The evolutionary construction and magnification of the human brain

Our brains are 3 times the size of the chimp and more complex.  Now that we have the complete genome sequences of both (and other monkeys) it is possible to look for the protein coding genes which separate us.

First some terminology.  Not every species found since the divergence of man and chimp is our direct ancestor.  Many banches are extinct.  The whole group of species are called hominins [Nature vol. 422 pp. 849 – 857 ‘ 03 ].  Hominids are species in the path between us and the chimp — sort of a direct line of descent.  However the terminology is in flux and confusing and I’m not sure this is right.   But we do need some terminology to proceed.

Hominid Specific genes (HS genes) result which result from recent gene duplications in hominid/human genomes.  Gene duplication is a great way for evolution to work quickly.  Even if one gene is essential, messing with the other copy won’t be fatal.  HS genes include >20 gene families that are dynamically expressed during the formation of the human brain.  It was hard for me to find out just how many HS genes there are.

Here are some examples. The human-specific NOTCH2NL genes increase the self-renewal potential of human cortical progenitors (meaning more brain cell can result from them).  TBC1D3and ARGHAP11B, are involved in basal progenitor amplification (ditto).

A recent paper [ Neuron vol. 111 pp. 65 – 80 ’23 ] discusses CROCCP2 (you don’t want to know what the acronym stands for) which is one of several genes in this family with at least 6 copies in various hominid genomes.  However, CROCCP2 is a duplicate unique to man.   It is highly expressed during brain development and enhances outer Radial Glial Cell progenitor proliferation.

The mechanism by which this happens is detailed in the paper and involves the cilium found on every neuron, mTOR, IFT20 and others.

But that’s not the point here, fascinating although these mechanisms are.   We’re watching a series of at least gene duplications with subsequent modifications build the brain that is unique to us over relatively rapid evolutionary times.  The split between man and chimp is thought to have happened only 8 million years ago.

What should we call this process?  Evolution?  The Creator in action? The Blind Watchmaker?   It is certainly is eerie to think about.  There are 17 more HS genes to go involving in building our brains remaining to be worked out.  Stay tuned

Overblown Stock Market Reaction to Simufilam results

The stock market reaction to Simufilam’s 1 year open label results is extremely overblown.  Here is a link to the results — https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-announces-positive-top-line-clinical-results

First: no other therapy has shown improvement in Alzheimer patients.  The best they can claim is a slower rate of decline.

Second: In 30+ years of clinical neurologic practice, I never saw anyone with Alzheimer’s get better after a year. One or two remained stable for a year, but everyone else got worse. Cassava’s results are impressive (with nearly half improving at one year)  and unique. There is little reason to doubt them, given the way the data has been handled.

Third: even though not a controlled study, a placebo effect is extremely unlikely given my clinical experience with Cognex (Tacrine) when it came out — for details please see — https://luysii.wordpress.com/2023/01/25/why-cassavas-simufilam-results-are-not-a-placebo-effect/

Fourth: the realities of clinical practice.  Assuming that Simufilam is released with data similar to the 1 year results, as a physician I would be remiss if I didn’t offer a drug with nearly a 50% chance of improvement at one year, given the current miserable therapeutic landscape.  Back in the day no patient refused trying Cognex.  Then there is the likelihood of being sued for NOT giving Simufilam, as people were sued for not giving tissue plasminogen activator for stroke, a therapy with minimal evidence for it when it came out — for details please see — https://luysii.wordpress.com/2015/09/02/reproducibility-and-its-discontents/

Fifth: the fact that not everyone responds to Simufilam is irrelevant to eventual FDA approval.  Given all the illnesses we are heir to, even the best drug for any particular illness among the many does not work for everyone with it.  For more on these thoughts please see – https://luysii.wordpress.com/2023/01/26/the-fact-that-not-everyone-responds-to-simufilam-is-irrelevant-to-its-eventual-fda-approval/

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.  

Why Cassava’s Simufilam results are not a placebo effect

Any open label study without controls is subject to the reasonable criticism that any benefits seen are due to the placebo effect.  Neurologic and Psychiatric disease trials can have large (33%) placebo effects (e.g. migraine, depression).

This is very unlikely to be the case with the 1 year results of the open label trial of Simufilam in 200 patients with Alzheimer’s disease.  “47% of patients improved on ADAS-Cog over 1 year, and this group improved by 4.7 points”

It is based on my clinical experience with a drug for Alzheimer’s disease released 30 years ago — Tacrine (Cognex).  Initially it was touted as helping Alzheimer’s disease (e.g. improving thinking and memory) although later it was held to slow the decline.   The local medical school advertised it aggressively (primarily as a marketing device).

So I put my Alzheimer patients on Cognex.  I wanted them to get better. They wanted to get better, and their families and caregivers certainly did.  Just about all of them thought it might have helped on followup visits in the first month.  I couldn’t see much difference.  By the second month, they weren’t sure, and later in the first year they didn’t think it helped, and most weren’t using the drug after 1 year.

Not only that, but I was in a call group with 4 other neurologists, and they saw exactly the same thing.  I was practicing in an area with a catchment area of over a million people, and every local neurologist I talked to had the same experience. People thought that “Cognex helped” for a month or two and then they didn’t

This a classic example of a placebo effect.  Moreover it occurred in a therapeutic trial for Alzheimer’s disease.  Crucially, the placebo effect was quite transient and  absent at 1 year.

This is why the Simufilam results mentioned above are not a placebo effect.

Those not interested in neuropharmacology can stop at this point.  There were excellent clinical and theoretical reasons for the use of Tacrine.

Clinically it was apparent that drugs that blocked the effects of the neurotransmitter acetyl choline on one type of its receptors (muscarinic) profoundly impaired memory. Scopolamine is one such drug.  One of the earliest and most invariable symptoms of Alzheimer’s disease is deficient memory.

That’s the clinical part.  Here’s the theory.  So logically, increasing acetyl choline should help memory.  How to do this?  Well there are enzymes that break acetyl choline down (the acetyl cholinesterases).  So by inhibiting cholinesterases, acetyl choline levels in the brain should increase, and memory should be improved.

Impeccable logic and theory.  Unfortunately, like many such it didn’t work.

Faure was doing jazz before there was jazz

My friends and I were playing Faure’s only piano trio a few days ago.  It was Opus 120 written toward the end of his long life (1845 – 1924). The second movement was nice and slow starting with the piano just playing Bill Evans 60’s and 70’s chords under the melody.   It really should swing gently, something beyond the ken of a purely classically trained musician.  Example: Jean Pierre Rampal trying to swing the Claude Bolling work for piano and flute — https://www.youtube.com/watch?v=Vh7HzrJkers.   Spoiler alert: despite being a fabulous flutist, Rampal just doesn’t swing.

Some jazz musicians can do classic — see Michaela Petri and Keith Jarrett  on the Bach flute sonatas — https://www.discogs.com/release/3888414-Keith-Jarrett-Michala-Petri-Bach-Sonatas

Jazz in the 20’s was about dixieland, the blues and big bands, so Faure was really influencing the jazz that came later.  Here’s a link to Evans playing Pavane for a dead Princess among other classics –https://en.wikipedia.org/wiki/Bill_Evans_Trio_with_Symphony_Orchestra.  I have the album, and Evans doesn’t muck about with the chord structure (he doesn’t need to)  although being jazz the Pavanne isn’t played entirely straight.

Afterwards, I remembered another very jazzy part in Faure’s first piano quartet (premiered in 1880 !)  It’s only a few measures long, but with chord shifts every quarter note, augmented fifths, major 7ths and a great descending base line, all under a 3 quarter note melody, which repeats 4 times as the chords shift under it.  Pure jazz.  Unfortunately my score doesn’t have measure numbers but if you happen to own the International Edition, it occurs just before K in the first movement on page 14.

If any of you know of further jazz in Faure’s work add your comment to this.

The synapse is not a oneway street

Back in the day when I was a Med student at Penn ’62 – ’66 and not that far away from the first programmable computer (The ENIAC) built at Penn in the 40’s using vacuum tubes (the transistor was far in the future) we ‘knew’ that information flowed across the synapse in one way, the same way that current flowed just one way in vacuum tubes.  Our conception of the synapse that way was that the presynaptic side was the master and the post synaptic side was the slave.  It worked well as a model of how the brain computes things initially, with current flowing through boolean diagrams of neurons.  It still works pretty well today with neural nets where information flows pretty much in one way through the layers of ‘neurons’.

Well that’s not the way we think about the synapse today, and an excellent paper [ Neuron vol. 110 pp. 4144 – 4161 ’22 ] brings it home.  It shows that the same axon releases its neurotransmitter (glutamic acid) differently depending on what post-synaptic neuron it is innervating.

When the axon from a pyramidal neuron synapses on a fast spiking parvalbumin containing interneuron there is a high probability of glutamic acid release with each nerve impulse (action potential).  The same axon when innervating another type of interneuron (containing somatostatin), the release probability is 10fold lower.

So it all depends on what is being innervated.  The somatostatin interneuron expresses Elfn1 (you don’t want to know what this acronym is for) which activates a presynaptic receptor for glutamic acid (mGluR7) which reduces synaptic release probability.

This isn’t seen in the parvalbumin interneurons.  Essentially the post-synaptic neuron is partially controlling the presynaptic neuron.

The work was done in the hippocampus, where the neuroanatomy and neurochemistry has been worked out better than most areas of the brain.  How widespread differential release of transmitter is, will have to wait until we understand the neuroanatomy of other brain areas better.

If you want to read about the building of the ENIAC at Penn, have a look at the following post — https://luysii.wordpress.com/2022/09/18/book-review-proving-ground-kathy-kleiman/.  Trigger warning — the women who figured out how to program the ENIAC were not treated particularly well but decades later received the recognition they deserved.

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/

The origin of runner’s high

There is a great moment (for the neuropharmacologist) in “Postcards from the Edge” with Meryl Streep.  She’s walking along with the bimbo who she just found out seduced the guy who seduced her, when the bimbo blurts out that she feels great because of her endolphins.

Well exercise may raise endorphins in the blood which many regarded as an explanation of the runner’s high.   But almost as soon as the endorphins were discovered, it was found that they don’t get into the brain when injected into the blood.   (If you’re wondering how we can know this, it is based on a synthetic endorphin containing a radioactive atom — injecting it into the blood stream shows it doesn’t get into the brain.

This shouldn’t be surprising, the brain is quite selective about what it lets in.  Consider the first useful treatment of Parkinson’s disease, L-DOPA (L DihydrOxy PhenylAlanine) which does get into the brain, which then breaks it down to dopamine losing two oxygens in the process, which doesn’t get into the brain (even though dopamine is a smaller and less complicated molecule).   Functionally, this is known as the blood brain barrier (BBB).

So maybe exercise raises endorphrins in the brain, but a better explanation for the runner’s high is now at hand [ Nature vol. 612 pp. 633 – 634, 739 – 747 ’22 ].  You won’t believe the answer, which involves the organisms in your gut, but the evidence is quite good, as you are about to read.

First, the composition of the gut microbiome predicts how much mice voluntarily run on exercise wheels or treatmills.  Treatment with antibiotics which diminishes the amount of microbiota diminishes exercise endurance.  Adding the gut microbiome from high exercise mice to germ free mice (gnotobiotic mice) raises running capacity to that of the donor.

Increased levels of dopamine are considered rewarding or pleasurable.  Cocaine prevents it from being taken up after neurons release it, an antidepressant (Monamine Oxidase — MAO) prevents it from being destroyed. etc. etc.

It is known that exercise increases the levels of dopamine in an area of the brain called the striatum.  Dopamine gets to the striatum by the axons of neurons in the ventral tegmental area (VTA).  Inhibition of neurons in the VTA decreases dopamine in the striatum and decreases the amount of exercise a mouse will do.

What does the gut microbiota have to do with this?

Well, germfree (gnotobiotic) mice didn’t change MAO levels in the striatum on exercise, and the dopamine surge and striatal neural activity were blunted.  And germfree mice don’t run as much.

Well, clearly the little bugs down there are producing some sort of signal which IS getting to the brain, not an easy feat getting past the blood brain barrier given the example of L-DOPA above.

We know the bugs produce all sorts of metabolites, the body uses.  One example is vitamin K, which is crucial in the biochemical maturation of coagulation factors, deficiencies of which produce hemorrhagic disease of the newborn. This may explain why the ritual circumcision of Jewish males occurs 8 days after birth, after the gut bacteria have had a chance to make it.

The work cited above shows that the bugs produce fatty acid amides (FAAs) which bind to the type I cannabinoid receptor (CB1) which binds marihuana.

Like just about everything else in the body, there are sensory nerves from the gut going to the spinal cord.  The FAAs activate some of these nerves by binding to CB1.   Giving FAAs to germfree mice increases physical activity.

Gut sensory nerves containing CB1 also have another protein called TRPV1.  Stimulating these nerves with a TRPV1 ligand increases physical activity.  This is true even in germfree mice.

Well we know marihuana has no trouble getting pCast the BBB, so why couldn’t the FAAs produced by the bugs do the same and increase exercise.   Well, it could but it doesn’t.  Severing the sensory nerve before it gets to the spinal cord abolishes the effects of the microbiome (which is still there) on exercise.

So, clearly the continuity of the nerve is crucial for the effect of gut bacteria on exercise, as are FAAs and the CB1 receptor found on the nerve.

Well the sensory nerve from the gut gets into the spinal cord, but there is a lot more work to be done, to determine the pathway by which stimulation of the nerve changes MAO levels in the striatum (as the striatum is a long way from the spinal cord).   So like all great experiments, it suggests further questions and work required to resolve them.

A  beautiful series of experiments.  Could brain ‘endolphins’ still play a role in exercise.  Sure,  but whether they do or not, doesn’t detract from the work here.

One could study the effect of exercise on brain (not blood) endorphins and the effect of cutting the sensory nerve from the gut on their brain levels.

 

 

 

New Year’s Wish

My wife and I are staying up until midnight to make sure that 2022 really comes to an end.

 

Orwell does Stanford, Stanford does Newspeak

At the end of 1984, Orwell adds a non-novelistic appendix — “The Principles of Newspeak”

” Newspeak was the official language of Oceania (what England and Europe had become).    . . ..  The purpose of Newspeak was not only to provide a medium of expression for the world-view and mental habits proper to the devotees of Ingsoc or English Socialism, but to make all other modes of thought impossible.”  …

“This was done partly by the invention of new words, but chiefly by eliminating undesirable words … ”

“It was intended that when Newspeak had been adopted once and for all and Oldspeak forgotten …  a thought diverging from the principles of Ingsoc — should be literally unthinkable, at least so far as thought is dependent on words.”

Which brings us to 20 December ’22 and an editorial in the Wall Street Journal titled “The Stanford Guide to Acceptable Words” — unfortunately behind a paywall.   Stanford administrators apparently published an index of forbidden words to be eliminated from the school’s websites and computer codes, with inclusive replacements.   Somehow it came to light this month, and Stanford has hidden it because of the hilarity it induced, so we can’t enjoy it.

Fortunately, the WSJ editorial does provide a few examples

American is to be replaced by U. S. Citizen

Immigrant is to be replaced with person who has immigrated

Master (as in mastering a subject) is out because of its slavery connocations

Not to beat a dead horse is gone because it “normalizes violence against animals”

The list was prefaced with a trigger warning (a phrase no  longer to be used) “This website contains language that is offensive or harmnful. Please engage with this website at your own pace.

The editorial concludes by noting that ‘stupid’ is on the list.

How prescient Orwell was

The previous post in the series shows how his idea of doublethink encapsulates what chemists must do to use quantum mechanics to understand atoms.  — https://luysii.wordpress.com/2022/12/27/orwell-does-quantum-mechanics/

The one before that anticipates the 180 degree reversal of COVID advice in China — https://luysii.wordpress.com/2022/12/26/orwell-does-china/