Magnetofiction – A Reader’s Guide

tl;dr:

This sub-genre of science fiction has made its way into mainstream science journals. I argue that the science is sketchy and the fiction is disappointing. Submit your own Biophyctional Journal abstracts in the comments!

Introduction

Science fiction rests on a compact between author and reader. The reader grants the author license to make some outrageous assumptions about the state of science and technology. In return the author spins an exciting yarn that may also hold some lessons about human nature. Recently a sub-genre of science fiction has made its entry into mainstream scientific journals. Again the authors ask readers to imagine that nature works very differently from what we know now, by factors of a million or up to 10 trillion. Then they speculate what might happen under those circumstances.

Magnetogenetics

This particular context has become known as “magnetogenetics”: the dream of controlling specific proteins and cells throughout the body with magnetic fields. To make this dream a reality, one needs an actuator, namely some particle that couples the magnetic field to a biological function. Ideally that particle would be produced endogenously by biological cells under genetic control, and the most promising candidate for this role is ferritin. This is a large spherical protein shell, about 12 nm in diameter, into which the cell stuffs thousands of iron atoms, primarily to get rid of them. That iron confers ferritin with magnetic properties that could be exploited for magnetic control.

How would a magnetic particle like ferritin interact with the biology of the cell? Two modes have been considered: The magnetic field might tug on ferritin, which would transmit that force to an ion channel, alter the channel’s ionic conductance, and thus control the membrane potential. Alternatively, an oscillating magnetic field could be used to heat the ferritin, which would transmit that heat to a connected ion channel, again modifying the membrane currents.

Reality lost

This is where trouble arises: Based on our conventional understanding of physics and the measured properties of ferritin, its coupling to magnetic fields is much too weak to allow any of this. The discrepancies are huge, anywhere between 5 and 10 orders of magnitude, depending on what specific mechanism of action one considers [1]. But that has not dissuaded a group of intrepid authors in this genre, who continue to put forward scenarios that wildly contradict how we think the world works.

In much of this literature the authors are perfectly aware that their explanations conflict with reality, and the contradictions are acknowledged front and center. Just a sampling of quotes:

  • “…the heat dissipation in the nanoparticles should be of the order of 0.1 GW/g, a completely unrealistic value (6 orders of magnitude above the expected value)…” [2].
  • “…the equivalent thermal resistances are 10 orders of magnitude higher than those predicted using the bulk thermal conductivity and the bead dimensions…” [3]
  • “The thermal conductance of the water shell around the nanoparticle can be written as g* G where G is the macroscopic thermal conductance and g* is a scaling factor … leading to an estimated g* of 1e-13 for nanoparticle suspensions.” [4]

The latter fudge factor of 1013 appeared in the otherwise reality-based Biophysical Journal. Note how the postulated deviations from reality grow with time of publication, escalating by about a log unit per year. By now, a fictional factor of a million seems almost tame and sheepish.

Can you heat a single protein molecule?

The collection of papers cited above are about heating of nanoparticles. They espouse the notion that one can heat a protein or similarly small particle without the heat escaping into the surrounding medium over time periods of many seconds. A steady trickle of experimental reports claim that this is possible [5, 6, 7, 8]. By contrast, the conventional treatment of heat diffusion predicts that the heat escapes in less than a nanosecond, and the temperature rise from magnetically heating a single nanoparticle is utterly insignificant [9, 10, 1]. Hence the need to invoke these enormous fudge factors. But why should we accept an explanation of experimental results that starts with a complete rejection of conventional wisdom? The common fig leaf is that “heat transport on the nanoscale is not well understood”. That argument is just not tenable.

An unusual amount of scrutiny has been applied to nanoscale heat transport, because it matters intimately to a trillion-dollar global industry. The cell phone in your pocket is powered by chips with transistors only a few nanometers on a side [11]. Electric current running through these devices generates substantial heat, and that heat must be carried away from the nanoscale of a transistor to the macroscale of your pants pocket. If there were any significant barrier to heat flow at the nanoscale, maybe as little as a factor of 10, these chip designs would be dead in the drawer. Fortunately nothing like that has emerged. One might wonder if there is something unusual about small particles floating in water, like ferritin in a cell. But an extensive review of experimental work concluded that “interpretation of the cooling rates of nanoparticles suspended in water and organic solvents does not appear to require any unusual thermophysical properties of the surrounding liquid to explain the experimental results” [12, 13]. On the theory side, it is now possible to compute full molecular dynamics simulations of heat flow that include every water molecule along the way; again, no unexpected heat barriers have emerged [14].

One has to conclude that the “single-protein heating” scenarios imagined in the Magnetofiction series simply can’t happen in this universe. The various claims in the literature surrounding single-particle hyperthermia must have other explanations, including the much more plausible one of human error.

What is the magnetic state of biogenic ferritin?

The latest title of the series [15] is instead about producing force or torque with ferritin. Here the author starts out by borrowing a factor of 10,000 from accepted reality, on the idea that the ferritin used in magnetogenetic applications to date [16] behaves very differently from all the other preparations of ferritin on which magnetic measurements have been made. He assumes that the ferritin core contains 4500 iron atoms that form a single superparamagnetic domain, such that they effectively respond to the external field as a cohesive magnetic spin. In reality, close to a century of measurements on natural ferritin suggest that it contains about 2400 iron atoms which assume a spin configuration that reduces rather than enhances the magnetic moment [17, 18, 19, 1]. Put simply, the experimentally measured magnetic susceptibility of ferritin is ∼10,000 times smaller than the author postulates here, and for some of the speculations in the article that factor gets squared.

What is the justification for departing so far from reality in this case? The reader is referred to reports about superparamagnetic behavior in so-called “magnetoferritin”. Chemists produce that material by emptying the native ferritin shell of its iron atoms and then refilling it with iron oxide under exotic reaction conditions, including precise control of oxidants at 70 deg C. The purpose of this unusual synthetic chemistry is precisely to produce nanomagnets with high magnetic moments, because biological cells don’t naturally do that. There is no reason to think that this material bears any resemblance to the biogenic ferritin construct used in all of the magnetogenetic applications to date. Indeed the creators of that construct [16] emphasized that it looks and behaves just like natural ferritin. But as the saying goes: “If it looks like a duck and walks like a duck and quacks like a duck, then it probably flies ten thousand times faster than a duck.”

New opportunities in creative science writing

Until recently this brand of speculative fiction was relegated to fringe publications. Why is it now breaking into mainstream Biology journals? Remember, we are not talking about string theory, where wild speculation is considered essential to progress. By comparison, heat flow is a perfectly stable and settled area of science. Perhaps classical physics just doesn’t have a big constituency among today’s journal editors. Would the reaction be different if the outrageous assumptions affected a more biologically sensitive subject? Imagine a genetics article whose discussion section starts with “We suppose that the human genome contains 1000 bases.” Or a paper on evolution that explains the observations with “All our results are consistent with the idea that the Burgess Shale is 1000 years old.” Would these articles get sent out for in-depth review? No-one has tried … until now.

Which brings me to a positive aspect of these developments: There is room for much more exciting fiction in this domain. Either of the two scenarios above (which depart from reality by only 6 log units) would make for fascinating consequences. Or imagine that we were wrong about the speed of light, and it’s actually the same as the speed of sound (6 log units again). One could explain so many things this way! Story lines come to mind that are much more enticing than the limited prospect of heating or wiggling a protein molecule by magnetic fields. So if you feel inspired, write your own Biofiction story, starting with an abstract (<150 words), and send it along in the comments. Be bold! And when you’ve finished the full length article, just submit it to your favorite Biology journal.

References

[1] M. Meister, “Physical limits to magnetogenetics.,” eLife, vol. 5, p. e17210, Aug. 2016.

[2] A. Riedinger, P. Guardia, A. Curcio, M. Garcia, R. Cingolani, L. Manna, and T. Pellegrino, “Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles,” Nano Letters, vol. 13, pp. 2399–2406, 2013.

[3] R. Pinol, C. Brites, R. Bustamante, A. Martinez, N. Silva, J. Murillo, R. Cases, J. Carrey,C. Estepa, C. Sosa, F. Palacio, L. Carlos, and A. Millan, “Joining time-resolved thermometry and magnetic-induced heating in a single nanoparticle unveils intriguing thermal properties,” ACS Nano, vol. 9, pp. 3134–3142, 2015.

[4] G. Duret, S. Polali, E. D. Anderson, A. M. Bell, C. N. Tzouanas, B. W. Avants, and J. T. Robin- son, “Magnetic Entropy as a Proposed Gating Mechanism for Magnetogenetic Ion Channels,” Biophysical Journal, vol. 116, pp. 454–468, Feb. 2019.

[5] H. Huang, S. Delikanli, H. Zeng, D. M. Ferkey, and A. Pralle, “Remote control of ion channels and neurons through magnetic-field heating of nanoparticles.,” Nat Nanotechnol, vol. 5, pp. 602– 6, Aug. 2010.

[6] J. T. Dias, M. Moros, P. del Pino, S. Rivera, V. Grazú, and J. M. de la Fuente, “DNA as a Molecular Local Thermal Probe for the Analysis of Magnetic Hyperthermia,” Angewandte Chemie International Edition, vol. 52, no. 44, pp. 11526–11529, 2013.

[7] L. Polo-Corrales and C. Rinaldi, “Monitoring iron oxide nanoparticle surface temperature in an alternating magnetic field using thermoresponsive fluorescent polymers,” Journal of Applied Physics, vol. 111, p. 07B334, Mar. 2012.

[8] J. Dong and J. I. Zink, “Taking the Temperature of the Interiors of Magnetically Heated Nanoparticles,” ACS Nano, vol. 8, pp. 5199–5207, May 2014.

[9] P. Keblinski, D. G. Cahill, A. Bodapati, C. R. Sullivan, and T. A. Taton, “Limits of localized heating by electromagnetically excited nanoparticles,” Journal of Applied Physics, vol. 100, p. 054305, 2006.

[10] Y. Rabin, “Is intracellular hyperthermia superior to extracellular hyperthermia in the thermal sense?,” International Journal of Hyperthermia, vol. 18, pp. 194–202, 2002.

[11] Wikichip.org, “A12 Bionic – Apple – WikiChip.” https://en.wikichip.org/wiki/apple/ax/a12, July 2019.

[12] D. G. Cahill, P. V. Braun, G. Chen, D. R. Clarke, S. Fan, K. E. Goodson, P. Keblinski, W. P. King, G. D. Mahan, A. Majumdar, H. J. Maris, S. R. Phillpot, E. Pop, and L. Shi, “Nanoscale thermal transport. II. 2003–2012,” Applied Physics Reviews, vol. 1, p. 011305, Jan. 2014.

[13] Z. B. Ge, D. G. Cahill, and P. V. Braun, AuPd metal nanoparticles as probes of nanoscale thermal transport in aqueous solution,” Journal of Physical Chemistry B, vol. 108, pp. 18870–18875, 2004.

[14] A. T. Pham, M. Barisik, and B. Kim, “Interfacial thermal resistance between the graphene- coated copper and liquid water,” International Journal of Heat and Mass Transfer, vol. 97, pp. 422–431, June 2016.

[15] M. Barbic, “Possible magneto-mechanical and magneto-thermal mechanisms of ion channel activation in magnetogenetics,” eLife, vol. 8, Aug. 2019.

[16] B. Iordanova, C. S. Robison, and E. T. Ahrens, “Design and characterization of a chimeric ferritin with enhanced iron loading and transverse NMR relaxation rate,” Journal of Biological Inorganic Chemistry, vol. 15, pp. 957–965, Aug. 2010.

[17] L. Michaelis, C. D. Coryell, and S. Granick, “Ferritin III. The magnetic properties of ferritin and some other colloidal ferric compounds,” Journal of Biological Chemistry, vol. 148, pp. 463–480, 1943.

[18] G. Schoffa, “Der Antiferromagnetismus des Ferritins bei Messungen der magnetischen Suszeptibilität im Temperaturbereich von 4,2 bis 300°K,” Zeitschrift für Naturforschung, vol. B 20, pp. 167–172, 1965.

[19] P. Jandacka, H. Burda, and J. Pistora, “Magnetically induced behaviour of ferritin corpuscles in avian ears: Can cuticulosomes function as magnetosomes?,” J R Soc Interface, vol. 12, p. 20141087, Jan. 2015.

4 thoughts on “Magnetofiction – A Reader’s Guide

  1. The incentives for work in magnetobiology are so misaligned with doing good, reproducible science that it no longer matters if there is proof of the underlying assumptions.

    Take, for instance, Nimpf and Keays, 2017 (“Is magnetogenetics the new optogenetics?”), in which the discussion of whether the exact findings of Stanley, Qin, or Wheeler even could replicate is reduced to a couple of sentences:

    “First, it is unclear how those that rely on genetically encoded ferritin nanoparticles, actually work. Whether it is a mechanical force or thermal induction, our current knowledge of the ferritin moiety indicates that it lacks the magnetic properties to activate either a mechanical or temperaturesensitive channel. For instance, the force generated by a single ferritin nano-particle, which contains about 4,500 iron atoms, in a 50 mT field with a gradient of 6.6 T/m is just 7 × 1023 N, well below the 2 × 1013 N required to open known mechanoreceptors (Meister, 2016). It is therefore important that the studies by Stanley et al (2012, 2016) and Wheeler et al (2016), both of which were well controlled, are independently replicated.”

    This is from a lab that knows that these studies are unreplicable* and instead of confronting that, it is relegated to less than a paragraph, because that is how you get a publication in EMBO. At the end of the day, that is all that matters to professional biologists- because that is all that is going to define their careers.

    I would take even a stronger position than this blogpost (and, perhaps- though it is hinted at, in the “Physical limits to magnetogenetics” paper in eLife, 2016). Other than in magnetotactic bacteria**, if anyone can show conclusive, or even replicable convincing, evidence of any animal using magnetic field information to make any decision I would be shocked.

    It doesn’t matter at all to the labs which study the field. That ‘magnetosensitivity/magnetoperception’ exists is a fait accompli, and now millions of research dollars, and years of young scientists lives, are being spent solving the final problem of the literature (‘what is the magnetoreceptor’) rather than the more foundational question of ‘is there such thing as a natural magnetoreceptor’

    *indeed, I wasted 3 years of my life trying to replicate each of these
    **cool and interesting in itself, but not a case of ‘perception’ of a magnetic field by any stretch

    Liked by 1 person

  2. The development of genetically-encoded light-sensitive microbial opsins (‘optogenetics’) that allow for control of neuronal activity with high temporal precision has led to advances in our understanding of how neural circuits influence behavior. However, optogenetic manipulation requires invasive, intracranial implantation of optical fibers to the target brain region for laser light delivery. In order to extend the depth of optical access for optogenetic applications, we integrated laser interferometry, which has recently been employed to detect cosmic gravitational waves, into our optogenetics setup to create LIGOgenetics. When the LIGOgenetic actuator ChR2001: A Space Odyssey was expressed in dopaminergic neurons in the ventral regimental area, the merger of a black hole and neutron star 217 light years away produced a robust conditioned place preference. Thus, LIGOgenetics overcomes optical scattering by leveraging gravitational waves for precise, cosmic control of neural circuit dynamics.

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  3. GRAVITO: A transducer protein for gravitational control of the nervous system
    LIGOgenetics aims to control neural activity with gravitational waves that can pass through tissue undisturbed. Here we report development of a new genetically-encoded gravity transducer. We reasoned that a protein with high gravitational activity would be strongly attracted to itself and thus form dimers or larger aggregates. A high-throughput screen for such gravitational proteins identified GP1, a 42-amino-acid peptide, apparently a product of the APP gene. Atomic force measurements revealed that monomers attract each other with a force of 130 pN, about 30 orders of magnitude larger than expected from the molecular weight and a classical treatment of gravity. We fused this polypeptide to the mechanosensitive membrane channel TRP4 to create GRAVITO, and expressed this construct in the zebrafish nervous system. Transgenic fish performed unexpected twitches every few days, consistent with the rate of cosmic encounters that produce gravitational waves. We conclude that GRAVITO serves as an effective transducer for LIGOgenetics, and that the conventional understanding of gravity breaks down on the scale of nanometers.

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