The fact that not everyone responds to Simufilam is irrelevant to its eventual FDA approval

A very intelligent friend does not share my optimism about Simufilam.

“Is the data really that positive? ADAS-Cog mean scores changed minimally over 1 year in patients with mild-to-moderate Alzheimer’s disease.  47% of patients improved ADAS-Cog over 1 year by 4.7 points. But 23% of patients declined by <5 points. Mild patients responded better than patients with moderate Alzheimer’s.”

Why are these thoughts irrelevant to the eventual approval of Simufilam by the FDA?

First: no drug for anything works for everyone with the condition

Second: The assumption that Alzheimer dementia is a single disease is based on just that: an assumption.

An example: When I was running a muscular dystrophy clinic in MonrN (’71 – ’87), we saw something called limb girdle muscular dystrophy , in which the patients were weak primarily in muscles about the shoulders and hips. Now we know that there are at least 13 different genetic causes of the disorder.

If the clinical picture of Alzheimer’s disease is due to multiple causes, it is unsurprising that Simufilam doesn’t help all of them.

Also it is time for some humility about our knowledge about Alzheimer’s disease.  We have misunderstood what the senile plaque of Alzheimer’s disease really is for 111 years — see the following post written 12/22 — https://luysii.wordpress.com/2022/12/13/111-years-of-study-of-the-alzheimer-plaque-still-got-it-wrong-until-now/

Third (and probably the most relevant for FDA approval):  Less that perfect drugs will be approved if every other treatment is worse.

The example of immune checkpoint blockade therapy for cancer is particularly relevant.

Some absolutely spectacular results for the therapy has led to the approval of 6 different drugs in this class (all of them monoclonal antibodies against proteins involving the immune system).

One example [ Cell vol. 162 pp. 1186 – 1190 ’15 ]:  “20% of metastatic melanoma patients are cured with Ipilimumab, a fully humanized anti-CTLA4 monoclonal antibody.”

Would that results like this were the rule not the exception. Unfortunately — [ Nature vol. 565 pp. 43 – 48 ’19 ] “Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it.”

So what.

Immune checkpoint blockade, despite being less than perfect,  is  still being offered to cancer patients, just the way Simufilam with its nearly 50% chance of improvement at 1 year should be offered to Alzheimer patients.  

Finally, an article in the press that’s not a hit piece on Cassava

Cassava Biosciences has had the worst press imaginable with hit pieces in the Wall Street Journal, Science magazine, the New Yorker and the New York Times.  Finally Nature News has a balanced article showing how the shorts have been attacking the company and its drug — https://www.nature.com/articles/d41586-023-00050-z.

I’d written about this before and that post can be found after the ***

The Nature article discusses concerns by Elizabeth McNally editor of the Journal of Clinical Investigation, that journals are being manipulated by short sellers claiming that an article is fraudulent.

“Typically, when a whistle-blower contacts a journal about concerns over manipulated images or otherwise questionable data, the allegations are taken on good faith, McNally told Nature. The idea that whistle-blowers could be doing this for their own financial gain “was very eye-opening to me”, she says.”

One particular criticism of Cassava found in the Nature article is rather amusing. “Amid the allegations about Cassava’s data, researchers have expressed concern over how Simufilam works. Aside from the preliminary studies by Cassava and its collaborators, the strategy of stablilizing filamin-A to tackle Alzheimer’s hasn’t been on anyone’s radar, says George Perry, an Alzheimer’s researcher at the University of Texas at San Antonio. “The fact that it hasn’t been widely studied means that it hasn’t been confirmed.”

The fact that filamin-A hasn’t been on anyone’s radar is actually in its favor, since aBeta, the great white whale of Alzheimer’s research has been impaled with multiple expensive harpoons, with minimal benefit to patients.

The Nature article notes that some of the FDA petitioners wanted the Simulfilam studies stopped, something any drug company with a competing product for Alzheimer’s might wish, but should never ask for.

****

The copy of this post was changed to respond to the valid criticisms of Dr. Elizabeth Bik.

 

Cassava shorts should be worried

Yesterday, 1 November ’22, a blockbuster  article was published in the Journal of Clinical Investigation (JCI) written by its editor Elizabeth McNally — https://www.jci.org/articles/view/166176.

It is just over a year ago since the first of the articles attacking Cassava Sciences appeared.  The first was in the New Yorker which profiled Jordan Thomas as the second coming of Christ for exposing supposed fraudulent data published by Cassava principals —

Radden Keefe P. The Bounty Hunter. The New Yorker. Updated January 17, 2022. Accessed October 11, 2022. https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers.

There were similar articles in Science — 2022;377(6604):358–363

and the New York Times https://www.nytimes.com/2022/04/18/health/alzheimers-cassava-simufilam.html.

They relied on the same assertions given to the FDA asking that the clinical trials be stopped because of ‘danger’ to the patients.

It’s worth reading McNally’s article completely.  It isn’t very long.

A few highlights (“the Journal” refers to the JCI)

“Throughout 2022, the Journal has been repeatedly contacted to comment on the 2012 JCI paper. Although we cannot be certain, there now appear to be new “short and distorters.” A recent round of emails was sent simultaneously to multiple journals and editors, identifying 25 articles with potential problems and providing recommendations on how the journals should respond. Importantly, these accusatory emails do not identify any financial conflicts of interest on the part of the whistleblowers. The emails insist that an investigation begin within 24 hours and request that the journals update them on investigative progress. As an editor, I am expressing concern because this represents a new means of manipulating the scientific publishing industry.”

So journal editors are like docs. They talk to each other to find out what’s really going on.  It is likely that McNally called up other journal editors to find out if her experience was common.

Here is why those sending the eMails should not sleep well of a night.

“Last, if the Journal uncovers allegations made for the purposes of stock manipulation, with evidence of misinformation, the JCI may elect to express its concern to the US Securities and Exchange Commission or the Department of Justice.”

It’s about time.

Whether the ‘whistle-blowers’ are guilty of anything will be determined by the suits (from investors losing money on Cassava, or perhaps Cassava itself) which are almost sure to follow.

As some of you know, I think Cassava’s data is even better than they realize. Be warned the following link is long, detailed and will require your concentration  — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

I called the current state in China in March of this year

https://www.cnn.com/2022/12/14/china/beijing-zero-covid-easing-streets-impact-intl-hnk-mic/index.html?utm_term=16710088517904a0e1f78c2ad&utm_source=cnn_Meanwhile+in+China+-+12.14.2022&utm_medium=email&bt_ee=UJOa6AAdoMdpv8zVd3R8kqP0vvKzTdQEV38THfAQNCVnL8dBJWuzcCiELZKliS9c&bt_ts=1671008851894 of

Back on March 15  2022,  I wrote a post about what was likely to happen in China.  It included older posts along the same line.   The basic argument was that the Chinese populace is a bunch of immunologic virgins to the pandemic virus due to several factors (1) the zero covid policy (2) the low rate of vaccination in the most susceptible –e.g. the elderly (3) the ineffectiveness of the vaccines they’ve been given.   Fortunately the newer variants don’t appear as malignant as the original SARS-CoV-2

Here’s the old post

China will be near collapse due to COVID19 — here’s why

Here is why I think China will be near collapse due to COVID19 in the next few months.

Due to a strict containment policy, the only experience the Chinese population (excepting Wuhan) has had with the pandemic virus has been by vaccination, mostly with Sinopharm and Coronavac.  These are known to be less effective against the Omicron variant than the western mRNA vaccines (Pfizer, etc.) which themselves are not terribly effective against infection.  So most Chinese are immunologic virgins for exposure to the variants of the pandemic virus and the omicron variant of the virus is incredibly infectious.

In contrast, western populations have been exposed to variant after variant of the pandemic virus, building up immunity to coronaviruses.  The vast majority of cases are mild not requiring hospitalization, and many are completely asymptomatic.

One small piece of evidence for this — there are many more —

The following is from a post July/2020.

https://www.nytimes.com/2020/07/09/nyregion/nyc-coronavirus-antibodies.html–https://www.cnbc.com/2020/04/23/new-york-antibody-study-estimates-13point9percent-of-residents-have-had-the-coronavirus-cuomo-says.html.

New York State  randomly tested 3,000 people at grocery stores and shopping locations across 19 counties in 40 localities to see if they had the antibodies to fight the coronavirus, indicating they have had the virus and recovered from it. With more than 19.4 million people residents, according to U.S. Census data, the preliminary results imply that at least 2.7 million New Yorkers have been infected with Covid-19.They weren’t all hospitalized.

If you’re into authoritative statements, here is Dr. Fauci 3 months ago –Source — https://nypost.com/2021/12/12/omicron-appears-to-evade-some-protection-from-covid-vaccines/

“We’re getting anecdotal information … not necessarily confirmed yet, that the level of severity appears to be maybe a bit less than in the Delta. But there are a lot of confounding issues that it may be due to the underlying protection in the community due to prior infections,”

Omicron spreads like wildfire.  For example, we had to call our plumber a week ago.  He has trained his teenage daughter to enter the trade.  We talked about the pandemic.  Teenagers love crowded parties (well I did, and so did our kids). His daughter  told us that apparently one irresponsible kid came to a party while sick in the early stages of what turned out to COVID19 and transmitted the virus to NINETEEN people.

Here is the Hong Kong experience.  It began with an aircrew member from Cathay Pacific Airways Ltd., who was subsequently found to be infected with omicron.  He ate lunch at a restaurant 27 December ’21 with his family. . Five other customers later tested positive.   By the first week in March there were over 50,000 new cases each day.  Fortunately Hong Kong appears to have passed the peak with ‘only’ 20 – 30 thousand new cases each day.

The South China Morning Post of 16 March notes that 90% of Hong Kong residents have received one dose of a vaccine.  This hardly speaks well for the efficacy of whatever they received.

The Hong Kong experience has been rationalized by several reasons perhaps peculiar to Hong Kong:

l. A very low vaccination rate among the most vulnerable (e.g. over 80)

2. Very high population density — 50% of the population in Hong Kong live in public housing which is mostly very tall, very skinny high rises, due to the lack of buildable land in Hong Kong.  The elevators are a perfect way to transmit the virus.

I can’t speak to how common this is elsewhere in China.

5 days ago the number of cases in China was 1,000.  Today (16 March) I read that there were 5,100 on 15 March — https://www.scmp.com/news/china/science/article/3170631/china-reports-another-3000-covid-19-cases-latest-surge-continues?module=lead_hero_story&pgtype=homepage

So the elevator pitch is — a highly infectious virus is loose in a huge, previously uninfected population with minimal vaccine protection.

I was very worried that something like this could happen all over China in posts  written 2 and 3months ago, long before the number of cases in Hong Kong took off.  You can find my reasoning in the following post — https://luysii.wordpress.com/2022/01/15/i-hope-to-hell-i-was-wrong-about-china/   It was published 15 January ’22, and can be found below and it contains the 12 December ’21 post:

Addendum 16 March — https://www.shine.cn/news/nation/2203163160/–Mainland China now has 1,860 locally transmitted cases — with most in the province next to North, but in 20 other locations all over China including Shanghai and Beijing. This is is not good news given how infectious Omicron is.

 

I hope to Hell I was wrong about China

From the South China Morning Post — 9:52pm, 15 Jan, 2022

“The Chinese capital reported its first community case of the Omicron coronavirus variant on Saturday, with local and imported infections of the strain now detected in about half of the country’s provinces and municipalities.”

https://www.scmp.com/news/china/politics/article/3163525/china-braces-omicron-variant-extends-its-reach-and-lunar-new-

If true, containment, quarantine, lockdowns and isolation are hopeless.  The quote implies that they’ve already failed.

I find this very worrisome for reasons listed in a post 12 December 2021, a copy of which is below.

The short answer is that the mainland Chinese are immunologic virgins to exposure to the variants of the pandemic virus.  Hopefully their vaccines will work better against omicron than those of the west, but there is no reason to think they will.

Is China following a Smokey the Bear policy on the pandemic?

China is following a prevent pandemic virus infection policy, just as Smokey the Bear followed a prevent forrest fires policy.  The latter didn’t work out well, as although fires were prevented for a while. However, when fires did occur, they were much much worse than the smaller ones Smokey prevented.  There was much more tinder and stuff to burn.

Actually Smokey has changed his tune slightly.

https://en.wikipedia.org/wiki/Smokey_Bear  SmokeyBear.com’s current site has a section on “Benefits of Fire” that includes this information: “Fire managers can reintroduce fire into fire-dependent ecosystems with prescribed fire. Under specific, controlled conditions, the beneficial effects of natural fire can be recreated, fuel buildup can be reduced, and we can prevent the catastrophic losses of uncontrolled, unwanted wildfire.”

Revision 14 December 2021 — China’s policy of prevention has resulted in a Chinese population which has been vaccinated using two killed virus vaccines (Sinopharm, Coronavac).  They have not had any natural infections with the virus (aside from the original cases) as far as we know given what China has allowed out.

Infection with the virus itself exposes you to all its proteins, with your immune system responding to all of them.   Western vaccines are just to the spike protein.

It tends to be forgotten that moist cases of pandemic viral infection are asymptomatic.

Given 800K deaths  from COVID19  in the USA, how can I possibly say this is good. Here’s how :>

If you had an infection with the virus, you develop antibodies.  Nowadays, everyone who is vaccinated has antibodies so there is no point in testing for them, but what were things like in the days before vaccines?

The following is from a post July/2020.

https://www.nytimes.com/2020/07/09/nyregion/nyc-coronavirus-antibodies.html–https://www.cnbc.com/2020/04/23/new-york-antibody-study-estimates-13point9percent-of-residents-have-had-the-coronavirus-cuomo-says.html.

New York State  randomly tested 3,000 people at grocery stores and shopping locations across 19 counties in 40 localities to see if they had the antibodies to fight the coronavirus, indicating they have had the virus and recovered from it. With more than 19.4 million people residents, according to U.S. Census data, the preliminary results imply that at least 2.7 million New Yorkers have been infected with Covid-19.They weren’t all hospitalized.

Here’s some work the same month from Queens — https://www.nytimes.com/2020/07/09/nyregion/nyc-coronavirus-antibodies.html

At a clinic in Corona, a working-class neighborhood in Queens, more than 68 percent of people tested positive for antibodies to the new coronavirus. At another clinic in Jackson Heights, Queens, that number was 56 percent. But at a clinic in Cobble Hill, a mostly white and wealthy neighborhood in Brooklyn, only 13 percent of people tested positive for antibodies.

So the disease has already to spread to half the population in some neighborhoods in Queens. If even 10% of them were sick that would have been 140,000 hospitalizations.  They didn’t happen.

OK, so a lot more people were infected than got sick.  Why is this good?

Enter the omicron variant of the pandemic virus.  It can evade the antibodies produced by all the current vaccines (in the West — protection against the Chinese killed viral vaccines CoronaVac and Sinopharm isn’t known yet).   Yet omicron doesn’t appear to produce severe disease. Thus far…

 

The CDC in the past week said of the 40+ omicron cases it knows about (there certainly are more out there, and more to come), there was one hospitalization (for two days) and no deaths.

Here is Dr. Fauci 12 December 2021 — “We’re getting anecdotal information … not necessarily confirmed yet, that the level of severity appears to be maybe a bit less than in the Delta. But there are a lot of confounding issues that it may be due to the underlying protection in the community due to prior infections,”

Source — https://nypost.com/2021/12/12/omicron-appears-to-evade-some-protection-from-covid-vaccines/

So the Chinese population may be sitting ducks for omicron having been given vaccines (Sinopharm, Coronavac) of unknown potency against omicron.  If their statistics are true there has been little or no natural infection with the pandemic virus in the Chinese population (which Fauci has just implicated is protective),.  Given that I have a son, daughter in law and two grandkids living in Hong Kong, I find this extremely disconcerting.

Why you should never see a doctor who couldn’t pass organic chemistry

Because Maitland Jones is front page stuff in the New York Times and CNN, being fired from NYU because his tests in organic chemistry are too hard, it is worth republishing a post of 13 years ago about why passing organic chemistry is so important in weeding out people unable to muster the type of thinking they will need in practice.

Disclaimer:  I spent a pleasant hour with Dr. Jones over 15 years ago in his office chatting about the Princeton Chemistry department of the late 50s, and the Harvard Chemistry department of the early 60s.  He seemed like a reasonable guy.  I’ve also read and own his textbook of organic chemistry which is excellent.

For those new to the blog, I was a practicing clinical neurologist from 1967 to 2000. Prior to that I did some graduate work in Chemistry picking up a Masters (Harvard ’62)

Here is the post of 2009.

Why premeds should be required to take (and pass) organic chemistry

This post is to be mentioned in the 2 Nov C&EN. I’m reposting it so people can find it. The original came out 1 Sep.

Back when I was posting on “The Skeptical Chymist”, the editor (Stuart Cantrill), told me that noises were being made about dropping organic chemistry from the pre-med curriculum and asked me to comment. I didn’t because the idea seemed so ridiculous. There is no possibility of really understanding anything about cellular biology, drug action, molecular biology etc. etc. without a firm grounding in organic chemistry. You simply must have some idea what vitamins, proteins, DNA and RNA and the drugs you’ll be using look like and how they chemically interact — which is what organic chemistry gives you the background for. Not that you can stop there — but all medical schools teach biochemistry — which starts at organic chemistry and takes off from there. Organic certainly helped me follow molecular biology as it exploded starting in the 60s.

Cynics might say that docs don’t synthesize things or crystallize the drugs they use. Knowing what’s going on under the hood is just esthetic filigree. Just tell them what ‘best practice’ is, and let them follow it like robots. Who cares if they know the underlying science. People drive cars without really understanding what a carburator or a manifold does (myself included).

It wasn’t until I got about 400 pages into the magnificent textbook of Organic Chemistry by Clayden, Greeves, Warren and Wothers (only 1100 action packed pages to go !) that the real answer became apparent. The stuff is impossible to memorize. Only assimilating principles and applying them to novel situations will get you through — exactly like the practice of medicine.

Let us suppose you have an eidetic memory, and know the best treatment for every condition. You wouldn’t have to know any science at all, would you?

What’s wrong with this picture? First of all, there isn’t a best treatment known for every condition. Second, every doc will see conditions and problems that simply aren’t in the books. When I first started out, I was amazed at how much of this there was. I asked an excellent internist who’d been in practice for 30 years if he’d seen it all. He thought he saw something completely new each week. Third, conditions occur in combinations, and many patients (and nearly all the elderly) have many more than one problem. The conditions and treatments interact in a highly nonlinear fashion. The treatment for one problem might make another much worse (see below).

Here is a concrete example using a familiar person (Sonia Sotomayor) and a disorder which should be known to all (the new Swine Flu which swept America and the world this spring). Let’s say that you’re that lucky soul with the perfect memory who knows all the best treatments (well those that exist anyway) and as such you’ve been given the responsibility of taking care of her.

It is public knowledge (e.g. Wikipedia) that Justice Sotomayor has had diabetes since age 8, requiring insulin since that time. Pictures show, that like many diabetics, she is overweight — depending on how tall she is I’d guess by 25 – 45 pounds. Influenza is usually a disease of the fall and winter, and the new Swine Flu is now down in South America, but it’s likely to sweep back up here this fall. We know it’s extremely infectious, but so far fortunately rather benign. There is no guarantee that it will stay that way. Suppose that while down in S. A. it mutated and has become more virulent (a possibility that the CDC takes extremely seriously).

What if she gets the new Swine flu next month? At this point there is no ‘best treatment’ known. Diabetics don’t do well with infections — they get more of them, and have more complications when they do. Her diabetes is certainly going to get worse. What if some think the ‘best treatment’ is corticosteroids (which is often used for severe lung infections) — which will really raise hell with her diabetes? Should you give it? Recall that corticosteroid use during the Asian SARS epidemic (another serious lung infection) seemed to hurt rather than help (Journal of Infection, Volume 51, Issue 2, Pages 98-102). There is no data to help you here and you and your patient don’t have the luxury of waiting for it. Don’t forget that her father died at 42 of heart disease. That could be relevant to what you do. Suppose, like many overweight diabetics she has high blood pressure and elevated lipids as well. How will that affect her management?

Your perfect eidetic memory of medicine will not be enough to help you with her management — you are going to have to think, and think hard and apply every principle of medicine you know to a new and unfamiliar situation with very little data to help you.

Sounds like Organic Chemistry doesn’t it? Anyone without the particular type of mind that is able absorb and apply multiple and (often) conflicting principles doesn’t belong in medicine. A hardnosed mathematician I audited a course from a few years ago, said that people would come up to him saying that if they couldn’t pass Calculus, they wouldn’t get into medical school. He felt that if they couldn’t, he didn’t want them in medical school (I’m not sure he told them this — probably he did). The same thing holds in spades for Organic Chemistry.

The staggering implications of one axon synapsing on another

It isn’t often that a single paper can change the way we think the brain works.  But such is the case for the paper described in the previous post (full copy below *** ) if the implications I draw from it are correct.

Unfortunately this post requires a deep dive into neuroanatomy, neurophysiology, neuropharmacology and cellular molecular biology.  I hope to put in enough background to make some of it comprehensible, but it is really written for the cognoscenti in these fields.

I’m pretty sure that some of these thoughts are both original and unique

Briefly, the paper provided excellent evidence for one axon causing another to fire an impulse (an action potential).   The fireror was from a neuron using acetyl choline as a neurotransmitter, and the fireree was a dopamine axon going to the striatum.

Dopamine axons are special.  They go all over the brain. The cell body of the parent neuron of the axon to be synapsed on uses dopamine as a neurotransmitter.  It sits in the pars compacta of the substantia nigra a fair piece away from the target they studied (the striatum). “Individual neurons of the pars compacta are calculated to give rise to 4.5 meters of axons once all the branches are summed”  — [ Neuron vol. 96 p. 651 ’17 ].”  These axons release dopamine all over the brain.  There aren’t many dopamine neurons to begin with just 80,000 which is 1 millionth of the current (probably unreliable) estimate of the number of neurons in the brain 80,000,000,000.

Now synapses between neurons are easy to spot using electron microscopy.  The presynaptic terminal contains a bunch of small vesicles and is closely apposed (300 Angstroms — way below anything the our eyes can see) to the post synaptic neuron which also looks different, usually having a density just under the membrane (called, logically enough, post-synaptic density).  Embedded in the postsynaptic membrane are proteins which conduct ions such as Na+, K+, Cl- into the postsynaptic neuron triggering an action potential.

But the dopamine axons going all over the brain have a lot of presynaptic specialization, but in many of the cases the post-synaptic neuron and its postsynaptic density is nowhere to be found (or the receptors for dopamine aren’t near the presynaptic specialization).  This is called volume neurotransmission.

However, in the nuclei studied (the striatum) dopamine synapses on dendrites of the major cell type (the medium spiny neuron) are well described and the 5 receptors for dopamine (called G Protein Coupled Receptors — GPCRs) are found there.  None of the GPCRs conduct ions or trigger action potentials (immediately anyway).  Instead, they produce their effects much more slowly and change the metabolism of the interior of the cell.  This is true for all GPCRs, regardless of the ligand activating them — and humans have 826 GPCR genes.

Note also that volume neurotransmission means that dopamine reaches nonNeuronal tissue — and there is good evidence that dopamine receptors are present on glial cells, pericytes and blood vessels.

The story doesn’t end with dopamine.  There are 3 other similar systems of small numbers of neurons collected into nuclei, using different neurotransmitters, but whose axons branch and branch so they go all over the brain.

These are the locus coeruleus which uses norepinephrine as a neurotransmitter, the dorsal raphe nucleus which uses serotonin and the basal nucleus of Meynert which uses acetyl choline.  There is excellent evidence that the first two (norepinephrine and serotonin) use volume neurotransmission. I’m not sure about those of the basal nucleus of Meynert.

What is so remarkable about the paper, that it allows the receiving neurons to (partially) control what dopamine input it gets.

All norepinephrine receptors are GPCRs, while only one of the 16 or so serotonin receptors conducts ions, the rest being GPCRs.

Acetyl choline does have one class of receptors (nicotinic) which conducts ions, and which the paper shows is what is triggering the axon on axon synapse.  The other class (muscarinic) of acetyl choline receptor is a GPCR.

Addendum 29 September — it goes without saying (although I didn’t say it) that any molecule released by volume neurotransmission doesn’t confine itself to finding targets on neurons.  Especially with norepinephrine, it could bind to receptors for it on the vasculature causing circulatory effects.  They could also bind to GPCRs on pericytes and glia.

Now the paper tested axon to axon firing in one of the four systems (dopamine) in one of the places its axons goes (the striatum).  There is no question that the axons of all 4 systems ramify widely.

Suppose axon to axon firing is general, so a given region can control in someway how much dopamine/serotonin/norepinephrine/acetyl choline it is getting.

Does this remind you of any system you are familiar with?  Perhaps because my wife went to architecture school, it reminds me of an old apartment building, with separate systems to distribute electricity, plumbing, steam heat and water to each apartment, which controls how much of each it gets.

Perhaps these four systems are basically neurological utilities, necessary for  the function of the brain, but possibly irrelevant to the computations it is carrying out, like a mother heating a bottle for her baby in water on a gas stove on a cold winter night.  The nature of steam heat, electricity, water and gas tell you very little about what is going on in her apartment.

The paper is so new (the Neuron issue of 21 September) that more implications are sure to present themselves.

Quibbles are sure to arise.  One is that fact that the gray matter of our brain doesn’t contain much in the way of neurons using acetyl choline as a neurotransmitter.  What it does have is lots of neurons using GABA which we know can act on axons, inhibiting axon potential generation.  This has been well worked out with synapses where the axon emerges from the neuron cell body (the initial segment).  However the different ionic composition of axons in the developing brain results in GABA having an excitatory effect.  Perhaps ionic composition varies in different parts of the neuron.

The work was done in living animals, so the paper contains no electron micrographs.  Such work is sure to be done.  No classical presynaptic apparatus may be present, just two naked axons touching each other and interacting by ephaptic transmission (the term does not appear in the paper).

So a lot of work should be done, the first of which should be replication. As the late Carl Sagan said “extraordinary claims require extraordinary evidence”.

Finally:

As Mark Twain said ” There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.”

 

Understanding the Riemann curvature tensor is like doing a spinal tap

Back in the day when I was doing spinal taps, I spent far more time setting them up (positioning the patient so that the long axis of the spinal column was parallel to the floor and the vertical axis of the recumbent patient was perpendicular to the floor) than actually doing the tap.  Why? because then, all I had to do was have the needle parallel to the floor, with no guessing about how to angle it when the patient had rolled (usually forward into the less than firm mattress of the hospital bed).

So it is with finally seeing what the Riemann curvature tensor actually is, why it is the way it is, and why the notation describing it is such a mess.  Finally on p. 290 of Needham’s marvelous book “Visual Differential Geometry and Forms” the Riemann curvature tensor is revealed in all its glory.  Understanding it takes far less time than understanding the mathematical (and geometric) scaffolding required to describe it, a la spinal taps.

Over the years while studying relativity, I’ve seen it in one form or other (always algebraic) without understanding what the algebra was really describing.

Needham will get you there, but you have to understand a lot of other things first. Fortunately almost all of them are described visually, so you see what the algebra is trying to describe.  Along the way you will see what the Lie bracket of two vector fields is all about along with holonomy.  And you will really understand what curvature is.  And Needham will give you 3 ways to understand parallel transport (which underlies everything — thanks Ashutosh)

Needham starts off with Gauss’s definition of curvature of a surface — the angular excess of a triangle, divided by its area.

Here is why this definition is enough to show you why the surface of a sphere is curved.   Go to the equator.  Mark point one, then point two 1/4 of the way around the sphere.  Form longitudes (perpendiculars) there and extend them as great circles toward the North pole. You now have a triangle containing 3 right angles, (clearly an angular excess from Euclid who states that the sum the angles of a triangle is two right angles).  The reason, of course, is because the sphere is curved.

Ever since I met a classmate 12 years ago at a college reunion who was a relativist working with Hawking, I decided to try to learn relativity so I’d have something intelligent to say to him if we ever met again (COVID19 stopped all that although we’re still both alive).

Now that I understand what the math of relativity is trying to describe, I may be able to understand general relativity.

Be prepared for a lot of work, but do start with Needham’s book.  Here are some links to other things I’ve written about it.  It will take some getting used to as it is very different from any math book you’ve ever read (except Needham’s other book).

12 July 21 — https://luysii.wordpress.com/2021/07/12/a-premature-book-review-and-a-60-year-history-with-complex-variables-in-4-acts/

4 Dec 21 — https://luysii.wordpress.com/2021/12/04/a-book-worth-buying-for-the-preface-alone-or-how-to-review-a-book-you-havent-read/

7 Mar 22 — https://luysii.wordpress.com/2022/03/07/visual-differential-geometry-and-forms-q-take-3/

27 June 22 — https://luysii.wordpress.com/2022/06/27/the-chinese-room-argument-understanding-math-and-the-imposter-syndrome/

17 July 22 — https://luysii.wordpress.com/2022/07/17/a-visual-proof-of-the-the-theorem-egregium-of-gauss/

4 diseases explained at one blow said the protein chemist — part 1

A brilliant paper [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] explains how changing a single amino acid (proline) to another  can cause 4 different diseases, depending on the particular protein it is found in (and which proline of many is changed).

There is so much in this paper that it will take several posts to go over it all.  The chemistry in the paper is particularly fine.  So it’s back to Biochemistry 101 and the alpha helix and the beta sheet.

Have a look at this

https://cbm.msoe.edu/teachingResources/proteinStructure/secondary.html

If you can tell me how to get a picture like this into a WordPress post please make a comment.

The important point is that hydrogen bonds between the amide hydrogen of one amino acid and the carbonyl group of another hold the alpha helix and the beta pleated sheet together.

Enter proline : p//en.wikipedia.org/wiki/Proline.  Proline when not embedded in a protein has a hydrogen on the nitrogen atom in the ring.  When proline is joined to another amino acid by a peptide bond in a protein, the hydrogen on the nitrogen is no longer present.  So the hydrogen bond helping to hold the two structures (alpha helix and beta sheet) is no longer present at proline, and alpha helices and beta sheets containing proline are not has stable.  Prolines after the fourth amino acid of the alpha helix (e. g. after the first turn of the helix) produce a kink.  The proline can’t adopt the alpha helical configuration of the backbone and it can’t hydrogen bond.

But it’s even worse than that (and this observation may even be original).  Instead of a hydrogen bonding to the free electrons of the oxygen in the carbonyl group you have the two electrons on the nitrogen jammed up against them.  This costs energy and further destabilizes both structures.

Being a 5 membered ring which contains the alpha carbon of the amino acid, proline in proteins isn’t as flexible as other amino acids.

This is why proline is considered to be a helix breaker, and is used all the time in alpha helices spanning cellular membranes to cause kinks, giving them more flexibility.

There is much more to come — liquid liquid phase separation, prion like domains, low complexity sequences, frontotemporal dementia with ALS, TDP43, amyloid, Charcot Marie Tooth disease and Alzheimer’s disease.

So, for the present stare at the link to the diagram above.

Why Cassava’s 1 year results should allow compassionate use of Simufilam

Cassava reported results on 100 Alzheimer patients in an open label (e.g. no controls) trial of Simufilam for 1 year — https://finance.yahoo.com/news/cassava-sciences-reports-second-quarter-131500494.html.  The average results were unimpressive (to the uninitiated) with only a minimal average overall improvement of an ADAS-Cog11 score of 1.5 points.  This is probably why the stock (SAVA) dropped a point yesterday after the news.  Since everything turns on ADAS-Cog11 here is a link to a complete description — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/.  The test takes about 45 minutes placing it out of reach of a busy practicing clinical neurologist.

Why is even the 1.5 point improvement impressive to the initiated (me)?  Over 32 years in clinical neurology, I’d estimate that I saw at least 1 demented patient each week.  Now probably only 300 or so of the 1,664 were followed for a year.  Guess what?  None of them remained stable for a year, and all got worse.  Absolutely none of them  ever got better after a year.  So at least some stabilization of the disease is possible for a year.  The statistics say that Alzheimer patients lose 5 points a year on ADAS-Cog.

But that’s pretty small beer.  Who wants to keep a demented patient around but stable.  Here is the remarkable part of the Cassava results at a year.

63% of the 100 Patients Showed an Improvement in ADAS-Cog11 Scores, and This Group of Patients Improved an Average of 5.6 Points (S.D. ± 3.8). The statistics say that Alzheimer patients lose 5 points a year on ADAS-Cog.

This is unprecedented and is a strong argument for quick approval of Simufilam (or at least compassionate use).

The cynic will say that I’m just looking at the happy part of the Bell curve.  There must have been people who declined to average the improvement in the 63% down to a measly 1.5 points on the ADAS-Cog.

This is where clinical experience comes in.  No drug helps everyone with a given disease.  “Only 20% of cancer patients respond long term to a type of immune checkpoint blockade (of PD-1)” Science vol. 363p. 1377 ’19.  Nonetheless immune checkpoint blockade of several types was approved by the FDA, simply because there was nothing better available.

So if nearly 2/3 of Alzheimer patients will improve at one year on Simufilam, why not  let the FDA offer it to them now under compassionate use.

 

 

When to get your booster — a possibly useful post

I thought everyone knew that vaccines and boosters against the pandemic flu reach maximum protection against infection in a week or two, and then start declining.  Each of the zillions of papers on the subject say exactly this.

So if you’ve been isolating yourselves, as my wife and I have because of our age, the time to get that booster is a week or so before a time of likely exposure — in our case a visiting grandchild.

I thought everyone knew this, but maybe not.  My wife got an eMail today from her  85 year old cello teacher.   She summers on an island off the Maine coast near Mt. Desert Island (the home of Acadia National Park)

 

“We’re so far well, thanks to xxxx, I took his advice and got 2nd booster just before leaving middle of June. The whole island was shut down, the  only grocery store had signs SHUT TODAY, NO STAFF, went to Kneisel Hall in Blue Hill, people had not been able to rehearse together because they were actively sick, and so on. He and news are proving to be a blessing!

For this, we all thank you.”

Amyloid Structure at Last ! 3 The Alzheimer mutations

I am republishing this post from last October, because the excellent paper I’m going to write about has similar thinking.

Although the chemistry explaining why these mutations are associated with Alzheimer’s disease is exquisite and why they point to ‘the’ cause of Alzheimer’s disease — the amyloid fibril, billions have been spent in attempts to remove amyloid fibrils with no useful therapeutic result (and some harm)

Here’s the old post

The structure of the amyloid fibril formed by the aBeta42 peptide exactly shows why certain mutations are associated with hereditary Alzheimer’s disease.   Here is a picture

https://www.alzforum.org/news/research-news/danger-s-bends-new-structure-av42-fibrils-comes-view

Scroll down to the picture above “Bonds that Tie”

If you need some refreshing on the general structure of amyloid, have a look at the first post in the series — https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/

Recall that in amyloid fibrils the peptide backbone is flat as a flounder (well in a box 4.8 Angstroms high) with the amino acid side chains confined to this plane.  The backbone winds around in this plane like a snake.  The area in the leftmost loop is particularly crowded with bulky side chains of glutamic acid (single letter E) at position 22 and aspartic acid (single letter D) at position 23 crowding each other.  If that wasn’t enough, at the physiologic pH of 7 both acids are ionized, hence negatively charged.  Putting two negative charges next to each other costs energy and makes the sheet making up the fibril less stable.

The marvelous paper (the source for much of this) Cell vol. 184 pp. 4857 – 4873 ’21 notes that there are 3 types of amyloid — pathological, artificial, and functional, and that the pathological amyloids are the most stable. The most stable amyloids are the pathological ones.  Why this should be so will be the subject of a future post, but accept it as fact for now

In 2007 there were 7 mutations associated with familial Alzheimer’s disease (10 years later there were 11). Here are 5 of them.

Glutamic Acid at 22 to Glycine (Arctic)

Glutamic Acid at 22 to Glutamine (Dutch)

Glutamic Acid at 22 to Lysine (Italian)

Aspartic Acid at 23 to Asparagine (Iowa)

Alanine at 21 to Glycine (Flemish)

All of them lower the energy of the amyloid fiber.

Here’s why

Glutamic Acid at 22 to Glycine (Arctic) — glycine is the smallest amino acid (side chain hydrogen) so this relieves crowding.  It also removes a negatively charged amino acid next to the aspartic acid.  Both lower the energy

Glutamic Acid at 22 to Glutamine (Dutch) — really no change in crowding, but it removes a negative charge next to the negatively charged Aspartic acid

Glutamic Acid at 22 to Lysine (Italian)– no change in crowding, but the lysine is positively charged at physiologic pH, so we have a positive charge next to the negatively charged Aspartic acid, lowering the energy

Aspartic Acid at 23 to Asparagine (Iowa) –really no change in crowding, but it removes a negative charge next to the negatively charged Glutamic acid next door

Alanine at 21 to Glycine (Flemish) — no change in charge, but a reduction in crowding as alanine has a methyl group and glycine a hydrogen.

As a chemist, I find this immensely satisfying.  The structure explains why the mutations in the 42 amino acid aBeta peptide are where they are, and the chemistry explains why the mutations are what they are.

Abeta peptide, Amyloid structure, Arctic familial Alzheimer mutation, Dutch familial Alzheimer mutation, Familial Alzheimer’s disease, Flemish familial Alzheimer mutation, Iowa familial Alzheimer mutation, Italian familial Alzheimer mutation. No