The impeccable timing of the New York Times

After putting ex-Weatherman Bill Ayers on page 1 saying he wished he’d ‘bombed more’ the day of the attack on the World Trade Center in 2001, the New York Times kept its unenviable timing record intact by posting “Dreams of my Muslim Son” about Islamophobia on the editorial page the day of the Orlando massacre. Usually they run their invariable innocent Muslims fearing hate crimes by American rednecks story a day or so after the latest atrocity.

Unfortunately Orlando can’t be camouflaged as workplace violence or the response to some video or other a la Benghazi. The perp was far too explicit. Nor can it be blamed on the failure of ‘the MidEast Peace Process’ or Israel, although undoubtedly some will try.

If I were the Muslim leadership in this country, I’d try to put together a Million Muslim March on Washington to protest the Orlando, San Bernadino, Boston etc. etc. massacres, as blots on the name of Islam. ISIS would probably try to kill a few, but it’s time for them to stand up, assuming there are large numbers of US Muslims that actually think this way.

Reproducibility and its discontents

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

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

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

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

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

ONTX Good news and semibad news.

The stock I recommended 1 June (ONTX) was up 11% today on a fourfold increase in volume. The rationale based on a Cell paper (vol. 165 pp. 643 – 655 ’16 ) will be found in a copy of the entire post below the ****

It is worth looking at the chart — https://finance.yahoo.com/echarts?s=ONTX+Interactive#{“range”:”1d”,”allowChartStacking”:true}

After a delay in opening, it exploded most of the way up on high volume (for it). Why? My guess is that people looked at the poster of the study in progress using their Ras blocking drug Rigosertib. Who looked? Why some of the 30,000 attendees at the 2016 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Why is this good (aside from the rise)? Assuming the people who bought ONTX were attendees at the convention, these are very informed buyers (e.g. professional oncologists) laying down their long green (e.g. very smart money).   In one of the many books I read about the Bernie Madoff Ponzi scheme, the people who invested with him were described as ‘dumb money’. They’d made their pile elsewhere and were babes in the woods when it came to investing.

Why is this also bad for what I predicted? Have a look at the abstract of one of the posters. Here’s a link to it —
http://meetinglibrary.asco.org/content/165681-176

The skinny is that the phase III study I was so excited about began only last December. It likely will be years before the results will be in. So goodbye 10x – 100x pop in the stock right away. Possibly big pharma will be impressed with their work and buy out the company which should also mean a significant gain.

Now 30,000 people can’t crowd around a single poster presentation. The stock is likely to continue moving up on volume this week as word spreads from the people who’ve already bought it and more people see the possibilities.

Here’s the post of 1 June — note that I didn’t own ONTX when I wrote the first post 3 May ’16, but did when I wrote the 1 June post.

*****

In a gambling mood?

If a pair of posters to be presented Monday 6 June at the 2016 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, contains the results of a phase III clinical trial of rigosertib, and if the results are as good as a paper discussed below the stock Onconova Therapeutics (ONTX) will jump by a factor of 10 to 100.

Full disclosure: I own some. The posters may just describe the clinical trial rather than report the results in which case all bets are off. In that case, I’ll just hold the stock until the results are in. This isn’t the ‘pump and dump’ beloved of boiler room operators everywhere. The rationale for the drug and my take on the original paper (3 May ’16) are reproduced below.

Has the great white whale of oncology finally been harpooned?

The ras oncogene is the great white whale of oncology. Mutations in 20 – 40% of cancer turn its activity on so that nothing can turn it off, resulting in cellular proliferation. People have been trying to turn mutated ras off for years with no success.

A current paper [ Cell vol. 165 pp. 643 – 655 ’16 ] describes a new and different way to attack it. Once ras is turned on (either naturally or by mutation) many other proteins must bind to it, to produce their effects — they are called RAS effectors, among which are the uneuphoniously named RAF, RalGDS and PI3K. They bind to activated ras by the cleverly named Ras Binding Domain (RBD) which has 78 amino acids.

The paper describes rigosertib, a not that complicated molecule to the chemist, which inhibits the binding (by resembling the site on ras that the RBD binds to). It is a styryl benzyl sulfone and you can see the structure here — https://en.wikipedia.org/wiki/Rigosertib.

What’s good about it? Well it is in phase III trials for a fairly uncommon form of cancer (myelodysplastic syndrome). That means it isn’t horribly toxic or it wouldn’t have made it out of phase I.

Given the mechanism described, it is possible that Rigosertib will be useful in 20 – 40% of all cancer. Can you say blockbuster drug?

Do you have a speculative bent? Buy the company testing the drug and owning the patent — Onconova Therapeutics. It’s quite cheap — trading at $.40 (yes 40 cents !). It once traded as high as $30.00 — symbol ONTX. I don’t own any (yet), but for the price of a movie with a beer and some wings afterwards you could be the proud owner of 100 shares. If Rigosertib works, the stock will certainly increase more than a hundredfold.

Enough kidding around. This is serious business. In what follows you will find some hardcore molecular biology and cellular physiology showing just what we’re up against. Some of the following is quite old, and probably out of date (like yours truly), but it does give you the broad outlines of what is involved.

The pathway from Ras to the nucleus

The components of the pathway had been found in isolation (primarily because mutations in them were associated with malignancy). Ras was discovered as an oncogene in various sarcoma viruses. Mutations in ras found in tumors left it in a ‘turned on’ state, but just how ras (and everything else) fit into the chain of binding of a growth factor (such as platelet derived growth factor, epidermal growth factor, insulin, etc. etc.) to its receptor on the cell surface to alterations in gene expression wasn’t clear. It is certain to become more complicated, because anything as important as cellular proliferation is very likely to have a wide variety of control mechanisms superimposed on it. Although all sorts of protein kinases are involved in the pathway it is important to remember that ras is NOT a protein kinase.

l. The first step is binding of a growth factor to its receptor on the cell surface. The receptor is usually a tyrosine kinase. Binding of the factor to the receptor causes ‘activation’ of the receptor. Activation usually means increasing the enzymatic activity of the receptor in the tyrosine kinase reaction (most growth factor receptors are tyrosine kinases). The increase in activity is usually brought about by dimerization of the receptor (so it phosphorylates itself on tyrosine).

2. Most activated growth factor receptors phosphorylate themselves (as well as other proteins) on tyrosine. A variety of other proteins have domains known as SH2 (for src homology 2) which bind to phosphorylated tyrosine.

3. A protein called grb2 binds via its SH2 domain to a phosphorylated tyrosine on the receptor. Grb2 binds to the polyproline domain of another protein called sos1 via its SH3 domain. At this point, the unintiated must find the proceedings pretty hokey, but the pathway is so general (and fundamental) that proteins from yeast may be substituted into the human pathway and still have it work.

4. At last we get to ras. This protein is ‘active’ when it binds GTP, and inactive when it binds GDP. Ras is a GTPase (it can hydrolyze GTP to GDP). Most mutations which make ras an oncogene decrease the GTPase activity of RAS leaving it in a permanently ‘turned on’ state. It is important for the neurologist to know that the defective gene in type I neurofibromatosis activates the GTPase activity of ras, turning ras off. Deficiencies (in ras inactivation) lead to a variety of unusual tumors familiar to neurologists.

Once RAS has hydrolyzed GTP to GDP, the GDP remains bound to RAS inactivating it. This is the function of sos1. It catalyzes the exchange of GDP for GTP on ras, thus activating ras.

5. What does activated ras do? It activates Raf-1 silly. Raf-1 is another oncogene. How does activated ras activate Raf-1 ? Ras appears to activate raf by causing raf to bind to the cell membrane (this doesn’t happen in vitro as there is no membrane). Once ras has done its job of localizing raf to the plasma membrane, it is no longer required. How membrane localization activates raf is less than crystal clear. [ Proc. Natl. Acad. Sci. vol. 93 pp. 6924 – 6928 ’96 ] There is increasing evidence that Ras may mediate its actions by stimulating multiple downstream targets of which Raf-1 is only one.

6. Raf-1 is a protein kinase. Protein kinases work by adding phosphate groups to serine, threonine or tyrosine. In general protein kinases fall into two classes those phosphorylating on serine or threonine and those phosphorylating on tyrosine. Biochemistry has a well documented series of examples of enzymes being activated (or inhibited) by phosphorylation. The best worked out is the pathway from the binding of epinephrine to its cell surface receptor to glycogen breakdown. There is a whole sequence of one enzyme phosphorylating another which then phosphorylates a third. Something similar goes on between Raf-1 and a collection of protein kinases called MAPKs (mitogen activated protein kinases). These were discovered as kinases activated when mitogens bound to their extracellular receptors.There may be a kinase lurking about which activates Raf (it isn’t Ras which has no kinase activity). Removal of phosphate from Raf (by phosphatases) inactivates it.

7. Raf-1 activates members of the MAPK family by phosphorylating them. There may be several kinases in a row phosphorylating each other. [ Science vol. 262 pp. 1065 – 1067 ’93 ] There are at least three kinase reactions at present at this point. It isn’t known if some can be sidestepped. Raf-1 activates mitogen activated protein kinase kinase (MAPK-K) by phosphorylation (it is called MEK in the ras pathway). MAPK-K activates mitogen activation protein kinase (MAPK) by phosphorylation. Thus Raf-1 is actually mitogen activated protein kinase kinase kinase (sort of like the character in Catch-22 named Junior Junior Junior). (1/06 — I think that Raf-1 is now called BRAF)

8. The final step in the pathway is activation of transcription factors (which turn genes off or on) by MAP kinases by (what else) phosphorylation. Thus the pathway from cell surface is complete.

Mind the gap (junction that is)

Gap junctions don’t get much play in pharmacology, or even in neurology, where they are widespread in the central nervous system, linking neurons to neurons, astrocytes to astrocytes. They may get quite a bit more if blocking them is a way of treating metastatic disease (see later).

A bit of background if you’re unfamiliar with them. This is from my notes Molecular Biology of the Cell 4th Edition p. 1074

The gap junction is a cylindrical oligomer composed of 6 identical rod shaped subunits (called connexins). They have 4 transmembrane segments and two extracellular loops which contain a beta-strand structure (and which are an essential structural basis for the docking of the two connexons). Multiple connexons in a membrane tend to form hexagonal arrays.

The gap junction spans the lipid bilayer creating a channel along the central axis. The pore is made of two such protein hexamers one from each cell (called a hemichannel or a connexon) arranged end to end. Different tissues have different specific gap junction proteins (connexins). Man has 14 distinct connexins each encoded by a separate gene (20 homologous proteins in man PNAS 103 pp. 5213 – 5218 ’06). Most cell types express more than one. Connexins are capable of assembling into a heteromeric connexon Adjacent cells expressing different connexins can form intercellular channels in which the two aligned dihalf-channels are different. Each gap junction can contain a cluster of a few to MANY THOUSANDS of CONNEXONs.

Neuroscientists should be interested in them as they form a functional ‘synapse’ between cells, e.g. a way of transferring information between them. For the afficienado there will be much more at the end. To flog a nearly dead horse, this is yet another way a wiring diagram of the brain won’t help you understand it — gap junctions don’t show up when you’re looking at classic synapses. For details see https://luysii.wordpress.com/2011/04/10/would-a-wiring-diagram-of-the-brain-help-you-understand-it/

A recent paper in Nature implied that cancer cells can form gap junctions with astrocytes (a glial cell of the brain). Usually we think of gap junctions being of the same cell type, but not here apparently.

Then they describe a mechanism for the cancer cell tweak the astrocyte so it produces something enabling the cancer cell to survive. Here’s whqt they claim

[ Nature vol. 533 pp. 493 – 498 ’16 ] Human and mouse breast and lung cancer cells express protocadherin7 (PCDH7) whicboth promotes (how?) the assembly of carcinoma – astrocyte gap junctions made of connexin43. PCDH7 normally is only expressed in brain. It joints the stialyl transferase ST6GALNAC5 and neuroserpin as brain restricted proteins which metastastic cells from breast and lung cancer use to colonize the brain.

Metastastic cells then uswe the channels to transfer cGAMP to astrocytes activating the STING pathway, which results in InterferonAlpha (IFNalpha) and Tumor Necrosis Factor (TNF), paracrine signals. These activate STAT1 and NFkappaB in the metastatic cells, supporting tumor growth and chemoresistance.

Meclofenamate and tonabersat are ‘modulators’ of gap junctions, breaking the loop between metastatic cancer cell and the astrocyte. Adding them to the tissue culture studied in the paper, inhibited tumor growth. So here might be a way treat metastatic cancer — particularly since meclofenamate is an FDA approved generic drug available without a prescription.

I think the mechanism described above is incomplete — why should a tumor cell transfer something to another cell to have it secrete something which makes the original cell use something it already had.

Now for a few of the things gap junctions are doing in the brain.
****

[ Neuron vol. 90 pp. 810 – 823 ’16 ] ManhyGABAeric interneurons (are there other kinds?) IN VITRO are coupled by gap junctions. This work used dual patch clamp recordings of interneurons IN VIVO. They studied coupled cerebellar Golgi cells, and showed that, in the presence of spontaneous background synaptic activity, electrically coupled cerebellar Golgi cells showed robust milliSecond precision correlated activity. This was further enhanced by sensory stimulation.

The electrical coupling equlized membrane potential fluctuations, so that coupled neurons approach action potential threshold together. They say that something called spike triggered spikelets transmitted through gap junctions conditionally triggered postJunctional spikes, if both neurons were close to threshold.

Spikelets are brief low amplitude potentials which look like action potentials but which are much smaller. A spike cannot be generated without a much larger potential change than provided by a spikelet, because the spikelet voltage is too small to activate the ion channels of electrically excitable membranes.

So gap junctions controls the temporal precision and degree of both spontaneous and sensory evoked correlated activity betwen interneurons, by the cooperative effects of shared synaptic depolarization and spikelet transmission.

[ Neuron vol. 90 pp. 912 – 913, 1043 – 1056 ’16 ] It has been found that the strength of electrical coupling between neurons in a network is highly variable (even in the same neuron, so it could be coupled at different strengths with each of its partners). Site specific modulation of electrical coupling quickly reconfigures networks of electrically coupled neurons in the retina. Phosphorylation of connexin36 alters its conductivity.

The number of gap junctions determines the strength of ele tical coupling between cerebellar Golgi cells. Ultrastructural analysis shows that gap junctions vary widely in size, which also influences coupling strength (according to a computer simulation). These are dendro-dendritic electrical synapses (widespread in the brain between inhibitory interneurons).

Only 18% or so of the channels present at the gap junctions account for the boserved strength of electrical transmission between cerebellar golgi cells.

Somato-somatic junctions occur in the mammalian trigeminal mesencephalic nucleus. Could the excess junctions be acting as adhesion molecules.

In one system, the turnover of gap junction channel proteins is rapid and comparable with that of glutamic acid receptors.

Gap junctions are ‘low pass filters’ (they pass slow fluctuations of membrane potential better than they pass rapid fluctuations). This is why the electrical synapses are inhibitory — each action potential from a Golgi cell consists of a rapid (but brief) depolarizing spike followed by a relatively deep and protracted afterhyperpolarization — which is 200 times longer than the spike — and transmitted much more effectively.

Inhibition by sparse excitatory input breaks up Golgi network synchronization, because the coupling to adjacent cells is different for each one, causing dispersion of the spikes.

In quietly attentive animals cerebellar Golgi cells generate rhythmic synchronous activity at 8 Hertz. The same behavior is seen in cerebellar slices. The hyperpolarizing electrical post-synaptic potentials (PSPs) are the only synchronizing force. This is the default state, but it can be disrupted by a variety of sensory stimuli (or by movements) which reduce spiking frequency and rhythmicity.

Golgi cells can inhibit thousands of granule cells, and every granule cell gets inhibitory input from 4 – 8 Golgi cells. The transient nature of network desynchronization ‘could’ allow the cerebellar input layer to act as a timing device over the 10 milliSecond to 1 second timescale.

In a gambling mood?

If a pair of posters to be presented Monday 6 June at the 2016 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, contains the results of a phase III clinical trial of rigosertib, and if the results are as good as a paper discussed below the stock Onconova Therapeutics (ONTX) will jump by a factor of 10 to 100.

Full disclosure: I own some. The posters may just describe the clinical trial rather than report the results in which case all bets are off. In that case, I’ll just hold the stock until the results are in. This isn’t the ‘pump and dump’ beloved of boiler room operators everywhere. The rationale for the drug and my take on the original paper (3 May ’16) are reproduced below.

Has the great white whale of oncology finally been harpooned?

The ras oncogene is the great white whale of oncology. Mutations in 20 – 40% of cancer turn its activity on so that nothing can turn it off, resulting in cellular proliferation. People have been trying to turn mutated ras off for years with no success.

A current paper [ Cell vol. 165 pp. 643 – 655 ’16 ] describes a new and different way to attack it. Once ras is turned on (either naturally or by mutation) many other proteins must bind to it, to produce their effects — they are called RAS effectors, among which are the uneuphoniously named RAF, RalGDS and PI3K. They bind to activated ras by the cleverly named Ras Binding Domain (RBD) which has 78 amino acids.

The paper describes rigosertib, a not that complicated molecule to the chemist, which inhibits the binding (by resembling the site on ras that the RBD binds to). It is a styryl benzyl sulfone and you can see the structure here — https://en.wikipedia.org/wiki/Rigosertib.

What’s good about it? Well it is in phase III trials for a fairly uncommon form of cancer (myelodysplastic syndrome). That means it isn’t horribly toxic or it wouldn’t have made it out of phase I.

Given the mechanism described, it is possible that Rigosertib will be useful in 20 – 40% of all cancer. Can you say blockbuster drug?

Do you have a speculative bent? Buy the company testing the drug and owning the patent — Onconova Therapeutics. It’s quite cheap — trading at $.40 (yes 40 cents !). It once traded as high as $30.00 — symbol ONTX. I don’t own any (yet), but for the price of a movie with a beer and some wings afterwards you could be the proud owner of 100 shares. If Rigosertib works, the stock will certainly increase more than a hundredfold.

Enough kidding around. This is serious business. In what follows you will find some hardcore molecular biology and cellular physiology showing just what we’re up against. Some of the following is quite old, and probably out of date (like yours truly), but it does give you the broad outlines of what is involved.

The pathway from Ras to the nucleus

The components of the pathway had been found in isolation (primarily because mutations in them were associated with malignancy). Ras was discovered as an oncogene in various sarcoma viruses. Mutations in ras found in tumors left it in a ‘turned on’ state, but just how ras (and everything else) fit into the chain of binding of a growth factor (such as platelet derived growth factor, epidermal growth factor, insulin, etc. etc.) to its receptor on the cell surface to alterations in gene expression wasn’t clear. It is certain to become more complicated, because anything as important as cellular proliferation is very likely to have a wide variety of control mechanisms superimposed on it. Although all sorts of protein kinases are involved in the pathway it is important to remember that ras is NOT a protein kinase.

l. The first step is binding of a growth factor to its receptor on the cell surface. The receptor is usually a tyrosine kinase. Binding of the factor to the receptor causes ‘activation’ of the receptor. Activation usually means increasing the enzymatic activity of the receptor in the tyrosine kinase reaction (most growth factor receptors are tyrosine kinases). The increase in activity is usually brought about by dimerization of the receptor (so it phosphorylates itself on tyrosine).

2. Most activated growth factor receptors phosphorylate themselves (as well as other proteins) on tyrosine. A variety of other proteins have domains known as SH2 (for src homology 2) which bind to phosphorylated tyrosine.

3. A protein called grb2 binds via its SH2 domain to a phosphorylated tyrosine on the receptor. Grb2 binds to the polyproline domain of another protein called sos1 via its SH3 domain. At this point, the unintiated must find the proceedings pretty hokey, but the pathway is so general (and fundamental) that proteins from yeast may be substituted into the human pathway and still have it work.

4. At last we get to ras. This protein is ‘active’ when it binds GTP, and inactive when it binds GDP. Ras is a GTPase (it can hydrolyze GTP to GDP). Most mutations which make ras an oncogene decrease the GTPase activity of RAS leaving it in a permanently ‘turned on’ state. It is important for the neurologist to know that the defective gene in type I neurofibromatosis activates the GTPase activity of ras, turning ras off. Deficiencies (in ras inactivation) lead to a variety of unusual tumors familiar to neurologists.

Once RAS has hydrolyzed GTP to GDP, the GDP remains bound to RAS inactivating it. This is the function of sos1. It catalyzes the exchange of GDP for GTP on ras, thus activating ras.

5. What does activated ras do? It activates Raf-1 silly. Raf-1 is another oncogene. How does activated ras activate Raf-1 ? Ras appears to activate raf by causing raf to bind to the cell membrane (this doesn’t happen in vitro as there is no membrane). Once ras has done its job of localizing raf to the plasma membrane, it is no longer required. How membrane localization activates raf is less than crystal clear. [ Proc. Natl. Acad. Sci. vol. 93 pp. 6924 – 6928 ’96 ] There is increasing evidence that Ras may mediate its actions by stimulating multiple downstream targets of which Raf-1 is only one.

6. Raf-1 is a protein kinase. Protein kinases work by adding phosphate groups to serine, threonine or tyrosine. In general protein kinases fall into two classes those phosphorylating on serine or threonine and those phosphorylating on tyrosine. Biochemistry has a well documented series of examples of enzymes being activated (or inhibited) by phosphorylation. The best worked out is the pathway from the binding of epinephrine to its cell surface receptor to glycogen breakdown. There is a whole sequence of one enzyme phosphorylating another which then phosphorylates a third. Something similar goes on between Raf-1 and a collection of protein kinases called MAPKs (mitogen activated protein kinases). These were discovered as kinases activated when mitogens bound to their extracellular receptors.There may be a kinase lurking about which activates Raf (it isn’t Ras which has no kinase activity). Removal of phosphate from Raf (by phosphatases) inactivates it.

7. Raf-1 activates members of the MAPK family by phosphorylating them. There may be several kinases in a row phosphorylating each other. [ Science vol. 262 pp. 1065 – 1067 ’93 ] There are at least three kinase reactions at present at this point. It isn’t known if some can be sidestepped. Raf-1 activates mitogen activated protein kinase kinase (MAPK-K) by phosphorylation (it is called MEK in the ras pathway). MAPK-K activates mitogen activation protein kinase (MAPK) by phosphorylation. Thus Raf-1 is actually mitogen activated protein kinase kinase kinase (sort of like the character in Catch-22 named Junior Junior Junior). (1/06 — I think that Raf-1 is now called BRAF)

8. The final step in the pathway is activation of transcription factors (which turn genes off or on) by MAP kinases by (what else) phosphorylation. Thus the pathway from cell surface is complete.

Internal Energy, Enthalpy, Helmholtz free energy and Gibbs free energy are all Legebdre transformations of each other

Sometimes it pays to be persistent in thinking about things you don’t understand (if you have the time as I do). The chemical potential is of enormous interest to chemists, and yet is defined thermodynamically in 5 distinct ways. This made me wonder if the definitions were actually describing essentially the same thing (not to worry they are).

First, a few thousand definitions

Chemical potential of species i — mu(i)
Internal energy — U
Entropy — S
Enthalpy — H
Helmholtz free energy — F or A (but, maddeningly, never H)
Gibbs free energy — G
Ni — number of elements of chemical species i
Pressure — p
Volume — V
Temperature — T

Just 5 more
mu(i) == ∂H/∂Ni constant S, p
mu(i) == ∂S/∂Ni constant U, V
mu(i) == ∂U/∂Ni constant S, V
mu(i) == ∂F/∂Ni constant T, V
mu(i) == ∂G/∂Ni constant T, p

Clearly, at a given constellation of S, U, F, G the mu(i)’s won’t all be the same number, but they’re essentially the same thing. Here’s why.

Start with a simple mathematical problem. Assume you have a simple function (f) of two variables (x,y), and that f is continuous in x and y and that its partial derivatives u = ∂f/∂x and w = ∂f/∂y are continuous as well so you have

df = u dx + w dy

u and dx are conjugate variables, as are w and dy

Suppose you want to change df = u dx + w dy to

another function g such that

dg = u dx – y dw

which is basically flipping a pair of conjugate variables around

Patience, the reason for wanting to do this will become apparent in a moment.

The answer is to use what is called the Legendre transform of f which is simply

g = f – y w

dg = df – y dw – w dy

plug in df

dg = u dx + w dw – y dw – w dy == df – y dw – w dy Done.

Where does the thermodynamics come in?

Well, you have to start somewhere, so why not with the fundamental thermodynamic equation for internal energy U

dU = ∂U/∂S dS + ∂U/∂V dV + ∑ ∂U/∂Ni dNi

We already know that ∂U/Ni = mu(i)

Because of the partial derivative notation (∂) it is assumed that all the other variables say in the expression for dU e.g. V and Ni are held constant in ∂U/∂S. This will reduce the clutter in notation which is already cluttered enough.

We already know that ∂U/∂Ni is mu(i). One definition of temperature T, is as ∂U/∂S, and another for p is -∂U/∂V (which makes sense if you think about it — decreasing volume relative to U should increase pressure).

Suddenly dU looks like what we were talking about with the Legendre transformation.

dU = T dS – p dV + ∑ mu(i) dNi

Apply the Legendre transformation to U to switch conjugate variables p and V

H = U + pV ; looks suspiciously like enthalpy (H) because it is

dH = dU + p dV + V dp + ∑ mu(i) dNi

= T dS – p dV + ∑ mu(i) dNi + p dV + V dp

= T dS + V dp + ∑ mu(i) dNi

Notice how mu(i) here comes out to ∂H/dNi at constant S and P

Start with the fundamental thermodynamic equation for internal energy

dU = T dS – p dV + ∑ mu(i) dNi

Now apply the Legendre transformation to T and S and you get
F = U – TS ; looks like the Helmholtz free energy (sometimes written A, but never as H) because it is.

You get

dF = – S dT – p dV + ∑ mu(i) dNi

Who cares? Chemists do because, although it is difficult to hold U constant or S constant (and it is impossible to measure them directly) it is very easy to keep temperature and volume constant in a reaction, meaning that changes in Helmholtz free energy under those conditions is just
∑ mu(i) dNi. So here mu(i) = ∂F/∂Ni at constant T and p

If you start with enthalpy

dH = T dS + V dp + ∑ mu(i) dNi

and do the Legendre transform you get the Gibbs free energy G = H – TS

I won’t bore you with it but this gives you the chemical potential mu(i) at constant T and p, conditions chemists easily arrange all the time.

To summarize

Enthalpy (H) is one Legendre transform of internal energy (U)
Helmholtz free energy (F) is another Legendre transform of U
Gibbs free energy (G) is the Legendre transform of Enthalpy (H)

It should be clear that Legendre transforms are all reversible

For example if H = U + PV then U = H – PV

If you think a bit about the 5 definitions of chemical potential, you’ll see that it can depend on 5 things (U, S, p, V and T). Ultimately all thermodynamic variables (U, S, H, G, F, p, V, T, mu(i) ) often have relations to each other.

Examples include H = U + pV, F = U – TS, G = H -TS

Helping keep things clear are equations of state from the things you can easily measure (p,V, T). The most famous is the ideal gas law p V = nRT.

Back from the 50th Med School Reunion

Mostly some social notes from my 50th Med School reunion (Penn), but first some serious science.

I did two years of graduate work in chemistry between college and med school, and one of the guys I taught organic to is an academic research neurologist. He told me that they had some encouraging results using antisense oligonucleotides to remove the excessive repeat CTGs from myotonin, the gene defective in myotonic dystrophy. They were able to get it into cells, and even showed some clinical benefit in animal models. So he’s still using chemistry.

Myotonic dystrophy is one of the few triplet expansion diseases that makes sense to me, because unlike most of them, it affects a wide variety of tissues, not just the nervous system.

Just about everyone had a great time at the reunion. On entering med school I was told, that I’d know my classmates better than my spouse. Well, I certainly spent more time with them in the clinical years.

It was a happy time and yet sad as well, as we all knew that this was probably the last time we’d all see each other.

The previous post https://luysii.wordpress.com/2016/05/11/off-to-the-50th/ had a lot about (the lack of) minority representation back then.

Things have improved, as there is now an office of diversity (so Penn is now doing more than paying hypocritical lip service to it — vide Elizabeth Warren).

Our Nigerian classmate came back. He’d spent 17 years back home in Africa but left because he was unable to fight the corruption there, even as a native son. He hassled a black medical student from Africa, finding that she was of the Yoruba tribe, telling her to go back and serve her country (at least for a while).
So things have improved, but not enough. An an affair Friday night, all 5 or so of the blacks present were sitting at the same table. I barged in saying I was bringing some diversity to their table, and initially got some strange looks. But then I told them a few of the events of the previous post and they warmed up. At least the country is  now getting the benefit of their brains.

We’ll know things have really improved, when black physicians feel comfortable enough to mingle with the crowd.

About 65 of the 125 of us were back. Only 18 people were listed as having died, which seems like a very small number for a group of 125 26 year olds 50 years later. I do know of one unreported death of a classmate from AIDS.

This is actually nothing new — and here are my notes on a study done nearly 30 years ago. My speculation is that, docs get a lot of reinforcement, seeing the effects of negative health choices. I doubt that all of it is due to social or economic class, although some must be.

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[ J. Am. Med. Assoc. vol. 259 p. 3158 ’88 ] This is an overview of the Physicians’ Health study in which 22,000 American physicians took either aspirin or placebo in a double blind study. They were only taking 5 grains of aspirin every other day. Cardiovascular mortality was cut, but overall mortality was not. However the group experienced just 88 deaths when 733 would have been expected. . This may be due to a beneficial life style, or social class. Thus the EIGHTFOLD lower mortality throughout makes the study harder to interpret. Amazingly, the authors of the study don’t really focus on why the study group (even those on placebo) did so well, but whether the aspirin added anything extra. What we need is to reduce mortality in our patients eightfold and then worry about giving aspirin.

****

Here is a tale of the bad old days for the feminists among you. There were under 10 women in our class of 125. One very bright woman wanted to be a surgeon. She asked Dr. Everett Koop about it. This was when Koop was basically inventing the specialty of pediatric surgery at Children’s Hospital of Philadelphia (CHOP), and long before he became Surgeon General.

He gave her some very hard and very honest advice (this was Koop after all). He told her that the first rate surgery residencies simply were not accepting women. To rise to the true level of her ability, she’d need to choose something else. She didn’t like this one bit, but did follow his advice, went into another field and became department chair at another Ivy League med school.

Lastly two stories about the All American basketball player in our Class (Jerry Gardner Kansas ’62). He’s about 6′ 2″ now, and using a cane as he’d had hip surgery a few months ago. He did note that back then Freshman weren’t allowed to play, so he still has a year of eligibility left. Jerry went to NIH after graduation and established a lab studying GI hormones.

Further proving that time does not heal all wounds, Jerry reminisced about the two foul shots he missed at the tail end of a game in the NCAA final (or semifinal) which might have won them the game. For further examples of the phenomenon see — https://luysii.wordpress.com/2010/10/25/time-does-not-heal-all-wounds/

Off to the 50th

No posts for a while as I’ll be going to my 50th Med School Reunion (Penn ’66) tomorrow. If there is a creator, he has a fairly sardonic sense of humor

Here’s why.

I arrived in the fall of ’62 having spent 2 years as a grad student in the Harvard Chemistry department (Woodward the last year or so), quite full of myself. The biochemistry (and chemistry) being taught at Penn was quite primitive compared to what I’d been exposed to, and I was a fairly obnoxious prick about it.

How could I have known that classmate (Mike Brown) would win a Nobel for his work on the LDL receptor which led to the statins. The work involved some fairly brilliant chemistry (particularly on regulated intramembrane proteolysis). I hope he doesn’t remember me when we meet, but he probably will.

In defense, although none of us knew it at the time, the Harvard Chemistry department back then was probably one of the greatest in world history. Here’s why. There were 7 future Nobel laureates in the department when I was there from ’60 to ’62 — Woodward, Corey, Lipscomb, Bloch, Herschbach, Gilbert and Karplus. Even better, these guys weren’t sitting on their laurels having already won, but were engaged in doing the work which won them the  Nobels.

But there are far more issues to address at Penn than just this. Here’s a copy of an old post —

Two American (social) tragedies

When the team members entered the clinic, they were appalled, describing it to the Grand Jury as ‘filthy,’ ‘deplorable,’ ‘disgusting,’ ‘very unsanitary, very outdated, horrendous,’ and ‘by far, the worst’ that these experienced investigators had ever encountered. There was blood on the floor. A stench of urine filled the air. A flea-infested cat was wandering through the facility, and there were cat feces on the stairs. Semi-conscious women scheduled for abortions were moaning in the waiting room or the recovery room, where they sat on dirty recliners covered with blood-stained blankets. All the women had been sedated by unlicensed staff – long before Gosnell arrived at the clinic – and staff members could not accurately state what medications or dosages they had administered to the waiting patients. Many of the medications in inventory were past their expiration dates… surgical procedure rooms were filthy and unsanitary… resembling ‘a bad gas station restroom.’ Instruments were not sterile. Equipment was rusty and outdated. Oxygen equipment was covered with dust, and had not been inspected. The same corroded suction tubing used for abortions was the only tubing available for oral airways if assistance for breathing was needed…”[29]
[F]etal remains [were] haphazardly stored throughout the clinic– in bags, milk jugs, orange juice cartons, and even in cat-food containers… Gosnell admitted to Detective Wood that at least 10 to 20 percent… were probably older than 24 weeks [the legal limit]… In some instances, surgical incisions had been made at the base of the fetal skulls. The investigators found a row of jars containing just the severed feet of fetuses. In the basement, they discovered medical waste piled high. The intact 19-week fetus delivered by Mrs. Mongar three months earlier was in a freezer. In all, the remains of 45 fetuses were recovered … at least two of them, and probably three, had been viable.”

A classic back alley abortion mill, except that it was all quite legal.

This wasn’t supposed to happen after Roe vs. Wade. It is so uncanny that the doc (Kermit Gosnell) convicted yesterday of these 3 infanticides graduated from a med school in Philly (Jefferson) the same year (1966) that I graduated from another (Penn). At the time Philly had 3 more (Hahnemahn, Women’s and Temple).

What is so socially tragic about Gosnell, is that he was one of very few blacks in medical school back then. Our class of 125 at Penn had one, but he was a Nigerian Prince. Whether Gosnell liked it or not he was a standard bearer for what we hoped (at the time) was the wave of the future (it was). For just how very few Blacks were being educated at elite institutions back then please see

https://luysii.wordpress.com/2012/05/22/warren-harvard-and-penn-sanctimony-hypocrisy-and-fraud/ — copy to be found below

The second tragedy is a black woman M. D twenty or so years younger (Harvard undergrad, Penn Med followed by an MBA from Wharton) who lost her license to practice in NY State after she went off the deep end and became a holistic practioner (or whatever). She treated a new onset juvenile diabetic with diet and juice after which he came to the ER in diabetic ketoacidosis with a sugar over 300.

My father was an attorney as was my uncle, later a judge. They took it very personally when an attorney was disbarred for some malfeasance or another. I feel the same way when this happens to an M. D. Imagine how the black docs must feel about Gosnell, or the idiot, Conrad Murray, who basically killed Michael Jackson with Diprivan.

If you didn’t follow the link, I’ll close with a more uplifting ending from it.

My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist, having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references her cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents and grandparents of today’s black MDs, Attorneys, teachers etc. etc. were likely just as intelligent as their offspring of today. This country certainly pissed away an awful lot of brains of their generations.

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Warren, Harvard and Penn — Sanctimony, Hypocrisy and Fraud

I find the behavior of Elizabeth Warren, Harvard and Penn incredibly disturbing and sad. It’s the perfect storm of sanctimony, hypocrisy and fraud. I imagine that I’m a lot older than the readership, so let’s revisit the bad old days of the 50’s and 60s to see how things were back then and why the behavior of all three besmirches heroic attempts to set things right.

Fall 1956: Enter Princeton along with 725+ others. The cast of characters included about 5 Asians, 1 Indian Asian, no hispanics and/or latinos as I recall, and all of 2 blacks. I was the first to attend from a small (212 kids in 4 grades) NJ High School. I’d never been west of Philly, and immediately appreciated what passed for diversity back then — a roommate from Florida, and 2 guys next door from Wisconsin and Tennessee, the four of us packed like sardines into two miniscule rooms (each of which is now a single).

Although my High School was above the Mason Dixon line, there was only 1 black student in all 4 classes when I was there. A 2nd cousin who graduated 6 years before I entered, noted that there were NO blacks when she was there and asked why, and was told “we don’t encourage them to attend”. To be fair, there were very few black families in the area.

So, because we were musicians, and in the marching band, I got to know one of the blacks. At away games there were postgame parties (what’s the point of having games after all?). Girls would come up to Harvey and tell him that he must meet Virginia, she’s wonderful. etc. etc. Virginia being the black girl at their school, as Harvey was the black boy at ours. There was no condescension involved, and I never saw anyone at Princeton give Harvey a hard time, and we had plenty of southerners. It was the way things were, and we had no idea that things could be different.

Spring 1958: Back at the H. S. The one black girl in the class 2 years behind me was very smart. She graduated as the Salutatorian. However, she should have been the Valedictorian, the powers that be having decided that it wouldn’t do to have a black in that position. That didn’t stop her of course. The high school was so small that it was folded into a regional H. S. the next year. So our little school has reunions every 5 years or so for anyone who ever went there, and I saw her 40 – 50 years later. She’d become a very high powered R. N. with a very responsible position.

Fall 1960: Harvard Chemistry department. Not a black, not a latino, not an Asian to be found in the grad school (there was one Sikh). I don’t recall seeing any as undergraduates. There were a fair number of Japanese, and Asian Indian postdocs however. Fast forward to the present for what it looks like now — https://luysii.wordpress.com/2012/04/19/the-harvard-chemistry-department-reunion-part-i/.

Fall 1962: Entering Penn Med school — 125 students, one black (a Nigerian) no latinos/hispanics, no asians of any sort, under 10 women. They really can’t be blamed for this, the pipeline was empty.

Summer 1963: Visiting my wife to be at her home in Alexandria Virginia. A drive perhaps 10 – 20 miles south toward Richmond finds restaurants with Colored entrances.

2008: My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references the cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents (grandparents) of today’s blacks , are likely just intelligent as their MD, Attorney, teacher etc. etc. offspring today. This country certainly pissed away an awful lot of brains of these generations. So clearly, I’m all for letting the best into our elite institutions whatever they look like.

This is why Warren, and the behavior of Harvard and Penn is such a perversity.

First the sanctimony. Many at Harvard think they are head, neck and groin above you in every sense, intellectual and moral. Do not think for a minute that their previous rejection of a military presence on campus had anything to do with the military’s treatment of gays. It was a cover for their antiwar and antimilitary agenda (present when I was there ’60 -’62 long before Vietnam). They were what my father called “Bible-backed Bastards”, using scripture as cover for what they wanted to do.

Second and Third. That Warren would claim to be Indian and that Penn and Harvard would tout her as evidence of their commitment to diversity, is hypocritical in the extreme and fraudulent as well.

Well, it’s just another scam.like all the rest. Isn’t it? We’ve got State Troopers sitting on their ass in their cars with lights flashing on the Mass. Pike at construction sites. We’ve got politically connected drones handing out tickets on the Pike standing next to machines which do the job when they’re not around. No one seems to mind. It may be one of the reasons unenlightened Florida and Texas grew faster in the last 10 years and acquired one of our representatives (along with 5 more from NY, NJ, Illinois and Pennsylvania).

But it isn’t like the rest. It perverts something the country desperately needed to do and gives arms to those opposing it. Ironic that it wasn’t done by rednecks, but by the very institutions that led the charge.

I hope the powers that be at Penn don’t cluck about diversity at the reunion,  but if they do I plan to find my inner obnoxious prick again.

Spot the flaw

Mathematical talent varies widely. It was a humbling thing a few years ago to sit in an upper level college math class on Abstract Algebra with a 16 year old high school student taking the course, listening with one ear while he did his German homework. He was later a double summa in both math and physics at Yale. So do mathematicians think differently? A fascinating paper implies that they use different parts of their brain doing math than when not doing it. The paper has one methodological flaw — see if you can find it.

[ Proc. Natl. Acad. Sci. vol. 113 pp. 4887 – 4889, 4909 – 4917 ’16 ] 15 expert mathematicians and 15 nonMathematicians with comparable academic qualifications were studied (3 literature, 3 history 1 philosophy 2 linguistics, 1 antiquity, 3 graphic arts and theater 1 communcation, 1 heritage conservation — fortunately no feminist studies). They had to listen to mathematical and nonMathematical statements and decide true false or meaningless. The nonMathematical statements referred to general knowledge of nature and history. All this while they were embedded in a Magnetic Resonance Imager, so that functional MRI (fMRI) could be performed.

In mathematicians there was no overlap of the math responsive network (e.g. the areas of the brain activated by doing math) with the areas activated by sentence comprehension and general semantic knowledge.

The same brain networks were activated by all types of mathematical statement (geometry, analysis, algebra and topology) as opposed to nonMathematical statement. The areas activated were the dorsal parietal, ventrolateral temporal and bilateral frontal. This was only present in the expert mathematicians (and only to mathematical statements) These areas are outside those associated with language (inferior frontal gyrus of the left hemisphere). The activated areas are also involved in visual processing of arabic numbers and simple calculation. The activated areas in mathematicians were NOT those related to language or general knowledge.

So what’s wrong with the conclusion? The editorialist (pp. 4887 – 4889) pointed this out but I thought of it independently.

All you can say is that experts working in their field of expertise use different parts of their brain than they use for general knowledge. The nonMathematicians should have been tested in their field of expertise. Shouldn’t be hard to do.

A Touching Mother’s Day Story

Yes, a touching mother’s day story for you all. It was 49 years ago, and I was an intern at a big city hospital on rotation in their emergency room. The ER entrance was half a block from an intersection with a bar on each corner. On a Saturday night, we knew better than to try to get some sleep before 2AM or until we’d put in 2 chest tubes (to drain blood from the lungs, which had been shot or stabbed). The bartenders were an intelligent lot — they had to be quick thinking to defuse situations, and we came to know them by name. So it was 3AM 49 years ago and Tyrone was trudging past on his way home, and I was just outside the ER getting some cool night air, things having quieted down.

“Happy Mother’s day, Tyrone” sayeth I

“Thanks Doc, but every day is Mother’s day with me”

“Why, Tyrone?”

“Because every day I get called a mother— “

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