Category Archives: Chemistry (relatively pure)

How general anesthesia works

People have been theorizing how general anesthesia works since there has been general anesthesia.  The first useful one was diethyl ether (by definition what lipids dissolve in).  Since the brain has the one of the highest fat contents of any organ, the mechanism was obvious to all.  Anesthetics dissolve membranes.  Even the newer anesthetics look quite lipophilic — isoflurane CF3CHCL O CF2H screams (to the chemist) find me a lipid to swim in.  One can show effects of lipids on artificial membranes but the concentrations to do so are so high they would be lethal.

Attention shifted to the GABA[A] receptor, because anesthetics are effective in potentiating responses to GABA  — all the benzodiazepines (valium, librium) which bind to it are sedating.  Further evidence that a protein is involved, is that the optical isomers of enflurane vary in anesthetic potency (but not by very much — only 60%).  Lipids (except cholesterol) just aren’t optically active.  Interestingly, alfaxolone is a steroid and a general anesthetic as well.

Well GABA[A] is an ion channel, meaning that its amino acids form alpha helices which span the membrane (and create a channel for ion flow).  It would be devilishly hard to distinguish binding to the transmembrane part from binding to the membrane near it. [ Science vol. 322 pp. 876 – 880 2008 ] Studied 4 IV anesthetics (propofol, ketamine, etomidate, barbiturate) and 4 gasses (nitrous  oxide, isoflurance, devoflurane, desflurane) and their effects on 11 ion channels — unsurprisingly all sorts of effects were found — but which ones are the relevant.

All this sort of stuff could be irrelevant, if a new paper is actually correct [ Neuron vol. 102 pp. 1053 – 1065 ’19 ].  The following general anesthetics (isoflurane, propofol, ketamine and desmedtomidine) all activate cells in the hypothalamus (before this anesthetics were thought to work by ultimately inhibiting neurons).  They authors call these cells AANs (Anesthesia Activated Neurons).

They are found in the hypothalamus and contain ADH.  Time for some anatomy.  The pituitary gland is really two glands — the adenohypophysis which secretes things like ACTH, TSH, FSH, LH etc. etc, and the neurohypophysis which secretes oxytocin and vasopressin (ADH) directly into the blood (and also into the spinal fluid where it can reach other parts of the brain.  ADH release is actually from the axons of the hypothalamic neurons.  The AANs activated by the anesthetics release ADH.

Of course the workers didn’t stop there — they stimulated the neurons optogenetically and put the animals to sleep. Inhibition of these neurons shortened the duration of general anesthesia.

Fascinating (if true).  The next question is how such chemically disparate molecules can activate the AANs.  Is there a common receptor for them, and if so what is it?

Happy fiscal new year !

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A sad (but brilliant) paper about autophagy

Over the past several decades I’ve accumulated a lot of notes on autophagy (> 125,000 characters).  It’s obviously important, but in a given cell or disease (cancer, neurodegeneration) whether it helps a cell die gracefully or is an executioner is far from clear.  Ditto for whether enhancing or inhibiting it in a given situation would be helpful (or hurtful).

A major reason for the lack of clarity despite all the work that’s been done can be found in the following excellent paper [ Cell vol. 177 pp.1682 – 1699 ’19 ].  Some 41 proteins are involved in autophagy in yeast and more in man.  Many are described as ATGnn (AuTophagy Gene nn).

Autophagy is a complicated business: forming a membrane, then engulfing various things, then forming a vacuole,  then fusing with the lysosome so that the engulfees are destroyed.

The problem with previous work is that if a protein was found to be important in autophagy, it was assumed to have that function and that function only.   The paper shows that core autophagy proteins are involved in (at least) 5 other processes (endocytosis, melanocyte formation, cytokinesis, LC3 assisted phagocytosis and translocation of vesicles from the Golgi to the endoplasmic reticulum).

Experiments deleting or  increasing a given ATGnn were assumed to produce their biological effects by affecting autophagy.

The names are unimportant.  Here is a diagram of 6 autophagy proteins forming a complex producing autophagy

1 2 3

4 5 6

So 2 binds to 1, 3 and 5

But in endocytosis

1 2 3

5

form an important complex

In cytokinesis the complex formed by

2 3

5

is important.

Well you get the idea.  Knocking out 2 has cellular effects on far more than autophagy.  So a lot of work has to be re-thought and probably repeated.

Notice that all 6 functions involve movement of membranes.  So just regard the 6 proteins as gears of different diameters which can form the guts of different machines as they combine with each other (and proteins specific to the other 5 processes mentioned) to move things around in the cell.

Will flickering light treat Alzheimer’s disease ? — Take II

30 months ago, a fascinating paper appeared in which flickering light improved a mouse model of Alzheimer’s disease.  The authors (MIT mostly) have continued to extend their work.   Here is a copy of the post back then.  Their new work is summarized after the ****

Big pharma has spent zillions trying to rid the brain of senile plaques, to no avail. A recent paper shows that light flickering at 40 cycles/second (40 Hertz) can do it — this is not a misprint [ Nature vol. 540 pp. 207 – 208, 230 – 235 ’16 ]. As most know the main component of the senile plaque of Alzheimer’s disease is a fragment (called the aBeta peptide) of the amyloid precursor protein (APP).

The most interesting part of the paper showed that just an hour or so of light flickering at 40 Hertz temporarily reduced the amount of Abeta peptide in visual cortex of aged mice. Nothing invasive about that.

Should we try this in people? How harmful could it be? Unfortunately the visual cortex is relatively unaffected in Alzheimer’s disease — the disease starts deep inside the head in the medial temporal lobe, particularly the hippocampus — the link shows just how deep it is -https://en.wikipedia.org/wiki/Hippocampus#/media/File:MRI_Location_Hippocampus_up..png

You might be able to do this through the squamous portion of the temporal bone which is just in front of and above the ear. It’s very thin, and ultrasound probes placed here can ‘see’ blood flowing in arteries in this region. Another way to do it might be a light source placed in the mouth.

The technical aspects of the paper are fascinating and will be described later.

First, what could go wrong?

The work shows that the flickering light activates the scavenger cells of the brain (microglia) and then eat the extracellular plaques. However that may not be a good thing as microglia could attack normal cells. In particular they are important in the remodeling of the dendritic tree (notably dendritic spines) that occurs during experience and learning.

Second, why wouldn’t it work? So much has been spent on trying to remove abeta, that serious doubt exists as to whether excessive extracellular Abeta causes Alzheimer’s and even if it does, would removing it be helpful.

Now for some fascinating detail on the paper (for the cognoscenti)

They used a mouse model of Alzheimer’s disease (the 5XFAD mouse). This poor creature has 3 different mutations associated with Alzheimer’s disease in the amyloid precursor protein (APP) — these are the Swedish (K670B), Florida (I716V) and London (V717I). If that wasn’t enough there are two Alzheimer associated mutations in one of the enzymes that processes the APP into Abeta (M146L, L286V) — using the single letter amino acid code –http://www.biochem.ucl.ac.uk/bsm/dbbrowser/c32/aacode.html.hy1. Then the whole mess is put under control of a promoter particularly active in mice (the Thy1 promoter). This results in high expression of the two mutant proteins.

So the poor mice get lots of senile plaques (particularly in the hippocampus) at an early age.

The first experiment was even more complicated, as a way was found to put channelrhodopsin into a set of hippocampal interneurons (this is optogenetics and hardly simple). Exposing the channel to light causes it to open the membrane to depolarize and the neuron to fire. Then fiberoptics were used to stimulate these neurons at 40 Hertz and the effects on the plaques were noted. Clearly a lot of work and the authors (and grad students) deserve our thanks.

Light at 8 Hertz did nothing to the plaques. I couldn’t find what other stimulation frequencies were used (assuming they were tried).

It would be wonderful if something so simple could help these people.

For other ideas about Alzheimer’s using physics rather than chemistry please see — https://luysii.wordpress.com/2014/11/30/could-alzheimers-disease-be-a-problem-in-physics-rather-than-chemistry/

****

The new work appears in two papers.

First [ Cell vol. 1777 pp. 256 – 271 ’19 ] 7 days of auditory tone stimuli at 40 cycles/second (40 Hertz) for just one hour a day reduced amyloid in the auditory cortex of the same pathetic mice described above (the 5XFAD mice).  They call this GENUS (Gamma ENtrainment Using sensory Stimuli).  Neurologists love to name frequencies in the EEG, and the 40 Hertz is in the gamma range.

The second paper [ Neuron vol. 102 pp. 929 – 943 ’19 ] is even better.  Alzheimer’s disease is characterized by two types of pathology — neurofibrillary tangles inside the remaining neurons and the senile plaque outside them.  The tangles are made of the tau protein, the plaques mostly of fragments of the amyloid precursor protein (APP).  The 5XFAD mouse had 3 separate mutations in the APP and two more in the enzyme that chops it up.

The present work looked at the other half of Alzheimer’s the neurofibrillary tangle.  They had mice with the P301S mutation in the tau protein found in a hereditary form of dementia (not Alzheimer’s) and also with excessive levels of CK-p25 which also results in tangles.

Again chronic visual GENUS worked in this (completely different) model of neurodegeneration.

This is very exciting stuff, but I’d love to see a different group of researchers reproduce it.  Also billions have been spent and lost on promising treatments of Alzheimer’s (all based on animal work).

Probably someone is trying it out on themselves or their spouse.  A EE friend notes that engineers have been trying homebrew transcranial magnetic and current stimulation using themselves or someone close as guineapigs for years.

What is legionella trying to tell us?

10 years out of Med School, a classmate in the Public Health service had to deal with the first recognized outbreak of Legionnaire’s disease, at the Bellevue Stratford hotel in Philly, about one air mile from Penn Med where we went.   The organism wasn’t known at the time and caused 182 cases with 29 deaths.  We’ve learned a lot more about Legionella Pneumophila since 1976 and the organism continues to instruct us.

The most recent lesson concerns one of the 300 or so proteins Legionella injects into a cell it attacks.  This is remarkable in itself.  The organism uses them to hijack various cellular mechanisms to build a home for itself in the cell (the LCV — Legionella Containing Vacuole).  Contrast this with diphtheria which basically uses one protein (diphtheria toxin) to kill the cell.

One of the 300 proteins is called SidJ and looks like a protein kinase (of which our genome has over 500).  However [ Science vol. 364 pp. 787 – 792 ’19 ] shows that SidJ carries out a different different reaction.SidJ is activated by host-cell calmodulin to polyglutamylate the SidE family of ubiquitin (Ub) ligases inhibiting them. Crystal structures of the SidJ-calmodulin complex reveal a protein kinase fold that catalyzes ATP-dependent isopeptide bond formation between the amino group of free glutamate and the gamma carboxyl group in the catalytic center of SidE a ubiquitin ligase.   This, instead of just esterifying the hydroxyl group of serine or threonine or tyrosine with the terminal phosphate of ATP as a kinase is supposed to do.

Why is this important? The only protein known to have polyglutamic acid added to it is tubulin, the protein from which microtubules (neurotubules to the neurologist).  The work is important because some of the 500+ protein kinases in our genome might be doing something else.  Has the chemistry each and every member of the group been studied?  Probably not..

The authors close with “In summary, our results underscore the diversity and catalytic versatility of the protein kinase superfamily. We propose that ATP-dependent ligation reactions may be a common feature among the vast diversity of eukaryotic protein kinase–like enzymes found in nature (25). There are more than 500 protein kinases in humans and our results suggest that they should be ex- amined for alternative activities.”

I couldn’t agree more.

Forgotten but not gone — take III

It’s pretty clear that life originated in the RNA world.  Consumed by thinking of proteins, enzymes, DNA etc. we tend to forget that there is a lot of RNA out there doing things we didn’t suspect.  Here are two more examples, one of which may explain why even genes coding  for proteins are relatively free of codons transcribed into amino acids.  The champ of course is dystrophin, discussed in the last post — https://luysii.wordpress.com/2019/05/05/duchenne-muscular-dystrophy-a-novel-genetic-treatment/.  The gene is a monster with  2,220,233 nucleotides coding for just 3,685 amino acids, meaning that less than 1/200th of the gene is actually coding for protein. The work below should make us think about just what else the 199/200th of dystrophin might be doing,

Unsuspected use of RNA #1.   [ Neuron vol. 102 pp. 507 – 509, 553 – 563 ’19 ]  The Tumor protein p53 inducible nuclear protein 2 (Tp53inp2) gene codes for a low complexity protein of 222 amino acids, all in one exon.  However the ‘3 untranslated region (3’UTR)  of the RNA for it is nearly 5 times longer (3,121 nucleotides) vs. 666 amino acid coding nucleotides.  The protein is made from the mRNA in some cells, but not in sympathetic neurons, even though the mRNA for Tp53inp2 is the most abundant RNA in the axons of these neurons.

Why do animals lick their wounds?  Because their saliva contains nerve growth factor (NGF) among other things.  NGF is crucial for the growth of sympathetic neuron axons, and their very survival in embryonic life.  It is a protein, which binds to a receptor for it (TrkA) on the axon membrane.  The receptor/NGF complex is then internalized and transported back to the nucleus turning on the genes necessary for axon growth and cell survival.

Even though the mRNA for Tp53inp2 is NOT translated into protein in the axon, it is crucial for the internalization of TrkA/NGF.

People have studied proteins whose function it is to bind RNA for years.  They are called RBPs (RNA Binding Proteins), and our genome has 750 of them.  200 RBPs are associated with genetic disease.  This work turns everthing on its head.  Here is an RNA whose function it is to bind a protein (e.g. TrkA).

How many more mRNAs have nonCoding (for protein) parts with other functions?

Unsuspected use of RNA #2. Circular RNAs had been missed for years (although known since 1976).  The classic sequencing methods isolate only RNAs with characteristic tails (such as polyAdenine).  Circular RNAs don’t have any.    They are formed by back splicing of 3′ end of exon N to the 5′ end of exon N.  Fortunately this is only 1% as efficient as the normal way.

So what?  Circular RNAs are crucial in the innate immune response to microbial invaders.  Double stranded DNA belongs inside the nucleus.  When it gets into the cytoplasm when some organism brings it there,it binds to Protein Kinase R (PKR) activating it so it phosphorylates eukaryotic initiation factor 2 (eiF2) bringing protein synthesis to a screeching halt.

This means that the cell needs a mechanism to keep PKR quiet.  This is where circular RNAs come in   [ Cell vol. 177 pp. 797 – 799, 865 – 880 ’19 ].  If the nucleotides in the circle can reach across the circle and base pair with each other forming a duplex of any length, it will bind to PKR inhibiting it.  Most circular RNAs are expressed at only a handful of copies/cell, the cell containing just 10,000 of them.

The work found that overexpression of a single circular RNA able to form duplexes (dsRNA) inhibits PKR.  Over expression of linear RNA of the same sequence does not, nor does overexpression of circular RNA which can’t form dsRNA.

So when an invader with dsDNA or dsRNA gets into the cell, RNAase L, a cytoplasmic endonuclease is activated, cleaving circular RNA, and uninhibiting PKR.

So it’s back to the drawing board for mRNA and those parts (introns, 3’UTRs) we didn’t think were doing anything.  Perhaps that’s why there are so many of them, and why they take up more room in mRNA and genes than the ones coding for amino acids.  Also it’s time to look at RNAs as protein binders and modifiers, rather than the other way around as we have been doing.

Here’s a link to an earlier member of the series — https://luysii.wordpress.com/2019/04/15/forgotten-but-not-gone-take-ii/xa

Forgotten but not gone — take II

The RNA world from whence we sprang strikes again, this time giving us a glimpse into its own internal dynamic.  18 months ago I wrote the following post — which will give you the background to follow the latest (found at the end after the (***)

Life is said to have originated in the RNA world.  We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA.  But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about.  These areRNAs, whose primary (and possibly only) function is to interact with other RNAs.

Start with microRNAs (of which we have at least 1,500 as of 12/12).  Their function is to bind to messenger RNA (mRNA) and inhibit translation of the mRNA into protein.  The effects aren’t huge, but they are a more subtle control of protein expression, than the degree of transcription of the gene.

Then there are ceRNAs (competitive endogenous RNAs) which have a large number of binding sites for microRNAs — humans have a variety of them all with horrible acronyms — HULC, PTCSC3 etc. etc. They act as sponges for microRNAs keeping them bound and quiet.

Then there are circular RNAs.  They’d been missed until recently, because typical RNA sequencing methods isolate only RNAs with characteristic tails, and a circular RNA doesn’t have any.  One such is called CiRS7/CDR1) which contain 70 binding sites for one particular microRNA (miR-7).  They are unlike to be trivial.  They are derived from 15% of actively transcribed genes.  They ‘can be’ 10 times as numerous as linear RNAs (like mRNA and everything else) — probably because they are hard to degrade < Science vol. 340 pp. 440 – 441 ’17 >. So some of them are certainly RNA sponges — but all of them?

The latest, and most interesting class are the nonCoding RNAs found in viruses. Some of them function to attack cellular microRNAs and help the virus survive. Herpesvirus saimiri a gamma-herpes virus establishes latency in the T lymphocytes of New World primates, by expressing 7 small nuclear uracil-rich nonCoding RNAs (called HSURs).  They associate with some microRNAs, and rather than blocking their function act as chaperones < Nature vol. 550 pp. 275 – 279 ’17 >.  They HSURs also bind to some mRNAs inhibiting their function — they do this by helping miR-16 bind to their targets — so they are chaperones.  So viral Sm-class RNAs may function as microRNA adaptors.

Do you think for one minute, that the cell isn’t doing something like this.

I have a tendency to think of RNAs as always binding to other RNAs by classic Watson Crick base pairing — this is wrong as a look at any transfer RNA structure will show. https://en.wikipedia.org/wiki/Transfer_RNA.  Far more complicated structures may be involved, but we’ve barely started to look.

Then there are the pseudogenes, which may also have a function, which is to be transcribed and sop up microRNAs and other things — I’ve already written about this — https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/.  Breast cancer cells think one (PTEN1) is important enough to stop it from being transcribed, even though it can’t be translated into protein.

*****

[ Proc. Natl. Acad. Sci. vol. 116 pp. 7455 – 7464 ’19 ] The work reports a fascinating example of that early world in which the function of one denizen (a circular RNA called cPWWP2A) binds to another denizen of that world (microRNA 579 aka miR-579) acting as a sponge sopping up so it can’t bind to the mRNAs for angiopoetitin1, occludin and SIRT1.

So what you say?  Well it may lead to a way to treat diabetic retinopathy. How did they find cPWWP2A?  They used the Shanghai BIotechnology Company Mouse Circular RNA microArray which measures circular RNAs.  They found that 400 or so that were upregulated in diabetic retinopathy and another 400 or so that were downregulated.  cPWWP2A was on of the 3 top upregulated circular RNAs in diabetic retinopathy.  cPWWP2A comes from (what else?) PWWP2A, a gene coding for a protein which specifically binds the histone protein H2A.Z.

Overexpression of cPWW2PA or inhibition of miR-579 improves retinal vascular dysfunction in experimental diabetes.

So here is all this stuff going on way down there in the RNA world, first interacting with other players in this world and eventually reaching up to the level we thought we knew about and controlling gene expression.  It’s sort of like DOS (Disc Operating System) still being important in Windows.

How much more stuff like this is to be discovered controlling gene expression in us is anyone’s guess

Apologies to Hamlet

Apologies to Shakespeare and Hamlet.  Serotonin does “more things in heaven and Earth, Horatio, than are dreamt of in your philosophy.”  How about chemically modifying histones?We all know about serotonin and depression (or at least we think we know).  Block serotonin reuptake by the releasing neuron and bingo you’ve  cured depression (sometimes).  Do not ask the lecturer which of the 15 known serotonin receptors in the brain the increased serotonin actually binds to and what effects the increased levels produce after binding (and which are important for the alleviation of depression).The two body organs producing the most serotonin are the brain and the gut.  Chemical modification of proteins by serotonin has been known for 10 years.  The enzyme responsible is transglutaminase2, it takes the NH2 group of serotonin and replaces the NH2 of glutamine with it — forming an isopeptide bond.

Interestingly, the serotonylation of histones is quite specific.  Only glutamine #5 on histone H3 is modified this way.  For the reaction to occur lysine #4 on histone H3 must be trimethylated (H3K4Me3) — now you can begin to see the combinatorial possibilities of the various histone modifications known.  Over 130 post-ranslational modifications of histones were known by 2013 [ Cell vol. 155 p. 42 ’13 ].

The H3K4Me3Q5Ser is enriched in euchromatin and correlates with permissive gene expression.  Changing glutamine #5 to something else so it can’t be serotonylated changes the transcription pattern, and deficits in cellular differentiation.  You can read more about it in Nature vol. 567 pp. 464 – 465, 535 – 539 ’19 ]

Another research idea yours for the taking

How many of our 20,000 or so protein coding genes are essential for human existence?  There is a way to find out with no human experimentation whatsoever.  Even better, probably all the data is out there.  Looking at it the right way, finding and collating it is where you come in.  Be warned, it would be a lot of work.

Previous work [ Science vol. 350 pp. 1028 – 1029, 1092 – 1096, 1096 – 1101 ’15 ] came up with the idea that only 2,000 or so of our protein coding genes were truly essential.  The authors cleverly looked at a ‘near haploid’ chronic myelogenous leukemia cell line (KBM7).  Then because only one copy of a gene was present, they systematically knocked out gene after gene using CRISPR and looked at viability.

Similar work in yeast stated that only 1,000 of its 6,000 protein coding genes were essential.

But this is single cell stuff.  What about living breathing people?

Where is this data?  How should it be interrogated?  See if you can figure it out before reading further.

Probably more has been done since Science vol. 337 pp. 64 – 69 ’12 sequenced just the portion of our genome coding for proteins (the exomes) in 1,351 Europeans and 1,088 Africans.  Each individual had 35 premature termination codons, meaning that the gene likely didn’t produce a functional protein.  The average person also had 13,595 single nucleotide polymorphisms (from the standard genome), and probably some of them a less than functional protein.

Do you see how you could use this sort of thing to find out which genes are essential to our existence?

People sequence exomes because it’s easy and because the exome accounts for only 2% of our genome.

My guess is that probably a million exomes have been sequenced thus far, if not more.

So all you have to do is look at all million exome sequences and all 20,000 protein coding genes, and see —

In one of the Sherlock Holmes stories the following dialog appears

Gregory (Scotland Yard): “Is there any other point to which you would wish to draw my attention?”
Holmes: “To the curious incident of the dog in the night-time.”
Gregory: “The dog did nothing in the night-time.”
Holmes: “That was the curious incident.”

The curious incident would be a gene which never (or rarely) had a premature termination codon in the 1,000,000 or so exomes.  That would imply that it was essential for the existence of a living breathing human being.

Cute !  Well I’m a retired neurologist with no academic affiliation — take the idea and run with it.

Addendum 31 Mar ’19 – I received the following comment from Bryan

You may be interested in reading this pre-print on the topic:
Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes https://www.biorxiv.org/content/10.1101/531210v2

To which I replied
    • Bryan– thanks for the link. It was a good enough idea that the people at the Broad Institute had thought of it and carried it out. As people in grad school used to say when they got scooped on a paper — at least we were thinking well.

      It was hard to tell from reading the preprint whether there were genes with no pLoF (predicted loss of function) proving them essential. They do say that the 678 genes essential for human cell viability (characterized by CRISPR screening were ‘depleted’ for pLoF.

 

Good to see Charlie’s still at it

Good to see Charlie Perrin is still pumping out papers, and interesting ones to boot.  I knew him in grad school.  He’s got to be over 80.

This one —J. Am. Chem. Soc. 141, 4103 (2019) –is about something that any undergraduate organic chemist can understand (if not the techniques he used) — keto/enol tautomerism, in which the hydrogen bounces between two oxygens, so that, given N molecules in solution, N/2  have the hydrogen bound to one oxygen and N/2 have it bound to the other.

No so in what Charlie found — a compound where the hydrogen is smack dab in the middle.  Some fancy NMR techniques were used to show this.

Hydrogen bonds are extremely subtle (which is why we don’t understand water as well as we might).  Due to the small mass of the proton it isn’t appropriate to treat the proton in hydrogen bonded systems as a classical particle.  When quantum mechanics enters, aspects such as zero point motion, quantum delocalization and tunneling come into play.  These are called quantum nuclear effects (aka Ubbelohde effects).

Why Organic Chemistry should always be taken (and passed) by pre-meds — take II

An old friend’s mother died of a ruptured intracranial aneurysm and he asked me what his risk was.  So I looked up my old notes on the medical literature that I took when I was in practice (copied below).  They show once again why someone who can’t pass organic chemistry doesn’t belong in medicine.  They are far too out of date to be of clinical use, and hopefully more work has been done since I retired in 2000.

But look at the notes.  All are in reputable journals and have been refereed.  But they conflict.  You have to evaluate this data to give decent advice, just as you have to weigh conflicting steric effects, electronegativity, bond strength, electrostatic effects in solving an organic chemistry problem.  Memorization of the various effects is necessary, but you have to keep them in your head and weigh them.   A perfect memory alone just won’t do.

Here are my notes, followed by the first post on this point (which was almost 10 years ago). You don’t have to go to medical school to see how conflicting they are.

      [ New England J. Med. vol. 341 pp. 1344 – 1350 ’99 ] 626 first degree relatives of 160 patients with subarachnoid hemorrhage were screened for aneurysm by MRI angiography.  Aneurysms were found in 25/626 (not much higher than the literature would imply in any of us — they use the figure of 2.3%) — total number of aneurysms were 33.  18/25 had surgery and 11/18 had a decrease in function (disabling in 1).    They estimate the increase in life expectancy due to the surgery at 2.5 years.   They don’t think the morbidity of surgery is worth it.  The study is from the Netherlands.
      These results can’t be extrapolated to cases were there is more than one member affected by aneurysm (they may have a higher yield of aneurysms, and the risk of rupture may be different).   The screening led to 5 angiographies in patients who didn’t turn out to have an aneurysm — thus exposing a normal person to risk.
      [ Brit. Med. J. vol. 320 pp. 141 – 145 ’00 ] A study of 6175 patients with aneurysmal subarachnoid hemorrhage and 14781 first degree relatives (of whom 11640 were children followed for 108933 patient years showed 19 subarachnoid hemorrhages during followup.   This is an increased risk 3 times that of the general population — however, this translates to an absolute risk of under 1/500 per year.
      [ J. Neurosurg. vol. 66 pp 522 – 528 ’87 ]  A review of the literature on familial aneurysms shows that familial aneurysms tend to rupture at a smaller size and when the patient is younger.   There is a similar incidence of multiple aneurysms and predominance of females over males with multiple aneurysms in the familial cases.  Anterior communicating artery aneurysms are slightly less frequent.  In sibling pairs, the aneurysms occur at the same or at mirror sites and rupture within the same decade twice as frequently as randomly selected nonfamilial aneurysm patient pairs.
      [ Stroke vol. 27 pp. 630 – 632 ’96 ] Familial subarachnoid hemorrhage is said to account for 6 – 9% of all such cases.  The outcome is said to be worse in familial than sporadic subarachnoid hemorrhage.
      [ Stroke vol. 25 pp. 2028 – 2037 ’94 ]  Since the initial report in ’54, there have been 238 families with 560 affected members reported in the literature through ’93. Only 3% of these families had 5 or more affected.   Siblings of an affected male proband are more likely to be affected than siblings of an affected female.  After review of 73 families, the authors conclude that no single pattern of inheritance can account for all families (unsurprise ! ).
        [ Neurosurg. vol. 12 pp. 214 – 216 ’83 ] A family with 4 members with intracranial aneurysms is reported.  Two of these were in an unusual location, the distal anterior cerebral artery.
        The 5th case report of identical twins with multiple aneurysms is given [ Acta. Neurochir. vol. 95 pp 121 – 125 ’88 ]
        [ Neurosurg. vol. 20 pp 226 – 239 ’87 ]  A prospective study of 579 consecutive patients with subarachnoid hemorrhage was done.  1/250 siblings had an aneurysm, but an aneurysm occurred in another family member in 1/14.
      [ Stroke vol. 22 pp. 1426 – 1430 ’91 ]  3 families (among 175 patients with spontaneous dissections of the cervical arteries seen at the Mayo Clinic between 1970 and 1989) were found with intracranial aneurysms.  No patient had both conditions.  Both Ehlers Danlos type IV (ED – IV ) and Marfan’s syndrome can have aneurysm and cervical artery dissection as components.
       [ Stroke vol. 25 pp. 2028 – 2037 ’94 ]  Intracranial aneurysms have been associated with the following hereditary disorders.  However, only polycystic kidney disease, Ehlers Danlos, Marfan’s neurofibromatosis and pseudoxanthoma elasticum are at increased risk of aneurysm.  The others may be fortuitous.  Among the others a alpha-glucosidase deficiency, alpha-antitrypsin deficiency, alkaptonuria, Fabry’s disease, hereditary hemorrhagic telangiectasia, Noonan’s syndrome, tuberous sclerosis, and multiple endocrine neoplasia type I syndrome.
      [ Brit. Med. J. vol. 311 pp. 288 – 289 ’95 ] A study of the first degree (1290) and second degree (3038) relatives of 163 patients with subarachnoid hemorrhage from the Netherlands showed that 10/1290 first degree and 4/3038 second degree relatives had had a subarachnoid hemorrhage.  This is a 6 fold higher risk for first degree relatives than the population at large (however, fewer than 1% of first degree relatives had had a subarachnoid hemorrhage).   3 other studies (which the authors criticize) hadn’t found this.  [ Stroke vol. 27 pp. 7 – 9 ’96 ] A further study of this group showed that hypertension was 2.3 times as common in first degree relatives, stroke was 1.8 times as common and coronary heart disease was 1.9 times as common in first degree relatives (as compared to second degree relatives).  Thus the increased risk of subarachnoid hemorrhage in first degree relatives may reflect an increase in known risk factors for subarachnoid hemorrhage rather than a ‘new’ defect in the arterial walls.
       [ Arch. Neurol. vol. 52 pp. 202 – 204 ’95 ] A much higher incidence of subarachnoid hemorrhage in first degree relatives of the 149 cases of subarachnoid hemorrhage in Seattle over 2 years is reported.  An astounding 11.4% of cases had a first degree relative with a history of subarachnoid hemorrhage (vs. 6.4% of controls through random digit dialing).    When I take family histories (which I do for every patient I see), I don’t get anything nearly this high (I think, but I’ll have to look).   Another study estimated that the percentage of first degree relatives should be 5.5% [ Stroke vol. 23 pp. 1024 – 1030 ’92 ].
     [ Neurol. vol. 53 pp. 982 – 988 ’99 ] Another study on aneurysm risk of first degree relatives of patients who suffered a subarachnoid hemorrhage from an intracranial aneurysm.  There were 193 index patients and 626 first degree relatives studied 78% of those eligible).    Aneurysms were found in 25/626 — a 4% incidence.  The group with aneurysm didn’t have a high number of atherosclerotic risk factors.    This only twice the 2.3% prevalence of unruptured aneurysms in the general population.    The rate of subarachnoid hemorrhage in first degree of aneurysmal bleeders is 3- 7 fold that of the general population.   Given the only twofold increased prevalence of aneurysm found in this study, this may mean that there may be two types of aneurysms which run in families — the bleeding kind and the nonbleeding kind.
     [ Stroke vol. 27 pp. 1050 – 1054 ’96 ] In a study of 30 patients with ruptured aneurysm from 14 families in which another member had an aneurysm 24/30 were women.
        [ Lancet vol. 349 pp. 380 – 384 ’97 ] A study from Finland screened first degree relatives over the age of 30 of index cases of subarachnoid hemorrhage with magnetic resonance angiography (MRA)  There were 698 available of whome 438 were screened with magnetic resonance angiography.  38/438 had aneurysms (families with polycystic kidney disease, Marfan’s, Ehlers Danlos IV were excluded).
        [ Can. J. Neurol. Sci. vol. 24 pp. 326 – 331 ’97 ] The Saguenay Lac Saint Jean area of Quebec contains  ~ 300,000 people (all inbred).  The incidence of familial aneurysm is very high (related to the total aneurysm burden) and 144/502 individuals with ruptured intracranial aneurysm had another affected family member (first to third degree relative).   However, they think this is due to accidental aggregation as the families are large (average number of siblings is 7 ! ).
        [ Neurol. vol. 51 pp. 1125 – 1130 ’98 ] A study of 125 relatives of patients in 23 families in which 2  more individuals had aneurysmal subarachnoid hemorrhage.  116 had no history of aneurysm themselves and 7/116 had an asymptomatic ruptured aneurysm.  9 had a history of aneurysm and 3/9 had new asymptomatic intracranial aneurysms.   MRA was used to study the 116 and CT angiography was used to study the 9.
Here is the first post on the subject, written almost 10 years ago

Why Organic Chemistry should always be taken (and passed) by pre-meds

Back when I was posting on “The Skeptical Chymist”, the editor (Stuart Cantrill), told me that noises were being made about dropping organic chemistry from the pre-med curriculum and asked me to comment. I didn’t because the idea seemed so ridiculous. There is no possibility of really understanding anything about cellular biology, drug action, molecular biology etc. etc. without a firm grounding in organic chemistry. You simply must have some idea what vitamins, proteins, DNA and RNA and the drugs you’ll be using look like and how they chemically interact — which is what organic chemistry gives you the background for. Not that you can stop there — but all medical schools teach biochemistry — which starts at organic chemistry and takes off from there. Organic certainly helped me follow molecular biology as it exploded starting in the 60s.

Cynics might say that docs don’t synthesize things or crystallize the drugs they use. Knowing what’s going on under the hood is just esthetic filigree. Just tell them what ‘best practice’ is, and let them follow it like robots. Who cares if they know the underlying science. People drive cars without really understanding what a carburator or a manifold does (myself included).

It wasn’t until I got about 400 pages into the magnificent textbook of Organic Chemistry by Clayden, Greeves, Warren and Wothers (only 1100 action packed pages to go !) that the real answer became apparent. The stuff is impossible to memorize. Only assimilating principles and applying them to novel situations will get you through — exactly like the practice of medicine.

Let us suppose you have an eidetic memory, and know the best treatment for every condition. You wouldn’t have to know any science at all, would you?

What’s wrong with this picture? First of all, there isn’t a best treatment known for every condition. Second, every doc will see conditions and problems that simply aren’t in the books. When I first started out, I was amazed at how much of this there was. I asked an excellent internist who’d been in practice for 30 years if he’d seen it all. He thought he saw something completely new each week. Third, conditions occur in combinations, and many patients (and nearly all the elderly) have many more than one problem. The conditions and treatments interact in a highly nonlinear fashion. The treatment for one problem might make another much worse (see below).

Here is a concrete example using a familiar person (Sonia Sotomayor) and a disorder which should be known to all (the new Swine Flu which swept America and the world this spring). Let’s say that you’re that lucky soul with the perfect memory who knows all the best treatments (well those that exist anyway) and as such you’ve been given the responsibility of taking care of her.

It is public knowledge (e.g. Wikipedia) that Justice Sotomayor has had diabetes since age 8, requiring insulin since that time. Pictures show, that like many diabetics, she is overweight — depending on how tall she is I’d guess by 25 – 45 pounds. Influenza is usually a disease of the fall and winter, and the new Swine Flu is now down in South America, but it’s likely to sweep back up here this fall. We know it’s extremely infectious, but so far fortunately rather benign. There is no guarantee that it will stay that way. Suppose that while down in S. A. it mutated and has become more virulent (a possibility that the CDC takes extremely seriously).

What if she gets the new Swine flu next month? At this point there is no ‘best treatment’ known. Diabetics don’t do well with infections — they get more of them, and have more complications when they do. Her diabetes is certainly going to get worse. What if some think the ‘best treatment’ is corticosteroids (which is often used for severe lung infections) — which will really raise hell with her diabetes? Should you give it? Recall that corticosteroid use during the Asian SARS epidemic (another serious lung infection) seemed to hurt rather than help (Journal of Infection, Volume 51, Issue 2, Pages 98-102). There is no data to help you here and you and your patient don’t have the luxury of waiting for it. Don’t forget that her father died at 42 of heart disease. That could be relevant to what you do. Suppose, like many overweight diabetics she has high blood pressure and elevated lipids as well. How will that affect her management?

Your perfect eidetic memory of medicine will not be enough to help you with her management — you are going to have to think, and think hard and apply every principle of medicine you know to a new and unfamiliar situation with very little data to help you.

Sounds like Organic Chemistry doesn’t it? Anyone without the particular type of mind that is able absorb and apply multiple and (often) conflicting principles doesn’t belong in medicine. A hardnosed mathematician I audited a course from a few years ago, said that people would come up to him saying that if they couldn’t pass Calculus, they wouldn’t get into medical school. He felt that if they couldn’t, he didn’t want them in medical school (I’m not sure he told them this — probably he did). The same thing holds in spades for Organic Chemistry.