Category Archives: Social issues ( be civil ! )

An experiment of nature

Back in day genetic diseases were called experiments of nature, which I thought rather cruel, as it implied a conscious intent to set them up (to me at least).  Well, we’re in the middle of one presently, and it may tell us something about climate change.  The New York Times today has a pious article “What the Pandemic Means for Climate Change” full of treacle.

However, it is possible that the drop in carbon dioxide (CO2) emissions (25% in China in February) if it goes on long enough might tell us something about the effect of CO2 on climate.

Suppose global CO2 drops and the temperature along with it.  This should convince the hardiest climate skeptic (not denier) that CO2 and global temperature are related.

I’m far from knowing enough to even guess, if a mild decline in emissions would change global CO2 levels and with it global temperatures, but both are being continuously measured so we’ll soon have the data.

Probably nothing will happen to either as there is so much CO2 in the atmosphere, that a blip of a 25% decline (even worldwide) won’t do anything.

I’m posting this, because the article said nothing about the possibility.

Any thoughts, particularly from people more knowledgeable than me

Some sanity (and hope) about the Wuhan flu

There is an excellent article in the following link,  https://news.harvard.edu/gazette/story/2020/03/public-urged-to-ramp-up-social-distancing-increase-coronavirus-tests/

Epidemiology Professor Marc Lipsitch, head of the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health, called the pace of coronavirus testing in the U.S. “utterly inadequate” and “a debacle” that robs public health officials of information crucial to devising an effective response and protecting health care workers. Testing has been so slow that no one knows the extent of the U.S. epidemic, though scientists guess at somewhere between “tens of thousands and hundreds of thousands” of cases.

Let’s say that is true that 100,000 people in the USA have already been infected.  What does that mean?  It means that most people with it aren’t very sick (we don’t have 100K people in ICUs on respirators).  This is the hope anyway

The CDC monopolized testing for Corona virus for a while and then distributed faulty test kits (while you may not like Trump, this isn’t his fault). So we have no way of knowing what’s out there.

That’s information gap #1 — we don’t know how many people are actively infected with the virus

Information gap #2 is even worse, and very likely longer to be corrected.  We don’t know how many people are out there who have fought the infection off and are no longer sick.  This will require a test for the antibodies to the virus they’ve developed (something that doesn’t happen right away during the acute infection although that’s where it begins).  Such information  is not available now, and likely won’t be for a month or two.

Addendum: Not everyone reading this knows what an antibody is so this is in response to a few questions.  Antibodies are proteins made by your body in response to an invading organism (which kill it).  This is why your kids have measles, mumps and rubella vaccines — they give the kids proteins from the viruses (not the whole organism), and your kids react as if infected by the intact virus (which is why they often seem to have the flu after vaccination), producing antibodies to those proteins, so when the real thing comes sneaking around, your kid’s antibodies recognize it and fight it off.  Having an antibody to the Wuhan flu is perfect evidence that you’ve been infected with it (even if the virus is long gone).  They aren’t something you’d have normally.  It isn’t simple to develop and validate a test for anti-Wuhan antibodies which why I think it will be a while before we have a test we can trust.

This will tell us just how much to worry about the virus.  Most reading this are too young  to remember the polio epidemic (which also put people on respirators). https://en.wikipedia.org/wiki/Polio  After antibody tests finally became available it was found that only one out of every one hundred people infected developed paralysis.

 

4 quotes saying the same thing — who wrote them?

Here are 4 longish quotes (with no ellipses) from 4 different writers on politics.  They all say pretty much the same thing.  What is remarkable is the political spectrum of the writers.  Answers at the end

Quote #1: “Donald Trump was in many ways an unappealing figure. He never hid that. Voters knew it.  They just concluded that the options were worse — and not just Hillary Clinton and the Democratic Party, but the Bush family and their donors and the entire Republican leadership, along with the hedge fund managers and media luminaries and corporate executives and everyone else who created the world as it was in the fall of 2016: the people in charge.

Trump might be vulgar and ignorant, but he wasn’t responsible for the many disasters America’s leaders created.  Trump didn’t invade Iraq or bail out Wall Street.  He didn’t lower interest rates to zero, or open the borders, or sit silently by as the manufacturing sector collapsed and the middle class died.  You couldn’t really know what Trump might do as president, but he didn’t do any of that.

There was also the possibility that Trump might listen. At times he seemed interested in what voters thought.  The people in charge demonstrably weren’t.  Virtually none of their core beliefs had majority support from the population they governed.  It was a strange arrangement for a democracy.  In the end, it was unsustainable.”

Quote #2: “The American white-collar class just spent the year rallying around a super-competent professional (who, it turns out, really wasn’t all that competent) and either insulting or silencing everone who didn’t accept their assessment.  And then they lost.  Maybe it’s time to consider whether there’s something about ear-splitting self-righteousness, shouted from a position of high social status, that turns people away.

The even larger problem is that a chronic complacency has been rotting American liberalism for years, a hubris that tells Democrats they need do nothing different, they need deliver nothing really to anyone — except their friends on the Google jet and those nice people at Goldman.  The rest of us are treated as though we have nowhere else to go and no role to play except to vote enthusiastically on the grounds that these Democrats are the ‘last thing standing’ between us and the end of the world.  It is a liberalism of the rich, it has failed the middle class, and now it has failed on its own terms of electibility.  The time is up for these comfortable Democrats and their cozy Washington system.  Enough is enough.”

Quote #3: “In 2018, Hillary Clinton told Britain’s Channel Four News: “The real question is how did the Russians know how to target their messages so precisely to undecided voters in Wisconsin or Michigan or Pennsylvania —that is really the nub of the question.”

No, the real question is why so much of the US and European establishment accepted and promulgated Clinton’s alibi for her failure to follow her husband into the office of president of the United States.  A Clinton or Bush was president, vice president, or secretary of state in every year between 1981 and 2013, years in which working class incomes stagnated, offshoring devastated US and European manufacturing, the world suffered the worst economic collapse since the Great Depression of the 1930s, and the US lunged into multiple disastrous wars in the Middle East and Central Asia. Trump became president by running against a Bush in the Republican primaries and a Clinton in the general election.  The desire of many American voters to disrupt the quarter-century cycle of nearly identical versions of technocratic neoliberalism under alternating Bushes and Clintons is quite sufficient to explain the presidential election of 2016.”

Quote #4: “Iowa was the real “beginning of the end” to a story that began in the Eighties.

Following the wipeout 49-state, 512 electoral-vote loss of Walter Mondale in 1984, demoralized Democratic Party leaders felt marooned, between the awesome fundraising power of Ronald Reagan Republicans and the irritant liberalism of Jesse Jackson’s Rainbow Coalition.
To get out, they sold out. A vanguard of wonks like Al From and Sen. Sam Nunn at the Democratic Leadership Council devised a marketing plan: two middle fingers, one in each direction.
They would steal financial support for Republicans by out-whoring them on economic policy. The left would be kneecapped via “triangulation,” i.e., the public reveling in the lack of choices for poor, minority, and liberal voters.
Young pols like Bill Clinton learned they could screw constituents and still collect from them. What would they do, vote Republican? Better, the parental scolding of disobedient minorities like Sister Souljah combined with the occasional act of mindless sadism (like the execution of mentally ill Ricky Ray Rector) impressed white “swing” voters, making “triangulation” a huge win-win — more traction in red states, less whining from lefty malcontents.
Democrats went on to systematically rat-fuck every group in their tent: labor, the poor, minorities, soldiers, criminal defendants, students, homeowners, media consumers, environmentalists, civil libertarians, pensioners — everyone but donors.
They didn’t just fail to defend groups, but built monuments to their betrayal. They broke labor’s back with NAFTA, embraced mass incarceration with the 1994 Crime Bill, and ushered in the Clear Channel era with the Telecommunications Act of 1996. Welfare Reform in 1996 was a sellout of the Great Society (but hey, at least Clinton kept the White House that year!). The repeal of the Glass-Steagall Act gave us Too Big to Fail. Shock Therapy was the Peace Corps in reverse. They sold out on Iraq, expanded Dick Cheney’s secret regime of surveillance and assassination, gave Wall Street a walk after 2008, then lost an unlosable election, which they blamed on a conspiracy of leftist intellectuals and Russians.
Still, if you were black, female, gay, an immigrant, a union member, college-educated, had been to Europe, owned a Paul Klee print, or knew Miller’s Crossing was a good movie, you owed Democrats your vote. Why? Because they “got things done.”
Now they’re not getting much done, except a lost reputation. That feat at least, they earned. To paraphrase Joker: What do you get when you cross a political party that’s sold out for decades with an electorate that’s been abandoned and treated like trash?
Answer: What you fucking deserve!”
Quote #1: Tucker Carlson “Ship of Fools” p. 3 — a classic conservative
Quote #2: Thomas Frank: “Rendesvous with Oblivion” p. 185.  A classic liberal
Quote #3 Michael Lind:  “The New Class War” p. 98.  Although he’s been writing for 25 years, I was unfamiliar with his work
Quote #4 Michael Taibbi: — a reporter who writes incredibly well for Rolling Stone, probably very liberal. https://www.rollingstone.com/politics/politics-features/iowa-caucus-democrats-disaster-trump-sanders-949655/amp/
I find it remarkable that 4 writers, from nearly as wide a political spectrum as it is possible to get, are basically saying the same thing.

What would Woodward do — take II

“It’s no wonder that truth is stranger than fiction. Fiction has to make sense.”  Mark Twain.

The Harvard Chemistry Department chair arrested?  And for what?  For lying and hiding research work he was doing for China.

“The arrangement between Lieber and the Chinese institution spanned “significant” periods of time between at least 2012 and 2017, according to the affidavit. It says the deal called for Lieber to be paid up to $50,000 a month, in addition to $150,000 per year “for living and personal expenses.”

Who knew betraying your country could be so lucrative?  Of course these are allegations, and have to be proved in court.

What would the great Robert Burns Woodward (https://en.wikipedia.org/wiki/Robert_Burns_Woodward) say to this?  He’s already spinning in his grave over the slings and arrows heaped on pure synthetic organic chemistry.  For details see part of an old post at the end.

Interesting how the department has changed.  No Chinese there at all ’60 – ’62 (even postdocs).  There were several Japanese and Sikh postdocs along with a fair number of happy go lucky Australians.

Chemistry applications can be lucrative.  The new Princeton Chemistry Building was built thanks to professor Ted Taylor, whose royalties on Alimta (Pemetrexed), an interesting molecule with what looks like guanine, glutamic acid, benzoic acid and ethane all nicely stitched together to form an antifolate, to the tune of over 1/4 of a billion dollars built it.

It’s interesting to note that the Princeton undergraduate catalog for ’57 – ’58 has Dr. Taylor basically in academic slobbovia — he’s only teaching Chem 304a, a one semester course “Elementary Organic Chemistry for Basic Engineers” (not even advanced engineers)

For details please see  — https://luysii.wordpress.com/2011/05/16/princeton-chemistry-department-the-new-oberlin/

What would Woodward do ?

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”

I returned from my father’s 100 year birthday blowout and band camp and began attacking a giant pile of accumulated unread journals.  In the 9 August Nature (p. 630 – 631)  2007 he was amazed to read criticism of a 64 step 22 year synthesis of an exquisitely complex molecule (azadirachtin) — a molecule in which it is easier to count the number of optically INactive carbons than the optically active ones.  Back in the 60s we were all impressed with how Woodward got the 5 asymmetric centers in a 6 membered ring of reserpine (which was in use as an antihypertensive at the time, and whose fairly common side effect of depression was one of the clues leading to the amine theory of affect).  Rip was surprised to find that the criticism was not that the synthesis was incorrect, but that the project shouldn’t have been done at all.  Apparently a significant body of organic chemists think this way.

Political correctness has left few groups which it is safe to disparage.  With apologies to one of them (Christians) I’ve got to ask “What would Woodward do?”

3 physicists and a slimeball

3 physicists and a slimeball.  How can they be related? Here’s how.

Back in the day, there were a lot of self-proclaimed math and physics geniuses when I was a cowed high school graduate starting out at an Ivy League school.  One who was not like that (but who actually was quite brilliant) was classmate Heinz Pagels.  Here’s a list of the books he subsequently wrote — https://www.amazon.com/s?k=heinz+pagels&ref=nb_sb_noss_1.  He was subsequently described as flamboyant, which I found hard to believe, but which was confirmed by his graduate student (physicist #2) and Tony Zee.

Physicists don’t hold meetings and summer schools in North Platte Nebraska.  So he and his (only) graduate student went mountain climbing while at an Aspen summer school in physics.  Heinz had polio when young (remember he grew up in the 40s and 50s) which weakened his ankle and he fell to his death at age 49.  His grad student had to break the news to his wife Elaine Pagels — https://en.wikipedia.org/wiki/Elaine_Pagels.

Fast forward 34 years to the same department, and physicist #3 who tore the place up, being class salutatorian, Harvard Junior Fellow and later full professor at his alma mater.  His name is Steven Gubser and he died in a rock climbing accident in France at age 47.

Incredible that two brilliant physicists from the same department would die this way.   You could never put this into a novel — way too farfetched.

The whole business was brought to mind by a New York Times article about physicist #2 Pagels’ grad student Seth Lloyd.  I’ve enjoyed his book “Programming the Universe” and corresponded with him about the book and what Heinz was like (apparently he was flamboyant).

Way back in the day when I was a kid, my mother would read Uncle Remus (https://en.wikipedia.org/wiki/Uncle_Remus) stories to me (probably banned now as politically incorrect).  The one I remember is about the tar baby, which stuck to and trapped anyone touching it.  This is the slimeball — Jeffrey Epstein who gave Lloyd money for research, along with many others at MIT.  Lloyd has been placed on administrative leave, for accepting it or not reporting it or just general principles.  The  ‘Tar-Baby ain’t
sayin’ nothin’ because Epstein is dead.

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.