I was going to comment upon the comment you made in another post about Gilbert Ling. I'd never heard of them or their ideas and had to go looking the other night. As a result I now know why I never did.
I am extremely tired right now and in the middle of preparing for my thesis committee meeting, so I cannot give this the attention it deserves right now. Come back in a day or three and I will either expand this reply or make another one.
For now:
*From what I've seen, Ling's ideas seem to originally be based upon a few equivocal experiments from the sixties and seventies that have since been contradicted by just about all cellular electrophysiology, enzymology, and membrane biology known.
*All the odd results they point to about ion balance requiring too much energy to be accounted for via active-transport ion pumps in the membrane have been solved to my satisfaction by more recent work, especially in neurons, and all their talk about cells with compromised membranes maintaining ion balance seem like they can be explained by work on calcium-triggered membrane vesicle fusion from the nineties.
*This proposed role for ATP in unwinding proteins is experimentally unsupported by an...
I think this post illustrates the kind of thinking that made me hate molecular biology. I started studying bioinformatics with the plan of afterwards making a master in neuroinformatics and do congitive enhancement. I used to believe.
You basically think that there something called intelligence with has a clear definition which you don't have to establish. Then you say that evolution tried to maximize that intelligence and think that the thing that contrains intelligence obviously falls in your domain of molecular biology and has to be ATP.
A while ago I tried to get a performance metric for my brain functioning and did it through a bunch of reaction tests. At the beginning I called it intelligence. I talk with a psychology phd and he told me if I wanted to speak to an academic audience I shouldn't use the word intelligence but rather speak about cognitive performance.
Ten million years ago our ancestors made decisions very differently than todays humans do. Today's humans use very different heustrics to make decisions and there no good reason to assume that we spent a lot of time from an evolutionary perspective to optimize our brains to make decisions based on those heuristics.
Thos...
The massive variation in human intelligence and the positive correlation between IQ and pretty much everything good implies that "Any simple major enhancement to human intelligence is a net evolutionary disadvantage" isn't true
Also, it's possible that humans were quickly evolving towards being more intelligent when they got interrupted by the invention of civilization and there's still more low-hanging fruit to be picked.
Not in this case. This is a good example of how you can go wrong by overcontrolling (or maybe we should chalk this up as an example of how correlations!=causations?)
Suppose the causal model of Genes->Intelligence->Education->Less-Reproduction is true (and there are no other relationships). Then if we regress on Less-Reproduction and include Intelligence & Education as predictors, we discover that after controlling for Education, Intelligence adds no predictive value & explains no variance & is uncorrelated with Less-Reproduction. Sure, of course: all Intelligence is good for is predicting Education, but we already know each individual's Education. This is an interesting and valid result worth further research in our hypothetical world.
Does this mean dysgenics will be false, since the coefficient of Intelligence is estimated at ~0 by our little regression formula? Nope! We can get dysgenics easily: people with high levels of Genes will cause high levels of Intelligence, which will cause high levels of Education, which will cause high levels of Less-Reproduction, which means that their genes will be be selected against and the next generation start with lower Ge...
Birds (especially corvids and parrots) seem to pack surprising amounts of intelligence into small brains. Could there be some efficiencies worth studying there?
My understanding was that when humans learned to cook, this essentially allowed us to outsource our digestion to fire, use fewer calories digesting, and thus dramatically increase the net number of calories we got from eating (or something like that), and that this energy jackpot played a big role in our evolution of larger brains.
Anyway, interesting post. RomeoStevens suggested consuming foods high in glucose the other day when I was complaining about being tired, and that actually seemed to work pretty well. So I'm eager to hear about research along th...
To Casiothesane and others, or anyone reading in the future, it’s probably bad form to comment on a 6 year-old post and also, probably not fair to the opinions of those who have had six years to emend them, even if they still have the same views they may express them more persuasively, now, or in ways I could not anticipate. That qualification given, I suggest people interested in this topic look into the work of Thoke, Olsen, Bagatolli and colleagues, who have made progress on Ling’s AI theory in the last three years (like Google those names and “water” “
Brain energy is often confused with motivation, but these are two distinct phenomena. Brain energy is the actual metabolic energy available to the neurons, in the form of adenosine triphosphate (ATP) molecules. ATP is the "energy currency" of the cell, and is produced primarily by oxidative metabolism of energy from food.
I think you are right but it isn't as obvious as that. See Roy Baumeister and the thesis that will power is due to blood glucose levels.
Brains use less energy when they're doing familiar skills than when they're learning. Perhaps there's some energy to be freed up if learning can be made more efficient.
I don't see how
maintaining the low entropy living state in a non-firing neuron requires little energy. This implies that the brain may already be very efficient, where nearly all energy is used to function, grow, and adapt.
leads to the assertion that intelligence is cell-energy limited and that increasing brain metabolism (on timescales shorter than evolutionary) will lead to increased IQ. In particular, I don't know of evidence that starving people become stupid.
https://freethoughtblogs.com/pharyngula/2022/10/24/one-way-to-be-less-wrong-is-to-avoid-faulty-premises/
I'm gonna split up this reply, since I think part of it is important enough to be seen more and will go into a higher-level reply to the post itself. I will also preface this by saying that my primary areas of expertise are in energy metabolism (mostly glycolysis) and the cell division cycle, along with all the basic enzymology you need to know to do molecular biology.
As for ATP thermodynamics, I looked deeper into Ling's writings before replying and was more and more distressed by what I saw. They literally cannot correctly do thermodynamics and biochemistry that I learned in my senior year of high school. The end result of several extremely basic math and conceptual errors in their justification for their theories is that their calculated value for the free energy available from cellular metabolism to pump sodium and potassium across the membrane is approximately 1/12 the true value! Given that this is approximately the figure they give for the factor of insufficiency of cellular metabolism to provide enough energy to run the pumps (they give a factor of 15-30 [without stating the error bars] ), and that I have other reasons to distrust almost everything this person has ever done, it is safe to say that Ling's objection to the sodium/potassium pump on thermodynamic grounds is quite simply unjustified.
I will be walking through this in more detail in my other top-level reply along with other reasons that you shouldn't accept their work at face value.
I will only say more about the thermodynamics of the sodium potassium pump by pointing to a paper that I found after a few moments of google scholar searching indicating that hepatocytes under oxygen starvation conditions not dissimilar to those described in Ling's experiments put about 75% of their cellular energy into maintaining the ion gradient, but that under normal circumstances they use a much more reasonable less than one quarter. This is not an unexplored area of research and insinuating that there is some sort of controversy here is simply false.
I will summarize the research on membrane formation and calcium-mediated membrane vesicle fusion before linking to a paper that you can see figures of without a paywall.
Membrane lipids and the contents of membrane-bound compartments move around between compartments via vesicles. Proteins are extruded into the interior of the endoplasmic reticulum compartment before being packaged through a series of other membrane-bound organelles before being secreted, and all the membrane-lipid-building enzymes are for the most part embedded in the ER membrane so the lipids have to get from there to all the other membranes somehow. This turns out to be done via extremely tiny submicroscopic vesicles. They are rather smaller than the wavelength of light because they are pinched off their parent membranes by molecular machines consisting of single-digit numbers of protein molecules and thus are invisible to a light microscope but you can see them with an electron microscope and in some places, like the growing tips of fungal threads, they are densely packed enough that they make the cytoplasm milky.
These vesicles are attached to their destination membranes by a complex of proteins called SNARES which require calcium to work. V-SNARES on the vesicles bind to T-SNARES on the destination membranes and as the complex forms they warp the membranes and cause them to fuse. I've seen very interesting molecular simulations from the Folding@Home project of this process, which if I recall correctly indicated that as the membranes get warped and pushed together by the binding together of the SNARES, the hydration shells of the hydrophilic head groups of the lipids clash and produce interesting ordered structures that suddenly exclude all solvent from between the two membranes, causing the membranes to rapidly fuse.
Calcium is ordinarily excluded from the cytoplasm almost entirely, being sequestered into the ER compartment and the extracellular fluid. As a result SNARE function is normally very slow, except near the surface of membranes that bear calcium channels. In neurons, calcium rushes in for a miniscule fraction of a second after the neuron fires and this is what mediates the fusion of neurotransmitter-carrying vesicles to the presynaptic membrane allowing the signal to be passed to another neuron.
Cells DO get rips and tears in their membranes but often manage to repair them before losing undue cell contents. The main research on how this happens was done in starfish and echinoderm egg cells and embryos because they are cheap ways of getting lots of cytoplasm. A representative paper can be seen here: “Large Plasma Membrane Disruptions Are Rapidly Resealed by Ca 2+ dependent Vesicle–Vesicle Fusion Events”.
Figure 1: something like an eigth of the membrane of a starfish egg is torn off and while there is an initial puff of cytoplasm that squirts out, a new membrane forms behind it and retains the cell contents within seconds.
Figure 2: same thing but in an egg that had been injected with a substance that only glows in the presence of calcium ions. Upon membrane tearing the calcium RUSHES in rapidly, and the area of very high concentration is where the new membrane forms. The remaining calcium that makes it past the new barrier then diffuses throughout the rest of the cell rather than being excluded from some kind of water matrix.
Figure 5: injecting fluorescent dye without calcium into a starfish egg lets the dye immediately diffuse throughout the cell, while injecting it with calcium ions causes a vesicle to form around the dye containing it and preventing it from getting into the cytosol.
Figure 7: the cytoplasm around a vesicle formed like in figure 5 is full of membrane vesicles of odd shapes and sizes.
Figure 9: starfish egg cytoplasm dripped out of a needle into non-calcium-containing media loses a fluorescent dye in it to the media, while when dripped into calcium-containing media it forms a membrane and holds it in.
Figure 10: cytoplasm centrifuged so that it no longer contains membrane-bound vesicles is unable to form a barrier in response to calcium while the centrifuged down membranous organelles and vesicles are able to.
Figure 11: a diagram of the proposed mechanism.
It appears that when the horrifically abnormally high levels of calcium that appear when a membrane is cut hit the small membrane vesicles present in the cytoplasm, they rapidly indiscriminately fuse until they manage to create a new membrane barrier from themselves and any other membranes they touch that holds the cytoplasm in and restores ion sequestration. Other papers both before and after this saw the resealing of membranes in normal body cells but were unable to closely examine it, the large egg cells made it possible to do all these interesting manipulations.
This immediately suggests an explanation for Ling's experiment in which they sliced frog muscle cells in half and put the cut ends in an ion solution (“Ringer's solution”) which they measured the ion flux in and out of and saw it was normal. I note that Ringer's solution contains large amounts of calcium. They claim that they checked via electron microscopy that the cytoplasm did not reseal, but the insides of muscle fibers are horrifically dense complicated places and there's no guarantee that it resealed RIGHT at the cut site – it could have resealed microns or even millimeters away.
Excellent post, thanks for putting so much work into a clear explanation. I will re-investigate Ling's work more carefully, and also see if I can find the mistakes in his thermodynamics calculations you mention. I have been biased towards his work and not looking critically enough, because it seems to explain some surprising observations about drug activity I've found in my own research- but that's no excuse.
I am interested in the possibility that Ling could be entirely wrong about membrane physiology, but this gel phase shift phenomena could still be impo...
Introduction
Brain energy is often confused with motivation, but these are two distinct phenomena. Brain energy is the actual metabolic energy available to the neurons, in the form of adenosine triphosphate (ATP) molecules. ATP is the "energy currency" of the cell, and is produced primarily by oxidative metabolism of energy from food. High motivation increases the use of this energy, but in the absence of sufficient metabolic capacity it eventually results in stress, depression, and burnout as seen in manic depression. Most attempts at cognitive enhancement only address the motivation side of the equation.
-Ray Peat, PhD
Cellular Thermodynamics
-Eliezer Yudkowsky (Algernon’s Law)
I propose that this constrain is imposed by the energy cost of intelligence. The conventional textbook view of neurology suggests that much of the brain's energy is "wasted" in overcoming the constant diffusion of ions across the membranes of neurons that aren't actively in use. This is necessary to keep the neurons in a 'ready state' to fire when called upon.
Why haven't we evolved some mechanism to control this massive waste of energy?
The Association-Induction hypothesis formulated by Gilbert Ling is an alternate view of cell function, which suggests a distinct functional role of energy within the cell. I won't review it in detail here, but you can find an easy to understand and comprehensive introduction to this hypothesis in the book "Cells, Gels and the Engines of Life" by Gerald H. Pollack (amazon link). This idea has a long history with considerable experimental evidence, which is too extensive to review in this article.
The Association-Induction hypothesis states that ion exclusion in the cell is maintained by the structural ordering of water within the cytoplasm, by an interaction between the cytoskeletal proteins, water molecules, and ATP. Energy (in the form of ATP) is used to unfold proteins, presenting a regular pattern of surface charges to cell water. This orders the cell water into a 'gel like' phase which excludes specific ions, because their presence within the structure is energetically unfavorable. Other ions are selectively retained, because they are adsorbed to charged sites on protein surfaces. This structured state can be maintained with no additional energy. When a neuron fires, this organization collapses, which releases energy and performs work. The neuron uses significant energy only to restore this structured low entropy state, after the neuron fires.
This figure (borrowed from Gilbert Ling) summarizes this phenomena, showing a folded protein (on the left) and an unfolded protein creating a low entropy gel (on the right).
To summarize, maintaining the low entropy living state in a non-firing neuron requires little energy. This implies that the brain may already be very efficient, where nearly all energy is used to function, grow, and adapt rather than pump the same ions 'uphill' over and over.
Cost of Intelligence
To quote Eliezer Yudkowsky again, "the evolutionary reasons for this are so obvious as to be worth belaboring." Mammalian brains may already be nearly as efficient as their physics and structure allows, and any increase in intelligence comes with a corresponding increase in energy demand. Brain energy consumption appears correlated with intelligence across different mammals, and humans have unusually high energy requirements due to our intelligence and brain size.
Therefore if an organism is going to compete while having a greater intelligence, it must be in a situation where this extra intelligence offers a competitive advantage. Once intelligence is adequate to meet the demands of survival in a given environment, extra intelligence merely imposes unnecessary nutritional requirements.
These thermodynamic realities of intelligence lead to the following corollary to Algernon’s Law:
Any increase in intelligence implies a corresponding increase in brain energy consumption.
Potential Implications
-Henry David Thoreau
This idea can be applied to both evaluate nootropics, and to understand and treat cognitive problems. It's unlikely that any drug will increase intelligence without adverse effects, unless it also acts to increase energy availability in the brain. From this perspective, we can categorically exclude any nootropic approaches which fail to increase oxidative metabolism in the brain.
This idea shifts the search for nootropics from neurotransmitter like drugs that improve focus and motivation, to those compounds which regulate and support oxidative metabolism such as glucose, thyroid hormones, some steroid hormones, cholesterol, oxygen, carbon dioxide, and enzyme cofactors.
Why haven't we already found that these substances increase intelligence?
Deficiencies in all of these substances do reduce intelligence. Further raising brain metabolism above normal healthy levels should be expected to be a complex problem because of the interrelation between the molecules required to support metabolism:
If you increase oxidative metabolism, the demand for all raw materials of metabolism is correspondingly increased. Any single deficiency poses a bottleneck, and may result in the opposite of the intended result.
So this suggests a 'systems biology' approach to cognitive enhancement. It's necessary to consider how metabolism is regulated, and what substrates it requires. To raise intelligence in a safe and effective way, all of these substrates must have increased availability to the neuron, in appropriate ratios.
I am always leery of drawing analogies between brains and computers but this approach to cognitive enhancement is very loosely analogous to over-clocking a CPU. Over-clocking requires raising both the clock rate, and the energy availability (voltage). In the case of the brain, the effective 'clock rate' is controlled by hormones (primarily triiodothyronine aka T3), and energy availability is provided by glucose and other nutrients.
It's not clear if merely raising brain metabolism in this way will actually result in a corresponding increase in intelligence, however I think it's unlikely that the opposite is possible (increasing intelligence without raising brain metabolism).