Category Archives: Social issues ( be civil ! )

Now is the Winter of our Discontent – II

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.

Add to that the recent loss of an excellent surgeon I practiced medicine with in Montana for 15 years.  Reading his obit was how I found out that he was a Fulbright scholar.  This is so typical of Montana and how great it was.  Don’t ever brag.  Show us how you are and what you can do, but never tell us.  There are so few people out there that you’ll bump up against each other again and again. They’ll figure out who you are without you telling them.  When I’d go back East, I noticed that city people (who a friend in Montana called decorated ants) would tell you what they were really like.  They had to as they’d likely never get another shot at you.

Which brings me to another greatness of Montana back in the 70s.  Back East your education pretty much pigeonholed you.  Right or wrong, you assumed intelligence correlated with the amount of education.  Not so in Montana. In the early 70s there were plenty of bright people who couldn’t go on to college growing up during the depression.  So you quickly learned to treat everyone the same.

Princeton?  Where is it?  Is is an Ag school?  You were free to create your own identity without being pigeonholed.   It was a fabulous feeling.

There were Ivy leaguers around (all Ivy Fullback, Brown, Dartmouth, Yale etc. etc.)  but we all kept it fairly low key.  One rancher acquaintance had gone through Harvard in 3 years.  His daughter went there as well, and was actually the centerfold of the Harvard alumni magazine, and this before she won a silver in the olympics.   The son of another rancher went to Harvard and was told that his father was a cow farmer.  When he did well academically, he was told that he was there to lower the curve.

The children of my friends continued the great Montana tradition of exporting its  brightest youth, going to Cornell, Princeton, Rice, Stanford, Harvard (and doing quite well there) but never coming back.

The one group of people that I didn’t (initially) treat ‘the same’ were the Indians, united only by their different appearance from what I was used to (maybe I met one in the years of college, grad school, med school, internship, residence and even the Air Force).   Calling them native americans back then would have gotten you some strange looks.  I worked with some excellent Indian nurses in the local hospitals, and did some consulting for the Indian Health Service, getting to know the culture much better.  My kids went to school with some.

If you wanted to invent an institution to produce social pathologies (alcoholism, child abuse in particular) you couldn’t do better than putting people on a reservation, giving them enough money to get by and giving them nothing to do.

My father and his brother had  the classic liberal conservative debate (before I knew what they were).  Uncle Irv would always say — it’s the system doing (whatever behavior that he didn’t like) — you must change the system.  My father would  counter saying that people would corrupt any system.

I basically bought my father’s position (being reinforced by living for the past 16 years in Massachusetts).

Now I’m not so sure. After one son moved to Hong Kong, I realized that uncle Irv had a point.  Hong Kong is dynamic, vibrant and clean (at least it was 2 years ago the last time I was there) with hordes of hardworking active people.

No so where my son lives along with many exPats — Lamma island, a 20 minute ferry ride from the city.   Walk home from the ferry and you’ll see a bunch of fat asian guys sitting around drinking and smoking.  Who are they?  They are the descendants of the tribes that lived there initially.  Either they own the place or they are continually supported and don’t need to work.

I looked at them and said, my God it’s the rez.  My son said, yup it’s the rez.

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 a chemical measuring stick actually works

The immune system knows something is up when a foreign peptide fragment is presented to it.  Here’s the hand holding the peptide — https://www.researchgate.net/figure/Overall-structure-of-HLA-peptide-complex_fig1_26490512.

There it sits, lying on top of a bed of beta sheets, with two side rails of alpha helices.  Proteins are big, way too big to fit into the hand, so the fragments must be chopped up into peptides no longer than 9 amino acids long (see the picture of it lying in state).

So the class assignment for today is to figure out how to design a protein which takes peptides from 10 – 16 amino acids long, and shortens them to 9 amino acids.

Obviously a trick question, because the actual amino acids making up the peptide don’t really matter much.  So somehow the protein is reacting to length rather than chemistry.

Tricky no?

ERAP1 (Endoplasmic Reticulum aminopeptidase associated with Antigen Processing has figured it out [ Proc. Natl. Acad. Sci. vol. 116 pp. 22709 – 22715 ’19 ].  It is a huge protein (948 amino acids) with four domains forming a large cavity (which it must have to accomodate a 19 amino acid paptide).  The peptide is chopped up from the amino terminal, stopping when the length reaches 9 amino acids.  The active site is at one end of the cavity, and at the other end there is a site which looks like it should cleave the carboxyterminal amino acid, but it doesn’t because the site is inactive.  However, even catalytically inactive enzymatic sites have enough structure left so they bind the substrate.

So binding of the carboxy terminal amino acid to the back site causes conformational changes transmitted through various alpha helices to the active enzyme at the other end.  It munches away removing amino acid after amino acid until the peptide gets short enough (translation 9 amino acids) so that it doesn’t push on the back site.

Incredibly clever, even though it hurts me as a chemist to see the enzyme essentially ignoring the chemistry of its substrate.

I far prefer this to politics where data is ignored.  Two examples

l. From a review of a book by Paul Krugman in the Jan/Feb 2020 Atlantic

“Krugman is substantively correct on just about every topic he addresses.” Yes except Peak Oil in 2010, Stock Market collapse in Nov 2016 and the coming recession in an article April 2019

2. Former Secretary of Labor Robert Reich in the Guardian 22 Dec ’19 — “How Trump has betrayed the working class” — by employing them and raising their wages no doubt.

Null hacking — Reproducibility and its Discontents — take II

Most scientific types have heard about p hacking, but not null hacking.

Start with p hacking.  It’s just running statistical test after statistical test on your data until you find something unlikely to occur by chance more than 5% of the time (a p of .05) making it worthy of publication (or at least discussion).

It’s not that hard to do, and I faced it day after day as a doc and had to give worried patients a quick lesson in statistics.  The culprit was something called a chem-20, which measured 20 different things (sodium, potassium, cholesterol, kidney tests, liver tests, you name it).  Each of the 20 items had a normal range in which 95% of the values from a bunch of (presumably) normal people would fall.  This of course means that 2.5% of all results would be outside the range on the low side, and 2.5% would be outside the range on the upside.

Before I tell you, how often would you expect to get a test where all 20 tests were normal?

The chance of a single test being normal is .95, two tests .95 * .95 = .90, 4 tests .90 * .90 = .81, 8 tests .81 * .81 = .65, 16 tests .65 *.65 = .42, 20 tests .42 * .81 = .32.

Less than 1/3 of the time.

That’s p hacking.  It has been vigorously investigated in the past few years in psychology, because a lot of widely cited results in supposedly high quality journals couldn’t be reproduced.  See the post of 6/16 at the end for the initial work.

It arose because negative results don’t win you fame and fortune and don’t get published as easily.

So there has been a very welcome and salutary effort to see if results could be confirmed — only 39% were — see the copy of the old post at the end.

So all is sweetness and light with the newly found rigor.  Not so fast says Proc. Natl. Acad. Sci. vol. 116 pp. 25535 – 25545 ’19.  The same pressures that lead investigators to p hack their result to get something significant and publishable, leads the replicators to null hack their results to win fame and fortune by toppling a psychological statue.

At this point it’s time for a Feynman quote “The first principle is that you must not fool yourself and you are the easiest person to fool.”

The paper talks about degrees of freedom available to the replicator, which in normal language just means how closely do you have to match the conditions of the study you are trying to replicate.

Obviously this is impossible for one of the studies and its replication they discuss — whether the choice of language used in a mailing  to urge people to vote in an election had any effect on whether they actually voted.  Obviously you can’t arrange to have the two hard fought elections in which there was a lot of interest of the initial study run again.  But the replicators choose a bunch of primaries in which interest and turnout was low, casting doubt on their failure to replicate the original results (which was that language DID make a difference in voter turnout).

Then the authors of the PNAS paper reanalyzed the data of the replicators a different way, and found that the original study was replicated.  This is the second large degree of freedom, the choice of the way to analyze the raw data — the same as the original authors or differently — “reasonable people may differ” about these matters.

There’s a lot more in the paper including something called the Bayesian Causal Forest which is a new method of data analysis which the authors favor (which I confess I don’t understand).

Here’s the old post  of 6/16

Reproducibility and its discontents

“Since the launch of the clinicaltrials.gov registry in 2000, which forced researchers to preregister their methods and outcome measures, the percentage of large heart-disease clinical trials reporting significant positive results plummeted from 57% to a mere 8%”. I leave it to you to speculate why this happened, but my guess is that probably the data were sliced and diced until something of significance was found. I’d love to know what the comparable data is on anti-depressant trials. The above direct quote is from Proc. Natl. Acad. Sci. vol. 113 pp. 6454 – 6459 ’16. The article looked at the 100 papers published in ‘top’ psychology journals, about which much has been written — here’s the reference to the actual paper — Open Science Collaboration (2015) Psychology. Estimating the reproducibility of psychological science. Science 349(6251):aac4716.

The sad news is that only 39% of these studies were reproducible. So why beat a dead horse? The authors came up with something quite useful — they looked at how sensitive to context each of the 100 studies actually was. By context they mean the time of the study (e.g., pre- vs. post-Recession), culture (e.g., individualistic vs. collectivistic culture), the location (e.g., rural vs. urban setting), or the population (e.g., a racially diverse population vs. a predominantly White or Black or Latino population). Their conclusions were that the contextual sensitivity of the research topic was associated with replication success (e.g. the more context sensitive, the less likely it was that the study could be reproduced). This was even after statistically adjusting for several methodological characteristics (e.g., statistical power, effect size, etc. etc). The association between contextual sensitivity and replication success did not differ across psychological subdisciplines.

Addendum 15 June ’16 — Sadly, the best way to say this is — The more likely a study is to be true (replicable) the more likely it is to be not generally applicable (e.g. useful).

So this is good. Up to now the results of psychology studies have been reported in the press as of general applicability (particularly those which enforce the writer’s preferred narrative). Caveat emptor is two millenia old. Carl Sagan said it best — “Extraordinary claims require extraordinary evidence.”

For an example data slicing and dicing, please see — https://luysii.wordpress.com/2009/10/05/low-socioeconomic-status-in-the-first-5-years-of-life-doubles-your-chance-of-coronary-artery-disease-at-50-even-if-you-became-a-doc-or-why-i-hated-reading-the-medical-literature-when-i-had-to/

 

The Battle of the Bulge

16 December marks the 75th anniversary of the Battle of the Bulge.  My uncle Irv was in it.  16,000 Americans died fighting Germany.  75 years later it passeth understanding why America is defending a Germany which refuses to pay 2% of its budget in defense.  Defense against what? Against Russia, a third world country with a first world army and educational system, which was unable to maintain its European empire 30 years ago?  Please.

Europe has a GDP of 18 trillion Russia of 3.5 trillion, a population which dwarfs that of Russia, whose own population is declining.  President Trump has supposedly offended our NATO “allies” by asking them to meet their 2% commitment.  Some progress has been made.  When he took office 3/30 were actually doing this, presently it’s up to 8.

Europe is quite a different ensemble of countries.  The two largest economies,  France and Germany have unemployment rates of 9 and 3.1%.

But joint action isn’t impossible.  Consider what the 13 colonies had to face, stitching together Virginia population 538,000 in 1780 with 4 colonies with populations under 10% of that (Delaware, Maine, Vermont and Rhode Island).  As Benjamin Franklin said at the time “We must, indeed, all hang together or, most assuredly, we shall all hang separately.”

Withdrawal of US funding would wonderfully concentrate the European mind.   They would need to make the guns vs. butter decision that we’ve postponed for them for the last 50 years. Perhaps we could use the money for our own social services, rather than theirs.

Back in college in the early stages of the Cold War, I took a wonderful course in Russian history, and even better had Cyril Black as a preceptor (https://www.historians.org/publications-and-directories/perspectives-on-history/november-1989/in-memoriam-cyril-e-black).  He noted that Russia was the only country in the world surrounded by hostile communist powers, and that the real problem of the cold war was not our security but Russia’s.   Mucking about in the  various Russia/Ukraine conflicts (which have been going on for a millennium) is not in our interest.

We are still scarred by 9/11.  Russian loses in World War II (civilian and military) were 27,000,000.  Their security is paramount to them, and they are operating on the theory that the best defense is a good offense. Ditto China.

Well that was fairly harsh.  I’ll end with how I found out uncle Irv was in the Battle of the Bulge.  I knew he’d been in North Africa at the battle of Kasserine pass, but I didn’t find out about europe until much later.

My father graduated Rutgers in 1928 and lived long enough (to 100) to be one of their oldest living alums.  He and I enjoyed going to Rutgers reunions each year where he would hold court.  Two other uncles went to Rutgers as well.  In 2001 one of them was at his 60th reunion.  Uncle Effie had been in the South Pacific with two other family uncles (one of whom was at Iwo Jima).  He introduced me to his old roommate, a tiny little man.  Eventually it came out that he wasn’t too small to fight and had been in the battle of the bulge as well.  The whole Rutgers class of 1941 served in the war.  I was amazed that this little guy was even in the army and mentioned it to uncle Irv, who said “I was in the Battle of the Bulge”.  That generation just didn’t talk about what they did in the war.

 

 

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.

 

Whiggish history

Whiggish historicism is (currently) frowned on in historical circles.  This is the presentation of history as a steady march toward our current perfection and enlightenment.  Scientific history used to be like this, but recently explorations of paths not taken have been more humane (Cauchy missing out on uniform convergence, Golgi inventing the technique proving that single neurons existed, yet not believing it, Lorentz inventing the transformation that Einstein would use in relativity, but not understanding what he did).

Current moral ideas among progressives are incredibly Whiggish, with each new step viewed as yet higher enlightenment.  Punishments are meted out to people in their adolescence who didn’t conform to current theology.  It’s the scarlet eMail instead of the Scarlet letter of Hester Prynne. Forgiveness is impossible.

Here are a few more examples of progressive ideology viewed as theology from an earlier post. The parallels are so uncanny and complete, they’re not even parallels.

Example1  — sinecures — a device used by the clerisy to support incompetent progeny — Hunter Biden and Burisma and the Chinese fund.

Example 2 — indulgences — buying forgiveness for sin by donating to the church — Jeffrey Epstein’s contributions to Planned Parenthood and NOW.  Martin Luther would have no problem recognizing this as such.

Example 3 — good works buying absolution for sin.  Clinton’s rape and abuse of women forgiven by legislation on reproductive rights.

Those are just the low hanging fruit.  Moving on to actual theology, social guilt and white privilege is simply original sin in modern garb.  You need do nothing to acquire it, and you can’t get rid of it.

Moving on to the old testament — there are sins which can not be forgiven, for which the punishment is personal destruction — wearing blackface as an adolescent, writing against homosexual marriage decades ago etc. etc.  Here comes the twitter mob.

Then there is heresy.   One such is admiring conventional religion.  This calls forth the twitter mob experiencing the rush that comes from expressing their moral superiority.

The worst (recent) example is the opprobrium heaped on Botham Jean for hugging his brother’s murderer.  The harpies were in full cry, but it is impossible for me to watch that video https://www.cbsnews.com/news/amber-guyger-sentence-former-officer-who-killed-neighbor-botham-jean-gets-10-years-today-live-updates-2019-10-02/ without being moved.  Viewed through the narrow lens of race it is disturbing, but viewed in the much wider and more appropriate lens of human emotion it is incredibly powerful.

Progressive secular theology (for that is what it is) gives no quarter.

 

Tough 60s chick disappoints woke young interviewer

Quanta — https://www.quantamagazine.org — always has science and math worth reading.   The following is worth reading for the contrasting mindsets of interviewer and interviewee — https://www.quantamagazine.org/virginia-trimble-has-seen-the-stars-20191111/.

Virginia Trimble — now 76 and in declining health, was once young, beautiful, brilliant and a grad student at Cal Tech in astronomy.  Now a prof a UC Irvine she was interviewed by a young woman, about her experiences.

The interviewer did her best to make her appear exploited, but Trimble was having none of it.

Q. So you get to Caltech, and you’re the only woman —

A. I wasn’t. There was this tiny little cluster of seven of us that went through all at the same time …

She was so gorgeous (see her picture in the article) that Feynman asked her to be a model as (presumably) he was learning to draw, paying her $5.50 an hour.

The interviewer couldn’t contain herself

Q. When you spoke to him, did he treat you collegially?

Trimble, never one to pussyfoot around, responds.

A. The obvious question, did we make love? As it happens, no, but not a big deal. It might just as well have been yes, and we would still have been good friends.

The intrepid interviewer persists.

Q: I want to talk about sexual harassment in academia.

I don’t particularly care for the word harassment.

Let’s go with “hanky-panky,” OK?

Sure.

When I was young and beautiful, I engaged in a great deal of hanky-panky. I could never see anything very wrong with it. You may claim that if a very distinguished senior scientist engages in hanky-panky with a much younger scientist — never mind which gender, and make it a conductor and a violinist if you wish, instead of senior and junior scientists — if that results in real injustice to people not involved in the hanky-panky, then, yeah, you have to have a rule against it. But I’m not so sure that that happens very often.

Clearly not the sort of thing the interviewer expected.  She persists and gamely frames a question so she can get the answer she wants

Q: I just want to clarify, when someone in power makes someone who is subordinate feel that they have to engage in sexual activities for the sake of their job or the sake of their academic career, that is what angers so many people right now.

Trimble is having none of it

A: The step in that syllogism where I part company is the younger — or whatever — person feeling they “have to,” and let me say again that a young attractive female has a lot of power, where older, less attractive men are concerned.

Defeated, the interviewer changes the subject.

Q: What are you most proud of in terms of your scientific work?

There’s a lot of interesting science in the article, but the clash of mindsets interested me more.

The Russian language

“The power of language is its ambiguity” sayeth I.  This came up because my nephew married a wonderful Russian expat a few weeks ago.  Plucky fellow that he is, he’s learning to speak Russian.  Like my wife’s friend of 50+ years ago he is amazed at how many words the language has.  Russian apparently has a word for everything so there is little ambiguity, which must make the language hard to pun in.

Someone Googled the number of words in Russian and English and they’re about the same.

Perhaps the lack of ambiguity makes Russian hard to learn (and use).  Computer languages (basic, C, pascal) are completely unambiguous.  Every reserved word and operator means exactly one thing, no more no less.

Most people find programming far from intuitive.  It’s hard to express our sloppy ideas in unambiguous computer language.  Given it’s difficulty giving concrete form to your ideas, computer languages aren’t as powerful (in the sense of being easy to use) as your sloppy sentences.

Why should language be so ambiguous?  My guess is, that it has to be this way given the way we perceive the world (and the way the world probably actually is — ontology if you want to impress your friends).

We don’t live in Plato’s world of perfect forms, but in a world of objects that only partially and rather poorly instantiate them.  This is as true of science as anything else — even supposedly well defined terms change their meaning — are the giant viruses really viruses?  What do we really mean by a gene?  It used to be a part of DNA coding for a protein, but what about the DNA that controls when and where a protein is made.   Mutations here can cause disease, so are they genes?

Language, to be useful, must express our imperfect ways of rigidly classifying the world (perhaps because such a classification is impossible).

Socially, I never thought of our family as inhibited, but the Russians I met seemed more alive and vibrant than our lot (this without them living up to their reputation of hard drinking).

50 years later . . .

50 years ago, I was a US Air Force physician taking care of the maimed and wounded at Fitzsimons Army Hospital in Denver.  It was the first in a series of military adventures foisted on our soldiers by ‘the best and the brightest’ (aka our elites). None have gone well — Desert Storm, regime change in Libya, Afghanistan, you name it.

Presently President Trump is taking heat from congress and just about the entire mainstream press (right and left) for pulling our soldiers out of Syria, and ‘letting Putin win’.  Never questioned is why we were there in the first place.  We should equip anyone  in the press who wishes to defend the Kurds with a rifle (never call it a gun if you live in the barracks) and send them over.  I doubt that many have served (or would serve now)

74 years ago as a boy I saw firetrucks and cars parading around town making as much noise as possible.    It was Victory in Europe day (VE day).  It meant that one of the four uncles in our families could come home although I didn’t understand it at the time.  The other three were island hopping in the Pacific as a marine, helping guerillas in the Philippines, and running a company of MPs in China.

Just under 75 years ago the other uncle was in the Battle of the Bulge fighting against Germany.

Why in the world are we still defending Germany 3/4 of a century later?  President Trump has been criticized for offending our European allies by asking them to pay more for their defense.  They will not be sufficiently offended to stop taking our money.  It’s welfare dependency on the national level.

Defense against what?  Russia — a third world country with a first world army and educational system which is barely maintaining its population.  Europe has 3 times the population and GNP.  As Franklin said “We must all  hand together, or assuredly we shall all hang separately” (1776). If European nations won’t, so be it.

President Trump is asking questions that should have been asked long ago.  He is doing exactly what he was elected to do.