A skewed distribution

100 faculty at Columbia wrote a letter defending ‘robust inquiry’, e.g. students supporting Hamas shortly after their attack of 7 October 2023.

Here’s a link to the letter and the signatories — https://docs.google.com/document/u/1/d/1cVLg6RTnqd2BTzuouWbfACnFEex7GQeImDZJnMlUReM/mobilebasic

Some 100 faculty signed the letter and their departmental home can be found in the list in the link.  Among the 100 are 1 mathematician, 1 physicist and 1 pediatrician.  That’s it for STEM.

This is hardly representative of the faculty as a whole being top heavy on the liberal arts, which may explain the 30% decline in liberal arts majors from 2012 t0 2020.

Charm School

It was nice to get back to the science (https://luysii.wordpress.com/2024/04/17/cholesin/) after several long detours through current events but reality continues to intrude.  The firing of 30 Google staffers who protested Google’s choice of clients and the mass arrests and academic suspension of the Columbia University students who set up a protest encampment on campus is worth a post about a bit of history.

Just shy of 56 years ago I entered the service under the Berry Plan as an Air Force doctor.

After serving as an army doc for two years in ’68 – ’70, a time when we had 500,000 troops in Vietnam, I left with little respect for its leadership. I was stateside at Fitzsimons General Hospital, one of the Army’s premier hospitals, which was a plum assignment (because the army was very short of neurologists). This meant that 2 year docs who’d served their first year in Vietnam got their choice of assignment when returning stateside. So I saw plenty of them and  NOT ONE thought we were winning over there, despite what the top brass said to the press and the president.

So who would have thought that 33 years later I’d be friendly with and respect a retired Major General, George Baker. Never say never. He was a very intelligent man, an orthopedic surgeon, who’d been chief at Walter Reed and found retirement boring, so he practiced at my hospital. He told me about something he called charm school. It was where officers newly promoted to  General  rank were sent for training. They were told to toe the straight and narrow sexually and in other matters, and that if a planeload of them went down, the army would have no trouble at all filling their shoes.

Why should future protestors hear about this? Because, according to the net, Columbia accepts under one in 25 applicants and Google accepts around one in five hundred (look it up).  They are not so wonderful that they can’t be easily replaced with people of comparable quality.

Cholesin

You wouldn’t think that there was anything more to be said about cholesterol metabolism after decades of work by med school classmate Mike Brown and a host other researchers.  But there is.

The body can synthesize cholesterol starting from scratch and Mike found out how this is inhibited when cholesterol levels get too high.  Here is a brief summary of how this happens from a recent paper [ Cell vol. 187 pp. 1685 – 1700 ’24 ]

“Cholesterol biosynthesis and uptake are tightly regu-lated through a negative feedback mechanism that senses the cellular cholesterol levels. When cells are deficient in cholesterol, SREBP2, along with its escort protein SREBP cleavage-acti- vating protein (SCAP), is transported in coat protein complex II (COPII) vesicles from the endoplasmic reticulum (ER) to the Golgi apparatus. In the Golgi, SREBP2 is sequentially cleaved by site-1 and site-2 proteases. The N-terminal domain of SREBP2, released by this cleavage, travels to the nucleus, where it func- tions as a transcription factor to enhance the expression of genes involved in cholesterol synthesis and uptake. Conversely, when cellular cholesterol levels rise, cholesterol molecules bind to SCAP, triggering its interaction with insulin-induced gene (INSIG). This interaction retains SREBP in the ER and prevents the subsequent activation of SREBP and the expression of genes involved in cholesterol metabolism”.

 

Well now you can see why this took decades to figure out.

However a recently discovered protein cholesin cuts off cholesterol synthesis when you eat and absorb cholesterol, which is much more proactive as it doesn’t wait for cholesterol levels to increase.   Cholesin is secreted into the blood by the gut when cholesterol is absorbed (secretion into the blood is what makes it a hormone).   Human cholesin contains 195 amino acids and works its magic by binding to a G Protein Coupled Receptor (GPCR) called GPCR146 which shuts off signaling by protein kinase A (PKA). This prevents  SREPB2 from turn on cholesterol synthesis (primarily in the liver).

So obviously GPCR146 and cholesin do a biochemical dance together.  Amazingly, dance is more than a metaphor, and the two proteins are coded (and entwined) on opposite strands of the same genetic locus of chromosome #7 with the code for GPCR146 on one strand inside the code for cholesin on the other.

I find this both bizarre and fantastic.  The discoveries of molecular biology never cease to amaze (me at least, and you too if your molecular biological soul isn’t completely dead).

The viruses in our brains

PNMA2 (ParaNeoplastic antigen MA2) is a protein initially found as the target of the immune response (autoantibodies) producing a nasty dementing neurologic disease (Paraneoplastic encephalitis).  The PNMA2 protein is exclusively expressed in neurons which implies that neurons are using it for something.   This is teleological thinking, usually looked down on, but always needed in molecular biology and cellular physiology.

What PNMA2 does is amazing.  It forms icosahedral viral capsids which are released from cells (in culture) as nonEnveloped capsids.  It isn’t clear if this normally happens in our  brains.    Probably it doesn’t, and when the capsid somehow gets out of the producing cell or neuron immunological hell breaks loose and autoimmune encephalitis is the result.

PNMA2 is derived from one of the long terminal repeat retrotransposons (LTR retrotransposons), viral remnants that make up 8% of the human genome (https://en.wikipedia.org/wiki/LTR_retrotransposon). This explains why it makes particles that look like viruses.  Such particles can contain RNA, so big pharma is interested in them as a way of delivering mRNA drugs.

Totally off topic but yesterday I read a paper about E. Coli DNA gyrase, an amazing enzyme which untangles DNA ( Science vol. 384 pp. 227 – 232 ’24 ).

Here is what it does.   If you’ve got some venetian blinds in your home twist it 20 or so times (keeping the ends fixed, and you have the DNA double helix, with two strands winding around each other.  Now to read or copy a single strand, you must grab both strands where you want this to happen  and pull them apart keeping the ends of the venetian blind fixed.  This immediately increases the coiling elsewhere. Since there are only 10 nucleotides/turn of the double helix, copying a gene for a 100 amino acid protein means you are removing 33 twists from the separated strands (and producing new ones elsewhere).   The cords of the venetian blind quickly become a tangled mess when this happens.  This is where DNA gyrase comes in.  It cuts both strands of the DNA double helix, holding on to the cut ends, and slides an intact double helix of the twisted DNA through the cut.   Sounds fantastic doesn’t it?  Hard to see how evolution could come up with something like this but it did.

The paper contains the following passage toward the end

“A second model based on a sign-inversion reaction wassuggested to describe introduction of (–)SC by this enzyme (28). This model proposed that the enzyme binds to a positive crossover followedby a DNA strand passage through a DNA double-strand break that results in a sign inversion.”

(28) is 28. P. O. Brown, N. R. Cozzarelli,Science206, 1081–1083 (1979).

The paper is 45 years old and has now been shown to be correct.  N. R.  Cozzarelli is my late good friend and Princeton classmate Nick, and it is very nice to see him honored here.

A few words about Nick.  Although Princeton was full of rich kids, they still had the brains to take in someone like Nick whose father was an immigrant shoemaker in Jersey City.  Nick worked his way through Princeton waiting on tables in commons (where all Freshmen ate).  I can still see the time that some rich preppie jerk gave him a hard time about the service.

Nick got his PhD at Harvard and later became a professor at Berkeley where he did his great work.  Nick later edited the Proceedings of the National Academy of Sciences (USA) for 10 years before his very untimely death over 20 years ago from Burkitt’s lymphoma.  R. I. P. Nick.

Harvard closes a library ” “driven primarily by financial considerations,”

Unless someone has taken over the Harvard Crimson website the following isn’t fake news:  here’s a link — https://www.thecrimson.com/article/2024/3/19/wolbach-library-closure/.

The Harvard Endowment was the largest in the world as of June ’22 approaching 50 billion.  Yet here is the lede from the article — “The John G. Wolbach Library — which carries one of the world’s largest astronomical collections — will shutter its doors on Friday, in a move that was “driven primarily by financial considerations,” according to an email from Harvard Center for Astrophysics Director Lisa J. Kewley.”

The two undergraduate reporters Neeraja S. Kumar and Annabel M. Yu Crimson Staff Writers totally missed the forest for the trees spending the rest of the article interviewing unhappy users of the library, and never digging into the ‘financial considerations’.  

Perhaps they were told not to dig too deeply by the powers that be. Something similar happened 20+ years ago to a nephew writing for the Daily Princetonian.  He found something about a person high up in the administration which would have been front page news, but was told that it wouldn’t be published.

Combine this with the 17% drop in early admission applicants and the 5% drop in overall applications and it’s hard to avoid the conclusion that Harvard is in trouble.  It certainly was a great place to be when I was there ’60 – ’62 and I find it very sad.

There is hope however.  Randall Kennedy (another Princetonian and Harvard Law professor ) had  the following article in the Crimson 2 Aprilhttps://www.thecrimson.com/column/council-on-academic-freedom-at-harvard/article/2024/4/2/kennedy-abandon-dei-statements/.  Kennedy is not a disgruntled WASP.

The there is an  old saying “You can always tell a Harvard man but you can’t tell him much” .   Maybe Harvard is beginning to listen to what the world is telling it.

 

See how well you think outside the box

The next total eclipse of the sun visible in the USA will occur 8 April 2024.   I well remember one in Montana 26 February 1979.  People flocked to Lewistown where the eclipse was to be total, the weather perfect, yet there was a disaster which ruined their trip.  It wasn’t the weather. See if you can figure out what it was.  No one I’ve told the story to over the years, has been able to.

See if you can figure out what it was.

Answer will appear 25 Feb in this space.

Win fame and fortune for yourself by posting your answer in a comment.

Watching the eclipse in Billings 135 miles away where it was partial was impressive.  The birds stopped singing, and it got much colder very quickly.

Addendum 25 March ’24 Congratulations to REearthable

The street lights automatically came on, confused by the darkness?

• • Bravo — that’s what happened. Fortunately Lewistown is small and people hopped in their cars and went out to the country which is quite empty and dark (except around ranch houses where yard lights usually come on automatically.

    You win a free trip on the Lewistown subway (when built)

Axiomatize This !

“Analyze This”, is a very funny 1999 sendup of the Mafia and psychiatry with Robert DeNiro and Billy Crystal.  For some reason the diagram on p. 7 of Barrett O’Neill’s book “Elementary Differential Geometry” revised 2nd edition 2006 made me think of it.

O’Neill’s  book was highly recommended by the wonderful “Visual Differential Geometry and Forms” by Tristan Needham — as “the single most clear-eyed, elegant and (ironically) modern treatment of the subject available — present company excpted !”

So O’Neill starts by defining a point  as an ordered triple of real numbers.  Then he defines R^3 as a set of such points along with the ability to add them and multiply them by another real number.

O’Neill then defines tangent vector (written v_p) as two points (p and v) in R^3 where p is the point of application (aka the tail of the tangent vector) and v as its vector part (the tip of the tangent vector).

All terribly abstract but at least clear and unambiguous until he says — “We shall always picture v_p as the arrow from point p t0 the point p + v”.

The picture is a huge leap and impossible to axiomatize (e.g. “Axiomatize This”).   Actually the (mental) picture came first and gave rise to all these definitions and axioms.

The picture is figure 1.1 on p. 7 — it’s a stick figure of a box shaped like an orange crate sitting in a drawing of R^3 with 3 orthogonal axes (none of which is or can be axiomatized).  p sits at one vertex of the box, and p + v at another.  An arrow is drawn from p to p + v (with a barb at p + v) which is then labeled v_p.  Notice also, that point v appears nowhere in the diagram.

What the definitions and axioms are trying to capture is our intuition of what a (tangent) vector really is.

So on p. 7 what are we actually doing?  We’re looking at a plane in visual R^3 with a bunch of ‘straight’ lines on it.  Photons from that plane go to our (nearly) spherical eye which clearly is no longer a plane.  My late good friend Peter Dodwell, psychology professor at Queen’s University in Ontario, told me that the retinal image actually preserves angles of the image (e.g. it’s conformal). 1,000,000 nerve fibers from each eye go back to our brain (don’t try to axiomatize them).   The information each fiber carries is far more processed than that of a single pixel (retinal photoreceptor) but that’s another story, and perhaps one that could be axiomatized with a lot of work.

100 years ago Wilder Penfield noted that blood flowing through a part of the brain which was active looked red rather than blue (because it contained more oxygen).  That’s the way the brain appears to work.  Any part of the brain doing something gets more blood flow than it needs, so it can’t possibly suck out all the oxygen the blood carries.  Decades of work and zillions researchers have studied the mechanisms by which this happens.  We know a lot more, but still not enough.

Today we don’t have to open the skull as Penfield did, but just do a special type of Magnetic Resonance Imaging (MRI) called functional MRI (fMRI) to watch changes in vessel oxygenation (or lack of it) as conscious people perform various tasks.

When we look at that simple stick figure on p. 7, roughly half of our brain lights up on fMRI, to give us the perception that that stick figure really is something in 3 dimensional space (even though it isn’t).  Axiomatizing that would require us to know what consciousness is (which we don’t) and trace it down to the activity of billions of neurons and trillions of synapses between them.

So what O’Neill is trying to do, is tie down the magnificent Gulliver which is our perception of space with Lilliputian strands of logic.

You’ve got to admire mathematicians for trying.

Chip Wars by Chris Miller — Part IV — beating China with silicon will be a lot harder than beating Russia

China as shown by Huawei has the capacity to design state of the art chips, and they certainly have the brains.  Morris Chang did a lot of his work at Texas Instruments before running TSMC (Taiwan Semiconductor Manufacturing Company).  Jensen Huang runs NVIDIA.  In retirement, I pass the time by reading 5 journals (Cell, Nature, Neuron, Science, PNAS), whose interesting material I report on in this blog.  You will not find a single issue without at least one high quality, state of the art article from mainland China.  These articles were not chosen by affirmative action.

So we beat Russia because they could steal and copy our chips, but could not manufacture them.

China certainly has tried to steal our manufacturing expertise — this is detailed pp. 306 – 310 with a Chinese company called Jinhua which stole manufacturing details (translation: hard won knowhow from years of experimentation) from the only American company (Micron) making memory chips.  After much argumentation between National Security types and Treasury in the Trump administration, the US banned export by US firms to Jinhua of chipmaking tools, and Jinhua stopped making them in a few months.

Xi realizes just how dependent China is on machinery and software produced elsewhere, but replicating it in country is nearly impossible given its price and political meddling (see next paragraph).

The factory making chips is called a fab (for fabrication plant).  China certainly tried with something called SMIC, but the politicians that controlled them meddled incessantly in business decisions.  Every governor wanted a chip fab in his province, so China wound up with an inefficient collection of small facilities spread across the country (p. 251).

The book contains a blow by blow description of how the USA lost the ability to make the most advanced fabrication facilities and most advanced lithography machines — needed by the fabs.  It’s too painful to recount here.

So our (fragile) lead on China depends on manufacturing prowess, as well as the brains we import and integrate from all over the world.

I suggest you read Miller’s book, even if you’re not a techie.  Your future may depend on it

 

 

Chip Wars by Chris Miller — Part III — why smaller is better

The following quote from part II says it all — “As Silicon valley crammed more transistors onto silicon chips, building them became steadily harder.    Russia stole the equipment to make them, but they had no way to get spare parts.  The Russian military didn’t trust the chips produced in country, so they minimized the use of electronics and computers in military systems.    The math they put into  their guidance computers was simpler to minimize the strain on the onboard computer.”

The more transistors you put on a chip of a given size, the more computing it can do in a given time, particularly when time is of the essence with missiles, and artillery.  So making transistors smaller and smaller makes them able to do more things and faster as well.

The non-techies can skip the rest, but it’s too fascinating (to me at least) to see how it’s done.   Please note that most of this material is based on Miller’s book.

As of 9/22 “The smallest transistor size that has been used in commercial central processing units (CPUs) or graphics processing units (GPUs) is currently 5 nanometers (nm). Several semiconductor companies, such as Intel, AMD, and TSMC, have released or are in the process of releasing CPUs (central processing units) and GPUs (graphics processing units) with 5nm transistors.”

I’m a chemist and chemists think in Angstroms, because the smallest atom (Hydrogen) has a diameter of 1 Angstrom.  A nanoMeter is 10^-9 meters (a billionth of a meter), and 1 nanoMeter is 10 Angstroms.

The nearest neighbor distance between silicon atoms in crystalline silicon is 2.35 Angstroms (which has the diamond structure of carbon which is a tetrahedral structure — the angle between bonds in a tetrahedron is 109 degrees, so the distance between any two silicon atoms linked by a common silicon atom is 2 times sin 54.5 (.814) times 2.35 or 3.8 Angstroms), so the actual number of atoms along a distance of  500Angstroms  (5 nanoMeters) in a silicon crystal is only 132 !  That’s how small lithography at this distance is chopping up Silicon.  Get much smaller than this and quantum mechanical effects come in to play (if they aren’t there already)

The smallest wavelength of visible light is around 4,000 Angstroms.  Waves will only be reflected by something of the order of their wavelength. Surfers ride waves in to shore, but they don’t change the speed or direction of the waves they ride.  Essentially waves can’t ‘see’ the surfers riding on them.

Similarly to ‘see’ and carve objects as small as 500 Angstroms, you need light of much shorter wavelength — called extreme ultraviolet light (EUV).  Producing such light isn’t easy — here’s how it’s done currently. To be honest the book calls EUV 135 nanoMeters, and doesn’t explain how this could make features nearly 3 times smaller (50 nanoMeters)

Producing  EUV requires pulverizing a small ball of tin with a laser.  A 30 micron ball of tin moving at 200 miles/hour was shot twice with a laser: the first pulse to warm it up, the second to vaporize it into a plasma with a temperature of 500 kiloKelvin.  The process is repeated 50,000 times each second to produce enough EUV to fabricate a chip.  The lasers produced to do this contain 457,329 parts.   Cymer, a company founded by two laser experts in the USA does this.

Focusing EUV to carve patterns on silicon requires extraordinarily precise optics done by Zeiss. The mirrors to reflect the EUV are the smoothest objects ever made.

The EUV lithography machine has hundreds of thousands of components that took 10s of billions of dollars and several decades of research.   The machines cost 100 million dollars each.

Zeiss is in Germany, ASML ,the company that makes the lithography machines is in the Netherlands, Cymer is in the USA, so it is impossible for a single country to duplicate the supply chain for EUV.  The book contains an estimate that it would cost China 1 trillion dollars to do this for computer chip production, and there is no guarantee that politics wouldn’t get in the way (as it already has in China and Russia).

So, as I said, Chip Wars is really about manufacturing (of which I and probably most of the readership were blissfully unaware).

Next up:  Chip Wars by Chris Miller — part IV beating China with silicon will be much harder than beating Russia

 

Chip Wars by Chris Miller — Part II beating Russia with silicon

Just about everything in this post is from Chip Wars by Chris Miller, some are direct quotes, others are paraphrases.   A few things are my own, but they’re pretty obvious.

Even though I was vitally interested in computers as a neurologist starting in the early 70s and got one as soon as I could afford it (an Alpha Micro which I really couldn’t), Chip Wars covering the early history of silicon based computers taught me a lot.  It starts with Shockley’s invention of the transistor in 1948 and goes from there.   I won’t try to summarize that, but if you want an extremely well written early history of the period, read this book.  It isn’t dry and the personalities of the main characters are well fleshed out.

What I didn’t realize was just how much of the early development of silicon computers was driven by the military.  In particular Defense Advanced Research Projects Agency (DARPA) funded a lot of academics and their research into computation. Today every chip company uses tools from one of 3 chip design companies founded and built by graduates of DARPA programs

Guided munitions during the early Vietnam war used vacuum tubes that were hand soldered (Sparrow III) they broke down 2/3 of the time only 10% hit their target.  Bombs fell 420 feet from target.    Some 800 bombs had tried to take out a bridge in Vietnam and failed.   A set of wings was added to direct the bomb’s flight along with a laser guidance system which worked as follows.  A small silicon wafer was divided into 4 quadrants and placed behind a lens.  The laser reflecting off the target would shine through the lens onto the silicon,.  If the bomb veered off course one quadrant would receive more of the laser’s energy than the others and circuits would move the wings to reorient the bomb’s trajectory so the laser was shining straight through the lens.    A simple laser sensor and a few transistors made the bomb accurate.  This was 1972.  Spoiler alert — we still lost.

Photolithography is a crucial technology for drawing circuits on silicon, and it is mentioned many times throughout the book.   It’s basically a simple idea— turning a microscope lens upside down to make something big look smaller.  It was initiated by  Lathrop at Texas Instruments in 1958  It took thousands of experiments and a lot of interaction with suppliers etc to make it work.   There will be much more about photolithography in the next posts.

When owning a copy machine was a crime and no one without security clearance could use a computer, Russia had no way to educate a truly huge number of computer programmers.  So they basically used espionage to copy our technology.

This didn’t work.   The Soviet copy it strategy was flawed, because they couldn’t scale up the manufacturing process reliably, something Grove at Intel and Chang at Texas Instruments fixated on and spent countless hours improving.  Moreover the US had access to technology in optics, chemistry purified materials.  They knew the temperature at which chemicals needed to be heated or how long photoresist should be exposed to light.  Every step of the process of making chips involved specialized knowledge that was rarely shared outside a specific company — often not written down.    So it couldn’t be stolen.

As Silicon valley crammed more transistors onto silicon chips, building them became steadily harder.    Russia stole the equipment to make them, but they had no way to get spare parts.  The Russian military didn’t trust the chips produced in country, so they minimized the use of electronics and computers in military systems.    The math they put into guidance computers was simpler to minimize the strain on the onboard computer.

The copy it strategy left the Russians 5 years behind.

Russia’s defense chief of staff Ogarkov knew this and said in ’83 to Leslie Gelb  “The Cold War is over and you have won”.  Interestingly, Star Wars begun the same year is nowhere mentioned in the book.  It was derided as implausible, but the Russians knew they couldn’t match it.

The Soviets only customer for computers was the military, while the US had a large civilian market which created companies with a wide variety of expertise in everything needed for them (pure silicon wafers, advance optic for lithography).  The Russians also had no international supply chain. The Gulf War ’91 on Saddam Hussein — US smart weapons (Paveway) using more advanced electrons decimated the best equipment of Russia.

As I said in part I (https://luysii.wordpress.com/2024/03/10/chip-wars-by-chris-miller-part-i/) Chip Wars is really about manufacturing, not the abstract computational problems and programming I was interested in.

The denouemont came in 1991 with the Gulf War. US smart weapons (Paveway) using more advanced electronics decimated the best equipment of Russia.

Things haven’t changed much in Russia. p335

“The fact that Russia faced shortages of guided cruise missiles within several weeks of attacking Ukraine is partly due to the sorry state of its semiconductor industry.”

Next up: The coming competition with China