When does a description of something become an explanation ?

“It’s just evolution”. I found this explanation of the molecular biology underlying our brain’s threefold expansion relative to the chimp extremely unsatisfying.  The molecular biology of part of the expansion is fascinating and beautifully worked out. For details see a copy of the previous post below the ***.

To say that these effects are ‘just evolution’ is using the name we’ve put on the process to explain the process itself, e.g.  being satisfied with the description of something as an explanation  of it.

Newton certainly wanted more than that for his description of gravity (the inverse square law, action at a distance etc. etc.) brilliant and transformative though it was.  Here he is in a letter to Richard Bentley

“That gravity should be innate inherent & {essential} to matter so that one body may act upon another at a distance through a vacuum without the mediation of any thing else by & through which their action or force {may} be conveyed from one to another is to me so great an absurdity that I believe no man who has in philosophical matters any competent faculty of thinking can ever fall into it. ”

But the form of the force law for gravity combined with Newton’s three laws of motion (1687) became something much more powerful, a set of predictions of phenomena as yet unseen.

The Lagrange points are one example.  They are points of equilibrium for small-mass objects under the influence of two massive bodies orbiting their common center of gravity.  The first Lagrange points were found by Euler in 1750, Lagrange coming in 10 years later.  One of the Lagrange points of the Earth Sun  system is where the James Webb telescope sits today remaining stable without expending much energy to keep it there.  In a rather satisfying sense the gravitational force law explains their existence (along with Newton’s laws of motion and a lot of math).  So here is where a description (the force law) is actually an explanation of something else.

But Newton wanted more, much more than his description of the gravitational force (the inverse square law).  It took Einstein centuries later to come up with General Relativity — the theory of the gravitational force.  Just as a ball rolls down an incline here under the force of gravity, planets roll down the shape of Einstein’s spacetime, which is put there by the massive bodies it contains.  By shaping space everywhere, masses give the illusion of force, no action at a distance is needed at all.

It is exactly in that sense that I find the explanation for the 8 million year scuplting of our brain as evolution unsatisfying.  It is essential a description trying to pass itself off as an explanation.  Perhaps there is no deeper explanation of what we’re finding out.  Supernatural explanations have been with us in every culture.

Hopefully if such an explanation exists, we won’t have to wait over two centuries for it as did Newton.

*****

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 20 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

 

Force in physics is very different from the way we think of it

I’m very lucky (and honored) that a friend asked me to read and comment on the galleys of a his book. He’s trying to explain some very advanced physics to laypeople (e.g. me). So he starts with force fields, gravitational, magnetic etc. etc. The physicist’s idea of force is so far from the way we usually think of it. Exert enough force long enough and you get tired, but the gravitational force never does, despite moving planets stars and whole galaxies around.

Then there’s the idea that the force is there all the time whether or not it’s doing something a la Star Wars. Even worse is the fact that force can push things around despite going through empty space where there’s nothing to push on, action at a distance if you will.

You’ve in good company if the idea bothers you. It bothered Isaac Newton who basically invented action at a distance. Here he is in a letter to a friend.

“That gravity should be innate inherent & {essential} to matter so that one body may act upon another at a distance through a vacuum without the mediation of any thing else by & through which their action or force {may} be conveyed from one to another is to me so great an absurdity that I beleive no man who has in philosophical matters any competent faculty of thinking can ever fall into it. “

So physicists invented the ether which was physical, and allowed objects to push each other around by pushing on the ether between them. 

But action at a distance without one atom pushing on the next etc. etc. is exactly what an incredible paper found [ Proc. Natl. Acad. Sci. vol. 117 pp. 25445 – 25454 ’20 ].

Allostery is an abstract concept in protein chemistry, far removed from everyday life. Far removed except if you like to breathe, or have ever used a benzodiazepine (Valium, Librium, Halcion, Ativan, Klonopin, Xanax) for anything. Breathing? Really? Yes — Hemoglobin, the red in red blood cells is really 4 separate proteins bound to each other. Each of the four can bind one oxygen molecule. Binding of oxygen to one of the 4 proteins produces a subtle change in the structure of the other 3, making it easier for another oxygen to bind. This produces another subtle change in structure of the other making it easier for a third oxygen to bind. Etc. 

This is what allostery is, binding of molecule to one part of a protein causing changes in structure all over the protein. 

Neurologists are familiar with the benzodiazepines, using them to stop continuous seizure activity (status epilepticus), treat anxiety (Xanax), or seizures (Klonopin). They all work the same way, binding to a complex of 5 proteins called the GABA receptor, which when it binds Gamma Amino Butyric Acid (GABA) in one place causes negative ions to flow into the neuron, inhibiting it from firing. The benzodiazepines bind to a completely different site, making the receptor more likely to open when it binds GABA. 

The assumption about all allostery is that something binds in one place, pushing the atoms around, which push on other atoms which push on other atoms, until the desired effect is produced. This is the opposite of action at a distance, where an effect is produced without the necessity of physical contact.

The paper studied TetR, a protein containing 203 amino acids. If you’ve ever thought about it, almost all the antibiotics we have come from bacteria, which they use on other bacteria. Since we still have bacteria around, the survivors must have developed a way to resist antibiotics, and they’ve been doing this long before we appeared on the scene. 

TetR helps bacteria resist tetracycline, an antibiotic produced by bacteria. When tetracycline binds to TetR it causes other parts of the protein to change so it binds DNA causing the bacterium, among other things, to make a pump which moves tetracyline out of the cell. Notice that site where tetracycline binds on TetR is not the business end where TetR binds DNA, just as where the benzodiazepines bind the GABA receptor is not where the ion channel is. 

This post is long enough already without describing the cleverness which allowed the authors to do the following. They were able to make TetRs containing every possible mutation of all 203 positions. How many is that — 203 x 19 = 3838 different proteins. Why 19? Because we have 20 amino acids, so there are 19 possible distinct changes at each of the 203 positions in TetR.  

Some of the mutants didn’t bind to DNA, implying they were non-functional. The 3 dimensional structure of TetR is known, and they chose 5 of nonfunctional mutants. Interestingly these were distributed all over the protein. 

Then, for each of the 5 mutants they made another 3838 mutants, to see if a mutation in another position would make the mutant functional again. You can see what a tremendous amount of work this was. 

Here is where it gets really interesting. The restoring mutant (revertants if you want to get fancy) were all over the protein and up to 40 – 50 Angstroms away from the site of the dead mutation. Recall that 1 Angstrom is the size of a hydrogen atom, a turn of the alpha helix is 5.4 Angstroms and contains 3.5 amino acids per turn.The revertant mutants weren’t close to the part of the protein binding tetracycline or the part binding to DNA. 

Even worse the authors couldn’t find a contiguous path of atom pushing atom pushing atom, to explain why TetR was able to bind DNA again. So there you have it — allosteric action at a distance.

There is much more in the paper, but after all the work they did it’s time to let the authors speak for themselves. “Several important insights emerged from these results. First, TetR exhibits a high degree of allosteric plasticity evidenced by the ease of disrupting and restoring function through several mutational paths. This suggests the functional landscape of al- lostery is dense with fitness peaks, unlike binding or catalysis where fitness peaks are sparse. Second, allosterically coupled residues may not lie along the shortest path linking allosteric and active sites but can occur over long distances “

But there is still more to think about, particularly for drug development. Normally, in developing a drug for X, we have a particular site on a particular protein as a target, say the site on a neurotransmitter receptor where a neurotransmitter binds. But the work shows that sites far removed from the actual target might have the same effect

Action at a distance comes to chemistry

Allostery is an abstract concept in protein chemistry, far removed from everyday life. Far removed except if you like to breathe, or have ever used a benzodiazepine (Valium, Librium, Halcion, Ativan, Klonopin, Xanax) for anything. Breathing? Really? Yes — Hemoglobin, the red in red blood cells is really 4 separate proteins bound to each other. Each of the four can bind one oxygen molecule. Binding of oxygen to one of the 4 proteins produces a subtle change in the structure of the other 3, making it easier for another oxygen to bind. This produces another subtle change in structure of the other making it easier for a third oxygen to bind. Etc.

This is what allostery is, binding of molecule to one part of a protein causing changes in structure all over the protein.

Neurologists are familiar with the benzodiazepines, using them to stop continuous seizure activity (status epilepticus), treat anxiety (Xanax), or seizures (Klonopin). They all work the same way, binding to a complex of 5 proteins called the GABA receptor, which when it binds Gamma Amino Butyric Acid (GABA) in one place causes negative ions to flow into the neuron, inhibiting it from firing. The benzodiazepines bind to a completely different site, making the receptor more likely to open when it binds GABA.

The assumption about all allostery is that something binds in one place, pushing the atoms around, which push on other atoms which push on other atoms, until the desired effect is produced. This is the opposite of action at a distance, where an effect is produced without the necessity of physical contact.

Even though Newton invented a theory of gravity, which worked beautifully, he was disturbed by the fact that it acted through empty space. Here’s what he wrote in a letter to Bentley

“That gravity should be innate inherent & {essential} to matter so that one body may act upon another at a distance through a vacuum without the mediation of any thing else by & through which their action or force {may} be conveyed from one to another is to me so great an absurdity that I beleive no man who has in philosophical matters any competent faculty of thinking can ever fall into it. “

So physicists invented the ether which was physical, and allowed objects to push each other around by pushing on the ether between them.

But action at a distance without one atom pushing on the next etc. etc. is exactly what an incredible paper found [ Proc. Natl. Acad. Sci. vol. 117 pp. 25445 – 25454 ’20 ]. Here’s a link but it’s probably behind a paywall — https://www.pnas.org/content/pnas/117/41/25445.full.pdf

The paper studied TetR, a protein containing 203 amino acids. If you’ve ever thought about it, almost all the antibiotics we have come from bacteria, which they use on other bacteria. Since we still have bacteria around, the survivors must have developed a way to resist antibiotics, and they’ve been doing this long before we appeared on the scene.

TetR helps bacteria resist tetracycline, an antibiotic produced by bacteria. When tetracycline binds to TetR it causes other parts of the protein to change so it binds DNA causing the bacterium, among other things, to make a pump which moves tetracyline out of the cell. Notice that site where tetracycline binds on TetR is not the business end where TetR binds DNA, just as where the benzodiazepines bind the GABA receptor is not where the ion channel is.

This post is long enough already without describing the cleverness which allowed the authors to do the following. They were able to make TetRs containing every possible mutation of all 203 positions. How many is that — 203 x 19 = 3838 different proteins. Why 19? Because we have 20 amino acids, so there are 19 possible distinct changes at each of the 203 positions in TetR.

Some of the mutants didn’t bind to DNA, implying they were non-functional. The 3 dimensional structure of TetR is known, and they chose 5 of nonfunctional mutants. Interestingly these were distributed all over the protein.

Then, for each of the 5 mutants they made another 3838 mutants, to see if a mutation in another position would make the mutant functional again. You can see what a tremendous amount of work this was.

Here is where it gets really interesting. The restoring mutant (revertants if you want to get fancy) were all over the protein and up to 40 – 50 Angstroms away from the site of the dead mutation. Recall that 1 Angstrom is the size of a hydrogen atom, a turn of the alpha helix is 5.4 Angstroms and contains 3.5 amino acids per turn.The revertant mutants weren’t close to the part of the protein binding tetracycline or the part binding to DNA.

Even worse the authors couldn’t find a contiguous path of atom pushing atom pushing atom, to explain why TetR was able to bind DNA again. So there you have it — allosteric action at a distance.

There is much more in the paper, but after all the work they did it’s time to let the authors speak for themselves. “Several important insights emerged from these results. First, TetR exhibits a high degree of allosteric plasticity evidenced by the ease of disrupting and restoring function through several mutational paths. This suggests the functional landscape of al- lostery is dense with fitness peaks, unlike binding or catalysis where fitness peaks are sparse. Second, allosterically coupled residues may not lie along the shortest path linking allosteric and active sites but can occur over long distances “

But there is still more to think about, particularly for drug development. Normally, in developing a drug for X, we have a particular site on a particular protein as a target, say the site on a neurotransmitter receptor where a neurotransmitter binds. But the work shows that sites far removed from the actual target might have the same effect