John Watterson


  1. Physical limits to magnetogenetics

    Comment on Meister’s Article “Physical Limits to Magnetogenetics”

    John Grant Watterson

    18 Tomanbil Terrace, Ashmore, 4214 Queensland, Australia

    (retired: formerly of Department of Science, Griffith University, Southport, Queensland, Australia).


    In his recent article, “Physical limits to magnetogenetics”, Meister criticised the claims of workers in the field of magnetic biosensing, and the journal, Nature, for publishing those claims. He used quantitative arguments to prove that the claims “conflict with the basic laws of physics”. The main law in question is the principle of equipartition of thermal energy, kT, in respect of degrees of freedom of molecular orientational motion. However, 8 decades of biological research has established that these degrees of freedom are not available to subcellular components, and therefore his arguments are irrevelant to observations of molecular motion made in this environment.


    In a recent article, Meister (2016) offers an adverse critique of publications by groups reporting on observations, in which nanosized cellular ferromagnets can detect the Earth’s magnetic field – ie, observations of magnetic biosensors (Stanley et al, 2015, 2016; Qin et al, 2016; Wheeler et al, 2016). He draws on quantitative comparisons between the physical strengths (energies, forces, torques) that would be expected from results claimed by the groups, and strengths which are quickly and easily calculated from the basic laws of physics. His numerical values show that the claimed effects must be weaker, by many orders of magnitude, than the disruptive influence that thermal motion must have on their magnets according to physical laws. With stern words for the editor and referees, he asserts the reports should not have been published, because firstly, the several biological explanations proposed by the authors must all be wrong, and secondly, the publications have therefore discouraged younger scientists from doing research in the field in future.

    In his analyses, Meister omitted to consider the “structure of biological matter” (his words), although he is clearly aware of this concept. Rather, he tacitly assumed that biological matter has no structure, and therefore that the orientation of nanosized magnets must be subject to thermal motion, kT, just as particles are in physics texts. The fact that biological matter is structured however, means that analyses of molecular movement in living systems must include environmental influences. In the following, I discuss broadly three aspects of his omission from a historical perspective under the headings: the medium, the membrane environment and protein structure.

    The Cytoplasmic Medium

    When the famed microscopist, Frey-Wyssling, examined various cell types in his light microscope, he discovered a puzzle. The cell interior appeared clear, as a solution, but it displayed the properties of a solid (Frey-Wyssling, 1940). In his description he used the term “liquid crystal” in the year 1940! Later he warned against viewing the interior as a clear solution in the fluid state because of “the double nature of the cytoplasm it is solid and liquid at the same time” (Frey-Wyssling, 1948). Newer technical developments in the 1950s and 60s, e.g. the polarized light microscope (Ho,2008) found layered order, such as birefringence, while further advances in electron microscopy showed some tissues in such regular alignment that they could be described as crystalline – a description validated as early as 1961 by the observation that insect flight muscle diffracts X-rays so coherently as to produce a pattern usually associated with solid crystals (Worthington, 1961). Later evidence from X-ray diffraction studies prompted workers to describe single fibers a “millimeter-long natural protein crystal” (Iwamoto, 2006).

    The solid character of the cell is well known to biologists (Ling, 1992). Live cells can be physically or chemically stripped of their outer membranes, without the 70 -80 % aqueous content flowing onto the bench. It has been known for 50 years that muscle fibers can be demembraned without loss of functional integrity shown by the fact that they contract just as intact fibers do. Today, direct measurement of mechanical force exerted by gels is readily achieved with the techniques of patch-clamping, tribology, optical tweezers and atomic force microscopy. It is common cell biological practice for cells to be bisected, sliced into pieces and decompartmentalized, for the purpose of preparing desired experimental samples. These laboratory techniques are possible because the sections produced are intact gel fragments that retain their physiological functions. Perhaps the most spectacular examples here are the pieces of living gel commonly used in medicine today to control fertility and embryonic health by transferring cellular components (mitochondria, single chromosomes) between cells.

    There is of course movement in cells, however, it is not the random motion of statistical thermodynamics driven by the energy pulses of kT. Prior to 1980, thermodynamics dictated that proteins should adopt the once popular “kicking and screaming stochastic model” (Weber, 1975; Cooper,1976). The image was that the cellular space is full of thermal movement of solvent and solute molecules, similar to that one would imagine happening to gas molecules in empty space. But the cellular medium is liquid, not gaseous, and there is no evidence that proteins are in a state of free thermal motion at the mercy of kT. For its internal movement, the cell controls the switch between the fluid and solid states of water through a biophysical mechanism known as the gel-sol transition, which is readily detected with the use of rheological and birefringent studies of cytoplasmic suspensions (Buxbaum, 1987). During cytoplasmic streaming, for example, we see sections of the cytoplasm moved to regions where they are presently needed, such as new points of anchor to external substrates for generating mechanical forces that cause motility. Forward streaming moves along stress fibers of polymerized actin, beside its associated retrograde streaming along actin fibers with the opposite polarity. It is thought that the macro movement of medium is achieved through reciprocal treadmilling action guided by the aligned fibers (for a thorough review see Case and Waterman, 2015). During the ordinary biological event of cell division, squillions of physical and chemical reactions occur in precise spaciotemporal sequence. In the space of a few minutes, a human cell synthesizes, packs and stores its old and new 2 meter long DNA polymers – a biochemical process in which every step of translation and reorientation is crucial. At the same time, vector highways of microtubule and protein motors are synthesized for the transport of the genes to their prescribed pole of the mother cell. These molecular rearrangements represent orchestrated dynamics on a vast scale. There is no place for a random step here, because there is zero tolerance for knotted DNA.

    The gelled state of cytoplasm is known from other equally old observations as well. When demembraned or fragmented cells are centrifuged at 300 000 rpm corresponding to pressures of up to 1 000 atmospheres, the sedimented pellet does not reach a protein concentration as high as 20%, that is, not even as high as in the original intact cell. Rather than the aqueous medium being squeezed out, the fragments take in water. For DNA suspensions the numbers are even more spectacular. Biological systems can also produce the nonfluid state of medium outside the cell. The mucosa of vascular lumen is an impressive barrier. This flexible gel contains layered mucin molecules which, in the case of the stomach lining, can hold back a pH gradient of 1 million fold – unambiguous evidence for the absence of the disruptive molecular battering by kT. Man-made chemical systems composed of soft matter functioning as impermeable barriers have so far not achieved such an impressive result (as far as I am aware).

    Plant, animal and bacterial cells in general are surrounded by a protective outer layer of water called the glycocalyx. It is composed of proteoglycan molecules, of which the active component are carbohydrate polymers such as cellulose and pectin (Palmer et al, 1948). The study of these gelling agents is today a rapidly expanding field of research, particularly in the food and medical industries. For decades, Usada’s group has studied the physical properties that these polymers can induce in water, and their crucial role in physiological function (Gong, 2006). Their powerful effect is typified by derivatives of hyaluronic acid, which can gel water in concentrations lower than 1/1000 w/w. Or consider the use of the common natural products, bacterial dextran and seaweed agarose, as coatings on biosensor chips composed of nanometer thin layers of gel on tissue implants to protect against fouling by non-specific protein adhesion – more water barriers! The wide-spread use of such materials – chemically benign but physically strong – in the pharmaceutical industry is accelerating even though a thermodynamic understanding of the phenomenon of gelation still eludes us.

    In support of Meister, Anikeeva and Jasanoff (2016) quote the Berg text book “Random Walks in Biology”, “to bring order to otherwise messy biological systems”. The term “gel” appears in one paragraph of the book on page 64, where Berg mentions electrophoresis as a laboratory technique, that is, the reference is to the use of the non-biological synthetic gel, polyacrylamide, and the dead biological gel, agarose, on samples of denatured proteins and DNA. Further, Figure 3.3 illustrates how exactly 50% of molecular metabolites, once released in the cytoplasm, diffuse in the opposite direction to their target, and of those diffusing in the right direction, only a tiny fraction reach their target for capture, while the bulk spreads outwards through the cytoplasmic space in accordance with the thermodynamic law of diffusion. The inescapable consequence here is that the metabolizing cell must be clogged with a chaotic mixture of waste products, which will never reach their target enzymes. This prediction is contrary to long established experimental facts, all predating Berg’s book. Apart from global metabolites such as ATP, there is no evidence of high concentrations of intermediate metabolites in cytoplasm. The reader soon discovers Berg’s entire book is a reductionist thesis on how diffusion drives cellular events. However, after reflecting on the picture of the contents of the cell his theory paints, the reader then realizes that the book fails to deliver on its promise – it describes mess, not order.

    Membrane Environment

    The scientific literature on the state of water at interfaces is truly vast. As a student in the 1960s, I learnt of results in the field of soil science obtained already in the 1930s. These reports indicated an extensive ordering effect on the molecues of water by contact with the silica surfaces of hydrophilic clays. For instance, it was already known that montmorillonite and bentonite swell against high imposed pressures (Langmuir, 1938; Norrish, 1954). Hydrophilic vermiculite was shown to produce a crystalline gel at a water to clay ratio of 30 to 1, in which 1 nm thick planar clay wafers are in parallel alignment at an interparticle distance of 50 nm (Walker, 1949, 1960). Already in 1947 Perutz’s group reported that gels of hemoglobin formed “crystals” of 50% water, which appeared to be in ordered layers (Boyse-Watson et al, 1947). Thirteen years later, the term was used with more confidence when the full X-ray structures of myoglobin and hemoglobin were published (Perutz et al,1960). For a comprehensive review from the time of those early results see Henniker (1949).

    Over the past 60 years observations of this effect stemming from both biological and non-biological fields have been continually amassed. This type of water has been given a variety of names: surface, associated, hydration, vicinal, structured, confined . . . . This confused picture stems from the fact that no clear, convincing explanation of its origin has been presented, reflecting the lack of a definitive technique to have emerged from the many and various methods used to detect it. I recommend Israelachvilli’s text “Intermolecular and Surface Forces” (1992) for its coverage of measurements on clay through to DNA systems. (This text is mathematically oriented – for a non-mathematical alternative consult the major review by Rand and Parsegian (1992)). Israelachvilli uses the term “hydration force”, and today it is recognized to exist at all hydrophilic surfaces. I attended the meeting “Biophysics of Water” in Cambridge in 1980 (Franks F and Mathias SF, eds 1981. Wiley Ltd), at which he detailed the apparatus that made the first direct measurement of the force exerted by ordered layers of water between two mica surfaces. Those experiments registered a force normal to the surfaces of up to 1 000 atmospheres. Today it is known, that so wide-spread is the phenomenon that the physical/chemical nature of the surface does not play a critical role in its formation. Heterogeneous biological tissue and even metals build solute-excluding zones of the pure solvent (Zheng and Pollack, 2003). Research of decades ago (Deryagin, 1966) demonstrated the powerful influence of the silica surface, whereby for example, tightly held water of up to 600 layers were readily formed (Pashley and Kitchener, 1979). Fast-forwarding now to more recent times, the presence of surfaces and solutes have been shown to have a long-range influence on the H-bond network, which Roke and coworkers call “orientational water” (Chen et al, 2016). Other dielectric response studies show strong anisotropy in confined water as revealed by an order-of-magnitude drop in orientational fluctuations extending as far as 100 nm from silica interfaces (De Luca et al, 2016). The regular array of such layers eases lateral, but restricts normal, surface movement (Dhopatkar et al, 2016).

    We saw in the previous section, how high concentratins of proteins can gel the aqueous medium producing a liquid-crystalline state. More modern research (infra red and terra Hz spectroscopy) has pinpointed the influence of single protein molecules on surrounding water structure and found extensive

    correlated motion in the H-bonded network beyond 2 nm from the protein surface (Ebblinghaus et al, 2007). These results have been recently supported by simulation studies (Heyden and Tobias, 2013; Nibali et al, 2014), with predictions that such structural effects travel through the medium as a phononlike

    mode (Elton and Fernandez-Serra, 2016).

    The powerful hydration force was observed also between lipid bilayers as early as the 1907s (for reviews see Rand and Parsegian, 1989; McIntosh and Simons, 1994). Pressures of up to 1 000 atmospheres are needed to force water out of the interlamellar space, or viewed in reverse, to prevent the layered water molecules from pulling in additional water (Higgins et al, 2006). These macro forces cannot be generated by the chaos of free independent molecular motions generated by kT. If they could, the medium would be readily removed by imposing pressure perperdicular to the layers. As a result, there would be no local forces remaining to orientate proteins embedded in membrane environments, which is needed to direct their highly vectorial functions. A text book example here is the mechanism

    of ATP synthesis (for an easy concise read, see Boyer, 1999). This multicomponent complex rotates about an axis perpendicular to the membrane plane, whereby each full turn delivers precisely three molecules of ATP. This means the core of the machine, the synthase complex, rotates in quantized steps of 120 degrees while simultaneously releasing one molecule of ATP. It is driven by the transmembrane displacement of four H+ per ATP. This non-random displacement of H+ supplying the energy for synthesis is an experimental fact known since Mitchell made the discovery of the chemo-osmosis drive in 1961. It is not driven by erratic pulses of energy kT on H+ ions, propelling them by chance in the right direction through the membrane.

    Since reading the comments of Anikeeva and Jasonoff cited above, I have also checked over other texts often recommended for biologists written by prominent physicists (Benedek and Villars, 1974; Nelson, 2008). I found the proposed mechanisms to explain the properties of membrane function quite amazing. For example, one reads claims that the chaotic influence of thermal motion, kT, on solutes, is “rectified” by membranes. Consequently, the build-up of mechanical effects across membranes is explained by a membrane rectifying force-field operating selectively on solutes – not water. However, as we’ve now seen, decades-long physical, chemical and biochemical research has clearly established the existence of the hydration force, which is generated by the influence of hydrophilic surfaces on molecules of water – not solutes.

    Over the past decade there has been made available extensive observations on membrane-bound proteins which are mechano-, pH-, and voltage-sensitive ion-channels. Researchers in this field interpret results as indicating that there are also forces directed parallel to the plane of the membrane. Special attention has been paid to the channels discovered in the 1980s which respond to osmotic and mechanical stimuli (Guharay and Sachs, 1984; Martinac et al, 1990), with the aim of identifying the type of stretching-squeezing action involved (reviewed by Kung et al, 2010). It is today widely accepted that gating events are controlled by switches between strong lateral tension in the plane of the lipid headgroups and strong lateral pressure exerted through the lipid leaflet (Cantor, 1999).

    In sum, biological membranes exist in a highly anisotropic environment – a space experiencing orthogonal forces controlling the orientation of protein complexes embedded therein. It has been suggested that, because of its solid-like characteristics, the layer of water itself may detect mechanical variations, making it the first link in the response chain (Osada and Gong, 1998). It is a requirement for their function, that membrane proteins be sensitive to small vectorial changes. Just like any agent expecting a stimulus, they must be poised ready for action. This requirement is provided by the geometric arrangement of forces, which prevents randomization. It is therefore expected that nanoscale structural changes due to osmotic, mechanical, electrical and magnetic variations in the surroundings

    must be able to be detected and amplified, so that resulting displacements occur in the correct direction, and not in any uncontrolled direction resulting from random re-orientations caused by kT. Just like our man-made machines, biological machinery functions with certainty, not chance, so that reliable oneway action is always ensured.

    Protein Structure

    In 1999 the computer corporate giant, IBM, launched the “Blue Gene Project” in a blaze of publicity. Its aim was to solve the “grand challenge problem” (their words) of our time, that is, protein structure. Since their advanced machine, “Blue”, had just defeated the world chess champion, Kasparov, a speedy

    result was implied. However, in my last correspondence with the project leaders, Ajay Royyuru (Computational Biology Center) and Ruhong Zhou (Research Manager, Protein Science) I understand there has been no progress. We are no further in understanding the mystery that lies behind protein structure than we were two decades ago.

    For readers unfamiliar with the problem, I feel some clarification is needed at this point. I am not referring to solving structure using sequence homology comparison (template based modelling). There are today several algorithms to do that job, which you can carry out on your own PC. Indeed, many volunteers are doing just that. (Interested readers unaware of this cooperative effort, the Community Wide Experiment, or CASP for short, will find it on Rather, I refer to elucidating the energetic principles that enable short amino acid sequences of alpha and beta primary structure along the main chain, to fold and pack into a unique stable globule in the 20 – 30 kDa size range. It’s important to emphasize that the stable fold was not predicted by thermodynamicists, and indeed up until the 1970s, it was even considered impossible – recall here the “kicking and screaming stochastic model” cited above. From correspondence with the structuralist, Ken Dill, a prominent leader in the field, I learn that workers today continue to rely on sequence homology for predictions (Dill and MacCallum, 2012). Also, many workers are even unware of, or at least do not refer to the ambitious IBM project.

    In his text “Statistical Mechanics of Chain Molecules”, the Nobel Laurate, P J Flory (1969) presents the theory of polymer structure as understood in the 1970s – the kicking and screaming random coil. Although they are the most important polymers, and the most important solutes on planet Earth, proteins are hardly covered. The suggestion is that their peculiar stability is explained by special internal bonds arising from packing constraints that hold the chain together. When these bonds failed to be found, thermodynamicists invented a new type of bonding called the “hydrophobic bond” (Kauzmann, 1959). When this special bond failed to materialize, the concept was changed to the “hydrophobic effect” (Tanford, 1968), and soon after to the more scientific sounding “hydrophobic interaction” (Tanford, 1973; Franks, 1975). This term is still in use today and stands for the expression “an unknown force of special attraction that operates between certain amino acid sequences inside the globule added together with a force of special repulsion that operates between certain amino acid sequences and water outside the globule”.

    The approach taken in the Blue Gene Project is the thermodynamically rigorous one of Free Energy minimization. In simple terms, one steps along the sequence testing the Free Energy at every twist and turn of each amino acid to arrive at a global minimum. This stochastic approach yields the average fold

    in the world ruled by kT. At the time of the launch there had been a few hundred X-ray crystal structures published. Today, on the combined US and European Protein Data Bases, there are many tens of thousands available. This means that researchers have at their disposal the precise co-ordinates of millions of atoms all defying kT.

    The reason for the failure is that the model ignores the influence of the large-scale ordering occurring in the surroundings. In other words, folding and crystallization emerge out of co-operative phenomena reaching up to the macro level, eminently exemplified, already down deeper, by the basic gel-sol transition in water. Confidence in the existence of high-level structuring has seen techniques evolve beyond X-ray analysis. Frey-Wyssling needed the highly crystalline cellulose fiber to see order, but today, even computer-assisted light microscopy can reveal switches in the conformations of huge complexes such as occurs during viral entry. So now with his words ringing in our ears – there is structure in there – we are confronted by the question of how does biology avoid kT?


    We do face basic problems in biology, and we need input from unbiased thermodynamicists to help solve them. Here are three:

    (1) what do water molecules do when they form a gel?

    (2) how do they produce the strongly repulsive hydration force?

    (3) what is the explanation of protein structure?

    Still today, thermodynamics dictates that proteins do not fold, do not crystallize, and do not adopt a definite orientation. Yet each of these claims is contrary to long-standing established experimental facts. Some 20 years ago, I gathered together some points relevant to these questions (Watterson, 1997), but our knowledge of the state of biological matter at that time has been overshadowed by the vast amount of supporting data gathered since then. Unlocking the secrets of magnetic biosensors is part of this endeavor, and I predict that continued work on these responsive proteins will be expanded to included them as tools for probing in situ the physical properties of biological matter.


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