Junk that isn’t

The more we understand, the more we realize how little we’ve understood what we thought we understood.   Here is a double example.

We have 1,400,000 Alu elements in our genome.  They are about 300 nucleotides long, meaning that there is over 1 every 3,000 nucleotides in our 3,200,000,000 nucleotide genome.  They don’t code for protein, and were widely thought to be junk, selfish genes whose only role was to ensure that the organism carrying them, kept them along as they reproduced.

This post contains a heavy dose of contemporary molecular biology.  If you’re a little shaky on some of it have a look at — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ — and follow the links.

Not so says Proc. Natl. Acad. Sci. vol. 117 pp. 415 – 425  ’20.  They are part of several important physiologic processes (1) T lymphocyte activation (2) heat shock stress (3) endoplasmic reticulum stress.  All 3 cause transcription of Alu’s by RNA polymerase III (pol III).

All RNA levels increase with heat shock, including RNAs made from Alu elements.  They bind directly and tightly (nanoMolar affinity) to RNA polymerase II (which transcribes protein coding genes) and co-occupy the promoters of repressed genes, preventing transcription of these genes and protein synthesis of them.  At least that was the state of play 11 years ago (PNAS 105 5569 – 5574 ’09)

This paper notes that Alu is not passive, but actually a self-cleaving ribozyme (an enzyme made of RNA), an entirely new role.  When complexed with another protein EZH2 (a polycomb protein thought to be a transcriptional repressor using its lysine methylation activity), the rate of Alu self-cleavage increases by 40%.

So what?

In addition to stoping transcription, Alu also retards transcription elongation.  So stress increases in EZH2 causes Alu to cleave itself faster, turning off  repression and improving the responses to the 3 types of stresses above.

So we really didn’t understand both Alu which has been studied for years, or EZH2 a polycomb protein (ditto).  Alu is a self-cleaving ribozyme, and EZH2 doesn’t just turn off genes by its enzymatic activity (lysine trimethylation), but binds to an RNA so it can cleave itself faster (e.g. its a cofactor).

Fascinating and humbling to see how much there is to know about things we thought we knew.  But it’s also exciting.  Who knows what else is out there to discover about the known, never mind the known unknowns.

Should your teen use marihuana?

Is marihuana bad for teen brain development?  The short answer is no one knows.  The long answer can be found here — https://www.pnas.org/content/117/1/7.  It’s probably the best thing out there on the question [ Proc. Natl. Acad. Sci. vol. 117 pp. 7 – 11 ’20 ].  The article basically says we don’t know, but lays out the cons (of which there are many) and the pros (of which there are equally many).

If you’re not a doc, reading the article with its conflicting arguments harmful vs. nonharmful, and then deciding what to tell your kid is very close to what practicing medicine is like.  Important decisions are to be made, based on very conflicting data, and yet the decisions can’t be put off.  Rote memory is of no use and it’s time to think and think hard.

Assuming you don’t have a PNAS subscription, or you can’t follow the link here are a few points the article makes.

It starts off with work on rats. “Tseng, based at the University of Illinois in Chicago, investigates how rats respond to THC (tetrahydrocannabinol), the main psychoactive ingredient in cannabis. He’s found that exposure to THC or similar molecules during a specific window of adolescence delays maturation of the prefrontal cortex (PFC), a region involved in complex behaviors and decision making”

Pretty impressive, but not if you’ve spent decades watching various treatments for stroke which worked in rodents crash and burn when applied to people (there are at least 50 such studies).  What separates us from rodents physically (if not morally) is our brains.  Animal studies, with all their defects of applicability to man is one of the two approaches we have — no one is going to randomize a bunch of 13 year olds to receive marihuana or not and watch what happens.

== Addendum 9 Jan ’20 — too good to pass up — Science vol. 367 pp. 83 – 87  ’20 shows just how different we are from rodents.  In addition to our cerebral cortex being 3 times thicker, human cortical neurons show something not found in any other mammal — These are graded action potentials in apical dendrites, important because they allow single neurons to calculate XORs (either a or b but not both and not none), something previously only thought possible for neuron ensembles.  XORs are important in Boolean algebra, hence in computation. ==

The other approach is observational studies on people which have led us down the garden path many times– see the disaster the women’s health study avoided here — https://luysii.wordpress.com/2016/08/23/the-plural-of-anecdote-is-not-data-in-medicine-at-least/.

45,000 Swedish military conscripts examined at conscription (age 19) and 15 years later.  Those who had used cannabis over 50 times before conscription were 6 times as likely to be diagnosed with schizophrenia.

Against that, is the fact that cannabis use has exploded since the 60s but schizophrenia has not (remaining at a very unfortunate 1% of the population).

In the Dunedin study, cannabis use by 15 was associated with a fourfold risk of schizophrenia at 26 (but not if they started using cannabis after 16 years of age. — https://en.wikipedia.org/wiki/Dunedin_Multidisciplinary_Health_and_Development_Study.

You can take the position that all drugs we use to alter mental state (coffee, cigarettes, booze, marihuana, cocaine, heroin) are medicating underly conditions which we don’t like.  Perhaps marihuana use is just a marker for people susceptible to schizophrenia.  Mol. Psychiat. vol. 19 pp. 1201 – 1204 ’14 — 2,000 healthy adults were studied looking a genome variants known to increase the risk of schizophrenia.  Those with high risk variants were ‘more likely’ to use marihuana — not having read the actual paper i don’t know how much more.

There is a lot more in the article about the effects of cannabis on cognition and cognitive development — the authors note that ‘they have not replicated well’.  You’ll have to read the text (which you can get by following the link) for this.

One hope for the future is the ABCD study (Adolescent Brain Cognitive Development Study) — aka the ABCD study.  By 2018 it reached its goal of  accumulating 10,000 kids between the ages of 9 and 10.  They will be followed for a decade (probably longer if the results are interesting).  It’s the hope for the future — but that doesn’t tell you what to say to your kid now.  Read the article, use your best judgement and welcome to the world of the physician.

What is sad, is how little the field has advanced, since I wrote the (rather technical) post on marihuana in 2014.

Here it is below

Why marihuana scares me

There’s an editorial in the current Science concerning how very little we know about the effects of marihuana on the developing adolescent brain [ Science vol. 344 p. 557 ’14 ]. We know all sorts of wonderful neuropharmacology and neurophysiology about delta-9 tetrahydrocannabinol (d9-THC) — http://en.wikipedia.org/wiki/Tetrahydrocannabinol The point of the authors (the current head of the Amnerican Psychiatric Association, and the first director of the National (US) Institute of Drug Abuse), is that there are no significant studies of what happens to adolescent humans (as opposed to rodents) taking the stuff.

Marihuana would the first mind-alteraing substance NOT to have serious side effects in a subpopulation of people using the drug — or just about any drug in medical use for that matter.

Any organic chemist looking at the structure of d9-THC (see the link) has to be impressed with what a lipid it is — 21 carbons, only 1 hydroxyl group, and an ether moiety. Everything else is hydrogen. Like most neuroactive drugs produced by plants, it is quite potent. A joint has only 9 milliGrams, and smoking undoubtedly destroys some of it. Consider alcohol, another lipid soluble drug. A 12 ounce beer with 3.2% alcohol content has 12 * 28.3 *.032 10.8 grams of alcohol — molecular mass 62 grams — so the dose is 11/62 moles. To get drunk you need more than one beer. Compare that to a dose of .009/300 moles of d9-THC.

As we’ve found out — d9-THC is so potent because it binds to receptors for it. Unlike ethanol which can be a product of intermediary metabolism, there aren’t enzymes specifically devoted to breaking down d9-THC. In contrast, fatty acid amide hydrolase (FAAH) is devoted to breaking down anandamide, one of the endogenous compounds d9-THC is mimicking.

What really concerns me about this class of drugs, is how long they must hang around. Teaching neuropharmacology in the 70s and 80s was great fun. Every year a new receptor for neurotransmitters seemed to be found. In some cases mind benders bound to them (e.g. LSD and a serotonin receptor). In other cases the endogenous transmitters being mimicked by a plant substance were found (the endogenous opiates and their receptors). Years passed, but the receptor for d9-thc wasn’t found. The reason it wasn’t is exactly why I’m scared of the drug.

How were the various receptors for mind benders found? You throw a radioactively labelled drug (say morphine) at a brain homogenate, and purify what it is binding to. That’s how the opiate receptors etc. etc. were found. Why did it take so long to find the cannabinoid receptors? Because they bind strongly to all the fats in the brain being so incredibly lipid soluble. So the vast majority of stuff bound wasn’t protein at all, but fat. The brain has the highest percentage of fat of any organ in the body — 60%, unless you considered dispersed fatty tissue an organ (which it actually is from an endocrine point of view).

This has to mean that the stuff hangs around for a long time, without any specific enzymes to clear it.

It’s obvious to all that cognitive capacity changes from childhood to adult life. All sorts of studies with large numbers of people have done serial MRIs children and adolescents as the develop and age. Here are a few references to get you started [ Neuron vol. 72 pp. 873 – 884, 11, Proc. Natl. Acad. Sci. vol. 107 pp. 16988 – 16993 ’10, vol. 111 pp. 6774 -= 6779 ’14 ]. If you don’t know the answer, think about the change thickness of the cerebral cortex from age 9 to 20. Surprisingly, it get thinner, not thicker. The effect happens later in the association areas thought to be important in higher cognitive function, than the primary motor or sensory areas. Paradoxical isn’t it? Based on animal work this is thought to be due pruning of synapses.

So throw a long-lasting retrograde neurotransmitter mimic like d9-THC at the dynamically changing adolescent brain and hope for the best. That’s what the cited editorialists are concerned about. We simply don’t know and we should.

Having been in Cambridge when Leary was just getting started in the early 60’s, I must say that the idea of tune in turn on and drop out never appealed to me. Most of the heavy marihuana users I’ve known (and treated for other things) were happy, but rather vague and frankly rather dull.

Unfortunately as a neurologist, I had to evaluate physician colleagues who got in trouble with drugs (mostly with alcohol). One very intelligent polydrug user MD, put it to me this way — “The problem is that you like reality, and I don’t”.

How little we really understand about proteins

How little we really understand about proteins.  We ‘know’ that the 7 transmembrane alpha helices of G Protein Coupled Receptors (GPCRs) all contain hydrophobic amino acids, so they dissolve in the (hydrophobic) lipids of the membrane.  GPCRs have been intensively by chemists, molecular biologists, pharmacologists and drug chemists with the net result that as of last year “128 GPCRs are targets for drugs listed in the Food and Drug Administration Orange Book. We estimate that ∼700 approved drugs target GPCRs, implying that approximately 35% of approved drugs target GPCRs.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820538/

So if you changed the hydrophobic amino acids found in the 7 transmembrane segments of GPCRs to hydrophilic ones — all hell should break loose.

Wrong says Proc. Natl. Acad. Sci. vol. 116 pp. 25668 – 25667 ’19 ].  The trick was to replace hydrophobic amino acids with hydrophilic ones with the same shape.

Thus leucine (L — single amino acid letter code) is replaced by glutamine (Q), Isoleucine (I) and Valine (V) is replaced by Threonine (T) and finally phenylalanine (F) is replaced by Tyrosine (Y).  They call this the QTY code.

Instead of destroying the structure of the GPCRs (CCR5 and CXCR4) they became water soluble, and bound their ligands CCL5 for CCR5  and CXCL12 for CXCR4 to the same extent.

Even more amazing, the QTYdesigned receptors exhibit remarkable thermostability in the presence of arginine and retained ligand-binding activity after heat treatment at 60 °C for 4 h and 24 h, and at 100 °C for 10 min.

I would never have expected this.  Would you?

Why did they even do it?  Because GPCR structures are hard to study. You either have to remove them en bloc from the membrane or dissolve them in other lipids so they don’t denature.  Why these two GPCR’s?    Because their ligands are proteins and can’t snuggle deep down inside the 7 alpha helices embedded in the membrane (they’re just too big), but bind to the outside surface.  CCL5 is an 8 kiloDalton protein (probably 80 amino acids, while CXCL12 has 93.  So just solublizing the GPCR without changing any of the amino acids external to the membrane, produces an object for study.

It would be amusing to do the same thing for a GPCR binding one of the monamines.  I doubt that they would bind, but I never would have believed this possible in the first place.

Now is the winter of our discontent

One of the problems with being over 80 is that you watch your friends get sick.  In the past month, one classmate developed ALS and another has cardiac amyloidosis complete with implantable defibrillator.  The 40 year old daughter of a friend who we watched since infancy has serious breast cancer and is undergoing surgery radiation and chemo.  While I don’t have survivor’s guilt (yet), it isn’t fun.

Reading and thinking about molecular biology has been a form of psychotherapy for me (for why, see the reprint of an old post on this point at the end).

Consider ALS (Amyotrophic Lateral Sclerosis, Lou Gehrig disease).  What needs explaining is not why my classmate got it, but why we all don’t have it.  As you know human neurons don’t replace themselves (forget the work in animals — it doesn’t apply to us).  Just think what the neurons  which die in ALS have to do.  They have to send a single axon several feet (not nanoMeters, microMeters, milliMeters — but the better part of a meter) from their cell bodies in the spinal cord to the muscle the innervate (which could be in your foot).

Supplying the end of the axon with proteins and other molecules by simple diffusion would never work.  So molecular highways (called microtubules) inside the axon are constructed, along which trucks (molecular motors such as kinesin and dynein) drag cargos of proteins, and mRNAs to make more proteins.

We know a lot about microtubules, and Cell vol. 179 pp. 909 – 922 ’19 gives incredible detail about them (even better with lots of great pictures).  Start with the basic building block — the tubulin heterodimer — about 40 Angstroms wide and 80 Angstroms high.  The repeating unit of the microtubule is 960 Angstroms long, so 12 heterodimers are lined up end to end in each repeating unit — this is the protofilament of the microtubule, and our microtubules have 13 of them, so that’s 156 heterodimers per microtubule repeat length which is 960 Angstroms or 96 nanoMeters (96 billionths of a meter).  So a microtubule (or a bunch of microtubules extending a meter has 10^7 such repeats or about 1 billion heterodimers.  But the axon of a motor neuron has a bunch of microtubules in it (between 10 and 100), so the motor neuron firing to  the muscle moving my finger has probably made billions and billions of heterodimers.  Moreover it’s been doing this for 80 plus years.

This is why, what needs explaining is not ALS, but why we don’t all have it.

Here’s the old post

The Solace of Molecular Biology

Neurology is fascinating because it deals with illnesses affecting what makes us human. Unfortunately for nearly all of my medical career in neurology ’62 – ’00 neurologic therapy was lousy and death was no stranger. In a coverage group with 4 other neurologists taking weekend call (we covered our own practices during the week) about 1/4 of the patients seen on call weekend #1 had died by on call weekend #2 five weeks later.

Most of the deaths were in the elderly with strokes, tumors, cancer etc, but not all. I also ran a muscular dystrophy clinic and one of the hardest cases I saw was an infant with Werdnig Hoffman disease — similar to what Steven Hawking has, but much, much faster — she died at 1 year. Initially, I found the suffering of such patients and their families impossible to accept or understand, particularly when they affected the young, or even young adults in the graduate student age.

As noted earlier, I started med school in ’62, a time when the genetic code was first being cracked, and with the background then that many of you have presently understanding molecular biology as it was being unravelled wasn’t difficult. Usually when you know something you tend to regard it as simple or unimpressive. Not so the cell and life. The more you know, the more impressive it becomes.

Think of the 3.2 gigaBases of DNA in each cell. At 3 or so Angstroms aromatic ring thickness — this comes out to a meter or so stretched out — but it isn’t, rather compressed so it fits into a nucleus 5 – 10 millionths of a meter in diameter. Then since DNA is a helix with one complete turn every 10 bases, the genome in each cell contains 320,000,000 twists which must be unwound to copy it into RNA. The machinery which copies it into messenger RNA (RNA polymerase II) is huge — but the fun doesn’t stop there — in the eukaryotic cell to turn on a gene at the right time something called the mediator complex must bind to another site in the DNA and the RNA polymerase — the whole mess contains over 100 proteins and has a molecular mass of over 2 megaDaltons (with our friend carbon containing only 12 Daltons). This monster must somehow find and unwind just the right stretch of DNA in the extremely cramped confines of the nucleus. That’s just transcription of DNA into RNA. Translation of the messenger RNA (mRNA) into protein involves another monster — the ribosome. Most of our mRNA must be processed lopping out irrelevant pieces before it gets out to the cytoplasm — this calls for the spliceosome — a complex of over 100 proteins plus some RNAs — a completely different molecular machine with a mass in the megaDaltons. There’s tons more that we know now, equally complex.

So what.

Gradually I came to realize that what needs explaining is not the poor child dying of Werdnig Hoffman disease but that we exist at all and for fairly prolonged periods of time and in relatively good shape (like my father who was actively engaged in the law and a mortgage operation until 6 months before his death at age100). Such is the solace of molecular biology. It ain’t much, but it’s all I’ve got (the religious have a lot more). You guys have the chemical background and the intellectual horsepower to understand molecular biology — and even perhaps to extend it.

 

The neuropharmacological brilliance of the meningococcus

The meningococcus can kill you within 12 hours after the spots appear — https://en.wikipedia.org/wiki/Waterhouse–Friderichsen_syndrome.  Who would have thought that it would be teaching us neuropharmacology.   But it is —  showing us how to make a new class of drugs, that no one has ever thought of.

One of the most important ways that the outside of a cell tells the inside what’s going on and what to do is the GPCR (acronym for G Protein Coupled Receptor).  Our 20,000 protein coding genome contains 826 of them. 108 G-protein-coupled receptors (GPCRs) are the targets of 475 Food and Drug Administration (FDA)-approved drugs (slightly over 1/3).   GPCRs are embedded in the outer membrane of the cell, with the protein going back and forth through the membrane 7 times (transmembrane segment 1 to 7 (TM1 – TM7). As the GPCR sits there usually the 7 TMs cluster together, and signaling molecules such as norepinephrine, dopamine, serotonin etc. etc. bind to the center of the cluster.   This is where the 475 drugs try to modify things.

Not so the meningococcus. It binds to the beta2 adrenergic receptor on the surface of brain endothelial cells lining cerebral blood vessels, turning on a signaling cascade which eventually promotes opening junctions of the brain endothelial cells with each other, so the bug can get into the brain.  All sorts of drugs are used to affect beta2 adrenergic receptors, in particular drugs for asthma which activate the receptor causing lung smooth muscle to relax.  All of them are small molecules which bind within the 7 TM cluster.

According to Nature Commun. vol 10 pp. 4752 –> ’19, the little hairs (pili) on the outside of the organism bind to sugars attached to the extracellular surface of the receptor, pulling on it activating the receptor.

This a completely new mechanism to alter GPCR function (which, after all,  is what our drugs are trying to do).  This means that we potentially have a whole new class of drugs, and 826 juicy targets to explore them with.

Here is one clinical experience I had with the meningococcus.  A middle aged man presented with headache, stiff neck and fever.  Normally spinal fluid is as clear as water.  This man’s was cloudy, a very bad sign as it usually means pus (lots of white blood cells).  I started the standard antibiotic (at the time)  for bacterial meningitis — because you don’t wait for the culture to come back which back then took two days.  The lab report showed no white cells, which I thought was screwy, so I went down to the lab to look for myself — there weren’t any.  The cloudiness was due to a huge number of meningococcal bacteria.  I though he was a goner, but amazingly he survived and went home. Unfortunately his immune system was quite abnormal, and the meningitis was the initial presentation of multiple myeloma.

Barking up the wrong therapeutic tree in Alzheimer’s disease

Billions have been spent by big pharma (and lost) trying to get rid of the senile plaque of Alzheimer’s disease.  The assumption has always been that the plaque is the smoking gun killing neurons.  But it’s just an assumption which a recent paper has turned on its ear [ Proc. Natl. Acad. Sci. vol. 116 23040 – 23049 ’19 ]

It involves a protein, likely to be a new face even to Alzheimer’s cognoscenti.  The protein is called SERF1A (in man) and MOAG-4 in yeast. It enhances amyloid formation, the major component of the senile plaque.  SERF1A is clearly doing something important as it has changed little from the humble single yeast cell to man.

The major component of the senile plaque is the aBeta peptide of 40 and/or 42 amino acids.  It polymerizes to form the amyloid of the plaque.  The initial step of amyloid formation is the hardest, getting a bunch of Abeta peptides into the right conformation (e.g. the nucleus) so others can latch on to it and form the amyloid fiber.   It is likely that the monomers and oligomers of Abeta are what is killing neurons, not the plaques, otherwise why would natural selection/evolution keep SERF1A around?

So, billions of dollars later, getting rid of the senile plaque turns out to be a bad idea. What we want to do is increase SERF1A activity, to sop up the monomers and oligomers. It is a 180 degree shift in our thinking. That’s the executive summary, now for the fascinating chemistry involved.

First the structure of SERF1A — that is to say its amino acid sequence.  (For the nonChemists — proteins are linear string of amino acids, just as a word is a linear string of characters — the order is quite important — just as united and untied mean two very different things). There are only 68 amino acids in SERF1A of which 14 are lysine 9 are arginine 5 Glutamic acid and 5 Aspartic acid.  That’s interesting in itself, as we have 20 different amino acids, and if they occurred randomly you’d expect about 3 -4 of each.  The mathematicians among you should enjoy figuring out just how improbable this compared to random assortment. So just four amino acids account for 33 of the 68 in SERF1A  Even more interesting is the fact that all 4 are charged at body pH — lysine and arginine are positively charged because their nitrogen picks up protons, and glutamic and aspartic acid are negatively charged  giving up the proton.

This means that positive and negative can bind to each other (something energetically quite favorable).  How many ways are there for the 10 acids to bind to the 23 bases?  Just 23 x 22 x 21 X 20 X 19 X 18 x 17 x 16 x 15 x 14 or roughly 20^10 ways.  This means that SERF1A doesn’t have a single structure, but many of them.  It is basically a disordered protein.

The paper shows exactly this, that several conformations of SERF1 are seen in solution, and that it binds to Abeta forming a ‘fuzzy complex’, in which the number of Abetas and SERF1s are not fixed — e.g. there is no fixed stoichiometry — something chemists are going to have to learn to deal with — see — https://luysii.wordpress.com/2018/12/16/bye-bye-stoichiometry/.  Also different conformations of SERF1A are present in the fuzzy complex, explaining why it has such a peculiar amino acid composition.  Clever no?  Let’s hear it for the blind watchmaker or whatever you want to call it.

The paper shows that SERF1 increases the rate at which Abeta forms the nucleus of the amyloid fiber.  It does not help the fiber grow.  This means that the fiber is good and the monomers and oligomers are bad.  Not only that but SERF1 has exactly the same effect with alpha-synuclein, the main protein of the Lewy body of Parkinsonism.

So the paper represents a huge paradigm shift in our understanding of the cause of at least 2 bad neurological diseases.   Even more importantly, the paper suggests a completely new way to attack them.

Vaping — don’t do it until we know more

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ several hundred cases of ‘lung injury’ and a few deaths  in a 300+ million population, but in any new illness (AIDs, SARs, Legionnaire’s diseases) only the most severe cases are seen first.  

This is exactly the way it was with AIDs, the first few cases seroconverting (showing they’d been infected with the virus) had their immune system collapse almost immediately after infection.  As time wore on, we’d see seroconverters who remained healthy for 1 year, 2 years, 5 years, because (for reasons we still don’t understand) they were resistant to the virus or had a stronger immune system.  But eventually they got sick and died as well.

So it is with vaping related lung illness.  How many more cases we’ll see in  more resistant individuals in the coming years isn’t known. Will we have a nation of 30 year olds crippled with chronic lung disease?  Unlike AIDS, SARS or Legionnaire’s disease where there is a single organism, there are thousands of vaping products, and what people are putting into the machines is completely unknown.  Perhaps it’s just one drug.  Perhaps it’s a contaminated drug.  Perhaps its the particular machine.  At this point we don’t know.  It’s just like the early days of the AIDs epidemic — plausible theories abound and reliable data is scarce.  I was practicing medicine when AIDs came out in the late 70s and it was scary as hell, not knowing what was causing it.  At least with this we’re pretty sure it’s the vaping, given the age distribution and the positive histories in all.

We have one excellent example of a genetic condition predisposing to lung disease — alpha1 antitrypsin deficiency predisposes to emphysema and chronic obstructive pulmonary disease  — https://en.wikipedia.org/wiki/Alpha1_antitrypsin.  It would be useful  to see how many of the vaping cases have this deficiency.

This just in – according to the Wall Street Journal 2 hours ago 31 October ’19 ago the CDC says there have been 1,888 cases with 37 deaths.  Hopefully this is NOT the tip of the iceberg  — but probably it is.

Addendum 1 Nov ’19 I wrote this to a niece who has an 18 year old daughter entering college.  She is a teacher in a standard American high school (not in the ghetto, not filthy rich).  If any one has boots on the ground she does. Her response:  “Yes it’s very common in high school” — scary.

Addendum 8 Nov ’19  — The following comment by Peter Shenkin is so important that it belongs in the body of the blog proper —

It’s pretty impressive, but these are early times in the investigation.

Peter Shenkin commented on Vaping — don’t do it until we know more

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ …

You wrote: “Vaping — don’t do it until we know more”

We now know more; source of the following quote is at the end.

—

“CDC Announces “Major Breakthrough” that I Recognized and Reported Two Months Ago; Outbreak is Almost Certainly Not Associated with Legal Nicotine Vapes
Minutes ago, the Centers for Disease Control and Prevention (CDC) announced what they called a “major breakthrough” in its investigation of the vaping-associated respiratory illness outbreak. They tested lung tissue samples from 29 case patients and all 29 (100%) were found to contain vitamin E acetate oil.

This finding does represent a major breakthrough for four reasons:

1. The vitamin E acetate oil was detected in the actual lung tissue of the case patients.

2. The vitamin E acetate oil was detected in every single one of the lung tissue samples from these 29 case patients.

3. The samples came from 10 different states, confirming that the outbreak seems to have a common cause, rather than geographic variation.

4. Three of the patients whose lung samples revealed vitamin E acetate had reported using only nicotine-containing products, thus confirming that there is significant under-reporting which may explain why about 11% of the patients do not report vaping THC.”

The above quote is from: https://tobaccoanalysis.blogspot.com/2019/11/cdc-announces-major-breakthrough-that-i.html.

—

Full disclosure: Michael Siegel, a Public Health and Epidemiology doc who writes this blog, is my first cousin once removed. In another blog entry, he lambasts the FDA for disallowing mint vaping liquids while giving cigarette companies a pass on mint-flavored cigarettes.

Eat meat without worry (but you can feel guilty if you want)

From an article in the New York Times 1 October 2019  “In a statement, scientists at Harvard warned that the conclusions “harm the credibility of nutrition science and erode public trust in scientific research” “.

Strong stuff indeed.  Are they talking about Trump and the post-truth era?

Not at all. They are talking about a study in the Annals of Internal Medicine saying that the evidence that meat is bad for you is lousy, and not to be relied on.

To which I say, Amen.

— Here’s a link to the actual article — https://annals.org/aim/fullarticle/2752326/effect-lower-versus-higher-red-meat-intake-cardiometabolic-cancer-outcomes  — which the journal claims is freely available.

The authors looked at large numbers articles on the health effects of meat consumption to see if the conclusions that meat was harmful were warranted by a statistical analysis of the study.  In most cases they weren’t, or if they were, the evidence was weak.

Naturally there has been a counterattack, saying that one of the authors accepted money from the meat industry.  So what.  The studies are out there in print.  Statistical analysis is statistical analysis, and critics are welcome to perform their own statistical analyses of the papers.

This is far from the only example of dietary advice based more on hope and ideology than anything else.  A copy of two old posts (11/18 and 3/15) on the subject appears after the **

“erode public trust in scientific research”

This is exactly what I used to worry about when hysteria about common things causing cancer was at its height.  Joe sixpack’s logical conclusion to such things was — what the Hell, if everything causes cancer I might as well smoke.

Here are four things which medicine knows which are very likely to be true 50 years from now

l. Don’t smoke
2. Don’t drink too much (over 2 drinks a day), or too little (no drinks). Study after study has shown that mortality is lowest with 1 – 2 drinks/day
3. Don’t get fat — by this I mean fat (Body Mass Index over 30) not overweight (Body Mass Index over 25). The mortality curve for BMI in this range is pretty flat. So eat whatever you want, it’s the quantities you must control.
4. Get some exercise — walking a few miles a week is incredibly much better than no exercise at all — it’s probably half as good as intense workouts — compared to doing nothing.

Not very sexy but likely to still be true in 50 years.

There is tremendous resistance of researchers to having their conclusions disputed.  Another brouhaha concerns how much you should weigh.  Over 50 the lowest mortality rates occur with body mass indices (BMIs) between 25 and 30 (which currently is called overweight). A post on the subject appears after the ****BMI

**

Published 11/18

Eat what you want, no one really knows what a healthy diet is.

All dietary recommendations are based on sand so eat what you want and enjoy your Thanksgiving meal.  How can I say this? Just in time for Thanksgiving, the  august pages of Science contain the following article entitled “Dietary Fat:  From Foe to Friend ?” [ Science vol. 362 pp.  764 – 770 ’18 ].  Think I’m kidding?  Here is a verbatim  list of NINE current controversies (translation — not settled science) from the article.

1. Do diets with various carbohydrate-to-fat proportions affect body composition (ratio of fat to lean tissue) independently of energy intake? Do they affect energy expenditure independently of body weight?

2. Do ketogenic diets provide metabolic benefits beyond those of moderate carbohydrate restriction? Can they help with prevention or treatment of cardiometabolic disease?

3. What are the optimal amounts of specific fatty acids (saturated, monounsaturated, polyunsaturated) in the context of a very-low-carbohydrate diet?

4. What is the relative importance for cardiovascular disease of the amounts of LDL cholesterol, HDL cholesterol, and triglycerides in the blood, or of lipoprotein particle size, for persons on diets with distinct fat-to-carbohydrate ratios? Are other biomarkers of equivalent or greater importance?

5. What are the effects of dietary fat amount and quality across the lifespan on risk of neurodegenerative, pulmonary, and other diseases that have not been well studied?

6. What are the long-term efficacies of diets with different carbohydrate-to-fat proportions in chronic disease prevention and treatment under optimal intervention conditions (designed to maximize dietary compliance)?

7. What behavioral and environmental interventions can maximize long-term dietary compliance?

8. What individual genetic and phenotypic factors predict long-term beneficial outcomes on diets with various fat-to-carbohydrate compositions? Can this knowledge inform personalized nutrition, with translation to prevention and treatment?

9. How does variation in the carbohydrate-to-fat ratio and in sources of dietary fat affect the affordability andenvironmental sustainability of diets?

Then totally ignoring the above controversies — they say they agree on such bromides as

l. With a focus on nutrient quality, good health and low chronic disease risk can be achieved for many people on diets with a broad range of carbohydrate-to-fat ratios.

2. Replacement of saturated fat with naturally occurring unsaturated fats provides health benefits for the general population. Industrially produced trans fats are harmful and should be eliminated. The metabolism of saturated fat may differ on carbohydrate-restricted diets, an issue that requires study.

Basically I think you can eat what you want. Perhaps some day the research needed to base dietary recommendations on solid data will have been done, but that day is not here.

Here is an older post (March 2015) written when the dietary guidelines were changed yet again.

The dietary guidelines have been changed — what are the faithful to believe now ?

While we were in China dietary guidelines shifted. Cholesterol is no longer bad. Shades of Woody Allen and “Sleeper”. It’s life imitating art.

Sleeper is one of the great Woody Allen movies from the 70s. Woody plays Miles Monroe, the owner of (what else?) a health food store who through some medical mishap is frozen in nitrogen and is awakened 200 years later. He finds that scientific research has shown that cigarettes and fats are good for you. A McDonald’s restaurant is shown with a sign “Over 795 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 Served”

Seriously then, should you believe any dietary guidelines? In my opinion you shouldn’t. In particular I’d forget the guidelines for salt intake (unless you actually have high blood pressure in which case you should definitely limit your salt). People have been fighting over salt guidelines for decades, studies have been done and the results have been claimed to support both sides.

So what’s a body to do? Well here are 4 things which are pretty solid (which few docs would disagree with, myself included)

l. Don’t smoke
2. Don’t drink too much (over 2 drinks a day), or too little (no drinks). Study after study has shown that mortality is lowest with 1 – 2 drinks/day
3. Don’t get fat — by this I mean fat (Body Mass Index over 30) not overweight (Body Mass Index over 25 and under 30). The mortality curve for BMI in this range is pretty flat. So eat whatever you want, it’s the quantities you must control.
4. Get some exercise — walking a few miles a week is incredibly much better than no exercise at all — it’s probably half as good as intense workouts — compared to doing nothing.

Not very sexy, but you’re very unlikely to find anyone telling you the opposite 50years from now.

Typical of the crap foisted on the public (vitamin D and fish oil prevents cancer, heart disease and all sorts of horrible things) is it’s refutation once a decent study has been done

A large-scale trial has found no evidence that two popular supplements reduce the risk of cancer or the combined risk for a trio of cardiovascular problems.

JoAnn Manson at Brigham and Women’s Hospital in Boston, Massachusetts, and her colleagues recruited more than 25,000 healthy men and women in their fifties or older for a trial examining the effects of fish oil and vitamin D supplements. Some participants took both, others took only one type and the remaining participants took two placebos.

After an average of 5.3 years in the trial, participants who had taken fish oil had essentially the same likelihood of cancer as people who hadn’t. Compared with the placebo group, the fish-oil group had a lower rate of heart attack but the same rate of total cardiovascular events, a category that included heart attacks, strokes and death from cardiovascular disease.

Vitamin D supplements conferred no clear health benefits against cardiovascular disease or cancer, compared with a placebo.

N. Engl. J. Med. (2018) N. Engl. J. Med. (2018)

***BMI

Published 3/19

If you are over 50 it’s healthier to be overweight than not

Seriously folks, the lowest mortality rates over 50 occur in people currently defined as overweight. This is not theory, but data based on millions of people (see later).

So how does medicine define who is overweight?  By the Body Mass Index (BMI) being over 25 and under 30.  Obesity is defined as a BMI over 30.

Saying that someone over 50 with a BMI between 25 and 30 is overweight is true by medical definition, but that doesn’t make being overweight unhealthy (which is of course the implication of the term).

Well medically, you can define words any way you want, but Abraham Lincoln had it right

” How many legs does a dog have if you call his tail a leg?

Four.

Saying that a tail is a leg doesn’t make it a leg.”

 

If you’re itching to find out what your BMI is, the following site works for meters and kilograms or pounds, feet and inches — https://bmicalculator.mes.fm/?gclid=CM66rIG2tc0CFYQ2gQodOdINEg.

Here is where you can read the paper summarizing data on nearly 3 million people– https://jamanetwork.com/journals/jama/fullarticle/1555137?__rtqa=f4c5e818aba04f769cfc65207b2199b9

It’s better to read the following article in Nature.  It actually includes  the mortality curves at different ages which you can inspect at your leisure —

http://www.nature.com/news/the-big-fat-truth-1.13039

The only thing I don’t like about the BMI vs. mortality diagram, is that it is rather compressed, with data from BMI’s ranging from 15 to 45.  So the overweight range (25 – 30) doesn’t take up much space.  But look carefully at the overweight range — the curve is pretty flat here regardless of age showing that it really doesn’t matter how overweight you are (as long as you’re not obese, or superskinny).

Naturally this did not sit well people who’d staked their research careers on telling people to lose weight. One study by a Harvard guy removed 900,000 people from the JAMA study.    Robert Eckel, an endocrinologist at University of Colorado in Denver made the great comment that  “It’s hard to argue with data. We’re scientists. We pay attention to data, we don’t try to un-explain them.”

Now here is an explanation which I’ve not seen elsewhere so it might be original.

The BMI is far from perfect, but to calculate it all you need are two simple measurements that anyone can make — height and weight. It doesn’t rely on what people remember (how much they usually eat, what they weighed in the past.   However the calculation of BMI is not a simple ratio of weight divided by height but weight divided by height squared.

People lose height as they age, so the BMI is quite sensitive to it (remember the denominator has height squared). As a high school basketball player my height was 6′ 1”+, (at age 75) it was 6’0″ (God knows what it is now). So even with constant weight my BMI goes up.

It is now time to do the calculation to see what a fairly common shrinkage from 73.5 inches to 72 would to to the BMI (at a constant weight). Surprisingly it is not trivial — (72/73.5) * (72/73.5) = .9596. So the divisor is 4% less meaning the BMI is 4% more, which is almost exactly what the low point on the curve does with each passing decade after 50 ! ! !

Neurons synapsing with tumor cells, unbelievable but true

As a neurologist, I’ve seen more than enough breast cancer metastatic to the brain.  I never, in a million years, would have though that brain neurons would be forming synapses with them, helping them grow in the process.  But that’s exactly what two papers in the current Nature prove [ Nature vol. 573 pp. 499 – 501, 526 – 531 ’19 ]

The evidence is pretty good.  There are electron micrographs of brain metastases showing breast cancer cells acting like glia, surrounding a synapse between two neurons.  There are synaptic vesicles right next to the presynaptic membrane of the neuron which is apposed to the postsynaptic neuron (that’s what a synapse is after all). They are also present in the same neuron, whose membrane is tightly apposed  to a tumor cell, which stains positive for a type of glutamic acid receptor (the NMDAR).

Breast cancer types have been subdivided by the proteins they contain and don’t contain.  A particularly nasty one, is called triple negative — lacking the estrogen receptor the progesterone receptor and the herceptin receptor. Triple negative breast cancers account for 15 – 20% of all breast cancers, and some 40% of this group will die of brain metastases.  This paper may explain why.

The paper did some work using immunodeficient mice, transplanting human triple negative breast cancer cells into the brain.  Synapses formed between the mouse neurons and the breast cancer cells.

It is known that NMDAR signaling promotes growth tumor growth in other cancer types, and that increased NMDAR expression in breast cancer cells is associated with poor prognosis.

It is incredible to think that the brain is forming synapses with metastatic tumor cells to help them grow, but that’s what must be faced.

The excellent study confined itself to breast cancer metastatic to brain, but the study of other tumors (particularly lung) is sure to follow.

Good luck, RBG

Once again the press seems to dancing around a serious health problem of major public figure without saying just what it is.  Just about everyone admires RBG, but saying “The tumor was treated definitively and there is no evidence of disease elsewhere in the body” as the Supreme Court announced yesterday sounds wonderful doesn’t it?  Except that it isn’t.  8 months ago she had two metastatic tumors removed from her lung.  Sometimes it is possible to tell the tissue of origin from slides made from the tumors, but, as far as I can tell, this information was never released.  Now they say there is no sign of tumor elsewhere in her body (just as they said 8 months ago).

One hopes for the best for her.  Agree or disagree with her political philosophy, she is an admirable, brilliant and likable individual who has overcome a lot over the years.

Unfortunately Justice Ginsburg has metastatic cancer.  Her prognosis is not good.  As President Trump said “I’m hoping she’s going to be fine. She’s pulled through a lot. She’s strong, very tough.”

She had better be.

Addendum 28 August ’19

We’ll see how the right responds when RBG passes.  Here’s leftist folk hero Bill Maher on the death of one of the Koch brothers.  There are other similar responses.

https://www.newsweek.com/bill-maher-david-kochs-death-jokes-real-time-end-painful-1456028