  molecular orbitals (e.g. HOMO, LUMO) they look awfully like atomic orbitals just forming localized bonds between two atoms to me.  In fact the whole notion of molecular orbital has disappeared in most of the explanations (except linguistically).  The notions of 50 years ago retain their explanatory power.  

p. 956 — How did Eschenmoser ever think of the reaction bearing his name?  Did he stumble into it by accident? 

p. 956 — The starting material for the synthesis of juvenile hormone looks nothing like it.  I suppose you could say its the disconnection approach writ large, but the authors don’t take the opportunity.   The use of fragmentation to control double bond stereochemistry is extremely clever.   This is really the first stuff in the book that I think I’d have had trouble coming up with.  The fragmentation syntheses at the end of the chapter are elegant and delicious.

On a more philosophical note, the use of stereochemistry and orbitals to make molecules is exactly what I mean by explanatory power.  Anti-syn periplanar is a very general concept, which I doubt was brought into being to explain the stereochemistry of fragmentation reactions (yet it does).  It appears over and over throughout the book in various guises.

Urysohn’s Lemma

“Now we come to the first deep theorem of the book,. a theorem that is commonly called the “Urysohn lemma”.  . . .  It is the crucial tool used in proving a number of important theorems. . . .  Why do we call the Urysohn lemma a ‘deep’ theorem?  Because its proof involves a really original idea, which the previous proofs did not.  Perhaps we can explain what we mean this way:  By and large, one would expect that if one went through this book and deleted all the proofs we have given up to now and then handed the book to a bright student who had not studied topology, that student ought to be able to go through the book and work out the proofs independently.  (It would take a good deal of time and effort, of course, and one would not expect the student to handle the trickier examples.)  But the Uyrsohn lemma is on a different level.  It would take considerably more originality than most of us possess to prove this lemma.”

The above quote is  from  one of the standard topology texts for undergraduates (or perhaps the standard text) by James R. Munkres of MIT. It appears on  page 207 of 514 pages of text.  Lee’s text book on Topological Manifolds gets to it on p. 112 (of 405).  For why I’m reading Lee see https://luysii.wordpress.com/2012/09/11/why-math-is-hard-for-me-and-organic-chemistry-is-easy/.

Well it is a great theorem, and the proof is ingenious, and understanding it gives you a sense of triumph that you actually did it, and a sense of awe about Urysohn, a Russian mathematician who died at 26.   Understanding Urysohn is an esthetic experience, like a Dvorak trio or a clever organic synthesis [ Nature vol. 489 pp. 278 - 281 '12 ].

Clearly, you have to have a fair amount of topology under your belt before you can even tackle it, but I’m not even going to state or prove the theorem.  It does bring up some general philosophical points about math and its relation to reality (e.g. the physical world we live in and what we currently know about it).

I’ve talked about the large number of extremely precise definitions to be found in math (particularly topology).  Actually what topology is about, is space, and what it means for objects to be near each other in space.  Well, physics does that too, but it uses numbers — topology tries to get beyond numbers, and although precise, the 202 definitions I’ve written down as I’ve gone through Lee to this point don’t mention them for the most part.

Essentially topology reasons about our concept of space qualitatively, rather than quantitatively.  In this, it resembles philosophy which uses a similar sort of qualitative reasoning to get at what are basically rather nebulous concepts — knowledge, truth, reality.   As a neurologist, I can tell you that half the cranial nerves, and probably half our brains are involved with vision, so we automatically have a concept of space (and a very sophisticated one at that).  Topologists are mental Lilliputians trying to tack down the giant Gulliver which is our conception of space with definitions, theorems, lemmas etc. etc.

Well one form of space anyway.  Urysohn talks about normal spaces.  Just think of a closed set as a Russian Doll with a bright shiny surface.  Remove the surface, and you have a rather beat up Russian doll — this is an open set.  When you open a Russian doll, there’s another one inside (smaller but still a Russian doll).  What a normal space permits you to do (by its very definition), is insert a complete Russian doll of intermediate size, between any two Dolls.

This all sounds quite innocent until you realize that between any two Russian dolls an infinite number of concentric Russian dolls can be inserted.  Where did they get a weird idea like this?  From the number system of course.  Between any two distinct rational numbers p/q and r/s where p, q, r and s are whole numbers, you can  always insert a new one halfway between.  This is where the infinite regress comes from.

For mathematics (and particularly for calculus) even this isn’t enough.  The square root of two isn’t a rational number (one of the great Euclid proofs), but you can get as close to it as you wish using rational numbers.  So there are an infinite number of non-rational numbers between any two rational numbers.  In fact that’s how non-rational numbers (aka real numbers) are defined — essentially by fiat, that any series of real numbers bounded above has a greatest number (think 1, 1.4, 1.41, 1.414, defining the square root of 2).

What does this skullduggery have to do with space?  It says essentially that space is infinitely divisible, and that you can always slice and dice it as finely as you wish.  This is the calculus of Newton and the relativity of Einstein.  It clearly is right, or we wouldn’t have GPS systems (which actually require a relativistic correction).

But it’s clearly wrong as any chemist knows. Matter isn’t infinitely divisible, Just go down 10 orders of magnitude from the visible and you get the hydrogen atom, which can’t be split into smaller and smaller hydrogen atoms (although it can be split).

It’s also clearly wrong as far as quantum mechanics goes — while space might not be quantized, there is no reasonable way to keep chopping it up once you get down to the elementary particle level.  You can’t know where they are and where they are going exactly at the same time.

This is exactly one of the great unsolved problems of physics — bringing relativity, with it’s infinitely divisible space together with quantum mechanics, where the very meaning of space becomes somewhat blurry (if you can’t know exactly where anything is).

Interesting isn’t it?

The New Clayden pp. 877 – 908

p. 878 — “The transition state has 6 delocalized pi electrons and thus is aromatic in character”.  Numerically yes, but the transition state isn’t planar, and there is all sorts of work showing how important planarity is to aromaticity. 

p. 881 — It seems to me that the arrow is wrong in the equation at the bottom. Entropy should increase when a Diels Alder product is broken apart, and since deltaG = deltaH  - T * deltaS heating the product should break it apart not cause it to form.  I guess the heat shown is required to increase molecular velocity so that collisions result in reaction.   Enough kinetic energy will blow anything apart (see Higgs particle).

p. 890 — “It is not cheating to use the regioselectivity of chemical reactions to tell us about the coefficients of the orbitals involved.”    I do think that this sort of thing is  cheating when you use the regioselectivity of chemical reactions as an explanation.  They are adding nothing new.  A real explanation predicts new phenomena, the way the anomeric effect does, for example.  You should contemplate the point at which a description of something becomes an explanation (e.g. epistemology).   It’s not the case here, but it was the case for Newton’s laws of gravitation.  Famously he said Hypotheses non dingo (“I frame no hypotheses”).  It appears in the following

I have not as yet been able to discover the reason for these properties of gravity from phenomena, and I do not feign hypotheses.

Yet his laws of gravity were used to predict all sorts of events never before seen, so they are explanatory in some sense.  

This sort of thing is just what a neurologist experiences learning functional neuroanatomy (e.g.  which part of the nervous system has which function).  Initially almost all of it was developed by studying neurologic deficits due to various localized lesions of the brain and spinal cord.  There’s a huge caveat involved — pulling the plug on a radio will stop the sound, but that isn’t how the sound is produced.  People with lesions of the occipital lobe lose the ability to see in certain directions (parts of their visual fields).  Understanding HOW the occipital lobe processes sensory input from the eyes has taken 50 years and is far from over.  

p. 892 — Unfortunately the rationale behind  the Woodward Hoffmann rules isn’t covered, so it appears incredibly convoluted and arbitrary.  Read the book — “The Control of Orbital Symmetry” which they wrote.  Also, unfortunately, the description of the rules uses the term ‘component’ in two ways.  At step two butadiene and the dienophile are each considered a component, as they are in steps 3, 4, and 5, then the two are mushed together into a single component in step 6. 

p. 894 — I haven’t been looking at the animations for a while, but those of the Diels Alder type reactions are incredible, and almost sexual.  You can rotate the two molecules in space and watch them come together and react.

p. 894 –”Remember, the numbers in brackets, [ 4 + 2 ] etc., refer to the numbers of atoms.  The numbers (4q +2)s and (4r)s in The Woodward Hoffman (should be Hoffmann) refer to the numbers of electrons.”  This is so very like math, where nearly identical characters are used to refer to quite different things.  Bold capital X might mean one thing, italic x another, script X still another.  They all sound the same when you mentally read them to yourself.  It makes life confusing. 

p. 894 — The Alder ene reactions — quite unusual.  The worst thing is that I remember nothing about them from years ago.  They must have been around as they were discovered by Alder himself (who died in 1958).  They produce some rather remarkable transformations, the synthesis of menthol from citronellal being one.  I wonder if they are presently used much in synthetic organic chemistry. 

p. 900 — How do you make OCN – SO2Cl, and why is it available commercially?

p. 904 — The synthesis of the sulfur containing 5 membered ring of biotin is a thing of beauty.  It’s extremely non-obvious beginning with a 7 membered ring with no sulfur at all. 

The New Clayden pp. 757 — 800

 

Chapter 30: There’s a lot more use of the disconnection approach in the discussions of the synthesis of heterocylic aromatic compounds than there was in the previous edition.  The analysis of the Viagra synthesis pp. 768 –> is particularly fascinating.

The sophistication of the chapter is much higher than what went on previously.  It’s great !  The writer assumes that you have all the previous reactions well under your belt, as well as disconnection and moves rapidly on from there.  

In a sense it’s like the switch from undergraduate math books where proofs are laid out in detail, to the graduate lectures, where proofs are sketched and you are expected to fill in the dots.  I wonder how a neophyte hitting this chapter for the first time would take it. 

One can take the analogy a bit further.  The target molecule can  be considered the theorem and and the synthesis the proof.  This is exactly why math is harder than organic chemistry.  The target molecule is almost telling you (thanks to the disconnection approach) how to make it.  The examples in this chapter are fairly simple.  Yet most accounts of syntheses focus on one or two most difficult steps and the target is far more complex — for an example see ttp://heterocyclist.com/2012/08/24/synthesis-of-kopsia-lapidilecta-alkaloids-the-rcm-approach-takes-a-hit-retraction/.

In medical school, the importance of taking an accurate history was stressed — “The patient is telling you the diagnosis” was said over and over, just as the structure of a synthetic target is telling you how to make it.  Certainly, with each passing year, the MD finds the history more and more valuable, and the physical exam less.  Medicine has one further wrinkle that math and synthetic organic chemistry do not.  The manner in which  the patient gives the history and answers your questions is incredibly important.  It’s not just the words, it’s the tune.  Is the patient depressed, angry, confused, hyped-up etc. etc.  That’s why I always took the history myself, and never had the patient fill out some checklist, it throws away information you can get in no other way

I don’t know enough math to know if proofs break down this way.  But there is another huge difference between math and orgo.  In math the definitions are incredibly precise.  A collection of subsets of a given set either satisfies 3 extremely specific criteria to make them open sets and the containing set into a topology, or they don’t.  Chemical reactions aren’t like that — Anslyn and Dougherty take you through Sn1 and Sn2 and their variants, and then show you how there are reactions that fall between them, containing aspects of both.   The idea of a Diels Alder reaction, is independent of any particular exemplar — so the concepts in chemistry are inherently fuzzy.  If you’re good at reasoning by analogy, then chemistry is your oyster.  Don’t try this in a mathematical proof.  So the zillion mathematical definitions (first countable, compactness, path connected in its varieties) must be memorized exactly as they are, and used in proofs that way, and that way only.   Medical concepts are even fuzzier.  It takes a very different type of mind to do math well, one which, unfortunately, I don’t posses, even though I love the stuff.

 Back to chemistry

p. 772 The example of the tautomer of the thioamide interacting with an alpha haloketone is a great example of hard/hard nucleophile/electrophile and soft/soft nucleophile/electrophile interactions occuring specifically in the same pair of molecules, while quite near to each other.  It should probably be pointed to in the next edition when  hard/soft nucleophiles and electrophiles are first discussed. 

p. 775 — Interesting that they didn’t call the reaction of an alkyne and an azide ‘click chemistry‘ which is what Sharpless calls it.  It has proved extremely useful in linking together molecules of biologic interest — e.g. seeing where a protein is binding to other proteins or to DNA.  The uses are endless and still being discovered. 

Here are a few examples:

       [ Proc. Natl. Acad. Sci. vol. 98 pp. 4740 - 4745 '01 ] Propargyl choline is a choline derivative which can be used to label choline containing phospholipids using Click chemistry  (forming cycloaddition products with a fluorophore containing an azide.  Total lipid analysis of labeled cells shows strong incorporation of propargyl choline into all classes of choline phospholipids — and the fatty acid composition of these lipids is quite normal. 

        [ Proc. Natl. Acad. Sci. vol. 105 pp. 2415 - 2420 '08 ] It was used to quickly label DNA using 5 ethynyl 2′ deoxy uridine — which can be detected using fluorescence. 

       [ Science vol. 320 pp. 868 - 869 '08 ] It is a modification of the Huisgen reaction — the trick was using Copper Iodide as a catalyst.  Polymer scientists love it.

        Another type of click reaction adds a thiol across an olefin using light. 

 

       [ Proc. Natl. Acad. Sci. vol. 107 pp. 15329 - 15334 '10 ] Oligonucleotides can be produced by automated solid phase phosphoramidite synthesis — chains over 100 (deoxy) nucleotides can be formed.  It’s harder with RNA because of the reactivity of the 2′ OH group which requires selective protection.  So the limit here is 50 nucleotides.  This work describes click ligation as a way to put them together. 

p. 793 — A very useful explanation of the nomenclature of heterocyclic ring compounds (which is actually or logical than it first appears). 

p. 794 — Aziridine is less basic than pyroldine and piperidine, because the hybridization of the nitrogen has more s character. But no mention is made of why this should mean less basicity — it’s because the s orbital experiences the positive charge of the nucleus more intensely than a p orbital (which has a node at the nucleus), lowering its energy and making it less likely to share (like a spoiled child). 

p. 796 – While coupling NMR is through bonds rather than throught space (e.g. more coupling between H’s trans to each other on a double bond, than cis — they never explained why this is so, nor do they here. 

p. 796 — It don’t see why the dihedral angle in the bicyclic compound shown is any different from 60 degrees, the axial equatorial bond separation, unless the ring configuration by compressing the C – C – C angle, expands the H – C – H angle.

p. 797 — Why is the shift of the  hydrogen on the carbon containing the OH groups so different between axial (3.5) and equatorial (4.0)? 

p. 799 — Neurologists are excellent at reading MRI scans of patients (or they should be), these vary in appearance depending on whether they use T1 or T2 relaxation.  But the whole issue of relaxation from a higher energy state to a lower one is rarely discussed.  

The text says “So far we have assumed that the drop back down (to a lower energy state) is spontaneous, just like a rock falling off a cliff.  In fact it isn’t — something needs to ‘help’ the protons to drop back again — a process called relaxation”.  Why is this the case? Is it similar to laser action, where something needs to stimulate the drop down to a lower energy state with the emission of laser light.  Perhaps one of the cognoscenti reading this can explain why help is needed for a transition to a lower energy state.  I don’t understand it.

Being able to admit you don’t know something and publicly asking for help is one of the joys of being a non-academic.  I doubt that I’d be able to do this if I were a chemistry department chair, as at least 3 – 4 of my fellow Harvard graduate students 52 years ago became (one of them is still at it and going strong — also to be noted is that he came out of a State University). 

Accordions and Molecular Evolution

[ Cell vol. 150 pp. 671 - 672, 831 - 841 '12 ] Describes a remarkable mechanism of molecular evolution under selection pressure.  No one has picked it up till now because it removes traces of itself.  Essentially the genome expands and contracts like an accordion.  But first a joke.

By and large classical musicians loathe the accordion.  So naturally at a chamber music get together for amateurs we were surprised when, at the opening meeting, the organizer told us that one of the piano coaches (Cary Lewis) actually loved the accordion and taught people how to play it.  He would go to the roughest neighborhoods to bring accordion knowledge to the masses.  One dark night, he parked his car leaving a spare accordion in it while he went inside to give a lesson.  When he came out he found the windshield smashed and inside — 3 more accordions.

The system described in Cell involves a poxvirus (vaccinia –used to vaccinate against smallpox, another poxvirus).  Cells have all sorts of viral defenses, on of which is called PKR (the actual mechanism is irrelevant).  Vaccinia has a protein called K3L which rather ineffectively negates the PKR effect (the mechanism is irrelevant).

The virus responds to this selection pressure by producing additional copies of the K3L gene, which means that the virus makes more of it when infecting a cell, increasing resistance.  If selection is relaxed (which happens in a permissive host), the K3L gene copy number drops — it takes a lot of metabolic energy to make more DNA.

If selection continues, eventually a rare mutation occurs in one of the gene copies of K3L, making it more effective in combating PKR.  When this happens the copy number of the K3L gene drops leaving the more effective variant as the only gene.

Essentially the K3L gene is expanding and contracting like an accordion in response to selection pressure.  The expansion allows far more rapid evolution of an effective response to PKR than would happen with a single copy.

The interesting point, is that once contraction occurs, there is no trace of the accordion mechanism left in the genome, just a more effective protein.  The same process has been shown to generate antibiotic resistance, and to explain the evolution of enzymes (in bacteria) that degrade man-made pollutants.

Whether accordions occur in our genome isn’t known.  Even if it doesn’t normally, it likely does occur in cancer cells. Similarly, whether accordions explain the emergence of genes with new functions from old ones isn’t known, but people are sure to be working to find out.

Just another reason to keep reading the literature.  There is always something new and unexpected.  Shakespeare knew this years ago.

There are more things in heaven and earth, Horatio,
Than are dreamt of in your philosophy.
- Hamlet (1.5.166-7), Hamlet to Horatio

 

How Badly Are Thy Genomes, Oh Humanity

With apologies to Numbers 24:5, “How goodly are thy tents, Oh Jacob” —  a recent paper shows how shockingly error ridden our genomes actually are [ Science vol. 337 pp. 64 - 69 '12 ].  The authors sequenced roughly three quarters of the genes coding for proteins in some 2,439 people — e.g. 15,585 protein coding genes.  This left 98% of the genome untouched, primarily because we really don’t know what it does or how it does it, despite the fact that it controls, when, where and how much of each protein is made.  So they basically looked at the bricks from which we are built (the proteins) and not the plans (the 98%).

The news is not very good.  The subjects came from two groups: 1,351 Europeans and 1,088 Africans (the latter, because genetic diversity is far higher among Africans as that’s where humanity arose, and where mutations have had the longest time to accumulate).

The news is not very good. First, some background.

Recall that each nucleotide is one of four possibilities (A, T, G, C), and that each 3 nucleotides therefore has 4^3 = 64 possibilities.  61/64 combinations code for amino acids which, since we have only 20 gives a certain redundancy of the famed genetic code.   The other 3 combinations code for no amino acid (usually) and tell the machinery making proteins to stop.  Although crucial to our existence, these are called nonsense codons.

The genetic code is therefore 3fold degenerate (on average).  However, some amino acids are coded for by just 1 combination of 3 nucleotides while others are coded by as many as 6.  So some single nucleotide variants (SNVs) leave the amino acid coded for the same (these are the synonymous SNVs), while others change the amino acid (nonSynonymous SNVs), and possibly protein function.

Ask some one with sickle cell anemia how much trouble just one nonSynonymous SNV can cause — it’s only 1 amino acid out of 147.  Even worse, ask someone with cystic fibrosis where just one of 1,480 amino acids is missing.

Here’s the bad news.  In the population as a whole, they found 500,000 single nucleotide variants (SNVs).  If you’re still not sure what is meant by this, the 5 articles in https://luysii.wordpress.com/category/molecular-biology-survival-guide/ should be all the background you need.

More than 400,000 of the variants were previously unknown.  Also more than 400,000 of them were found either in Africans or Europeans but not both.  If you divide 500,000 by 2,439 you get 205 variants per person.  However, SNVs are far more common than that, and each individual contains an average of 14,000.

Well, how many of the 500,000 or so CNVs they found are nonSynonymous? One would think about 1/3 statistically.  However, They found more than half 292,125/500,000 — nearly 60% — were nonSynonymous.

It get’s worse: 6,165 of the nonSynonymous variants are nonSense codons.  This means that the protein coded for by such a gene, terminates prematurely, meaning that it can terminate anywhere.  On average one would expect that half of these nonsense codons result in a protein of less than half the normal length.   This would very likely obliterate whatever function the protein had.

Obviously, they couldn’t test all 500,000 SNVs to see how they affected protein function (and we really only have a decent idea of what half our 20,000 or so proteins are doing).  They had to guess.  They came up with a figure of 2 – 4% of the 14,000 SNVs being functionally significant — That’s 280 – 560 significant mutations per individual.

Clearly, despite the horrible examples of cystic fibrosis and sickle cell anemia above, most of these can’t be doing very much, because these were normal people being studied.

There are all sorts of implications of this work.  One is the subject of a future post — how hard this diversity makes drug discovery.  Another reiterates the Tolstoy theme mentioned earlier about the genetic defects causing schizophrenia and autism — ““Happy families are all alike; every unhappy family is unhappy in its own way”.  Thus beginneth Anna Karenina.

For details please see http://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/  and  http://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/

A third is that this shows that the 1000 fold expansion of the human population has pretty much obviated much natural selection eliminating these variants.  I’ll leave it to the geneticists to figure out what this means for the eventual survival of the species, as these mutants continue to accumulate.

The paper is fascinating, and sure to change our conception of what a ‘normal’ genome actually is.  Nonetheless, all they did was follow Yogi Berra’s dictum – ”You can observe a lot by watching.”   It certainly wasn’t creative or ingenious in any sense.  Sometimes grunt work like this wins the day.  I’ll leave this to Ashutosh to write about its philosophical implications for research.

The New Clayden pp. 222 – 268

p. 228 A picture of a Dean Stark head would be useful. 

p. 230 — Second paragraph from the bottom, 4th line ‘hemiacetal’ should be ‘hemiaminal’

p. 231 — Hard (for me) to see why stereoisomers of imines should interconvert and those of oximes should not.  Perhaps the oxygen is also hybridized sp2?  On p. 232 this appears to be the case, in explaining the stability of oximes, hydrazones and semicarbazones. 

p. 238 — The 4 membered ring of the Wittig intermediate isn’t as strained as it might look because the P – O bond is 1.76 Angstroms, and the P-C bond is 1.87 giving the ring a bit more room, but the spiro bond shown can’t change much due to the cyclohexane ring.  If anyone has actually seen the intermediate and measured its shape it would be interesting to know exactly what it looks like. 

p. 246 — A way to think of enthalpy change, is to remember the first law of thermodynamics — energy is neither created or destroyed. Crudely, enthalpy is just a measure of internal energy.   Also rather crudely, if the products of a reaction are of lower energy than the starting material, some form of energy must be given off (usually heat), and the products have lower enthalpy (a measure of internal energy).  Why ‘crudely’?  Because the discussion ignores entropy. 

p. 247 — Amusing, how chemists possess a very intuitive understand of entropy and enthalpy giving them essentially all the thermodynamics they need.  Think of the hard intellectual work involved in the Clausius’ definition of entropy  – the reversible heat supplied divided by the temperature at which it is supplied.  Chemical thinking is far closer to Boltzmann –  S = k log W. 

p. 248 — It’s worth thinking why the enthalpy of a molecule doesn’t change much with temperature.  It’s basically the energy of the bonds it contains, which is pretty much the same until the bonds are broken (and the molecule changes). 

It’s also worthwhile pausing and thinking what we mean by a ‘strong bond’ — it’s one that requires a large input of energy to break.  So even though we describe a strong bond as high energy, it’s really much lower in enthalpy than separating the atoms that make it up. 

p. 248 — Le Chatelier’s principle may be the basis of a treatment to dissolve the senile plaques of Alzheimer’s disease (and help the condition if they are what’s causing the problem — something rather contentious as of 5/12).  For details see – http://luysii.wordpress.com/2012/03/04/could-le-chateliers-principle-be-the-answer-to-alzheimers-disease/

p. 251 — The concept of a transition state is valid (because we use it all the time and it appears to work).  But, by definition, a transition state can’t be isolated (unlike reaction intermediates), so is it as scientifically valid as the number of Angels which can fit on the head of pain or is it ‘real’ in a truly scientific sense?  

The transition state concept assumes that the states of a molecule are ‘complete’ in the following mathematical sense.  By complete, I mean the following.  Consider the rational numbers (ratios of whole numbers).  We can get as close as we wish to the square root of 2, but the fact that sort(2)  cannot be a rational number is said to have driven the Pythagoreans to murder one of their own who threatened to divulge this to the laity.  So while we today regard sqrt(2) as a number, it exists essentially by the assumption of any number of equivalent postulates. 

Personally, I find equivalence classes of Cauchy sequences the most intuitive definition of real number (of which rational numbers are a part).  The completeness property of the real numbers allows us to prove that any continuous function on a closed interval of real numbers reaches a maximum (the transition state) and a minimum.

Since energy levels are quantized, why not reaction states?  Then there would be no such thing as a continuous transition between reactant and product, and no transition state.

p. 258 — Proton transfers are fast.  Well how fast?

The Harvard Chemistry Department Reunion — Part IV — setting the record straight

While waiting for my copy of the new edition of Clayden to arrive, it’s time to apologize to Harvard for the first post in the series, which mostly blamed them for the total absence of blacks in the 150+ attendees at the reunion. For details see –https://luysii.wordpress.com/2012/04/19/the-harvard-chemistry-department-reunion-part-i/.

Well, silly me, I didn’t realize blacks were there all the time.  My problem was not counting them the way Harvard people do.  Consider Harvard Law Professor and senatorial candidate Elizabeth Warren, listing herself as a minority (native American variety) because she is 1/32nd Cherokee thanks to her great great great grandmother who was (perhaps).  The Law School celebrated her appointment in ’95 as one of the few women in the Law School, and then a year or so later celebrated her native American heritage. ““Of 71 current Law School professors and assistant professors, 11 are women, five are black, one is Native American and one is Hispanic,” The Harvard Crimson quotes then-Law School spokesman Mike Chmura as saying in a 1996 article.

Given those criteria for blackness, I’m sure blacks were well represented at the chemistry reunion.  Apologies to all.

Professor Warren doesn’t look native American, but then neither did one of my late father’s clients, a nice lady from Staten Island who was of the Sally Hemings family, and very proud of it.

I’m well aware of people attempting to glom on to an Indian heritage.  It happened all the time in Montana when I lived there.    The people wanting to get such recognition were after the (fairly minimal) benefits of tribal membership.  They weren’t something you’d want to be related to.  Neither did the Crows or the Cheyenne’s (the two tribes I knew best).  They drew the line at 1/32; just where Ms. Warren claims to be presently — I don’t remember if 1/32 meant acceptance or rejection.  Suffice it to say, it was harder to bluff your way in to those tribes than it was to get into Burke’s peerage.

I doubt that Warren used this to get into any of the places she’s taught.  But the places she’s taught have certainly used it, which shows you how even the best ideas (making sure minorities with brains aren’t arbitrarily excluded) can be ruined.  This sort of thing can’t help the cause, and frankly it stinks.  For just how minority free the Ivy league was 50+  years ago see the link above.

One more example.  One of my son’s Cornell friends (Asian) used her minority status to get a job in D. C. after graduation.  She certainly wasn’t disadvantaged, having been exposed to some of the country’s (and the world’s) finest intellectual capital for 4 years.

P. S. Having lived in Montana from ’72 to ’87 and taken care of perhaps 1,000 Indians,  you would have received some rather strange looks from a Crow or a Cheyenne if you called them a ‘native American’.  They called themselves Indians back then.  Perhaps they still do. I don’t know. I haven’t been back.