Non-patent trolling

A conversation with a son who is in high tech brought up what a blister on the body politic patent trolling is https://en.wikipedia.org/wiki/Patent_troll.  I told him that I’m having trouble simply trying to give an idea away.  The idea is basically that some cases of chronic fatigue syndrome are due to senescent cells.  There is a simple way to look for this — measure a master transcription factor for cellular senescence (p16INK^4a) in blood cells.  If correct, a rational therapy for CFS (senolytics) is immediately at hand.  I’ve shopped this around, and someone at Stanford involved with CFS claims that he will test it.  I’ve heard nothing so far.  The idea is free for the taking.  Therapy for CFS essentially  helps patients live their symptoms rather than diminishing them or attacking the underlying problem.

Since I”m going to Venice for 2 weeks to celebrate my wife’s birthday, there won’t be any new posts for a while — so here is the idea as presented in two posts from my blog — take it and run with it.  The patients are waiting.

Not a great way to end 2017

Not a great way to end 2017

2017 ended with a rejection of the following letter to PNAS.

As a clinical neurologist with a long standing interest in muscular dystrophy(1), I was referred many patients who turned out to have chronic fatigue syndrome (CFS) . Medicine, then and now, has no effective treatment for CFS.

A paper (2) cited In an excellent review of cellular senescence (3) was able to correlate an intracellular marker of senescence (p16^INK4a) with the degree of fatigue experienced by patients undergoing chemotherapy for breast cancer. Chemotherapy induces cellular senescence, and the fatigue was thought to come from the various cytokines secreted by senescent cells (Senescence Associated Secretory Phenotype—SASP) It seems logical to me to test CFS patients for p16^INK4a (4).
I suggested this to the senior author; however, he was nominated as head of the National Cancer Institute just 9 days later. There the matter rested until the paper of Montoya et al. (5) appeared in July. I looked up the 74 individual elements of the SASP and found that 9 were among the 17 cytokines whose levels correlated with the degree of fatigue in CFS. However, this is not statistically significant as Montoya looked at 51 cytokines altogether.

In October, an article(6) on the possibility of killing senescent cells to prevent aging contained a statement that Judith Campisi’s group (which has done much of the work on SASP) had identified “hundreds of proteins involved in SASPs”. (These results have not yet been published.) It is certainly possible that many more of Montoya’s 17 cytokines are among them.

If this is the case, a rational therapy for CFS is immediately apparent; namely, the senolytics, a class of drugs which kills senescent cells. A few senolytics are currently available clinically and many more are under development as a way to attack the aging process (6).

If Montoya still has cells from the patients in the study, measuring p16^INK4a could prove or disprove the idea. However, any oncology service could do the test. If the idea proves correct, then there would be a way to treat the debilitating fatigue of both chemotherapy and CFS—not to mention the many more medical conditions in which severe fatigue is found.
Chemotherapy is a systemic process, producing senescent cells everywhere, which is why DeMaria (2) was able to use circulating blood cells to measure p16^INK4a. It is possible that the senescent cells producing SASP in CFS are confined to one tissue; in which case testing blood for p16^INK4a would fail. (That would be similar to pheochromocytoma cells, in which a few localized cells produce major systemic effects.)

Although senolytics might provide symptomatic treatment (something worthwhile having since medicine presently has nothing for the CFS patient), we’d still be in the dark about what initially caused the cells to become senescent. But this would be research well worth pursuing.

Anyone intrigued by the idea should feel free to go ahead and test it. I am a retired neurologist with no academic affiliation, lacking the means to test it.
References

1 Robinson, L (1979) Split genes and musclar dystrophy. Muscle Nerve 2: 458 – 464

2. He S, Sharpless N (2017) Senescence in Health and Disease. Cell 170: 1000 – 1011

3. Demaria M, et al. (2014) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7: 165 – 176

4. https://luysii.wordpress.com/2017/09/04/is-the-era-of-precision-medicine-for-chronic-fatigue-syndrome-at-hand/

5. Montoya JG, et al., (2017) Cytokine signature associated with disease severity in chronic fatigue syndrome patients, Proc Natl Acad Sci USA 114: E7150-E7158

6. Scudellari M, (2017) To stay young, kill zombie cells Nature 551: 448 – 450

Is a rational treatment for chronic fatigue syndrome at hand?

If an idea of mine is correct, it is possible that some patients with chronic fatigue syndrome (CFS) can be treated with specific medications based on the results of a few blood tests. This is precision medicine at its finest.  The data to test this idea has already been acquired, and nothing further needs to be done except to analyze it.

Athough the initial impetus for the idea happened only 3 months ago, there have been enough twists and turns that the best way explanation is by a timeline.

First some background:

As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer then (nor did medicine).  Some of these patients were undoubtedly neurotic, but there was little question in my mind that many others had something wrong that medicine just hadn’t figured out yet — not that it hasn’t been trying.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/03/25/evil-scientists-create-virus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

The 1 June 2017 Cell had a long and interesting review of cellular senescence by Norman Sharpless [ vol. 169 pp. 1000 – 1011 ].  Here is some background about the entity.  If you are familiar with senescent cell biology skip to the paragraph marked **** below

Cells die in a variety of ways.  Some are killed (by infections, heat, toxins).  This is called necrosis. Others voluntarily commit suicide (this is called apoptosis).   Sometimes a cell under stress undergoes cellular senescence, a state in which it doesn’t die, but doesn’t reproduce either.  Such cells have a variety of biochemical characteristics — they are resistant to apoptosis, they express molecules which prevent them from proliferating and — most importantly — they secrete a variety of proinflammatory molecules collectively called the Senescence Associated Secretory Phenotype — SASP).

At first the very existence of the senescent state was questioned, but exist it does.  What is it good for?  Theories abound, one being that mutation is one cause of stress, and stopping mutated cells from proliferating prevents cancer. However, senescent cells are found during fetal life; and they are almost certainly important in wound healing.  They are known to accumulate the older you get and some think they cause aging.

Many stresses induce cellular senescence of which mutation is but one.  The one of interest to us is chemotherapy for cancer, something obviously good as a cancer cell turned senescent has stopped proliferating.   If you know anyone who has undergone chemotherapy, you know that fatigue is almost invariable.

****

One biochemical characteristic of the senescent cell is increased levels of a protein called p16^INK4a, which helps stop cellular proliferation.  While p16^INK4a can easily be measured in tissue biopsies, tissue biopsies are inherently invasive. Fortunately, p16^INK4a can also be measured in circulating blood cells.

What caught my eye in the Cell paper was a reference to a paper about cancer [ Cancer Discov. vol. 7 pp. 165 – 176 ’17 ] by M. Demaria, in which the levels of p16^INK4a correlated with the degree of fatigue after chemotherapy.  The more p16^INK4a in the blood cells the greater the fatigue.

I may have been the only reader of both papers with clinical experience wth chronic fatigue syndrome.  It is extremely difficult to objectively measure a subjective complaint such as fatigue.

As an example of the difficulty in correlating subjective complaints with objective findings, consider the nearly uniform complaint of difficulty thinking in depression, with how such patients actually perform on cognitive tests — e. g. there is  little if any correlation between complaints and actual performance — here’s a current reference — Scientific Reports 7, Article number: 3901(2017) —  doi:10.1038/s41598-017-04353.

If the results of the Cancer paper could be replicated, p16^INK4 would be the first objective measure of a patient’s individual sense of fatigue.

So I wrote both authors, suggesting that the p16^INK4a test be run on a collection of chronic fatigue syndrome (CFS) patients. Both authors replied quickly, but thought the problem would be acquiring patients.  Demaria said that Sharpless had a lab all set up to do the test.

Then fate (in the form of Donald Trump) supervened.  A mere 9 days after the Cell issue appeared, Sharpless was nominated to be the head of the National Cancer Institute by President Trump.  This meant Dr. Sharpless had far bigger fish to fry, and he would have to sever all connection with his lab because of conflict of interest considerations.

I also contacted a patient organization for chronic fatigue syndrome without much success.  Their science advisor never responded.

There matters stood until 22 August when a paper and an editorial about it came out [ Proc. Natl. Acad. Sci. vol. 114 pp. 8914 – 8916, E7150 – E7158 ’17 ].  The paper represented a tremendous amount of data (and work).  The blood levels of 51 cytokines (measures of inflammation) and adipokines (hormones released by fat) were measured in both 192 patients with CFS (which can only be defined by symptoms) and 293 healthy controls matched for age and gender.

In this paper, levels of 17 of the 51 cytokines correlated with severity of CFS. This is a striking similarity with the way the p16^INK4 levels correlated with the degree of fatigue after chemotherapy).  So I looked up the individual elements of the SASP (which can be found in Annu Rev Pathol. 21010; 5: 99–118.)  There are 74 of them. I wondered how many of the 51 cytokines measured in the PNAS paper were in the SASP.  This is trickier than it sounds as many cytokines have far more than one name.  The bottom line is that 20 SASPs are in the 51 cytokines measured in the paper.

If the fatigue of CFS is due to senescent cells and the SASPs  they release, then they should be over-represented in the 17 of the 51 cytokines correlating with symptom severity.  Well they are; 9 out of the 17 are SASP.  However although suggestive, this increase is not statistically significant (according to my consultants on Math Stack Exchange).

After wrote I him about the new work, Dr. Sharpless noted that CFS is almost certainly a heterogeneous condition. As a clinician with decades of experience, I’ve certainly did see some of the more larcenous members of our society who used any subjective diagnosis to be compensated, as well as a variety of individuals who just wanted to withdraw from society, for whatever reason. They are undoubtedly contaminating the sample in the paper. Dr. Sharpless thought the idea, while interesting, would be very difficult to test.

But it wouldn’t at all.  Not with the immense amount of data in the PNAS paper.

Here’s how. Take each of the 9 SASPs and see how their levels correlate with the other 16 (in each of the 192 CSF patients). If they correlate better with SASPs than with nonSASPs, than this would be evidence for senescent cells being the cause some cases of CFS. In particular, patients with a high level of any of the 9 SASPs should be studied for such correlations.  Doing so should weed out some of the heterogeneity of the 192 patients in the sample.

This is why the idea is testable and, even better, falsifiable, making it a scientific hypothesis (a la Karl Popper).  The data to refute it is in the possession of the authors of the paper.

Suppose the idea turns out to be correct and that some patients with CFS are in fact that way because, for whatever reason, they have a lot of senescent cells releasing SASPs.

This would mean that it would be time to start trials of senolyic drugs which destroy senescent cells on the group with elevated SASPs. Fortunately, a few senolytics are currently inc linical use.  This would be precision medicine at its finest.

Being able to alleviate the symptoms of CFS would be worthwhile in itself, but SASP levels could also be run on all sorts of conditions associated with fatigue, most notably infection. This might lead to symptomatic treatment at least.  Having gone through mono in med school, I would have loved to have been able to take something to keep me from falling asleep all the time.

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The chemical ingenuity of the AIDs virus

Pop quiz:  You are a virus with under 10,000 nucleotides in your genome.  To make the capsid enclosing your genome, you need to make 250 hexamers of a particular protein.  How do you do it?

 

Give up?

 

You grab a cellular metabolite with a mass under 1,000 Daltons to bind the 6 monomers together.  The metabolite occurs at fairly substantial concentrations (for a metabolite) of 10 – 40 microMolar.

What is the metabolite?

Give up?

 

It has nearly perfect 6 fold symmetry.

 

Still give up?

[ Nature vol. 560 pp. 509 – 512 ’18 ]  https://www.nature.com/articles/s41586-018-0396-4 says that it’s inositol hexakisphosphate (IP6)  — nomenclature explained at the end. http://www.refinebiochem.com/pages/InositolHexaphosphate.html

Although IP6 looks like a sugar (with 6 CHOH groups forming a 6 membered ring), it is not a typical one because it is not an acetal (no oxygen in the ring).  All 6 hydroxyls of IP6 are phosphorylated.  They bind to two lysines on a short (21 amino acids) alpha helix found in the protein (Gag which has 500 amino acids).  That’s how IP6 binds the 6 Gag proteins together. The paper has great pictures.

It is likely that IP6 is use by other cellular proteins to form hexamers (but the paper doesn’t discuss this).

IP6 is quite symmetric, and 5 of the 6 phosphorylated hydroxyls can be equatorial, so this is likely the energetically favored conformation, given the bulk (and mass) of the phosphate group.

I think that the AIDS virus definitely has more chemical smarts than we do.  Humility is definitely in order.

Nomenclature note:  We’re all used to ATP (Adenosine TriPhosphate) and ADP (Adenosine DiPhosphate) — here all 3 or 2 phosphates form a chain.  Each of the 6 hydroxyls of inositol can be singly phosphorylated, leading to inositol bis, tris, tetrakis, pentakis, hexakis phosphates.  Phosphate chains can form on them as well, so IP7 and IP8 are known (heptakis?, Octakis??)

Back from band camp for grownups

While at band camp, we heard a fabulously intense performance of a piece which must be witnessed rather than listened to on the radio or on a CD while you’re doing something else.  It was Messiaen’s Quartet for the End of Time. You couldn’t ask for a better audience — 150+ raptly attentive amateur musicians with all cell phones off and no program notes.  The piece takes an hour to play and is full of long silences.  In some parts just one instrument plays while the other players sit stock still staring ahead, so the piece really is part theater.

You can always tell when a string player or a pianist starts to play as something moves and your mind expects a sound.  No so with the many long silences of the clarinet solo.  Parts begin so softly that you can’t even be sure the clarinet is playing, as there is no motion to clue you in.  Then, suddenly you realize you’ve been hearing a sound for a while.   The piece ends with a violinist ascending slowly into the tonal stratosphere while producing a prolonged decrescendo.  She was in tears at the end.

The players (correctly) decided on no descriptive program notes (which were read aloud at the beginning) as they didn’t want to break up the intensity with rustling paper (or the spoken word).  Probably it’s better to hear the piece not knowing the background, but there’s a Wiki page for it which is pretty good if you already know its provenance.

Pianists don’t have to count.  When we get stuck we just stop and then start over.  Even with chamber music we have the score so we always know what the other players should be doing, so we can pretty much fake what we can’t play and keep things going.  Our only problems are the incessant page turns, sometimes with all the other instruments cutting out leaving us alone playing with both hands, turning the page and trying not to miss a beat.  All this was true until I got to play a piece with bassoon, clarinet, oboe, violin and cello by Martinu — https://en.wikipedia.org/wiki/La_revue_de_cuisine, which had only the piano part, and long 9 and 10 measure rests which I was supposed to count.  I thought it would be a total disaster, but the coach conducted it, and shouted out numbers when I was supposed to play. I bought him a beer later that week.  An interesting piece with a tango, and a Charleston in it.

Participants at the camp decided that there would be no talk of politics, just music, and the world did manage to spin on its axis for a week without our help.

I spent 300 miles or so of the 1,100 mile drive back on backroads through the verdant midwest countryside.  I made it a point to pace off a mile or so every now and then in a particularly beautiful stretch of country and then get out and walk it.  Typical of the midwest, each time I did, someone would stop and ask if I needed help.

The many miles of the country I went through on the way back look very good.  The stores and  restaurants and malls were full, the campgrounds crowded, and help wanted signs were everywhere. Much better than the previous trips of the past 5 years.

So then I get back to Massachusetts and the alternate universe of the New York Times.  When the Times talks about the longest bull market in history, they note in the same breath that it is only for rich people, ignoring the fact that all pension plans, IRAs and 401k’s have been beneficiaries.  Also on the front page was a story about a payoff to a porn star, something of minimal consequence to the daily lives of those outside the bubble.

Paul Krugman, Nobel Laureate in economics, appears on the opinion page, despite having declared election night the stock market would never recover, and a few years ago informing us that we were at peak oil production.  At least no articles by Larry Summers (smartest guy in the room and former president of Harvard) about secular stagnation and the impossibility of 3% economic growth.

Linus Pauling was one of the great chemists of the 20th Century — electronegativity, the nature of the chemical bond, the alpha helix etc. etc.  Yet when he said vitamin C could cure colds and cancer, he was proved wrong and his pronouncements on the subject roundly ignored.  No so with political and economic pundits.

The disconnect between the bicoastal mainstream media and the center of the country is profound.  The November elections should be fascinating.  Help stamp our minority employment — vote Democratic.

Off to band camp for adults 2018

No posts for a while, as I’ll be at a chamber music camp for adult amateurs (or what a friend’s granddaughter calls — band camp for adults).  In a week or two if you see a beat up old Honda Pilot heading west on the north shore of Lake Superior, honk and wave.

I expect the usual denizens to be there — mathematicians, physicists, computer programmers, MDs, touchy-feely types who are afraid of chemicals etc. etc. We all get along but occasionally the two cultures do clash, and a polymer chemist friend is driven to distraction by a gentle soul who is quite certain that “chemicals” are a very bad thing. For the most part, everyone gets along. Despite the very different mindsets, all of us became very interested in music early on, long before any academic or life choices were made.

So, are the analytic types soulless automatons producing mechanically perfect music which is emotionally dead? Are the touchy-feely types sloppy technically and histrionic musically? A double-blind study would be possible, but I think both groups play pretty much the same (less well than we’d all like, but with the same spirit and love of music).

A few years ago I had the pleasure of playing Beethoven with Heisenberg —   along with an excellent violinist I’ve played with for years, the three of us read Beethoven’s second piano trio (Opus 1, #2) with Heisenberg’s son Jochem (who, interestingly enough, is a retired physics professor).  He is an excellent cellist who knows the literature cold.  The violinist and I later agreed that we have rarely played worse.  Oh well. Heisenberg, of course, was a gentleman throughout.

Later that evening, several of us had the pleasure of discussing quantum mechanics with him. He didn’t disagree with my idea that the node in the 2S orbital (where no electron is ever found) despite finding the electron on either side of the node, forces us to give up the idea of electron trajectory (aromatic ring currents be damned).   He pretty much seemed to agree with the Copenhagen interpretation — macroscopic concepts just don’t apply to the quantum world, and language trips us up.

One rather dark point about the Heisenberg came up in an excellent book about the various interpretations of what Quantum Mechanics actually means: “What Is Real?” by Adam Becker.  I have no idea if the following summary is actually true, but here it is.   Heisenberg was head of the German nuclear program to develop an atomic bomb.  Nuclear fission was well known in Germany, having been discovered there.  An old girl friend wrote a book about Lise Meitner, one of the discoverers and how she didn’t get the credit she was due.

At the end of the war there was an entire operation to capture German physicists who had worked on nuclear development (operation Alsos).  Those captured (Heisenberg, Hahn, von Laue and others) were taken to Farm Hall, an English manor house which had been converted into a military intelligence center.  It was supplied with chalkboards, sporting equipment, a radio, good food and secretly bugged to high heaven.  The physicists were told that they were being held “at His Majesty’s pleasure.”.  Later they told the American’s had dropped the atomic bomb.  They didn’t believe it as their own work during the war led them to think it was impossible.

All their discussions were recorded, unknown to Heisenberg.  It was clear that the Germans had no idea how to build a bomb even though they tried.  However  Heisenberg  and von Weizsacker constructed a totally false narrative, that they had never tried to build a bomb, but rather a nuclear reactor.  According to Becker, Heisenberg was never caught out on this because the Farm Hall transcripts were classified.  It isn’t clear to me from reading Becker’s book, when they were UNclassified, but apparently Heisenberg got away with it until his death in 1978.

Amazing stuff if true

 

A modest proposal (with apologies to Jonathan Swift)

Sunday’s New York Times magazine was entirely devoted to global warming and our lack of response to it.  Doubtless it was read with great approval by the denizens of the upper East and West Sides as they sat in their million dollar apartments, vowing to fight until the last coal miner and oil field roughneck was out of work.  This will cost them nothing.

Virtue signaling notwithstanding, it’s time they had some skin of their own in the game. Having practiced medicine in the People’s Republic of New York, I know the love of New York state government for regulations and mandates, and the approval with which they have been met by the above denizens.

So here is a modest proposal for fighting global warming.  Mandate that governors be placed on air conditioners so that room temperatures can be no lower than 80 in the summer.  Similar governors should  be placed on heating, allowing room temperatures no warmer than 60 in the winter.  Start in the upper East and West sides of Manhattan, and if met with general approval extend it further.

I think it will be accepted as well they accepted the wind farms proposed off Martha’s Vineyard and Nantucket near their summer homes.

When the dissociation constant doesn’t tell you what you want to know

Drug chemists spend a lot of time getting their drugs to bind tightly to their chosen target.  Kd’s (dissociation constants) are measured with care –https://en.wikipedia.org/wiki/Dissociation_constant.  But Kd’s are only  a marker for the biologic effects that are the real reason for the drug.  That’s why it was shocking to find that Kd’s don’t seem to matter in a very important and very well studied system.

It’s not the small molecule ligand protein receptor most drug chemists deal with, it’s the goings on at the immunologic synapse between antigen presenting cell and T lymphocyte (a much larger ligand target interface — 1,000 – 2,000 Angstroms^2 — than the usual site of drug/protein binding).   A peptide fragment lies down in a groove on the Major Histocompatibility Complex (pMHC) where it is presented to the T lymphoCyte Receptor (TCR) — another protein complex.  The hope is that an immune response to the parent protein of the peptide fragment will occur.

 

However, the Kd’s (affinities)of strong (e.g. producing an immune response) peptide agonist ligands and those producing not much (e.g. weak) are similar and at times overlapping.  High affinity yet nonStimulatory interactions occur with high frequency in the human T cell repertoire [ Cell vol. 174 pp. 672 – 687 ’18 ].  The authors  determined the structure of both weak and strong ligands bound to the TCR.  One particular TCR had virtually the same structure when bound to strong and weak agonist ligands. When studied in two dimensional membranes, the dwell time of ligand with receptor didn’t distinguish strong from weak antigens (surprising).

In general the Kds  pMHC/TCR  are quite low — not in the nanoMolar range beloved by drug chemists (and found in antigen/antibody binding), but 1000 times weaker in the micromolar range.  So [ Proc. Natl. Acad. Sci. vol. 115 pp. E7369 – E7378 ’18 ] cleverly added an extra few amino acids which they call molecular velcro, to boost the affinity x 10 (actually this decreases Kd tenfold).

One rationale for the weak binding is that it facilitates scanning by the TCR of  the pMHC  repertoire allowing the TCR to choose the best.  So they added the velcro, expecting the repertoire to be less diverse (since the binding was tighter).  It was just the same. Again the Kd didn’t seem to matter.

https://en.wikipedia.org/wiki/Catch_bond

Even more interesting, the first paper noted that productive TCR/pMHC bonds had catch bonds — e.g. bonds which get stronger the more you pull on them. The authors were actually able to measure the phenomenon. Catch bonds been shown to exist in a variety of systems (white cells sticking to blood vessel lining, bacterial adhesion), but their actual mechanism is still under debate.  The great thing about this paper (p. 682) is molecular dynamics simulation showed the conformational changes which occurred during catch bond formation in one case..   They even have videos.  Impressive.

This sort of thing is totally foreign to all solution chemistry, as there is no way to pull on a bond in solution.  Optical tweezers allow you to pull and stretch molecules (if you can attach them to large styrofoam balls).

A creation myth

Sigmund Freud may have been wrong about penis envy, but most lower forms of scientific life (chemists, biologists) do have physics envy — myself included.  Most graduate chemists have taken a quantum mechanics course, if only to see where atomic and molecular orbitals come from.  Anyone doing physical chemistry has likely studied statistical mechanics. I was fortunate enough to audit one such course given by E. Bright Wilson (of Pauling and Wilson).

Although we no longer study physics per se, most of us read books about physics.  Two excellent such books have come out in the past year.  One is “What is Real?” — https://www.basicbooks.com/titles/adam-becker/what-is-real/9780465096053/, the other is “Lost in Math” by Sabine Hossenfelder whose blog on physics is always worth reading, both for herself and the heavies who comment on what she writes — http://backreaction.blogspot.com

Both books deserve a long discursive review here. But that’s for another time.  Briefly, Hossenfelder thinks that physics for the past 30 years has become so fascinated with elegant mathematical descriptions of nature, that theories are judged by their mathematical elegance and beauty, rather than agreement with experiment.  She acknowledges that the experiments are both difficult and expensive, and notes that it took a century for one such prediction (gravitational waves) to be confirmed.

The mathematics of physics can certainly be seductive, and even a lowly chemist such as myself has been bowled over by it.  Here is how it hit me

Budding chemists start out by learning that electrons like to be in filled shells. The first shell has 2 elements, the next 2 + 6 elements etc. etc. It allows the neophyte to make some sense of the periodic table (as long as they deal with low atomic numbers — why the 4s electrons are of lower energy than the 3d electons still seems quite ad hoc to me). Later on we were told that this is because of quantum numbers n, l, m and s. Then we learn that atomic orbitals have shapes, in some wierd way determined by the quantum numbers, etc. etc.

Recursion relations are no stranger to the differential equations course, where you learn to (tediously) find them for a polynomial series solution for the differential equation at hand. I never really understood them, but I could use them (like far too much math that I took back in college).

So it wasn’t a shock when the QM instructor back in 1961 got to them in the course of solving the Schrodinger equation for the hydrogen atom (with it’s radially symmetric potential). First the equation had to be expressed in spherical coordinates (r, theta and phi) which made the Laplacian look rather fierce. Then the equation was split into 3 variables, each involving one of r, theta or phi. The easiest to solve was the one involving phi which involved only a complex exponential. But periodic nature of the solution made the magnetic quantum number fall out. Pretty good, but nothing earthshaking.

Recursion relations made their appearance with the solution of the radial and the theta equations. So it was plug and chug time with series solutions and recursion relations so things wouldn’t blow up (or as Dr. Gouterman, the instructor, put it: the electron has to be somewhere, so the wavefunction must be zero at infinity). MEGO (My Eyes Glazed Over) until all of a sudden there were the main quantum number (n) and the azimuthal quantum number (l) coming directly out of the recursion relations.

When I first realized what was going on, it really hit me. I can still see the room and the people in it (just as people can remember exactly where they were and what they were doing when they heard about 9/11 or (for the oldsters among you) when Kennedy was shot — I was cutting a physiology class in med school). The realization that what I had considered mathematical diddle, in some way was giving us the quantum numbers and the periodic table, and the shape of orbitals, was a glimpse of incredible and unseen power. For me it was like seeing the face of God.

But what interested me the most about “Lost in Math” was Hossenfelder’s discussion of the different physical laws appearing at different physical scales (e.g. effective laws), emergent properties and reductionism (pp. 44 –> ).  Although things at larger scales (atoms) can be understood in terms of the physics of smaller scales (protons, neutrons, electrons), the details of elementary particle interactions (quarks, gluons, leptons etc.) don’t matter much to the chemist.  The orbits of planets don’t depend on planetary structure, etc. etc.  She notes that reduction of events at one scale to those at a smaller one is not an optional philosophical position to hold, it’s just the way nature is as revealed by experiment.  She notes that you could ‘in principle, derive the theory for large scales from the theory for small scales’ (although I’ve never seen it done) and then she moves on

But the different structures and different laws at different scales is what has always fascinated me about the world in which we exist.  Do we have a model for a world structured this way?

Of course we do.  It’s the computer.

 

Neurologists have always been interested in computers, and computer people have always been interested in the brain — von Neumann wrote “The Computer and the Brain” shortly before his death in 1958.

Back in med school in the 60s people were just figuring out how neurons talked to each other where they met at the synapse.  It was with a certain degree of excitement that we found that information appeared to flow just one way across the synapse (from the PREsynaptic neuron to the POST synaptic neuron).  E.g. just like the vacuum tubes of the earliest computers.  Current (and information) could flow just one way.

The microprocessors based on transistors that a normal person could play with came out in the 70s.  I was naturally interested, as having taken QM I thought I could understand how transistors work.  I knew about energy gaps in atomic spectra, but how in the world a crystal with zillions of atoms and electrons floating around could produce one seemed like a mystery to me, and still does.  It’s an example of ’emergence’ about which more later.

But forgetting all that, it’s fairly easy to see how electrons could flow from a semiconductor with an abundance of them (due to doping) to a semiconductor with a deficit — and have a hard time flowing back.  Again a one way valve, just like our concept of the synapses.

Now of course, we know information can flow the other way in the synapse from POST synaptic to PREsynaptic neuron, some of the main carriers of which are the endogenous marihuana-like substances in your brain — anandamide etc. etc.  — the endocannabinoids.

In 1968 my wife learned how to do assembly language coding with punch cards ones and zeros, the whole bit.  Why?  Because I was scheduled for two years of active duty as an Army doc, a time in which we had half a million men in Vietnam.  She was preparing to be a widow with 2 infants, as the Army sent me a form asking for my preferences in assignment, a form so out of date, that it offered the option of taking my family with me to Vietnam if I’d extend my tour over there to 4 years.  So I sat around drinking Scotch and reading Faulkner waiting to go in.

So when computers became something the general populace could have, I tried to build a mental one using and or and not logical gates and 1s and 0s for high and low voltages. Since I could see how to build the three using transistors (reductionism), I just went one plane higher.  Note, although the gates can be easily reduced to transistors, and transistors to p and n type semiconductors, there is nothing in the laws of semiconductor physics that implies putting them together to form logic gates.  So the higher plane of logic gates is essentially an act of creation.  They do not necessarily arise from transistors.

What I was really interested in was hooking the gates together to form an ALU (arithmetic and logic unit).  I eventually did it, but doing so showed me the necessity of other components of the chip (the clock and in particular the microcode which lies below assembly language instructions).

The next level up, is what my wife was doing — sending assembly language instructions of 1’s and 0’s to the computer, and watching how gates were opened and shut, registers filled and emptied, transforming the 1’s and 0’s in the process.  Again note that there is nothing necessary in the way the gates are hooked together to make them do anything.  The program is at yet another higher level.

Above that are the higher level programs, Basic, C and on up.  Above that hooking computers together to form networks and then the internet with TCP/IP  etc.

While they all can be reduced, there is nothing inherent in the things that they are reduced to which implies their existence.  Their existence was essentially created by humanity’s collective mind.

Could something be going on in the levels of the world seen in physics.  Here’s what Nobel laureate Robert Laughlin (he of the fractional quantum Hall effect) has to say about it — http://www.pnas.org/content/97/1/28.  Note that this was written before people began taking quantum computers seriously.

“However, it is obvious glancing through this list that the Theory of Everything is not even remotely a theory of every thing (2). We know this equation is correct because it has been solved accurately for small numbers of particles (isolated atoms and small molecules) and found to agree in minute detail with experiment (3–5). However, it cannot be solved accurately when the number of particles exceeds about 10. No computer existing, or that will ever exist, can break this barrier because it is a catastrophe of dimension. If the amount of computer memory required to represent the quantum wavefunction of one particle is Nthen the amount required to represent the wavefunction of k particles is N^k. It is possible to perform approximate calculations for larger systems, and it is through such calculations that we have learned why atoms have the size they do, why chemical bonds have the length and strength they do, why solid matter has the elastic properties it does, why some things are transparent while others reflect or absorb light (6). With a little more experimental input for guidance it is even possible to predict atomic conformations of small molecules, simple chemical reaction rates, structural phase transitions, ferromagnetism, and sometimes even superconducting transition temperatures (7). But the schemes for approximating are not first-principles deductions but are rather art keyed to experiment, and thus tend to be the least reliable precisely when reliability is most needed, i.e., when experimental information is scarce, the physical behavior has no precedent, and the key questions have not yet been identified. There are many notorious failures of alleged ab initio computation methods, including the phase diagram of liquid ³He and the entire phenomenonology of high-temperature superconductors (8–10). Predicting protein functionality or the behavior of the human brain from these equations is patently absurd. So the triumph of the reductionism of the Greeks is a pyrrhic victory: We have succeeded in reducing all of ordinary physical behavior to a simple, correct Theory of Everything only to discover that it has revealed exactly nothing about many things of great importance.”

So reductionism doesn’t explain the laws we have at various levels.  They are regularities to be sure, and they describe what is happening, but a description is NOT an explanation, in the same way that Newton’s gravitational law predicts zillions of observations about the real world.     But even  Newton famously said Hypotheses non fingo (Latin for “I feign no hypotheses”) when discussing the action at a distance which his theory of gravity entailed. Actually he thought the idea was crazy. “That Gravity should be innate, inherent and essential to Matter, so that one body may act upon another at a distance thro’ a Vacuum, without the Mediation of any thing else, by and through which their Action and Force may be conveyed from one to another, is to me so great an Absurdity that I believe no Man who has in philosophical Matters a competent Faculty of thinking can ever fall into it”

So are the various physical laws things that are imposed from without, by God only knows what?  The computer with its various levels of phenomena certainly was consciously constructed.

Is what I’ve just written a creation myth or is there something to it?

Will acyclovir be a treatment for Alzheimer’s ?

When I was a first year medical student my aunt died of probable acute herpes simplex encephalitis at Columbia University Hospital in New York City.  That was 55 years ago and her daughters (teenagers at the time) still bear the scars.  Later, as a neurologist I treated it, and after 1977, when acyclovir, which effectively treats herpes encephalitis came out, I would always wonder if acyclovir would have saved her.

The drug is simplicity itself.  It’s just guanosine (https://en.wikipedia.org/wiki/Guanosine) with two of the carbons of the ribose missing.  Herpesviruses have an enzyme which forms the triphosphate incorporating it into its DNA killing the virus.  Well, actually we have the same enzyme, but the virus’s enzyme is 3,000,000 times more efficient than ours, so acyclovir is relatively nontoxic to us.  People with compromised renal function shouldn’t take it.

What does this have to do with Alzheimer’s disease?  The senile plaque of Alzheimers is mostly the aBeta peptide (39 – 43 amino acids) from the amyloid precursor protein (APP).  This has been known for years, and my notes on various papers about over the years contain 150,000 characters or so.

Even so, there’s a lot we don’t understand about APP and the abeta peptide — e.g. what are they doing for us?  You can knockout the APP gene in mice and they appear normal and fertile.  The paper cited below notes that APP has been present in various species for the past 400,000,000 years of evolutionary time remaining pretty much unchanged throughout, so it is probably doing something useful

A recent paper in Neuron (vol. 99 pp. 56 – 63 ’18) noted that aBeta is actually an antimicrobial peptide.  When exposed to herpes simplex it binds to glycoproteins on its surface and then  oligomerizes forming amyloid (just like in the senile plaque) trapping the virus.  Abeta will protect mice against herpes simplex 1 (HSV1) encephalitis.  Even more important — infection of the mice with HSV1 induced abeta production in their brains.

People have been claiming infections as the cause of just about every neurodegeneration since I’ve been a neurologist, and papers have been written about HSV1 and Alzheimer’s.

Which brings me to the second paper (ibid. pp. 64 – 82) that looked for the viral RNAs and DNAs in over 900 or so brains, some with and some without Alzheimer’s.  They didn’t find HSV but they found two other herpes viruses known to infect man (HHV6, HHV7 — which cause roseola infantum).  Humans are subject to infection with 8 different herpes virus (Epstein Barr — mononucleosis, H. Zoster — chickenpox etc. etc.).   Just about everyone of us has herpes virus in latent form in the trigeminal ganglion — which gets sensory information from our faces.

So could some sort of indolent herpesvirus infection be triggering abeta peptide production as a defense with the senile plaque as a byproduct?  That being the case, given the minimal benefits of any therapy we have for Alzheimer’s disease so far, why not try acyclovir (Zovirax) on Alzheimer’s.

I find it remarkable that neither paper mentioned this possibility, or even discussed any of the antivirals active against herpesviruses.

Catching God’s dice being thrown

Einstein famously said “Quantum theory yields much, but it hardly brings us close to the Old One’s secrets. I, in any case, am convinced He does not play dice with the universe.”  Astronomers have caught the dice being thrown (at least as far as the origin of life is concerned).

This post will contain a lot more background than most, as I expect some readers won’t have much scientific background.  The technically inclined can read the article on which this is based — http://www.pnas.org/content/115/28/7166

To cut to the chase — astronomers have found water, a simple sugar, and a compound containing carbon, hydrogen, oxygen and nitrogen around newly forming stars and planets.  You need no more than these 4 atoms to build the bases making up the DNA of our genes, all our sugars and carbohydrates, and 18 of the 20 amino acids that make up our proteins. Throw in sulfur and you have all 20 amino acids.  Add phosphorus and you have DNA and its cousin RNA (neither has been found around newly forming stars so far).

These are the ingredients of life itself. Here’s a quote from the article — “What I can definitively say is that the ingredients needed to make biogenic molecules like DNA and RNA are found around every forming protostar. They are there at an early stage, incorporating into bodies at least as large as comets, which we know are the building blocks of terrestrial planets. Whether these molecules survive or are delivered at the late stage of planet formation, that’s the part of it we don’t know very well.”

So each newly formed star and planetary system is a throw of God’s/Nature’s/Soulless physics’ dice for the creation of life.

As of 1 July 2018, there are 3,797 confirmed planets around 2,841 stars, with 632 having more than one (Wikipedia).  And that’s just in the stars close enough to us to study.  Our galaxy, the milky way, contains 400,000,000,000.

Current estimates have some 100,000,000,000 galaxies in the universe.  https://www.space.com/25303-how-many-galaxies-are-in-the-universe.html.  That’s a lot tosses for life to arise.

Suppose that some day life is found on one such planet.  Does this invalidate Genesis, the Koran?  Assume that they are the word of God somehow transmitted to man.  If the knowledge we have about astronomy (above), biology etc. etc. were imparted to Jesus, Mohammed, Abraham, Moses — it never would have been believed.  The creator had to start with something plausible.

 

 

An incredible way to look at the brain

http://www.pnas.org/content/115/27/6940 [ Proc. Natl. Acad. Sci. vol. 115 pp. 6940 – 6945 ’18 ] demonstrates an incredible new way to visualize brain structures.  I don’t think the paper is behind a paywall, so follow the link and look at the movies.

The technique can be used on paraffin embedded brain.  Not to be tried at home unless you have a microCT with a liquid jet anode source, and a high resolution synchrotron instrument with special Xray waveguide optic.

No staining was involved, and they used electron contrast to show purkinje cells, granule cells, and the ramified dendritic tree of the Purkinje cells in a 1 cubic millimeter punch ‘biopsy’ of paraffin embedded cerebellum.

The moves are incredible, as unlike the standard CT or MRI, you can move a plane through the images (the movies show this), stop it at leisure.  Visualization of a plane moving through the material shows what the brain looks like in 3 d.  Then there are a few 3 d reconstructions (presented as 2 dimensional projective drawings we’re used to seeing), but even these can be moved around.

Words are inadequate.  Go to the link and look at the movies.  Let me know if you have trouble reaching it.