Off to Nova Scotia

No posts for a week or two.  If you’re ever up that way, the Hopewell Rocks in New Brunswick are not to be missed.  Our friends say Cape Breton is magnificent.  We hope to see it.   Taking Feynman vol. I along.  I can’t say enough good about it, but I doubt that it’s the way to learn physics the first time, but if you’ve had undergraduate physics, it will explain what is really going on.

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Hell of a way for a cell to defend itself

Imagine it’s Dodge City in the 1880’s and rustlers and gunslingers are shooting up the town.  What do Wyatt Earp and Bat Masterson do?  They don’t call in the cavalry.  They open the jail.   With the town in flames the army moves in, destroying much of the town in the process.

Crazy?  Yes.  But this is a pretty good analogy to how retroviruses are used to help fight off infection if Proc. Natl. Acad. Sci. vol. 116 pp. 17399 – 17408 ’19 is correct

Endogenous retroviruses constitute around 10% of our genome — that’s 320,000,000 nucleotides. Normally they are kept locked up in a tightly condensed mess of DNA and proteins called heterochromatin, so their genome can’t be transcribed and cause trouble.  It takes a lot to lock them up — TRIM28 acting in concert with zinc finger proteins, SUMO, a histone methyltransferase (SETDB1) and last but not least NuRD (not NeRD) — Nucleosome Remodeling and Deacetylation complex.

But when a variety of cells are infected with a variety of influenza viruses, they are let loose because the heterochromatin breaks up, the endogenous retroviruses are freed producing lots of double stranded RNA.  This is sensed as nonSelf, by Pattern Recognition Receptors (PRRs) strongly activating antiviral immunity.

The key thing in the repressive complex is SUMO, a protein resembling ubiquitin which gloms onto lysines like ubiquitin.  To be efficient in repressing the retroviruses, TRIM28 must be SUMOylated.  In some way influenza virus infection results in nonSUMOylated TRIM28.  The authors note that the mechanism of the switch in SUMOylation status ‘has yet to be precisely defined’.  I’m sure the authors are working on it, but who in the world would have thought that cells would use retroviruses as a defense mechanism.  Not me, certainly.

Prolegomena to reading Fall by Neal Stephenson

As a college freshman I spent hours trying to untangle Kant’s sentences in “Prolegomena to Any Future Metaphysics”  Here’s sentence #1.   “In order that metaphysics might, as science, be able to lay claim, not merely to deceitful persuasion, but to insight and conviction, a critique of reason itself must set forth the entire stock of a priori concepts, their division according to the different sources (sensibility, understanding, and reason), further, a complete table of those concepts, and the analysis of all of them along with everything that can be derived from that analysis; and then, especially, such a critique must set forth the possibility of synthetic cognition a priori through a deduction of these concepts, it must set forth the principles of their use, and finally also the boundaries of that use; and all of this in a complete system.”

This post is something to read before tackling “Fall” by Neal Stephenson, a prolegomena if you will.  Hopefully it will be more comprehensible than Kant.   I’m only up to p. 83 of a nearly 900 page book.  But so far the book’s premise seems to be that if you knew each and every connection (synapse) between every neuron, you could resurrect the consciousness of an individual (e.g. a wiring diagram).  Perhaps Stephenson will get more sophisticated as I proceed through the book.  Perhaps not.  But he’s clearly done a fair amount neuroscience homework.

So read the following old post about why a wiring diagram of the brain isn’t enough to explain how it works.   Perhaps he’ll bring in the following points later in the book.

Here’s the old post.  Some serious (and counterintuitive) scientific results to follow in tomorrow’s post.

Would a wiring diagram of the brain help you understand it?

Every budding chemist sits through a statistical mechanics course, in which the insanity and inutility of knowing the position and velocity of each and every of the 10^23 molecules of a mole or so of gas in a container is brought home.  Instead we need to know the average energy of the molecules and the volume they are confined in, to get the pressure and the temperature.

However, people are taking the first approach in an attempt to understand the brain.  They want a ‘wiring diagram’ of the brain. e. g. a list of every neuron and for each neuron a list of the other neurons connected to it, and a third list for each neuron of the neurons it is connected to.  For the non-neuroscientist — the connections are called synapses, and they essentially communicate in one direction only (true to a first approximation but no further as there is strong evidence that communication goes both ways, with one of the ‘other way’ transmitters being endogenous marihuana).  This is why you need the second and third lists.

Clearly a monumental undertaking and one which grows more monumental with the passage of time.  Starting out in the 60s, it was estimated that we had about a billion neurons (no one could possibly count each of them).  This is where the neurological urban myth of the loss of 10,000 neurons each day came from.  For details see https://luysii.wordpress.com/2011/03/13/neurological-urban-legends/.

The latest estimate [ Science vol. 331 p. 708 ’11 ] is that we have 80 billion neurons connected to each other by 150 trillion synapses.  Well, that’s not a mole of synapses but it is a nanoMole of them. People are nonetheless trying to see which areas of the brain are connected to each other to at least get a schematic diagram.

Even if you had the complete wiring diagram, nobody’s brain is strong enough to comprehend it.  I strongly recommend looking at the pictures found in Nature vol. 471 pp. 177 – 182 ’11 to get a sense of the  complexity of the interconnection between neurons and just how many there are.  Figure 2 (p. 179) is particularly revealing showing a 3 dimensional reconstruction using the high resolutions obtainable by the electron microscope.  Stare at figure 2.f. a while and try to figure out what’s going on.  It’s both amazing and humbling.

But even assuming that someone or something could, you still wouldn’t have enough information to figure out how the brain is doing what it clearly is doing.  There are at least 3 reasons.

l. Synapses, to a first approximation, are excitatory (turn on the neuron to which they are attached, making it fire an impulse) or inhibitory (preventing the neuron to which they are attached from firing in response to impulses from other synapses).  A wiring diagram alone won’t tell you this.

2. When I was starting out, the following statement would have seemed impossible.  It is now possible to watch synapses in the living brain of awake animal for extended periods of time.  But we now know that synapses come and go in the brain.  The various papers don’t all agree on just what fraction of synapses last more than a few months, but it’s early times.  Here are a few references [ Neuron vol. 69 pp. 1039 – 1041 ’11, ibid vol. 49 pp. 780 – 783, 877 – 887 ’06 ].  So the wiring diagram would have to be updated constantly.

3. Not all communication between neurons occurs at synapses.  Certain neurotransmitters are generally released into the higher brain elements (cerebral cortex) where they bathe neurons and affecting their activity without any synapses for them (it’s called volume neurotransmission)  Their importance in psychiatry and drug addiction is unparalleled.  Examples of such volume transmitters include serotonin, dopamine and norepinephrine.  Drugs of abuse affecting their action include cocaine, amphetamine.  Drugs treating psychiatric disease affecting them include the antipsychotics, the antidepressants and probably the antimanics.

Statistical mechanics works because one molecule is pretty much like another. This certainly isn’t true for neurons. Have a look at http://faculties.sbu.ac.ir/~rajabi/Histo-labo-photos_files/kora-b-p-03-l.jpg.  This is of the cerebral cortex — neurons are fairly creepy looking things, and no two shown are carbon copies.

The mere existence of 80 billion neurons and their 150 trillion connections (if the numbers are in fact correct) poses a series of puzzles.  There is simply no way that the 3.2 billion nucleotides of out genome can code for each and every neuron, each and every synapse.  The construction of the brain from the fertilized egg must be in some sense statistical.  Remarkable that it happens at all.  Embryologists are intensively working on how this happens — thousands of papers on the subject appear each year.

 

Feynman and Darwin

What do Richard Feynman and Charles Darwin have in common?  Both have written books which show a brilliant mind at work.  I’ve started reading the New Millennium Edition of Feynman’s Lectures on Physics (which is the edition you should get as all 1165 errata found over the years have been corrected), and like Darwin his thought processes and their power are laid out for all to see.  Feynman’s books are far from F = ma.  They are basically polished versions of lectures, so it reads as if Feynman is directly talking to you.  Example: “We have already discussed the difference between knowing the rules of the game of chess and being able to play.”  Another: talking about Zeno  “The Greeks were somewhat confused by such problems, being helped, of course, by some very confusing Greeks.”

He’s always thinking about the larger implications of what we know.  Example: “Newton’s law has the peculiar property that if it is right on a certain small scale, then it will be right on a larger scale”

He then takes this idea and runs with it.  “Newton’s laws are the ‘tail end’ of the atomic laws extrapolated to a very large size”  The fact that they are extrapolatable and the fact that way down below are the atoms producing them means, that extrapolatable laws are the only type of physical law which could be discovered by us (until we could get down to the atomic level).  Marvelous.  Then he notes that the fundamental atomic laws (e.g. quantum mechanics) are NOTHING like what we see in the large scale environment in which we live.

If you like this sort of thing, you’ll love the books.  I don’t think they would be a good way to learn physics for the first time however.  No problems, etc. etc.  But once you’ve had exposure to some physics “it is good to sit at the feet of the master” — Bill Gates.

Most of the readership is probably fully engaged with work, family career and doesn’t have time to actually read “The Origin of Species”. In retirement, I did,and the power of Darwin’s mind is simply staggering. He did so much with what little information he had. There was no clear idea of how heredity worked and at several points he’s a Lamarckian — inheritance of acquired characteristics. If you do have the time I suggest that you read the 1859 book chapter by chapter along with a very interesting book — Darwin’s Ghost by Steve Jones (published in 1999) which update’s Darwin’s book to contemporary thinking chapter by chapter.  Despite the advances in knowledge in 140 years, Darwin’s thinking beats Jones hands down chapter by chapter.

Good luck, RBG

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

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

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

She had better be.

Addendum 28 August ’19

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

What can dogs tell us about cancer, and (wait for it) sexually transmitted disease

What can 546 dogs tell us about cancer, and STDs (sexually transmitted diseases)?  An enormous amount ! [ Science vol 365 pp. 440 – 441, 464 3aau9923 1 –> 7 ’19 ].  You may have heard about the transmissible tumor that has reduced the Tasmanian Devil population from its appearance in ’96 by 80%.  The animals bite each other transmitting the tumor.  Only 10 – 100 cells are transferred, but death occurs within a year.  The cells survive because Tasmanian devels have low genetic diversity.

The work concerns a much older transmissible tumor (Canine Transmissible Venereal Tumor — aka CTVT) which appeared in Asia an estimated 6,000 year ago, and began dispersing worldwide 2,000 years ago.   Unlike the Tasmanian devil tumor, the tumor is usually cleared by the immune system.

The Science paper has 80+ authors from all over the world, who sequenced the protein coding part of the dog genome (the exome) to a > 100fold depth.   The exome contains 43.6 megabases.   The tumor is transmitted by sex, and the authors note that this mode of transmission nearly requires a rather indolent clinical course, as the animal must survive long enough to transmit the organism again.  This fits with syphilis, AIDs, gonorrhea.  Contrast this with anthrax, cholera, plague which spread differently and kill much faster.

So what does CTVT tell us about cancer?   Quite a bit.  First some background.  The Cancer Genome Atlas (CGA) was criticized as being a boondoggle, but it at least gave us an idea of how many mutations are present in various cancers– around 100 in colon and breast cancers.

Viewed across all dogs, the CTVT genome is riddled with somatic mutations (as compared to the genome of the dog carrying the tumor) –148,030 single nucleotide variants (3.4/1000 !) 12,177 insertion/deletions.  Of the 20,000 dog genes only 2,000 didn’t contain a mutation.   This implies that most genes in the mammalian genome aren’t needed by the cancer cells.  The CTVTs also show no signs of the high rates of chromosomal instability seen in human tumors.

The work provides evidence that cancer isn’t inherently progressive.  This gives hope that some relatively indolent human cancers (say cancer of the prostate) can be controlled.  This calls for ‘adaptive therapy’  — something that limits tumor  growth rather than trying to kill every cancer cell with curative therapy which, if it fails, essentially selects for more aggressive cancer cells.

Some 14,412 genes have 1 mutation changing the amino acid sequence (nonSynonymous) and 5,704 have protein truncating mutations.  The ratio of synonymous to non synonymous mutations is about 3 implying that the mutations which have arisen haven’t been selected for (after all the triplet code for 20 amino acids and 1 stop codon has 64 possibilities), so the average amino acid has 3 codons for it.  This is called neutral genetic drift.

They also found 5 mutated genes present in all 541 tumors — these are the driver mutations, 3 are well known, MYC, PTEN, and retinoblastoma1.

Tons to think about here.  I’ll be away for a few weeks traveling and playing music, but this work should keep you busy thinking about its implications.

 

 

Book recommendation

Tired of reading books about physics?  Want the real McCoy”?  Well written and informal?  Contains stuff whose names you know but don’t understand — Jones Polynomial, Loop Quantum Gravity, Quantum field theory, Gauge groups and transformations —  etc. etc.

Up to date?  Well no, it’s 25 years old but still very much worth a read, so very unlike molecular biology, chemistry, computer science etc. etc.

Probably you should know as much physics and math as a beginning chemistry grad student. If you studied electromagnetism through Maxwell’s equations it would be a plus.  I stopped at Coulomb’s Law, and picked up enough to understand NMR.

This will give you a sample of the way it is written

“Much odder is that we are saying the vector field v is the linear combination of . .  partial derivatives.  What we are doing might be regarded as rather sloppy, since we are identifying two different although related things: the vector  field and the operator v^i * d-/dx^i which takes a directional derivative in the direction of v.”

“Now let us define vector fields on a manifold M. .. . these will be entities whose sole ambition in life is to differentiate functions”

The book is “Gauge FIelds, Knots and Gravity” by John Baez and Javier P. Muniain.

The writing, although clear has a certain humility.  “Unfortunately understanding these new ideas depends on a through mastery of quantum field theory, general relativity, geometry, topology and algebra.  Indeed, it is almost certain that nobody is sufficiently prepared to understand these ideas fully.”

I’m going to take it with me to the amateur chamber music festival.  As usual, at least 2 math full professors will be there to help me out.  Buy it and enjoy

 

 

Clark Gesner R. I. P.

Clark Gesner Princeton ’60 was an incredibly creative individual who wrote at least 2 shows for the Princeton Triangle Club, which includes Jimmie Stewart, Josh Logan, Jose Ferrer and Brooke Shields among its alumni.  When I was there, club traveled by railroad to NYC, Albany, Cleveland, Chicago, Cincinnati etc. over Christmas vacation.  Quite an experience for a 19 year old who’d never been west of Allentown.

Despite his talent, Clark’s  musical chops weren’t that good and as a piano player in the pit band accompanying the show, I could play his stuff better than he could. We were housed in the homes of alumni for the most part, and Clark after shows would sit at the piano and play his stuff.  The girls would gather around and say “Clark, you’re going to write a broadway show some day”.  Cynical me thought they’d been watching too movies.

Well he did, writing “You’re a Good Man Charlie Brown”, and never had to work past his late 20s.

Which raises several points.  The first is that amateur musicians usually agree who is better (not so much in terms of their chops, but in terms of their ‘musicality’ a term like jazz of which Louis Armstrong said –“If you have to ask what jazz is, you’ll never know.”  This unlike composers, visual artists etc. etc.  Even chemists.  Who was the greatest chemist of the 20th century — Woodward, Pauling?  You’d get an argument.

2 years at Triangle cured me of theater.  The stage performers  never really left the stage, acting most of the time in ways that said ‘look at me, look at me’.  It became tiresome after a while.

We had real pros helping us put the shows together — Director Milt Lyon, Choreographer Peter Hamilton.  They weren’t perfect and 60 years ago Milt was always saying that ‘the unions are killing the theater’.  Milt was always in the back during performances as we traveled, leading the cheers.  Another quote –‘audiences want to clap, you just have to help them’.

There were a lot of gays in Triangle, but they were the obvious ones, florid, histrionic, effeminate.   That was the image of the gay male in the late 50s, and today’s gays owe a huge debt to the normal appearing gays who came out in that era and later.  Clark was gay and kept it well hidden, and a lot more classmates have come out subsequently.

For some, there were excellent reasons to remain in the closet.  A psychiatrist classmate from med school knew of people being thrown out of psychiatry residencies because they were gay — look at the early DMSs when homosexuality was thought to be a psychiatric disease.

 

The cold dead hand of the academy and classical music (US division)

For how the higher music criticism nearly strangled classical music in the US look no further than Roger Sessions — https://en.wikipedia.org/wiki/Roger_Sessions.  He was the eminence grise of the Princeton music department when I was an undergraduate

Purely by luck, I decided that music was one of the few things I knew something about (having had 8 years of piano lessons through High School) so I had nothing to do with the department.  So while Roger was saying things like “I’m a specialist writing for other specialists” and “The English Department doesn’t teach typing, why should the Music Department teach performance” — this according to someone from the class of ’75, I was hitchhiking down route 1 to NYC listening to Basie at Birdland, and other jazz musicians creating a new art form (Village Vanguard etc. etc.).   I was actually able to hire Coleman Hawkins to play for a dance at our Eating Club (Princeton’s version of fraternities).

So think of some music coming out of an academic music department from that era that you want to listen to.  Bartok doesn’t count.  He was supported with grants when he got here  in 1940, but was already a very well established composer.

For more on these points, see the previous post –https://luysii.wordpress.com/2019/07/30/some-thoughts-on-music/

So jazz, rock, country and western musics will take care of themselves.  They exist independently of what is written about them.  There still is a problem for people like me.  I’m not creative enough to make my own music, but classical music being written down allows me to explore and experience the great musical minds of Bach, Mozart etc. etc.  I want more stuff written by today’s people that my friends and I can play.  The difference between listening to music and playing it, is the difference between you know what and sex.

Some thoughts on music

I’m leaving for what one of my friend’s grandsons calls “Band Camp for Adults”. Mercifully we usually all agree to allow the world to spin on its axis without our help, meaning we talk only about music leaving politics behind (thank God).

I’ve agreed to play the Brahms horn trio with an excellent violinist and an equally excellent french horn player.  It’s scary. Brahms must have had enormous hands, asking you to play an octave with your right hand while trilling with the fifth finger.  He must also have had a huge technique, asking you to jump about playing octaves with your left hand.  Adding to the anxiety, is that the other two have performed the piece despite the fact that we’re amateurs.  They want to perform it as well, something that gives me the yips (they’re both very good).

I asked one of last year’s coaches to note whether the hard headed scientific types (mathematicians, physicists, computer programmers) play any differently than the touchy feely types (who are scared of ‘chemicals’ etc. etc.) both invariantly present in about equal numbers among amateur chamber musicians.  I don’t think so, but we’ll see what she says.  Probably she forgot, chamber musicians having to be extremely precise  when they play, leading them to be sloppy about most other things.  We’ll see.

There are excellent faculty concerts most nights and hopefully they won’t have much ‘eat your spinach’ contemporary work on the program.  You all know what it is, contemporary music with no rhythm, melody or structure and usually hideous sound, that you are supposed to sit through because it’s good for you.  A few years ago, there was a concert with no intermission where they literally locked the doors and played an awful Elliot Carter string quartet.  It wasn’t announced on the program so we couldn’t bail.

Which brings me to another point.  People who say they like all music, really like none of it.  To really like music there must be music that you hate.  I hate Shastakovich (which is tough as a cellist I play with has cats named Shasti and Kovich), my cousin hates Ravel.

Which brings me to another point — how musical criticism has brought classical music low (see the bit about Adorno later).  Classic composers if they want to be played and heard have to bow to current elite critical opinion.  Fortunately this seems to be ending.  There are several people composing in the area whose music has melody, rhythm, structure, tonality and is good to listen to.

One is Zeke Hecker — http://zekehecker.com — whose wife is an excellent violist that I played one of the Faure piano quartets with.  He’s written lots of stuff in classical form (symphonies etc. etc. ) which is musicly interesting.

Another is Scott Slapin — http://scottslapin.com — and we recently went to a concert where he wrote some very interesting music for 4 violas.  He has a sense of humor and since he lives in South Hadley Massachusetts, he wrote a 12 minute piece for 4 violas called the South Hadley Mass.

Now to the dark side — an article in the New Yorker described how a critic, Theordor Adorno, singlehandedly nearly destroyed the magnificent German musical tradition — https://www.newyorker.com/magazine/2003/03/24/ghost-sonata.

Here’s a quote from the article — “Implicit in his assault on mass culture is the belief that any work of art that attracts large numbers of people has no value.”  So the music he champions certainly doesn’t attract hordes.

Here’s more.  “In 1949, it worked: “The Philosophy of New Music” wowed the confused young minds who were seeking new certitudes, new laws, new gods. Adorno, together with his comrade-in-arms Boulez, probably succeeded in frightening more than a few composers of the neoclassical type into thinking that their music was not just bad but criminal. It is instructive to look at the names of works that were played at Darmstadt from 1946 on. In the first few years, you see titles such as Sonatine, Suite for Piano, Chamber Symphony, Scherzo, and Concerto in E Flat. After 1949, the year of the “Philosophy,” neoclassical titles dwindle and are replaced by phrases fit for a “Star Trek” episode: “Music in Two Dimensions,” “Schipot,” “Polyphonie X,” “Syntaxis,” “Anepigraphe.” There was a fad for abstractions in the plural: “Perspectives,” “Structures,” “Quantities,” “Configurations,” “Interpolations.” Audiences enjoyed “Spectogram,” “Seismogramme,” “Audiogramme,” and “Sphenogramme.”

How did such an idiot gain such power?  It’s worth reading the whole article in the link (although it’s pretty depressing)

Well there is a human urge to listen, play and create music and it’s coming back. To hell with the higher musical criticism.