James Hartle R. I. P.

Jim Hartle, one of the smartest guys in my college class has died, and of Alzheimer’s disease, showing once again that intelligence does not absolutely protect against Alzheimer’s (although the more educated you are the less likely you are to get it [ Int. J. Epidemiol. Volume 49, Issue 4, August 2020, Pages 1163–1172 ].

He studied with John Wheeler as a Princeton undergraduate, got his PhD with Murray Gell-Mann and worked so extensively with Stephen Hawking that he was asked to speak at Hawking’s funeral.

My total person to person contact with Jim may have lasted 10 minutes (at my 50th reunion).  I knew all sorts of physics majors in the class, but he wasn’t one of them.  I knew about him only because I read our  50th reunion book, and found out how distinguished he was.  I found him relaxed, friendly and far from overbearing, like some of the physics majors I knew.

This was typical of just about everyone at the 50th.  A classmate’s wife (from Chile) described classmates at the 25th as a bunch of roosters.

We did correspond a bit, and he did send me the answer sheets to the problems in his book on Gravity (which I’ve never gone through preferring to get the math under my belt first rather than mouth various incantations which I didn’t understand).  Jim is the reason I started studying Math and Physics in earnest, hoping to have something intelligent to say to him at the next reunion.  He wasn’t present at the 55th,   COVID19 ended the 60th and now he’s gone.

Two more examples of brilliant men you might know of who died of Alzheimer’s are Daniel Quillen Harvard ’61 who won the Fields Medal and Claude Shannon.

The physics department at University of California Santa Barbara has an obituary describing much of his work

https://www.physics.ucsb.edu/news/announcement/2132

A neuron synapsing on an immune cell.

The immunologic synapse is well known.  It occurs between two types of immune cells (not between neurons), an antigen presenting cell and a T lymphocyte.  An effective immunologic synapse produces T cell activation and proliferation to kick off the immune response.

Neuroinflammation is equally well known.  Stimulate a neuron responding to painful stimuli and it releases inflammatory mediators locally and fires impulses back to the brain.  The best known example of a receptor for pain (nociceptor) is the TRPV1 channel, which responds to capsaicin, an active component of red hot chili peppers.  TRPV1 also responds to other obviously painful stimuli — heat, acid etc.  Neurons containing TRPV1 are called nociceptor neurons.

Activation of TRPV1 on nociceptor neurons results in the release of inflammatory mediators such as substance P, and other things (CCL2, CGRP).

Many immune cells have receptors for inflammatory mediators and direct contact with nociceptor neurons isn’t necessary.  I’ve always wondered if something like a synapse between a nerve cell and immune cell existed.

Finally a paper just cultured nociceptor neurons and a type of immune cell (the dendritic cell) together [Science vol. 379 pp. 1301 – 1302, 1315 eabm5658 pp. 1 –> 1 ’23 ].  Figure 3c on p. 4 of the paper, shows a dendritic cell plastered up along an axon, which is about as close to synapse as you are going to get.  However, the area of contact is much longer than the usual synapse.  Whether such things occur in vivo is unknown, but I’ve never seen a picture like this one.

Capsaicin was used to stimuli the neurons, and they were found to communicate wth  dendritic cells three ways

l. By producing the chemokine CCL2 which attract dendritic cells

2, By releasing Calcitonin Gene Related Peptide (CGRP) which causes dendritic cells to release another inflammatory mediator — interleukin 1 beta (IL1beta)

3. By direct electrical coupling triggering calcium flux into the dendritic cell along with membrane depolarization.  This potentiates the dendritic cell response to inflammatory stimuli.

The experimental system is far out, but anything we can learn about pain is worth having, as present therapy is far from ideal.

The science behind Cassava Sciences (SAVA) — the latest as of 23 April ’23

It’s time for an update on the science  behind Cassava Sciences’ anti-Alzheimer drug, Simufilam.  It is  based on an older post of mine and a review of the published literature and my decades of experience as a clinical neurologist.

Disclaimer:  My wife and I have known Lindsay Burns, one of the Cassava Sciences principals since she was a teenager and we were friendly with her parents when I practiced neurology in Montana.

But as H. L. Mencken said, “A Professor must have a theory as a dog must have fleas”, and the reason I’m excited about Simufilam has nothing to do with the theory of the science behind it.  Simply put, the results of Cassava’s open label trial have never  been seen with Alzheimer’s patients.  10% improved by nearly 50% at 1 year, and over half did not deteriorate.  As a clinical neurologist with decades of experience seeing hundreds of demented people, I never saw anything like this, especially significant improvement after a year).  For more detail please see https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

Here is the science behind the drug.  We’ll start with the protein the drug is supposed to affect — filamin A, a very large protein (2,603 amino acids to be exact).  I’ve known about it for years because it crosslinks actin in muscle, and I read everything I could about it, starting back in the day when I ran a muscular dystrophy clinic in Montana.

Filamin binds actin by its amino terminal domain.  It forms a dimerization domain at its carboxy terminal end.  In between are 23 repeats of 96 amino acids which resemble immunoglobulin — forming a rod 800 Angstroms long.  The dimer forms a V with the actin binding domain at the two tips of the V, making it clear how it could link actin filaments together.

Immunoglobulins are good at binding things and 90 different proteins are known to which filamin A binds.  This is an enormous potential source of trouble.

As one might imagine, filamin A could have a lot of conformations in addition to the V, and the pictures shown in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099194/.

One such altered (from the V) conformation binds to the alpha7 nicotinic cholinergic receptor on the surface of neurons and Toll-Like Receptor 4 (TLR4) inside the cell.

Abeta42, the toxic peptide, has been known for years to bind tightly to the alpha7 nicotinic receptor — they say in the femtoMolar (10^-15 Molar) range, although I have my doubts as to whether such tiny concentration values are meaningful.  Let’s just say the binding is tight and that femtoMolar binding is tighter than picoMolar is tighter than nanoMolar is tighter than microMolar  binding etc., etc.

When aBeta42 binds to alpha7 on the outside of the neuronal plasma membrane  filamin A binds to alpha 7 on the inside making  aBeta42 binding even tighter.

The tight binding causes signaling inside the cell  to hyperphosphorylate the tau protein forming the neurofibrillary tangle, which is more directly correlated with dementia in Alzheimer’s disease than the number of senile plaques.

In more detail, the high affinity aBeta42-alpha7 nicotinic cholinergic receptor binding activates the MAPK cascade (Mitogen Activated Protein Kinase cascade), ending in activation of the protein kinases ERK2, and JNK1.  Activated protein kinases catalyze the addition of phosphate to proteins forming an ester with the free hydroxyl groups of serine and/or threonine.  Activating ERK2 and JNK1 allows them to phosphorylate the tau protein leading to the neurofibrillary tangle of  Alzheimer’s disease (which is just a mess of hyperphosphorylated tau protein).

But there is still more about the mechanism which isn’t clear.  Recall that MAPK stands for Mitogen Activated Protein Kinase where a mitogen binds to a receptor on the cell surface, and a mitogen is nowhere in sight here, so there are still a few missing steps between aBeta42 binding to the alpha7 nicotinic cholinergic receptor and MAPK activation.  The references do show that MAPK signaling, ERK2 and JNK1 are activated when aBeta42 binds to the alpha7 nicotinic acetyl choline receptor.

Also the mechanism is radical in the extreme. The nicotinic acetyl choline receptor is a receptor all right but for acetyl choline. It is an ion channel and   looks nothing like the receptors that proteins and peptides bind to which are usually G Protein Coupled Receptors (GPCRs) or Receptors with Tyrosine Kinase activity (RTKs).  Also aBeta42 is not a mitogen.

So what does Sumifilam actually do — it changes the ‘altered’ conformation of filamin A getting it away from the alpha7 acetyl choline receptor and “indirectly reducing the high femtoMolar binding affinity of aBeta42 for alpha7” (and however this binding triggers tau hyperphosphorylation)  How do they know the conformation of filamin A has changed?  They haven’t done cryoEM or Xray crystallography on the protein.  The only evidence for a change in conformation, is a change in the electrophoretic mobility (which is pretty good evidence, but I’d like to know what conformation is changed to what).

So there you have it, after a fairly deep dive into protein chemistry, cellular physiology and biochemistry, the current thinking of how Simufilam works.

But even if the theory is completely wrong, the data in the link above must be regarded with respect.  Clinical blinded studies are ongoing, and the soon to be released Cognition Maintenance Study should  give us more information –https://luysii.wordpress.com/2023/03/02/the-cognition-maintenance-study-of-simufilam/

How far we’ve come from the McCulloch Pitts neuron

The McCulloch Pitts neuron was described in 1943.  It consists of a bunch of inputs (dendrites) some excitatory, some inhibitory, which are just summed (integrated) the results determining the output (whether the  axon of the neuron fired or didn’t).  Hooking them together could instantiate a variety of boolean functions and ultimately a Turing machine.

The McCulloch Pitts neuron really isn’t that far from the ‘neurons’ in neural nets which underlie the spectacular achievements of artificial intelligence (ChatGTP etc. etc.)   The neuron of the neural net is nothing more than a set of inputs, a set of weights, and an activation function. The neuron translates these inputs into a single output, which can then be picked up as input for another layer of neurons later on.

The major difference between the computation a linked bunch of neurons in the two models (McCulloch Pitts and neural net) is that given the same set of inputs in McCulloch Pitts you always get the same output, while in neural nets you don’t.  The difference is that the set of weights on the inputs to each neuron in the net which can be and are adjusted which depends on how close the output of the net is to the target (which in the case of ChatGTP is how accurately it predicts the next word in a sample of text).

There is a huge debate going on as to whether ChatGTP and similar neural nets understand what they are doing and whether they are/will become conscious.

So does ChatGTP explain how our brains do what they do?  Not at all.  Our neurons are doing far more than integrating input and firing.  This was brought home in a paper focused on something entirely different, the gamma oscillations of brain electrical activity (Neuron vol. 111 pp. 936 – 953 ’23).  People have been studying brain rhythms since Hans Berger discovered alpha rhythm just shy of a century ago.  The electroencephalogram (EEG) measures the various rhythms as they occur over the brain.  Back in the day when I was starting out in neurology (1967), it was one of the few diagnostic tools we had.  It wasn’t very good, and a cynical attending described it as useless but not worthless (because you could charge for it).

The gray matter of the surface of our brains (cerebral cortex) is gray because it is packed with the cell bodies of neurons — some 100,000 under each square millimeter of cortex.  Somehow they are wired together so that they can produce coherent rhythmic electrical activity as they fire.

The best place to study how a bunch neurons produce rhythms is the hippocampus, an area crucial in forming memories and one of the earliest places the senile plaques of Alzheimer’s disease show up.

Unlike the jumble of neurons in the cortex, the large neurons of the hippocampus are all lined up and oriented the same way like trees in a forest.  All the cell bodies lie in roughly the same layer, with the major dendrite (apical dendrite) going up like the trunk of a tree, and the ones near the cell body spreading out like the roots of a tree.

Technology has marched on, and it is now possible to fashion electrodes, which can measure neuronal electrical activity along the trunk, and watch it in real time.

Figure 2b p. 941 shows that different parts of the trunk of the hippocampal  neurons show rhythmic activity at different frequencies at any given time.  Not only that, but as time passes each area of the trunk (apical dendrite) changes the frequency of its rhythmic activity.  This is light years away from the integrate and fire model of McCulloch Pitts, or the adjustment of weights on the inputs to the neurons of the neuronal net.

It shows that each of these neurons is a complex processor of information (a computer if you will).  Even though artificial intelligence has made great strides, it really isn’t telling us how the brain does what it does.

Finally if you want to see what genius looks like, check out the life of Walter Pitts — https://en.wikipedia.org/wiki/Walter_Pitts  — corresponding with Bertrand Russell about Principia Mathematica at age 12, studying with Carnap at the University of Chicago at 15, all while he was homeless.

 

The dark side of monoclonal antibodies against Abeta — take 2

An article in the 14 April Science (pp. 122 – 123) describes the case of a woman who died after receiving lecanumab, an antibody against a form of amyloid.  She had cerebral amyloid angiopathy (CAA), a condition likely to be unfamiliar to most readers, unlike neurologists such as yrs trly.

So here’s a bit of background on CAA.  Amyloid is the main component of the senile plaque.  However it also occurs in cerebral blood vessels in the parietal and occipital regions, areas where plaques are not prominent (the hippocampus, temporal lobe etc. etc.). Removing the amyloid weakens the vessels containing it.  The article even contains a picture of a broken vessel with amyloid in its walls.  CAA was found in 1/3 of 84 autopsies of patients from 60 – 97.  So, like most things in medicine, it’s a matter of degree as lots of neurologically  healthy people in this age range have plaques, and CAA.

Once CAA is diagnosed anticoagulation is verboten, which didn’t help Ariel Sharon who had CAA and was amazingly given anticoagulation which killed him  — https://luysii.wordpress.com/2014/01/12/who-chose-ariel-sharons-mds-arafat/

CAA may explain why 21% of patients in the recent trial of lecanumab had ARIA (Amyloid Related Imaging Abnormalities) which is brain swelling and bleeding.

A copy of the first post on the dark side of monoclonal antibodies against aBeta amyloid follows

The dark side of monoclonal antibodies against Abeta

An article in the 7 April ’23 [ Science vol. 380 pp. 19 ’23 ] notes that a monoclonal antibody treatment against the aBeta peptide for Alzheimer’s disease (lecanemab) is associated with brain shrinkage.  Even worse, 21% of the 898 receiving lecanemab had ARIA (Amyloid Related Imaging Abnormalities) which is brain swelling and bleeding.  Although most of these people were asymptomatic, it isn’t something you’d want going on in your brain.  However ‘some’ with ARIA became severely ill and there were two deaths.

Now Alzheimer’s disease is associated with brain shrinkage as neurons die, but at 18 months those receiving lecanemab had 28% greater brain loss than those receiving placebo.  That isn’t as bad as it sounds, because the absolute loss of brain tissue was 5 milliLiters more in the lecanemab group, and most brains (even the shrunken ones have a volume of over 1,000 milliLiters)

Addendum 9 April   Vincent Wong asked an excellent question — “Any reason why patients brains on Lecanemab shrink more than placebo group apart from potential ARIA?”

To which I responded

Part of neurology residency training is exposure to neuropathology, where you look at slide after slide after slide. Just as you don’t see senile plaques in an MRI, but do see them on slides, there are likely all sizes of the same pathology as ARIA visible on MRI (some microscopic), but the ultimate outcome the same, brain shrinkage.

Addendum 10 April : The 6 April Nature has an article (pp. 26 – 28) saying how wonderful lecanemab is, and how it shows that attacking the plaque is the way to go, quoting someone from Harvard who has “spent more than 30 frustrating years in Alzheimer’s research”. Nowhere mentioned is the fact that 21% of people receiving lecanemab had ARIA (Amyloid Related Imaging Abnormalities) which is brain swelling and bleeding, asymptomatic in most fortunately. Also not mentioned is recent work showing that the 800+ patients receiving the monoclonal had more loss of brain tissue with time than patients getting placebo. Of course Cassava is nowhere to be found.

Here’s a link to the article — https://www.nature.com/articles/d41586-023-00954-w

A clever friend sent the following reply to the article:

“Just amazing. Why abandon a perfectly bad drug when you can combine it with something else?”

The dark side of monoclonal antibodies against Abeta

An article in the 7 April ’23 [ Science vol. 380 pp. 19 ’23 ] notes that a monoclonal antibody treatment against the aBeta peptide for Alzheimer’s disease (lecanemab) is associated with brain shrinkage.  Even worse, 21% of the 898 receiving lecanemab had ARIA (Amyloid Related Imaging Abnormalities) which is brain swelling and bleeding.  Although most of these people were asymptomatic, it isn’t something you’d want going on in your brain.  However ‘some’ with ARIA became severely ill and there were two deaths.

Now Alzheimer’s disease is associated with brain shrinkage as neurons die, but at 18 months those receiving lecanemab had 28% greater brain loss than those receiving placebo.  That isn’t as bad as it sounds, because the absolute loss of brain tissue was 5 milliLiters more in the lecanemab group, and most brains (even the shrunken ones have a volume of over 1,000 milliLiters)

Addendum 9 April   Vincent Wong asked an excellent question — “Any reason why patients brains on Lecanemab shrink more than placebo group apart from potential ARIA?”

To which I responded

Part of neurology residency training is exposure to neuropathology, where you look at slide after slide after slide. Just as you don’t see senile plaques in an MRI, but do see them on slides, there are likely all sizes of the same pathology as ARIA visible on MRI (some microscopic), but the ultimate outcome the same, brain shrinkage.

Addendum 10 April : The 6 April Nature has an article (pp. 26 – 28) saying how wonderful lecanemab is, and how it shows that attacking the plaque is the way to go, quoting someone from Harvard who has “spent more than 30 frustrating years in Alzheimer’s research”. Nowhere mentioned is the fact that 21% of people receiving lecanemab had ARIA (Amyloid Related Imaging Abnormalities) which is brain swelling and bleeding, asymptomatic in most fortunately. Also not mentioned is recent work showing that the 800+ patients receiving the monoclonal had more loss of brain tissue with time than patients getting placebo. Of course Cassava is nowhere to be found.

Here’s a link to the article — https://www.nature.com/articles/d41586-023-00954-w

A clever friend sent the following reply to the article:

“Just amazing. Why abandon a perfectly bad drug when you can combine it with something else?”

How a small town dealt with a pedophile and a schizophrenic 70 – 80 years ago

“Never get in a car with Bert Sxxxxxx and never take candy from strangers” said mother.  She never said what would happen and at age 5 I had no idea about sex.  Bert Sxxxxxx was a mailman, and some family members lived on our street.  Everyone knew about him.  70 years later I mentioned him to a kid a few years older and he responded “Chester the molester”.

Why wasn’t he stopped?  For the same reason he was a postman —  political connections from what little I could understand about the adult world as a child.

Then there was my attorney father’s client Joe Lxxxxxx, a subject of much hilarity (my father having no psychiatric training).  Joe thought he was married to Queen Elizabeth, through ‘interceptor medium’.  He also said he had a room in his house with no doors or windows.   Joe was clearly crazy and everyone  knew it, but the town took care of him in its way.  People talked to him.  If he got excited, the cops would find him and take him home without a struggle.

Fast forward to Penn Med School maybe 10 – 20 years later and a trip to Norristown State hospital just outside Philly, and a tour of the wards (including the extremely creepy locked ones).  Infinitely worse for Joe Lxxxxx than the ‘social care’ our little town was able to give him.

These thoughts were brought on by the previous post about sexual predation by coaches on young female athletes.  It is reproduced below.

How did it happen? Take 2

Today’s New York Times had another long article about another long term sexual predator coach (Ted Nash) this time on female rowers.  The question always arises, how could he have gotten away with it so long with so many different victims?

So it’s worth republishing a post from January 2018 about another coach, and my own experience witnessing it as an adolescent and saying nothing nearly 70 years ago.

Regular posting should resume soon.  My time has been taken up by reading straight through a recently published book that I was a lay reader for (Quantum Field Theory as Simply as Possible), so I can publish a review on Amazon at the request of the author (Tony Zee).

Here’s the old post from January 2018

How did it happen ?

This is not a scientific post.  How in the world was “Dr” Nassar able to sexually abuse so many and for so long. In high school I saw the same thing and said nothing. But this was 60+ years ago, in a small rural high school.

By small I mean 212 kids in 4 grades.  By rural I mean it was a 16 mile ride on the school bus from my house.  This meant that away basketball games meant rides on that bus as long as 70 miles, and never shorter than 20 for me. Our school was too small  to even support 6 man football, so basketball and baseball it was.

So the sports outlet was basketball, even for a prepubertal 14 year old entering high school at 5 feet tall.  I got pretty good at playing a small man’s game (mostly positioning and being where the ball would go next) and when I’d grown a foot by my senior year, I could outmaneuver most people my size and a few taller ones.

By my senior year I was on the staring five.

On the way back from games, there would be the basketball coach sitting near the driver, necking with one of the cheerleaders.  No one ever said anything about it.  I never discussed it with my parents, or even my friends.  Initially it seemed to be one more incomprehensible thing about the adult world.  The administration of the high school consisted of the principal and his secretary.  The world back then was that teachers were to be obeyed and respected.

So I can see how someone emerging into adolescence would be totally cowed by such events, not know what to do and remain silent.

I hadn’t thought about this for years, until the scandal at Michigan State.  So I wrote the older sister of one of my teammates about it — her initial response was —  “I am inNew Orleans at a funeral so more later.  But yes we all knew about XXXXXX and his sexual predations. More on that when I get home.”

The Cognition Maintenance Study of Simufilam

Addendum and revision 11 May ’23 — Cassava announced today that dosing inthe Cognition Maintenance Study (CMS) is complete — https://finance.yahoo.com/news/cassava-sciences-completes-patient-dosing-131500155.html.  All that remains is to analyze and report the data  which will happen in the third quarter of 2023. The link notes that “The CMS dataset remains locked and blinded. After unlocking, the dataset will be analyzed by outside biostatisticians.”   This could be a game changer and lead to early FDA approval as the CMS study is double blinded.  So it’s worth republishing an earlier (5/22) post on the subject to explain how this might occur.

Cassava’s Cognition Maintenance Study may prove Simufilam works

The FDA will approve less than perfect therapies if there is nothing useful for a serious condition.  Consider the following from Proc. Natl. Acad. Sci. vol. 119 e2120512119 ’22

“KRAS is the most frequently mutated oncogene in human cancer, with mutations detected across many lineages, particularly in the pancreas, colon, and lungs. Among the most commonly activating KRAS mutations at codons 12, 13, and 61, G12C occurs in ∼13% of lung and 3% of colorectal carcinomas and at lower frequencies in other tumors.

“In locally advanced or metastatic non–small-cell lung cancer (NSCLC) patients with KRAS^G12C mutations who have received at least one prior systemic therapy”  treatment with sotorasib resulted in the following “objective response  in 37.1% of the patients, with a median duration of response was 11.1 months.”   This is hardly a cure, but nonetheless “This promising anticancer activity has resulted in accelerated approval from the US Food & Drug Administration”

Which brings me to the current CMS study from Cassava Sciences.  I’ll let them speak for themselves. https://finance.yahoo.com/news/cassava-sciences-reports-first-quarter-130000375.html

“Cognition Maintenance Study (CMS) – on-going
In May 2021, we initiated a Cognition Maintenance Study (CMS). This is a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer’s disease. Study participants are randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. The CMS is designed to evaluate simufilam’s effects on cognition and health outcomes in Alzheimer’s patients who continue with drug treatment versus patients who discontinue drug treatment. The target enrollment for the CMS is approximately 100 subjects. Over 75 subjects have been enrolled in the CMS and 35 have completed the study.”

Even though the open label study was not randomized, this one will be.

Only someone who has actually taken care of  patients would know the following.  People who are getting no benefit from a drug will soon stop taking it.  This was particularly true for my experience with Cognex for Alzheimer’s disease.

Which is exactly why the fact that 75 patients who’ve been on Simufilam have decided to continue on in the CMS study.  Presumably they feel they are getting some benefit.

There are two possible hookers to this

l. The patients are being paid to enter CMS

2. The original cohort was 200, not all of whom have finished the 1 year.  So we don’t know how many could have been in CMS but chose not to.

As I discussed in an earlier post, the most impressive thing (to me at least) was that at 9 months 5/50 had significant improvement in their cognition — here’s a link — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

The CMS study should give us an idea of how they fared at 1 year and  at 18 months.

If:

l. gains in cognition were maintained on Simufilam

2. gains in cognition were lost off Simufilam

FDA approval should follow quickly.

Results on the 75 will be available this year.   Also available this year will be 1 year results on all 200 entering the open label study.

There are two other double blind studies in progress which will provide  more definitive answers, but they are far from full and will take much longer to complete.  So stay tuned.

Clinical reality comes to animal models of genetic disease

“So you’re going to be experimenting on me, doc?”  I heard that a fair amount practicing neurology in Montana.  There is no guarantee that any drug we use will always work, particularly drugs for epilepsy (anticonvulsants).  When one of them didn’t, it was always obvious.

Being honest with patients, I’d always say we’ll try drug X, it has a high chance of working.  And that was the (actually quite intelligent) response I sometimes got.

I’d then launch into some sort of explanation, saying that people aren’t cars and not all the same so they don’t respond the medications the same way (cue up rare side effects).  Of course in the 70’s and 80’s we had no idea just how different each of us actually is.

Now we do and this is even true for children in which the copies of their parents genomes is far from exact– https://luysii.wordpress.com/wp-admin/post.php?post=3442&action=edit&classic-editor —

From the ENCODE study.  Some 2,976 parent child trios had their whole genomes sequenced.  There were 200,435 de novo mutations in the group (an average of 67 mutations/child).  The number of de novo mutations increases by 1.39% for each year of paternal age and .38% for each year of maternal age at the time of the birth of the child.  Earlier work with far less data implied that maternal age at conception was irrelevant to the mutation rate — this is clearly incorrect.

The same variation in genomes is another pitfall in understanding what effects a protein mutation has when studied in animals.  Up to now research has been done in very inbred animal strains which all have exactly the same genome, to cancel out the variability in response. Usually just one inbred strain is studied.  This is good.

No it’s bad !! [ Neuron vol. 111 pp. 539 – 556 ’23 ] studied one particular mutation in a protein called CHD8 which is associated with autism in man.  They put the mutated protein into 1,000 mice from 33 different strains and measured a variety of phenotypes (brain and body weights, cognition, activity, social behavior, exploratory activity in an open field, etc. etc.).

Guess what?  The same mutant in the same protein had a wide variety of phenotypes which depended on the strain and sex.  Some strains showed no phenotypic effects at all, while others showed many large effects.

So a lot of animal work on disease should be repeated (or at least taken with several grains of salt) on multiple strains.

So experimental animals are just like people responding to drugs that docs experiment with on them

Location bias

Location bias:  no this isn’t about real estate or red lining.  It’s about how drugs act differently depending on where they’re able to get.  If this sounds too abstract, location bias may explain why dimethyl tryptamine (DMT) is a hallucinogen (it is the main psychoactive component of ayahuasca) and why serotonin (5 hydroxy tryptamine) is not.

The psychoactive effects of many drugs (LSD, DMT) are explained by their binding to one of the many (> 13) subtypes of serotonin receptors, namely 5HT2AR.

Well serotonin certainly binds to 5HT2AR, so why doesn’t it produce hallucinations?  This is where [ Science vol. 379 pp. 700 – 706 ’23 ] (and local bias) comes in.

We tend to think of receptors for neurotransmitters (like serotonin) as being on the outer membrane of the cell (the plasma membrane).  This makes sense as neurotransmitters are released from neurons into the extracellular space.  However it is now known that some neurotransmitter receptors (such as 5HT2AR) are found inside the cell where they are found on endosomes and the Golgi apparatus.

The article claims that the hallucinogenic effects of DMT, LSD etc. etc. are due to their binding to 5HT2ARs found inside the cell, not those on the plasma membrane. Serotonin with its free OH and NH2 groups is simply too water soluble (hydrophilic) to pass through the lipids of the plasma membrane.   DMT and LSD are not.   Unfortunately we are a long way from understanding how activation of 5HT2ARs inside the cell leads to hallucinations, but if the authors are right, it’s time to look.

We don’t know if animals hallucinate, and use things like head twitch and effects on dendritic branching and size in tissue culture as markers for hallucinations as LSD, DMT produce these things,.

The authors do show that putting a serotonin transporter into neuronal cultures so serotonin gets inside, produces similar effects on dendritic branching and size.  While fascinating, these effects are  pretty far removed from clinical reality.

The authors do raise a fascinating point at the end of their paper.  Perhaps there are endogenous intracellular ligands for intracellular 5HT2AR which differ from serotonin.   Perhaps the hallucinations and mental distortions of schizophrenia and other psychiatric disease are due to too much of them.