Apart from viruses, everything living - from amoeba to humans - consists of cells. A cell is the elementary unit of living things. Despite its complexity, we know a lot about its structure and functions. This knowledge is framed in the form of cell theory, which is included not only in university courses, but also in school textbooks. However, along with the classical theory, another allows one to look at the structure of a cell in a completely different way. This theory is that of Gilbert Ling .
Gilbert Ling in 1962, after the publication of his first book, A Physical Theory of the Living State: the Association-Induction Hypothesis. Source.
Gilbert Nin Ling was born in 1919 in Nanjing, China. In China, Ling received a bachelor's degree in biology from the National Central University of Chongqing. In 1945, he won the Boxer scholarship to continue his education in the United States, where in 1946 he began his graduate study at the University of Chicago (Department of Biology). Having completed his Ph.D. in 1948, Gilbert Ling settled down in the USA and became an American citizen. Throughout most of his 27-year career, Ling worked at the University of Pennsylvania in Philadelphia, where he became Head of the Department of Molecular Biology. However, due to Ling's alternative views on cellular theory, funding for his laboratory was discontinued. He was forced to leave for the Fonar Corporation, founded by Raymond Damadian, one of the inventors of magnetic resonance imaging .
So, what is Gilbert Ling's theory about? To answer this question, let us first remember the cell's fundamental features and the classical view of its working principles. There are four essential fundamental properties of a living cell. Firstly, a cell selectively allows some substances to pass into itself and does not allow (or barely allows) others to pass. This property is called semi-permeability. This property implies the following - the so-called property of selectivity. Substances are unevenly distributed between the cell and the environment. Therefore, the concentration of potassium ions inside the cell is much higher than outside, and the opposite is true of sodium ions. The third property is that cells can generate electrical potential. The fourth is that cells can maintain osmotic equilibrium with the environment or, in other words, regulate the distribution of water and the substances dissolved in it inside and outside the membrane [3-6]. According to the classical membrane theory, all of these properties mainly occur due to the plasma membrane surrounding the cell [3, 5]. The plasma membrane structure model, which is still used today, was proposed as the 'fluid mosaic model' back in 1972 by American biologists S. J. Singer and G. L. Nicolson. Put very simply: the membrane is a double layer of phospholipids. Proteins (receptors, enzymes, channels and 'molecular machines') are built into this layer for the active transport of substances. Due to its structure, the membrane is permeable to some compounds and impermeable, or poorly permeable, to others. Osmotic equilibrium is maintained by the passive and active transport of substances through the membrane. In the former, the substances themselves move from a place with a higher concentration to a place with a lower concentration; in the latter, it is the other way around: to transfer the substance to a place where more energy is expended. Active transport substances are even called 'membrane pumps'. They use the energy of splitting chemical bonds of special molecules of adenosine triphosphates (ATP), the cell's 'fuel' [3, 5].
Schematic diagram of a unit of life, a "physiological atom", according to Ling: a protein enveloped in an aqueous shell, a multi-layer absorption of water molecules on its surface. In addition to water molecules, some substances (potassium ions) are selectively retained in the physiological atom, and others are displaced into the surrounding solution (such as sodium ions). The relative sizes of hydrated potassium and sodium cations are shown. Source: .
According to Ling, the role of the membrane in the framework of classical theory is largely distorted and even exaggerated. He believes that the source of the fundamental properties of the cell should be sought in its cytoplasm (internal contents), and not just in the membrane [1, 5]. The Gilbert Ling theory, or the 'association induction hypothesis', was first published in 1962, and acquired its finished form in 1965, supplemented by explanations of the nature of intracellular water . This theory claims that the most important properties of the cell are provided not by the membrane, but by the ability of the cell’s internal structures to adsorb certain molecules and ions. Therefore, for example, oxygen accumulates in red blood cells due to bonds with the protein haemoglobin. Moreover, there is no oxygen 'pump' on the surface of these cells [5, 6].
According to Ling, the protein-water-ion complex is the basis of a cell's functioning, a kind of 'physiological atom' . Intracellular proteins selectively bind certain ions and molecules, and structure intracellular water - hence the 'association' in the name of the theory [4-6]. Ling explains the higher concentration of potassium in the cell by its binding to proteins. A potassium ion has a positive charge, and proteins have free negatively charged carboxyl groups. It is worth remembering that a protein is a natural polymer, consisting of alternating amino acids linked by a peptide bond.
Example of protein structure: myoglobin.
The ordering or 'structuring' of water by proteins is facilitated by the polarity of the bond, in which 'negative' oxygen and 'positive' nitrogen form a dipole. This allows proteins with many peptide bonds to 'coat' themselves with water molecules (since they are also dipoles), orienting them in space and restricting their movement. Protein becomes a kind of structuring matrix. The first layer of water molecules is built on it; the second on the first, and so on. Intracellular water is not free and looks like a jelly or a gel. The more peptide bonds are available for water (this depends on how folded or unfolded the protein molecule is), the more efficiently the protein structures or 'gels' the water.
Thus, in accordance with the proposed theory, it is the water structured around a protein and not the membrane that performs the function of a barrier [4, 5, 9]. Only small ions and molecules can get through the multi-layer system of oriented water molecules, and the sodium ion, for example, has a sufficiently large hydration shell, and is eventually displaced from the cell. The cell functions, passing from a passive to an active state, due to a change in the adsorption properties of proteins depending on their environment and communication with various signalling molecules, such as hormones or ATP. Ling believes that ATP is the most powerful modifier of a protein's state. When combined with a protein, this molecule increases the affinity of the protein for K+ ions, the cell accumulates potassium, and the protein itself straightens out, 'opening up' to water binding. As a result, an aqueous 'cocoon' forms around the protein and the content of bound water in the cell increases. When ATP is split, this complex is destroyed, and water and potassium are discharged or 'desorbed'. The protein molecule coagulates, a significant part of its peptide bonds become inaccessible to water, and sodium ions are able to replace potassium at the binding sites. The water loses its arrangement, due to which the content of various substances in the cell can change dramatically. According to Ling, such cyclic changes in the protein-water-ion complex are fundamental to a cell's functioning [4-6, 9, 10].
The fundamental properties of a cell according to Gilbert Ling's theory are as follows. Firstly, the cell is semi-permeable due to protein-structured water. Secondly, the substances for which there are numerous intracellular binding centres accumulate in the cell. Thirdly, the electrical rest potential (adsorption potential) arises because of ions binding to proteins of the cell's surface layer that is in direct contact with the external environment. Finally, the osmotic equilibrium of the cell with the external environment is supported by water binding to proteins [4, 5, 9].
Ling questioned the generally accepted view of cell function, corroborating his hypothesis with not only theoretical, but also experimental data. He does not deny the important role of the plasma membrane, but he is convinced that the fundamental features of a cell are not just limited to the properties of its surface layer: they are a product of the entire cell.
Who is right - Gilbert Ling or the authors of the classical membrane theory? As is often the case, the truth is probably somewhere in between. It is possible that both approaches will become part of a more general theory in the future. Indeed, it is a known fact that cell water is structured [8, 10]. One way or another, a science-based alternative theory allows one to take a fresh look at established ideas, rethink them, and outline new potential fields for research.
1. Ling, Gilbert N (1962). A Physical Theory of the Living State: the Association-Induction Hypothesis. Blaisdell Publishing Company, A Division of Random House, Inc., London.
2. Ling, G. (2001). Life at the cell and below-cell level: the hidden history of a fundamental revolution in biology (Original ed.). Melville, NY: Pacific Press. pp. 371–373.
3. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. (2002). Molecular Biology of the Cell. 4th Ed., New York: Garland Science.
4. Ling GN. 2011. Truth in basic biomedical science will set future mankind free. Physiol Chem Phys Med NMR. 41: 19-48.
5. Matveev V.V. (1994). Membrane or protoplasm - a new round of an old dispute. The story of American biologist Gilbert Ling's unusual theory. Chemistry and life. No. 8. pp.42-47.
6. Matveev V.V., Wheatley D.N. (2005). “Fathers” and “sons” of theories in cell physiology: the membrane theory. Cellular and Molecular Biology. 51 (8): 797-801.
7. Ling GN. (1962). A Physical Theory of the Living State: the Association-Induction Hypothesis. Blaisdell Publishing Company, London. 680p.
8. Ling GN. (1965). The physical state of water in living cell and model systems. Ann. N.Y. Acad. Sci. 125 (2), 401-417.
9. Matveev, V. V. (2019). Cell theory, intrinsically disordered proteins, and the physics of the origin of life. Progress in Biophysics and Molecular Biology. In press.
10. Ling GN. 2014. Can we see living structure in a cell? Physiol Chem Phys Med NMR. 43:1-53; discussion 53-73.