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Book idea proposal

While up in Nova Scotia (where the people are as friendly as midwesterners) on vacation reading Feynman I got an idea for a book.  Unfortunately, I don’t think anyone has the breadth of knowledge of physics that Feynman did, so no single person can write it.

Remember that the Feynman lectures were delivered in 1963 – 4.  The authors of the Millennium edition noted that > 1,000 errors were corrected in the various editions (which is a good reason to buy it, if you’re studying it on your own).  But almost none of them were conceptual.

So the lectures are  true as of 1964 and brilliant to boot.  As Kip Thorne notes in “Modern Classical Physics”  — “The three-volume Feynman Lectures on Physics had a big influence on several generations of physicists and even more so on their teachers.Both of us (Blandford and Thorne) are immensely indebted to Richard Feynman for shaping our own approaches to physics”.

The idea for the book came as early as p. 2-7 in Volume I, where Feynman says “no phenomenon directly involving a frequency has yet been detected above approximately 10^12 cycles per second”.  Well we’re up to 10^18 presently and shooting higher.

p 3-5 “all enzymes are proteins.”  Not so and a Nobel was won for the first RNA enzyme to be discovered.

p. 7 – 7  What is holding galaxies together — a mention of dark matter would be interesting.

p. 9 – 9 “A very good computing machine may take 1 microsecond to do an addition”  — we’re up to 10^18 exaFlops (of floating point calculations) not addition.

Well you get the idea.  I have no idea what the size of the market would be, but I’d love to see something like this.

Something similar was actually done with the Origin of Species.  Darwin’s Ghost by Steve Jones (published in 1999) updates Darwin’s book, the Origin of Species (published 1999)  to contemporary thinking (and knowledge) chapter by chapter.   It is fascinating to go through both together.

The book would be one of the few things better done by a committee

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Off to Nova Scotia

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

Feynman and Darwin

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

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

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

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

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

‘Happy Fourth of July to the world’s worst economist — Paul Krugman

Stocks closed at record highs Wednesday as traders bet on a potential rate cut from the Federal Reserve later this month after the release of weaker-than-expected economic data.The Dow gained 179 points, notching intraday and closing all-time highs. The Nasdaq advanced 0.75%.The S&P 500 also rose 0.75% as the real estate and consumer sectors powered the broad index to record levels. Tech boosted the index, rising 0.7% to a record high. The S&P 500 closed just 0.1% below 3,000.

 

 

 

 

 

 

Here is Paul Krugman Nobel Laureate in Economics writing in the New York Times 9 November 2016, the day after Trump was elected

“It really does now look like President Donald J. Trump, and markets are plunging. When might we expect them to recover?

Frankly, I find it hard to care much, even though this is my specialty. The disaster for America and the world has so many aspects that the economic ramifications are way down my list of things to fear.

Still, I guess people want an answer: If the question is when markets will recover, a first-pass answer is never.

Under any circumstances, putting an irresponsible, ignorant man who takes his advice from all the wrong people in charge of the nation with the world’s most important economy would be very bad news. What makes it especially bad right now, however, is the fundamentally fragile state much of the world is still in, eight years after the great financial crisis.

It’s true that we’ve been adding jobs at a pretty good pace and are quite close to full employment. But we’ve been doing O.K. only thanks to extremely low interest rates. There’s nothing wrong with that per se. But what if something bad happens and the economy needs a boost? The Fed and its counterparts abroad basically have very little room for further rate cuts, and therefore very little ability to respond to adverse events.

Now comes the mother of all adverse effects — and what it brings with it is a regime that will be ignorant of economic policy (Luysii — praise be to God) and hostile to any effort to make it work. Effective fiscal support for the Fed? Not a chance. In fact, you can bet that the Fed will lose its independence, and be bullied by cranks.

So we are very probably looking at a global recession, with no end in sight. I suppose we could get lucky somehow. But on economics, as on everything else, a terrible thing has just happened.”

If that wasn’t enough here’s Krugman in 2010 writing about ‘peak oil

“Oil is back above $90 a barrel. Copper and cotton have hit record highs. Wheat and corn prices are way up. Over all, world commodity prices have risen by a quarter in the past six months.

So what’s the meaning of this surge?

Is it speculation run amok? Is it the result of excessive money creation, a harbinger of runaway inflation just around the corner? No and no.

What the commodity markets are telling us is that we’re living in a finite world, in which the rapid growth of emerging economies is placing pressure on limited supplies of raw materials, pushing up their prices. And America is, for the most part, just a bystander in this story.

Some background: The last time the prices of oil and other commodities were this high, two and a half years ago, many commentators dismissed the price spike as an aberration driven by speculators. And they claimed vindication when commodity prices plunged in the second half of 2008.

But that price collapse coincided with a severe global recession, which led to a sharp fall in demand for raw materials. The big test would come when the world economy recovered. Would raw materials once again become expensive?

Well, it still feels like a recession in America. But thanks to growth in developing nations, world industrial production recently passed its previous peak — and, sure enough, commodity prices are surging again.

This doesn’t necessarily mean that speculation played no role in 2007-2008. Nor should we reject the notion that speculation is playing some role in current prices; for example, who is that mystery investor who has bought up much of the world’s copper supply? But the fact that world economic recovery has also brought a recovery in commodity prices strongly suggests that recent price fluctuations mainly reflect fundamental factors.

What about commodity prices as a harbinger of inflation? Many commentators on the right have been predicting for years that the Federal Reserve, by printing lots of money — it’s not actually doing that, but that’s the accusation — is setting us up for severe inflation. Stagflation is coming, declared Representative Paul Ryan in February 2009; Glenn Beck has been warning about imminent hyperinflation since 2008.

Yet inflation has remained low. What’s an inflation worrier to do?

One response has been a proliferation of conspiracy theories, of claims that the government is suppressing the truth about rising prices. But lately many on the right have seized on rising commodity prices as proof that they were right all along, as a sign of high overall inflation just around the corner.

You do have to wonder what these people were thinking two years ago, when raw material prices were plunging. If the commodity-price rise of the past six months heralds runaway inflation, why didn’t the 50 percent decline in the second half of 2008 herald runaway deflation?

Inconsistency aside, however, the big problem with those blaming the Fed for rising commodity prices is that they’re suffering from delusions of U.S. economic grandeur. For commodity prices are set globally, and what America does just isn’t that important a factor.

In particular, today, as in 2007-2008, the primary driving force behind rising commodity prices isn’t demand from the United States. It’s demand from China and other emerging economies. As more and more people in formerly poor nations are entering the global middle class, they’re beginning to drive cars and eat meat, placing growing pressure on world oil and food supplies.

And those supplies aren’t keeping pace. Conventional oil production has been flat for four years; in that sense, at least, peak oil has arrived. True, alternative sources, like oil from Canada’s tar sands, have continued to grow. But these alternative sources come at relatively high cost, both monetary and environmental.

Also, over the past year, extreme weather — especially severe heat and drought in some important agricultural regions — played an important role in driving up food prices. And, yes, there’s every reason to believe that climate change is making such weather episodes more common.

So what are the implications of the recent rise in commodity prices? It is, as I said, a sign that we’re living in a finite world, one in which resource constraints are becoming increasingly binding. This won’t bring an end to economic growth, let alone a descent into Mad Max-style collapse. It will require that we gradually change the way we live, adapting our economy and our lifestyles to the reality of more expensive resources.

But that’s for the future. Right now, rising commodity prices are basically the result of global recovery. They have no bearing, one way or another, on U.S. monetary policy. For this is a global story; at a fundamental level, it’s not about us.  ”

Nonetheless Krugman can currently be found on the editorial pages of the New York Times authoritatively pronouncing on matters political

For the world’s second worse economist please see https://luysii.wordpress.com/2019/07/04/happy-4th-of-july-to-the-worlds-second-worst-economist-larry-summers/

Stock tip — update

The FDA approved esketamine (Spravato) last week (see copy of original post at the end).  I had recommended buying Johnson and Johnson if the FDA approved it.  I think it’s a good long term buy, but there is no rush for the following reason — Esketamine is not a drug you can get a prescription for and take on you own. Because of the psychiatric side effects it must be administered in a SPRAVATO REMS.

Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO™ is available only through a restricted program called the SPRAVATO™ REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.

Important requirements of the SPRAVATO™ REMS include the following:

  • Healthcare settings must be certified in the program and ensure that SPRAVATO™ is:
    • Only dispensed in healthcare settings and administered to patients who are enrolled in the program.
    • Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO™.
  • Pharmacies must be certified in the REMS and must only dispense SPRAVATO™ to healthcare settings that are certified in the program.

So you can’t go to some shady practitioner who’ll say you have treatment resistant depression and get some (e.g. the pill pushers for opiates, ‘medical’ marihuana  etc. etc.)

So there aren’t going to be hordes of users right away, although the stuff I’ve read implies that there will be eventually.

If you have a subscription to Cell have a look at vol. 101 pp. 774 – 778 ’19 by the guys at Yale who did some of the original work.  If not content yourself with this.

They are refreshingly honest.

Was the Discovery of Ketamine’s Antidepressant Serendipitous?Of course. However, its discovery emerged from the testing of a novel mechanistic hypothesis related to the pathophysiology of depression.”

Basically the authors rejected the regnant theory of depression, namely that the cause was to be found in monoamine neurotransmission (e.g. by dopamine, norepinephrine, serotonin).  There was some evidence that the cerebral cortex was involved in depression (not just the monamine nuclei of the brainstem), so they looked at the two major neurotransmitters in brain (glutamic acid, and GABA), and chose to see what would happen if they blocked one of the many receptors for glutamic acid, the NMDA receptor.  They chose ketamine to do this.
Here’s what they found,  A single dose of ketamine produced antidepressant effects that began within hours peaked in 24 – 72 hours and dissipated within 2 weeks (if ketamine wasn’t repeated).  This was in 50 – 75% people with treatment resistant depression.  Remarkable 1/3 of treated patients went into remission.    There simply has never been anything like this, which is why I thought the drug would be a blockbuster.
There is a lot of speculation about just which effect of esketamine is crucial (increase in glutamic acid release with AMPAR stimulation, brain derived neurotrophic factor (BDNF) release, TrkB receptor stimulation, mTORC1 activation, local protein synthesis, restoration of functional connectivity in functional MRI.   In animals one sees a rapid proliferation of dendritic spines.
As promised – here’s a copy of the first post

Stock tip

The past performance of stock recommendations is no guarantee that it will continue — which is fortunate as my first tip (ONTX) was a disaster.  I knew it was a 10 to one shot but with a 100 to 1 payoff.  People play the lottery with worse odds.  Anyway ONTX had a rationale — for the gory details see — https://luysii.wordpress.com/2016/06/01/in-a-gambling-mood/

For those brave souls who followed this recommendation (including yours truly) here’s another.

On 4 March 2019 if the FDA approves esketamine for depression, buy Johnson and Johnson.  Why?  Some people think that no drug for depression works that well, as big Pharma in the past only was reporting positive studies.  The following is from Nature 21 February 2019.

Depression drug A form of the hallucinogenic party drug ketamine has cleared one of the final hurdles towards clinical use as an antidepressant. During a 12 February meeting at the US Food and Drug Administration (FDA) in Silver Spring, Maryland,an independent advisory panel voted 14 to 2 in favour of recommending a compound known as esketamine for use in treating depression.

What’s so hot about esketamine?  First its mechanism of action is completely different than the SSRIs, Monoamine oxidase inhibitors, or tricyclic antidepressants.

As you likely know, antidepressants usually take a few weeks to work at least in endogenous depression.  My clinical experience as a neurologist is slightly different, as I only used it for patients with disease I couldn’t help (end stage MS etc. etc.) where the only normal response to the situation was depression.  They often helped patients within a week.

I was staggered when I read the following paper back in the day.  But there was no followup essentially.

archives of general psychiatry volume 63 pp. 856 – 864 2006
The paper is not from St. Fraudulosa Hospital in Plok Tic, but from the Mood Disorders Research Unit at the National Institute of Mental Health.
Here are the basics from the paper

Patients  Eighteen subjects with DSM-IV major depression (treatment resistant).

Interventions  After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.

Main Outcome Measure  Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

Results  Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

Read this again: showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week.

This is absolutely unheard of.  Yet the paper essentially disappeared.

What is esketamine?  It’s related to ketamine (a veterinary anesthetic and drug of abuse) in exactly the same way that a glove for your left hand is related to a right handed glove.  The two drugs are optical isomers of each other.

What’s so important about the mirror image?  It means that esketamine may well act rather differently than ketamine (the fact that ketamine worked is against this).  The classic example is thalidomide, one optical isomer of which causes horrible malformations (phocomelia) while the other is a sedative used in the treatment of multiple myeloma and leprosy.

If toxic side effects can be avoided, the market is enormous.  It is estimated that 25% of women and 10% of men will have a major depression at some point in their lives.

Initially, Esketamine ( SPRAVATOTM)  will likely be limited to treatment resistant depression.  But depressed people will find a way to get it and  their docs will find a way to give it.  Who wants to wait three weeks.  Just think of the extremely sketchy ‘medical indications’ for marihuana.

The Impeachment Trial of President Tester 2027

It’s almost Christmas. Time for some R&R. Here’s another science fiction story for the cognoscenti, which assumes you have some scientific chops.  Not all will be explained.

After the Taiwanese biologic agent turned the world’s armed forces into pacifists, you’d think that the end of history had arrived. For how this happened see the first story — https://luysii.wordpress.com/2018/11/19/a-science-fiction-story-for-the-cognoscenti-answer-to-the-puzzle-and-a-bit-morea-science-fiction-story-for-the-cognoscenti/.

Well, thought all sorts of garage molecular biologists, maybe humanity could be further improved, or those not of the right sort eliminated.   The Syrians learned this the hard way creating a biologic agent which attacked Jews, not realizing that Syrians were closer genetically to them than anyone else [ Proc. Natl. Acad. Sci. vol. 97 pp. 6769 – 6774 ’00 ].  The Israeli’s saw this coming and had a defense ready.   The midEast became a lot quieter.

The touchy feely types thought of other ways to improve humanity, particularly a group of vegetarian molecular biologists at Montana State University.

You probably thought of Montana State in Bozeman as Moo U, where the sons of the soil achieved a rudimentary education.  After Jon Tester was elected president in 2024, a lot of money was poured in.  Sophisticates were appalled that Tester made it after Trump.  They should have known better– the US has elected a peanut farmer, someone from Dogpatch, a broken down actor making movies with a chimp, and the ever appalling Donald Trump.

Actually as far back as the 70s Montana had a state legislator (Kenneth Nortvedt) Junior Fellow at Harvard writing papers on alternate theories of gravity.  Biologic research was alive in Montana since 1928 at Rocky Mountain Labs in Hamilton and still kicking with prion work as of 2015 — http://klyq.com/prion-disease-study-at-hamilton-lab-is-published-youtube/.

So what happened?  Have you ever heard of the Lone Star Tick?  https://acaai.org/allergies/types/food-allergies/types-food-allergy/meat-allergy.  A single bite can make you allergic to meat.  Your body’s immune response to a tick antigen, must also in some way react with meat, the same way that the response to strep infection can sometimes cross react with the heart causing rheumatic fever.

At first it was thought that the tick injected galactose linked (alpha 1 –> 3 )to galactose, but that was quickly debunked when taking alpha-galactosidase (available at your friendly local health food store) didn’t work.

Montana attracts all sorts of people, ranging from rugged individualists to touchy feely types and points between.  There’s plenty of room out there (more cows than people at last count) so the dominant zeitgeist is live and let live.  The one unforgivable sin is putting on airs or bragging.

Thus it came to pass in the year 2025 (anno Tester #1) when the federal funding spigot was turned full force on MSU that a group of smart vegetarians from Portland Oregon overcame their scruples about living in a land whose major function was producing meat, and wound up in the newly formed Mike Mansfield department of molecular genetics at MSU.

Basically they knocked out gene after gene in the tick and looked at what disappeared in the secretions of the tick as it bit.  There were plenty of glycoproteins some of which had galactose.  It was child’s play to isolate and sequence the gene.

By this time the technology to put any protein coding gene in adeno-associated virus (AAV) and infect people was well advanced.  So they experimented on themselves, injecting virus after virus, forcing themselves to swallow their scruples as well as meat and seeing which of the tick’s proteins made them ill when they did.

The rest is history.  The virus spread quickly and suddenly no one could eat beef or pork.  The ranching industry in Montana and elsewhere died.  Ecologists rejoiced that the prairie was no longer grazed.

A group of bankrupt ranchers from all over the state (and a few from Wyoming) invaded the lab and killed every scientist there.

They were not tried in Montana, as no one would convict them, instead being tried in Vermont (Birkenstock country) and sent to prison for life.

Which brings us to the Impeachment trial of President Tester.

Can you guess what it was for?  Answer next year.

In the meantime, a very Merry Christmas and Happy New Year to all

 

How art and science differ

The difference between art and science was really brought home to me on a visit to a museum on our recent trip to Venice.  I’d never heard about the Memphis Group of artists before — https://en.wikipedia.org/wiki/Memphis_Group.  They mostly made wacky looking furniture, as a revolt against the austere Bauhaus style –https://en.wikipedia.org/wiki/Bauhaus.   Back in the day, people living in the Harvard Law dorms Gropius (one of the Bauhaus founders) designed hated them as unlivable.  Similarly one can regard Pop art as a revolt against abstract expressionism, impressionism as a revolt against classicism, etc. etc.   The very notion of progress and building on the past is antithetical.

Science also produces a succession of theories, but they build on previously successful theories extending and incorporating them.  Special and general relativity subsume Newtonian mechanics, Maxwell’s laws merge electricity and magnetism.  Current molecular biology extends the classic dogma of the 60s and 70s — DNA makes RNA makes protein.  None of the older theories are rejected just improved.

So progress is inherent to the scientific enterprise, and is unheard of in the arts.  In one sense the arts are closer to the creative destruction of capitalism than its practitioners would like to admit.

I’ll be back to writing more scientific posts shortly, but here’s a question to be answered in a later post.

What extremely famous artist, spent more of his life as a mechanical and military engineer than as an artist?

 

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.

A pile of spent bullets — take II

I can tell you after being in neurology for 50 years that back in the day every microscopic inclusion found in neurologic disease was thought to be causative.  This was certainly true for the senile plaque of Alzheimer’s disease and the Lewy body of Parkinsonism.  Interestingly, the protein inclusions in ALS weren’t noticed for decades.

However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell, a marker for the cause of death rather than the cause itself.

An earlier post concerned work that implied that the visible aggregates of alpha-synuclein in Parkinson’s disease were protective rather than destructive — https://luysii.wordpress.com/2018/01/07/are-the-inclusions-found-in-neurologic-disease-attempts-at-defense-rather-then-the-cause/.

Comes now Proc. Natl. Acad. Sci. vol. 115 pp. 4661 – 4665 ’18 on Superoxide Dismutase 1 (SOD1) and ALS. Familial ALS is fortunately less common than the sporadic form (under 10% in my experience).  Mutations in SOD1 are found in the familial form.  The protein contains 153 amino acids, and as 6/16 160 different mutations in SOD1 have been found.  Since each codon can contain only 3 mutations from the wild type, this implies that, at a minimum,  53/153 codons of the protein have been mutated causing the disease.  Sadly, there is no general agreement on what the mutations actually do — impair SOD1 function, produce a new SOD1 function, cause SOD1 to bind to something else modifying that function etc. etc.  A search on Google Scholar for SOD1 and ALS produced 28,000 hits.

SOD1 exists as a soluble trimer of proteins or the fibrillar aggregate.   Knowing the structure of the trimer, the authors produced mutants which stabilized the trimer (Glycine 147 –> Proline) making aggregate formation less likely and two mutations (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine) which destabilized the trimer making aggregate formation more likely.  Then they threw the various mutant proteins at neuroblastoma cells and looked for toxicity.

The trimer stabilizing mutant  (Glycine 147 –> Proline) was toxic and the destabilizing mutants  (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine)  actually improved survival of the cells.  The trimer stabilizing mutant was actually more toxic to the cells than two naturally occurring SOD1 mutants which cause ALS in people (Alanine 4 –> Valine, Glycine 93 –> Alanine).  Clearly with these two something steric is going on.

So, in this experimental system at least, the aggregate is protective and what you can’t see (microscopically) is what kills cells.

Dynamic allostery

It behooves drug chemists to know as much as they can about protein allostery, since so many of their drugs attempt to manipulate it.  An earlier post discussed dynamic allostery which is essentially change in ligand binding affinity without structural change in the protein binding the ligand.  A new paper challenges the concept.

First here’s the old post, and then the new stuff

Remember entropy? — Take II

Organic chemists have a far better intuitive feel for entropy than most chemists. Condensations such as the Diels Alder reaction decrease it, as does ring closure. However, when you get to small ligands binding proteins, everything seems to be about enthalpy. Although binding energy is always talked about, mentally it appears to be enthalpy (H) rather than Gibbs free energy (F).

A recent fascinating editorial and paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 4278 – 4280, 4424 – 4429 ’17 ]shows how the evolution has used entropy to determine when a protein (CzrA) binds to DNA and when it doesn’t. As usual, advances in technology permit us to see this (e.g. multidimensional heteronuclear nuclear magnetic resonance). This allows us to determine the motion of side chains (methyl groups), backbones etc. etc. When CzrA binds to DNA methyl side chains on the protein move more, increasing entropy (deltaS) as well. We all know the Gibbs free energy of reaction (deltaF) isn’t just enthalpy (deltaH) but deltaH – TdeltaS, so an increase in deltaS pushes deltaF lower meaning the reaction proceeds in that direction.

Binding of Zinc redistributes these side chain motion so that entropy decreases, and the protein moves off DNA. The authors call this dynamics driven allostery. The fascinating thing, is that this may happen without any conformational change of CzrA.

I’m not sure that molecular dynamics simulations are good enough to pick this up. Fortunately newer NMR techniques can measure it. Just another complication for the hapless drug chemist thinking about protein ligand interactions.

A recent paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 6563  – 6568 ’17 ] went into more detail about measuring side chain motions  as a surrogate for conformational entropy.  It can now be measured by NMR.  They define complete restriction of  the methyl group symmetry axis as 1, and complete disorder, and state that ‘a variety of models’ imply that the value is LINEARLY related to conformational entropy making it an ‘entropy meter’.  They state that measurement of fast internal side chain motion is largely restricted to the methyl group — this makes me worry that other side chains (which they can’t measure) are moving as well and contributing to entropy.

The authors studied some 28 protein/ligand systems, and found that the contribution of conformational entropy to ligand binding can be favorable, negligible or unfavorable.

What is bothersome to the authors (and to me) is that there were no obvious structural correlates between the degree of conformation entropy and protein structure.  So it’s something you measure not something you predict, making life even more difficult for the computational chemist studying protein ligand interactions.

Now the new stuff [ Proc. Natl. Acad. Sci. vol. 114 pp. 7480 – 7482, E5825 – E5834 ’17 ].  It’s worth considering what ‘no structural change’ means.  Proteins are moving all the time.  Bonds are vibrating at rates up to 10^15 times a second.  Methyl groups are rotating, hydrogen bonds are being made and broken.  I think we can assume that no structural change means no change in the protein backbone.

The work studied a protein of interest to neurological function, the PDZ3 domain — found on the receiving side of a synapse (post-synaptic side).  Ligand binding produced no change in the backbone, but there were significant changes in the distribution of electrons — which the authors describe as an enthalpic rather than an entropic effect.  Hydrogen bonds and salt bridges changed.  Certainly any change in the charge distribution would affect the pKa’s of acids and bases. The changes in charge distribution the ligand would see due to hydrogen ionization from acids and binding to bases would certainly hange ligand binding — even forgetting van der Waals effects.