In Defense Of Gilbert Ling - Ion Pumps Not Needed To Explain Cell Physiology

haidut

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The purported existence of pumps is the official reason why Gilbert Ling's AI hypothesis was removed from Wikipedia. I posted a few days ago about the "newly" discovered role of ATP as a protein hydrotrope and co-solvent - something Ling postulated back in the 1950s.
Gilbert Ling's Theory Confirmed - ATP Required For Protein Solubility & Aggregation Control
This is an older study (1975) but it does a good job of explaining why a sodium pump is not needed for the exclusion of sodium form the cell, as Ling also explained 25 years prior.
I think @Kyle M , @Such_Saturation and @burtlancast may like this paper.


A ROLE FOR WATER IN THE EXCLUSION OF CELLULAR SODIUM—IS A SODIUM PUMP NEEDED?
"...It is also known that since the middle of the 19th century, theories have existed which maintain that water in cytoplasm is not free as in dilute solutions but bound to macromolecular constituents.9 The concept of bound water in living tissues was pursued actively during the 1920's and 1930's. Since the 1950's, a small but persistent group of biological scientists have insisted that a large part or all of the cellular water exists in a physical state significantly different from ordinary water.10" 3 Thus, two schools of thought emerged concerning the physical state of cellular water, and hence two schools of thought concerning transport and accumulation of solutes in living cells."

"...Electrolyte composition in milliequivalents per kilogram fat-free wet weight as a function of animal age is given in Figure 1. Potassium concentration increases, becoming constant between 32 and 64 days of age. Sodium and chloride concentrations exceed the potassium concentration at birth, but rapidly decrease during the first 10 days of postnatal life. Again, the concentrations of these muscle electrolytes become constant between 32 and 64 days of age. This general phenomenon was defined as chemical maturation by Moulton in 1923."

"...In a review of the literature, the evidence for active cellular transport is, at best, equivocal. To be more explicit, a report of a definitive experiment demonstrating the movement of sodium or any other ion from a free solution of low concentration within a cell to a free solution of high concentration outside the cell was not found (Fig. 5).: Even the experiments with extruded squid axons32-34 and red blood cell ghosts have failed to demonstrate active transport."

"...It is true that in the context of membrane theory the presence of an enzyme system such as the Na+ - K+ ATPase is mandatory and that the demonstration of the same would, at first glance, appear to be proof of the pump concept. It must be remembered, however, that the first and subsequent pumps were invented out of necessity stemming from the assumption that the cellular ions and water were in free solution. The sodium pump is presented anthropomorphically in Figure 6. The creation of a membrane-situated energy-requiring pump endowed with the capacity to transfer ions across membranes against concentration gradients and, sometimes, electrical gradients, requires first the demonstration of an adequate energy supply. Twelve years ago, Gilbert Ling published his book entitled "A Physical Theory of the Living State: The Association Induction Hypothesis." I call to your attention Figure 7, which is in Chapter 8, Table 8.9, page 211 of Ling's book."

"...According to this ledger sheet, a rather large discrepancy exists between energy required and energy available-indeed an alert to an impending energy crisis for the cell. Although Ling's book is often quoted, the data pointing to the energy crisis is largely ignored. One major rebuttal by R. D. Keynes published in a symposium stated:"

"...Now let us return to the problem. How does one explain the large drop in muscle fiber sodium that accompanies early postnatal growth? We might argue that the decrease in sodium is primary due to a change in the physical state of water. That is, the cytoplasmic water may become less solvent to sodium through enhanced interaction between water and the cellular proteins. If such wild speculation should be remotely possible, what is the evidence? Please consider the following: Nuclear magnetic resonance (NMR) spectroscopy may be used to obtain insight into certain physical properties of water. We have used NMR spectroscopy to study the state of water in muscle tissue.67 NMR is well suited to this task because the width of the signal produced by water hydrogens is dependent on the motional freedom of the water molecules. As the mobility of the water molecules increases, the line width decreases (Fig. 12)."

"...The question is then raised: Do the NMR water signals for skeletal muscle change with normal development? Figure 13 shows the results of such a study where the ordinate is the line width of the high resolution NMR signals in hertz for muscle water protons and the abscissa is animal age in days.71 The line width increases monotonically with normal development and we have interpreted these data to mean that there is an increase in the order or structure of muscle water with normal development."

"...Next, we looked for a correlation between these changes in the NMR water signals and the changes in tissue sodium concentration. Figure 14 summarizes the results of this study. The ordinate is the muscle sodium concentration in mEq/Kg FFWW, and the abscissa is the NMR line width for muscle water protons in hertz. The narrow water signals are correlated with high tissue sodium concentration. Broad water signals are correlated with low tissue sodium concentration. We hypothesized from this that muscle water exists in a less ordered state in the younger animals and that a large fraction of sodium can dissolve in the water, and with development, the water assumes more structure due to the increase in the concentration of the cellular macromolecules. As a result, the increase in water structure reduced the sodium concentration."

"...Potassium. Potassium is associated with fixed charges within the muscle fibers in both immature and mature skeletal muscle. A large subset of the total set of cellular macromolecules (probably proteins) exists in a physical state that preferentially adsorbs potassium over sodium. This subset of cellular macromolecules increases with normal development and the accumulation of potassium is proportional. It is likely that most of the adsorbed fraction of sodium reported for mature muscle is also associated with this major macromolecular subset.

"...Water. Skeletal muscles taken from newborn animals contain as much as 90% water. The percentage of water decreases to approximately 77% in the mature animal. Therefore, the cellular macromolecules increase during development at the expense of tissue water. The increase in the surface to volume ratio between birth and 65 days of age may account for the increase in the cellular water structure that has been proposed."

"...Sodium. It is proposed that the decrease in cellular sodium concentration results primarily from a relative increase in the structure of cellular water. The data gathered so far are consistent with this view. Obviously, it does not represent a truth. Yet, this general concept of the events occurring in developing muscle leads one to consider the following: In a general sense, we are observing events associated with controlled differentiation. If the differentiation process should falter as in tumorgenesis, would one expect to see differences in the NMR water signals?...The prediction of Damadian was yes, and he experimentally verified his prediction in dedifferentiated tissue in 1971.74 We extended his observation to an animal model system in which three morphological states could be defined. (These data are presented in Figure 16 and in reference 75.) The preneoplastic nodule and the malignant tissue were distinguishable from normal mammary tissue. Also, all three morphological states were distinguishable from pure water. Furthermore, significant differences were found in each of the NMR parameter studies. That is, T1, the longitudinal relaxation time, T2, the transverse relaxation time which is proportional to the line width, and the diffusion coefficient for water protons were all distinguishable.72 (A simplified description of the relaxation times and the diffusion coefficient are given in reference 72, and further review of the literature on NMR and malignant tissues is presented in other chapters in this referenced book.)"

"...Once again the predictions of the new view of the living cell are borne out. Furthermore, it seems evident that NMR spectroscopy should be evaluated in detail relative to its utility as a tool for cancer detection and for studying tumorgenesis. In addition, it should be pointed out that this new view predicts a physical role for water in fundamental cellular processes not predicted by the classical view. The cellular changes in water and electrolyte composition associated with congestive heart failure and other cardiovascular diseases related to edema formation, for example, are explained by the new view. Experiments in this domain are just beginning."
 
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So water is the element of life because it turns into a gel-like, crystalline form that facilitates complex, energetic, biological reactions inside living beings?
 

Kyle M

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Nice. There is some good stuff happening on Researchgate largely in Europe right now about this topic.
 

Xisca

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Thanks Haidut, I have read all Ling website and he is the "father" of the IRM, thanks and through its conceptor that believed Ling.
Gilbert Ling still lives?
 

nullredvector

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I've been discussing this topic with a phd biochemist buddy of mine and he always comes back to this:
"'you don't need a sodium pump to explain these phenomena.' But as you said, it's from the 70s, before we could change specific proteins at the atomic level. A major thing that I have seen no explanation of from Ling proponents is - if the protein colloquially called the na,k-atpase doesn't maintain the gradient, why is it that the gradient can be precisely controlled by changing the identity of one amino acid in that one protein?"
 
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tara

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DrJ

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Gerald Pollack's book, "Cells, Gels, and the Engines of Life" talks about this in a lot more detail, especially in how the combination of proteins, the oft-overlooked polar nature of the water molecule, and the 2+ cations (Ca, Mg, etc.) can easily create the ion gradients by charge/size ratio-based solute exclusion without the need for pumps, and his technical writing is prize-worthy, clear, and very approachable. He often cites Ling. His other book, "The Fourth Phase of Water" also has some material on this.

To @nullredvector 's point, precisely changing the amino acid makeup (the protein) would adjust the hydrophilicity of the amino acid chain(s), and also potentially the strength of its bonds with the 2+ cations, which would change how tightly/loosely the protein/water/cation induced 'gel' would behave, either excluding solutes (particularly the 1+/- cations/anions) more readily, or less readily, thus adjusting the gradient in a pretty precise manner.

Essentially, the idea is that the hydrophilic proteins in the cell attract the polar water molecules along their length, and the 2+ cations "pinch" or fold the protein chains by ionic attraction on two sides, creating little compartments that trap water, and either exclude or trap other ions (depending on the charge/size ratio of the ion) from these minute "compartments" within the cell. So a loss of the 2+ cations (in particular magnesium, which Ray talks a lot about as being a problem for hypothyroid people) reduces this compartmentalization, so more water and ions can get in (perhaps "inappropriately") and local water-driven swelling is one result; i.e. the cell's structure becomes less ordered, and that structure and energy production are tightly related is one of Peat's main themes; and it's backed up by this model. Thus the description of cells being bags of water with reactions happening in solution is wrong since the water isn't free as it's at least weakly bound to the proteins, and perhaps strongly trapped with adequate 2+ cations, and the description of cells being more like a gel more accurate. Beyond that, Pollack reviews a number of experiments that directly refute the cell-membrane hypothesis, and of course without a membrane, how is it possible that "pumps" function as said? Both books are highly recommended reading if you want to dig deeper into the school of thought that Ray appears to come from.
 

Xisca

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the water isn't free as it's at least weakly bound to the proteins, and perhaps strongly trapped with adequate 2+ cations
Our problem in life is to think we are free, when actually we are always bound and trapped...
-let's be as happy as water! ;)
 

Xisca

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and of course without a membrane, how is it possible that "pumps" function as said?
Without a membrane, how can they find it made of fat?
:hairpull
where is the "scratching head" smilie?
 

yerrag

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Gerald Pollack's book, "Cells, Gels, and the Engines of Life" talks about this in a lot more detail, especially in how the combination of proteins, the oft-overlooked polar nature of the water molecule, and the 2+ cations (Ca, Mg, etc.) can easily create the ion gradients by charge/size ratio-based solute exclusion without the need for pumps, and his technical writing is prize-worthy, clear, and very approachable. He often cites Ling. His other book, "The Fourth Phase of Water" also has some material on this.

To @nullredvector 's point, precisely changing the amino acid makeup (the protein) would adjust the hydrophilicity of the amino acid chain(s), and also potentially the strength of its bonds with the 2+ cations, which would change how tightly/loosely the protein/water/cation induced 'gel' would behave, either excluding solutes (particularly the 1+/- cations/anions) more readily, or less readily, thus adjusting the gradient in a pretty precise manner.

Essentially, the idea is that the hydrophilic proteins in the cell attract the polar water molecules along their length, and the 2+ cations "pinch" or fold the protein chains by ionic attraction on two sides, creating little compartments that trap water, and either exclude or trap other ions (depending on the charge/size ratio of the ion) from these minute "compartments" within the cell. So a loss of the 2+ cations (in particular magnesium, which Ray talks a lot about as being a problem for hypothyroid people) reduces this compartmentalization, so more water and ions can get in (perhaps "inappropriately") and local water-driven swelling is one result; i.e. the cell's structure becomes less ordered, and that structure and energy production are tightly related is one of Peat's main themes; and it's backed up by this model. Thus the description of cells being bags of water with reactions happening in solution is wrong since the water isn't free as it's at least weakly bound to the proteins, and perhaps strongly trapped with adequate 2+ cations, and the description of cells being more like a gel more accurate. Beyond that, Pollack reviews a number of experiments that directly refute the cell-membrane hypothesis, and of course without a membrane, how is it possible that "pumps" function as said? Both books are highly recommended reading if you want to dig deeper into the school of thought that Ray appears to come from.
It's been awhile since I read through these two books. "The Fourth Phase of Water" is the later book, and has evolved from some views he espoused concerning structured water in the earlier book "Cells, Gels, and the Engines of Life." I would have to re-read these book to specify what changed. It's interesting reading but really heavy for me, so I wasn't able to finish reading them. I'd have to dust off the cobwebs and give it another try.
 
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haidut

haidut

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So water is the element of life because it turns into a gel-like, crystalline form that facilitates complex, energetic, biological reactions inside living beings?

Yep, and it is the complex structure that it enters into with the proteins inside the cell that keep sodium and calcium out. ATP is also involved as I posted in that other study. Without it, the proteins would not dissolved well and probably won't form as good of layers with potassium.
 
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haidut

haidut

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Thanks Haidut, I have read all Ling website and he is the "father" of the IRM, thanks and through its conceptor that believed Ling.
Gilbert Ling still lives?

Yes, he is still alive and is 97 currently. Pretty cool guy.
 
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haidut

haidut

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I've been discussing this topic with a phd biochemist buddy of mine and he always comes back to this:
"'you don't need a sodium pump to explain these phenomena.' But as you said, it's from the 70s, before we could change specific proteins at the atomic level. A major thing that I have seen no explanation of from Ling proponents is - if the protein colloquially called the na,k-atpase doesn't maintain the gradient, why is it that the gradient can be precisely controlled by changing the identity of one amino acid in that one protein?"

Because it changes the protein structure inside the cell and as such the cell's affinity for ions. That sodium pump is also made of proteins and as such the water structure inside the cell depends on protein make up. I bet the polarity of the amino acids have something to do with it. What amino acid specifically was changed to control the gradient? Probably a non-polar amino acid was switched with a polar one. Polar amino acids include serine, threonine, asparagine, glutamine, histidine and tyrosine. The hydrophobic (non-polar) amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophane, cysteine and methionine."
 
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haidut

haidut

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Gerald Pollack's book, "Cells, Gels, and the Engines of Life" talks about this in a lot more detail, especially in how the combination of proteins, the oft-overlooked polar nature of the water molecule, and the 2+ cations (Ca, Mg, etc.) can easily create the ion gradients by charge/size ratio-based solute exclusion without the need for pumps, and his technical writing is prize-worthy, clear, and very approachable. He often cites Ling. His other book, "The Fourth Phase of Water" also has some material on this.

To @nullredvector 's point, precisely changing the amino acid makeup (the protein) would adjust the hydrophilicity of the amino acid chain(s), and also potentially the strength of its bonds with the 2+ cations, which would change how tightly/loosely the protein/water/cation induced 'gel' would behave, either excluding solutes (particularly the 1+/- cations/anions) more readily, or less readily, thus adjusting the gradient in a pretty precise manner.

Essentially, the idea is that the hydrophilic proteins in the cell attract the polar water molecules along their length, and the 2+ cations "pinch" or fold the protein chains by ionic attraction on two sides, creating little compartments that trap water, and either exclude or trap other ions (depending on the charge/size ratio of the ion) from these minute "compartments" within the cell. So a loss of the 2+ cations (in particular magnesium, which Ray talks a lot about as being a problem for hypothyroid people) reduces this compartmentalization, so more water and ions can get in (perhaps "inappropriately") and local water-driven swelling is one result; i.e. the cell's structure becomes less ordered, and that structure and energy production are tightly related is one of Peat's main themes; and it's backed up by this model. Thus the description of cells being bags of water with reactions happening in solution is wrong since the water isn't free as it's at least weakly bound to the proteins, and perhaps strongly trapped with adequate 2+ cations, and the description of cells being more like a gel more accurate. Beyond that, Pollack reviews a number of experiments that directly refute the cell-membrane hypothesis, and of course without a membrane, how is it possible that "pumps" function as said? Both books are highly recommended reading if you want to dig deeper into the school of thought that Ray appears to come from.

Ooops, did not see your post before posting mine about the affinity of various amino acids for water. Thanks for elaborating.
Btw, even mainstream medicine is already pushing the idea of the cell as gel (non-free water), blatantly plagiarizing Ling without ever mentioning his name or work.
The Cell Is Not A Bag Of Water, It Is An Elastic Gel
 

Kyle M

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I've been discussing this topic with a phd biochemist buddy of mine and he always comes back to this:
"'you don't need a sodium pump to explain these phenomena.' But as you said, it's from the 70s, before we could change specific proteins at the atomic level. A major thing that I have seen no explanation of from Ling proponents is - if the protein colloquially called the na,k-atpase doesn't maintain the gradient, why is it that the gradient can be precisely controlled by changing the identity of one amino acid in that one protein?"

How precise can the ion gradient be controlled in that fashion? If you're talking about mutating one residue, how could that be precise control, wouldn't that be an on/off? Or are the experiments mutating, say, a glu to an arg and then a his and then a tyr etc.? Usually mutagenic experiments identify a residue that is suspected to be important in the "active site" and mutates that to either the opposite (from hydrophilic to hydrophobic) type of AA, or to a neutral one. I've been doing experiments changing residues in the supposed active site of a glycine oxidase enzyme, and there is no precise control in that literature. Usually you either get 1) no change in function, 2) loss of function, 3) loss of a viable, stable protein at all or 4) a loss or gain of function (usually a loss) of varying degree. There is no dose that can be used in this technique, since it's either the residue is the wild-type or the mutant, to allow "precision."

Having said that, it isn't hard to imagine a protein or family of proteins who are more important in maintaining the ionic gradient, and are located closer to the outside of the cell to do so. There is a matrix of protein at the cells edge orders of magnitude larger than the supposed cell membrane that is denser than the inner cytoplasm. From an osmotic standpoint, since the outer edge of the cell is the part exposed to the aqueous environment, the proteins there should be more robust against bulk water and more able to control ingress into the cell of water and ions than you would expert from inner-cytoplasmic proteins.

Another point I'll make is don't believe everything you read in science, my relatively short and narrow experience in it has already given me ample view of dishonest reporting and interpretation of data. I can only imagine how intense this would be in sensitive, legacy topics of the field such as the pumps. Even if you aren't actively trying to lie to further the narrative, imagine how much your career would come under scrutiny of the powers that be if you published data disproving earlier stuff about the pump? It's hard to convey the amount of social pressure and fear about that, which is never talked about but can be smelled in the atmosphere in science buildings, to someone who hasn't experienced it.
 

DrJ

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Without a membrane, how can they find it made of fat?
:hairpull
where is the "scratching head" smilie?

Doesn't mean there can't be something like a 'membrane' made of fat, just that the water is not free on the interior of the membrane that's supposed to be holding it in like some sort of watery bag, so the membrane doesn't function as hypothesized. The interior of the cell is basically a complex structure of proteins that traps and holds the water in a gel-like scheme. One of the experiments that Pollack cites refuting the idea that the cell membrane holds in a bunch of water in which reactions happen "in solution" is that they can cut off a section of a cell's "membrane" and the cell contents don't leak out, and the cell survives for days. Another observation refuting the membrane theory is that cells can grow rapidly in size, meaning the surface area expands rapidly (more rapidly than the rate of volume expansion), so if the cell is dependent on this fatty membrane to keep it together, how does the fatty membrane expand? Where do the new fat molecules needed to support the larger surface area and keep the contents in (if that's what they're doing) come from? They don't since they can do the experiment in isolation. However, as Pollack explains in the book, the electrical effects of the 2+ cations with the proteins can easily support this rapid expansion through the force of electrical repulsion under the right circumstances, and since it's the proteins that bind the water on the interior of the cell, the cell can expand rapidly without loosing its contents, and without needing to acquire new fat molecules to support the larger surface area.
 

Kyle M

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One of the experiments that Pollack cites refuting the idea that the cell membrane holds in a bunch of water in which reactions happen "in solution" is that they can cut off a section of a cell's "membrane" and the cell contents don't leak out, and the cell survives for days.

My thoughts on that are that either 1) the fatty membrane is a reaction to, not a cause of, the difference in water behavior between the cell and it's surroundings, or 2) the fatty membrane protects the cell's protein edge by preventing bulk water from constantly attacking its matrix, which is why cells do tend to fail after many hours or days of membrane disruption. Those aren't mutually exclusive.
 

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