Physical Models of Living Systems, Second Edition

Physical Models of Living Systems, 2nd Edition,
by Philip Nelson.

In a 2015 blog post, I discussed Philip Nelson’s then-new book Physical Models of Living Systems. I wrote that “It’s an excellent book, well written and beautifully illustrated.” Recently, Nelson published a second edition of Physical Models of Living Systems. All the nice things I wrote about the first edition remain true in the second, but now there are four new chapters to increase your fun. In this post, I’ll focus on the new chapters.

Chapter 6: Random Walks on an Energy Landscape

I like how Nelson organizes each chapter around a biological question and a physical idea.

Biological question: How can pulling two things apart strengthen their bond?

Physical idea: Bond breaking is a first passage process, controlled by the lowest activation barrier, and that barrier can increase upon moderate loading.

The chapter describes slip bonds and catch bonds. A slip bond is the normal case when the bond’s strength decreases as you pull on it, and a catch bond is the unusual case when its strength increases as you pull. Wikipedia compares a catch bond to one of those Chinese finger traps.

Photograph by Carol Spears on Wikipedia. 

https://commons.wikimedia.org/wiki/File:Finger_trap_toys.jpg

 

Nelson explains catch bonds using random walk simulations; first a free random walk, then one with an applied force, next one in a harmonic oscillator potential, and finally one with a oscillator potential plus a barrier, where if you reach the top of the barrier the bond breaks. The “strength” of the bond then becomes the walking time before reaching the barrier (a “first passage process”). By manipulating the potential shape, he finds clutch bond behavior. He then relates these simple simulations (which the reader can easily perform on their own computer) to T cell activation and leukocyte rolling. In each chapter, he sums up the analysis with a section he calls “The Big Picture.” For this chapter, he writes

Our physical model… was absurdly simple, but it nevertheless contained a lot of buried treasure: the basic facts about free Brownian motion, drift under constant force, equilibration in a trapping potential field, the Boltzmann distribution in equilibrium, the Arrhenius rule for escape in quasiequilibrium, and the entire surprising phenomenon of catch bonding. The key step was to understand bond breaking as a first passage problem.

Chapter 8: Single Particle Reconstruction in Cryo-electron Microscopy

Biological question: How can we combine many noisy images of a viral protein to get one clean image?

Physical idea: We must first align the images, but our best estimate of the required alignment is actually a probability distribution.

In this chapter, Nelson examines how to take noisy electron microscope images of an object that are each rotated or shifted relative to each other, and align them to get a clear picture. He warns us “You can’t win by averaging noisy signals unless you know the proper alignment.” What biological example does he look at? The coronavirus spike protein! Apparently the procedure described in this chapter played a big role in the development of the covid-19 vaccine. The story makes me want to seek out the scientists who developed this method and give them a big hug. 

Chapter 14: Demographic Variation in Epidemic Spread

Biological question: Why do some outbreaks of a communicable illness spread explosively, whereas others, in similar communities, fizzle after the first few cases?

Physical idea: A tiny subpopulation of superspreader individuals can have a huge effect on the course of an epidemic.

This chapter starts with the SIR model of an epidemic (S = susceptible, I = infected, and R = recovered) that I’ve discussed before in this blog. Nelson tweaked it to examine what happens just as the epidemic begins if you have a handful of superspreaders. Once again, the model is applied to understanding covid. In the big picture Nelson writes

We have found that because outbreaks always begin with just one or a few infective individuals, the discrete, stochastic character of transmission has a large effect on outbreak dynamics. Thus, a community that is lucky to get only a mild outbreak in the first instance must not become complacent, imagining themselves to be somehow protected: Always some outbreaks fizzle, but any such instance is just as likely to be followed by a severe outbreak on a later introduction as in any other community. 

There are many ways to improve the realism of the SIR model, but we focused on just one: the well documented fact that some illnesses have superspreader individuals. The implications are profound. Although Figure 14.5a is frightening, such time courses can be replaced by the milder ones in Figure 14.3 by promptly identifying and quarantining just a few percent of the infected population. For example, backward contact tracing seeks to identify contacts of each sick individual who may have been the source of that person’s infection. When multiple backward trails point to the same person, that person may be a superspreader.

Chapter 15: Bet-Hedging Via Stochastic, Excitable Dynamics

Biological question: How can a pathogen hide from the immune system?

Physical idea: Positive feedback with small copy numbers can lead to a stochastic toggle that transiently changes state after a long, random delay.

I like this chapter because it makes good use of phase portrait plots. The pathogen behaves almost like a nerve, which can either sit at rest or fire an action potential, with the all-or-none response relying on a positive feedback loop. 

What bet is being hedged? If you’re in a situation where normally one type of behavior is favored, but on rare occasions the environment changes and an unusual behavior may be needed to save the species, then sometimes organisms will keep most individuals in the normal state but will have a few random individuals in the unusual state just in case.

The second edition of Physical Models of Living Systems still has all the good stuff from the first edition: lovely color figures (including some by David Goodsell), lots of homework problems, comparisons to real data, and a winning combination of words, pictures, equations, and computer code. Add in the four new chapters—and a kindle price under ten dollars!—and you have a masterpiece.

My favorite part of the second edition: Like in the first edition, Nelson cites Intermediate Physics in Medicine and Biology. And, he remembers to update the citation to IPMB's 5th edition!

Resource Letter BP-1: Biological Physics

The December, 2021 issue of the American Journal of Physics contains Resource Letter BP-1: Biological Physics (Volume 89, Pages 1071–1078), by Raghuveer Parthasarathy. A Resource Letter is a guide to the literature, websites, and other teaching aids about a particular topic. Parthasarathy’s abstract states

This Resource Letter provides an overview of the literature in biological physics, a vast, active, and expanding field that links the phenomena of the living world to the tools and perspectives of physics. While no survey of this area could be complete, this list and commentary are intended to help provide an entry point for upper-level undergraduates, graduate students, researchers new to biophysics, or workers in subfields of biophysics who wish to expand their horizons. Topics covered include subcellular structure and function, cell-scale mechanics and organization, collective behaviors and embryogenesis, genetic networks, and ecological dynamics.

I particularly like the opening paragraph of his resource letter, which reflects what Russ Hobbie and I have tried to convey in Intermediate Physics for Medicine and Biology.

Life is full of variety, vigor, and clever solutions to daunting challenges. Physics provides deep, elegant insights into how nature works and tools with which to gain ever-greater insights. In biological physics, we find the merger of physics and biology. The resulting combination of diversity and depth, together with a wealth of practical applications, contributes to the vitality and size of the field.

The Resource Letter cites many books that I have discussed in my blog: Physical Biology of the Cell, Biophysics: Searching for Principles, From Photon to Neuron, Molecular Biology of the Cell, Cell Biology by the Numbers, Physical Models of Living Systems, Sync, The Machinery of Life, The Eighth Day of Creation, Random Walks in Biology, Life in Moving Fluids, and On Being the Right Size. It also includes many items I have not written about, such as: Biological Physics/Physical Biology Virtual Seminars, BioRxiv, and The Way of the Cell: Molecules, Organisms, and the Order of Life. I’ve always wondered what exactly “systems biology” is, so I should read A First Course in Systems Biology. The Vital Question: Energy, Evolution, and the Origins of Complex Life sounds fascinating.

I am looking forward to Parthasarathy’s new book So Simple a Beginning: How Four Physical Principles Shape Our Living World, due out next year (I see there is even an audiobook version, so I can listen to it on my phone while dog walking!). For some reason, he didn’t cite his blog in the Resource Letter, so I will cite it here: the Eighteenth Elephant. You can find out what the name of his blog means by reading the charming story told here. Another item lacking in the Resource Letter are Parthasarathy’s wonderful watercolor paintings, which grace each post in his blog. You can see a few of them in the video below.

What is the best thing about Resource Letter BP-1: Biological Physics? It cites both Intermediate Physics for Medicine and Biology and this blog. As far as I know, this is the only citation my blog has ever received. Thanks Raghu! 

So Simple a Beginning: How Four Physical Principles Shape Our Living World. 

https://www.youtube.com/watch?v=fxnqq9Dv18o

BPPB Virtual Seminar, Raghuveer Parthasarathy, Seeing Gut Microbes Swim, Stick, and Survive.

(At the start of the video, you can see me in the zoom meeting, second row on the left.)

https://www.youtube.com/watch?v=g2gYKvMXh-s

When Death Becomes Life

When Death Becomes Life,
by Joshua Mezrich.

In last week’s post, I told you about a book I didn’t like. This week, I’ll tell you about one I liked. About a year ago, Russ Hobbie suggested I read When Death Becomes Life: Notes From a Transplant Surgeon, by Joshua Mezrich. Mezrich is a transplant surgeon at the Wisconsin School of Medicine and Public Health. The book starts

The following book is neither a memoir nor a complete history of transplantation. I am not old enough to write a memoir, and a few excellent complete histories of transplantation exist already (and are listed in the bibliography). My goal is not to provide a chronological depiction of my coming-of-age as a surgeon, but rather, to use my experiences and those of my patients to give context for the story of the modern pioneers who made transplantation a reality.

Russ and I discuss transplants briefly in Chapter 5 of Intermediate Physics for Medicine and Biology, when describing the artificial kidney.

The artificial kidney provides an example of the use of the transport equations to solve an engineering problem. The problem has been extensively considered by chemical engineers, and we will give only a simple description here… The reader should also be aware that this “high-technology” solution to the problem of chronic renal disease is not entirely satisfactory… The alternative treatment, a transplant, has its own problems, related primarily to the immunosuppressive therapy.

Mezrich describes the kidney in this way.

The kidney is an exquisite organ. I like to tell my residents that “the dumbest kidney is smarter than the smartest doctor.” In a healthy person with a working organ, blood flows into the kidney and goes through an ingenious system of glomeruli—that is, circular tufts of thin blood vessels surrounding the tubules of the kidney. Across the kidney’s membranes and structures, toxins, wastes, and electrolytes are filtered out into the tubules to be secreted as urine. Kidneys are also involved in controlling blood pressure and stimulating the production of red blood cells. It’s amazing how a working kidney seems to know exactly what to do with fluids and reabsorption, whereas we doctors have so much trouble regulating fluid in patients, no matter how many labs and vitals we check.

After Mezrich told of the challenges he faced in his first kidney transplant, he wrote

Since then, I have done hundreds of kidney transplants, and I promise much more smoothly than that first one. To this day, though, I experience the same feeling of amazement when the organ pinks up and urine squirts out. To this day, I still can’t believe it works—and not just for a few days or a few months. With a little luck, the little beans I successfully transplant into patients should keep pumping out urine for years.

Mezrich tells the story of Willem Kolff’s invention of the dialysis machine (the artificial kidney) in Nazi-occupied Holland. There’s a lot of physics in dialysis, but even more in Jack Gibbon’s development of the first heart-lung machine. Mezrich also reviews the discovery of the immunosuppressive drug cyclosporine (he calls it the penicillin of transplantation), which made long-term kidney, liver, pancreas, and heart transplants possible.

By juxtaposing the history of transplantation with his own career as a transplant surgeon, Mezrich makes clear both the historical development and the special challenges of his field. Anyone applying physics or engineering to medicine would benefit from his unique insights. His look at the human side of medicine contrasts with the more technical information found in Intermediate Physics for Medicine and Biology.

Somehow, Thanksgiving seems like the appropriate time to write about When Death Becomes Life. Certainly, we all owe a great debt to the doctors, nurses, support staff, researchers, organ donors, and their families for this lifesaving surgery. I urge you to sign up to be an organ donor at https://www.organdonor.gov/sign-up. 

I’ll give Mezrich the final word.

By illustrating what it took for me to practice transplantation, and by painting a picture, with the stories of my patients, of how the discipline has touched so many, I hope to highlight the incredible gift transplantation is to all involved, from the doctors to the recipients to those of us lucky enough to be the stewards of the organs. I also will show the true courage of the pioneers in transplant, those who had the courage to fail but also the courage to succeed.

How Death Becomes Life, by Joshua Mezrich. Talks at Google. 

https://www.youtube.com/watch?v=oA-EZ2Tsv1I

The Body Electric

The Body Electric,
By Robert Becker and Gary Selden

Go to www.amazon.com and look up the best selling book in the category “biophysics.” You’ll often find #1 is The Body Electric: Electromagnetism and the Foundation of Life, by Robert Becker and Gary Selden. (Selden helped with the writing, but the book tells Becker’s story.) The purpose of today’s post is to explain why this book is awful.

1. Let’s begin with Becker’s views on nerve conduction (page 86).

“According to the theory, an impulse should travel with equal ease in either direction along the nerve fiber. If the nerve is stimulated in the middle, an impulse should travel in both directions to opposite ends. Instead, impulses travel only in one direction; in experiments they can be made to travel ‘upstream,’ but only with great difficulty. This may not seem like such a big deal, but it is very significant. Something seems to polarize the nerve.”

I stimulated many nerves as a graduate student, back in the days when I did experiments. Action potentials propagate just fine in either direction. I had no difficulty making one travel upstream.

2. Becker didn’t understand why nerves, which fire all-or-none action potentials, can produce smooth, coordinated muscle movements (page 87).

“In addition, impulses always have the same magnitude and speed. This may not seem like such a big thing either, but think about it. It means the nerve can carry only one message, like the digital computer’s 1 or 0… The motor activities we take for granted—getting out of a chair and walking across the room, picking up a cup and drinking coffee, and so on—require integration of all the muscles and sensory organs working smoothly together to produce coordinated movements that we don’t even have to think about. No one has ever explained how the simple code of impulses can do all that.”

A muscle contains many motor units. Each motor unit is controlled by a single motor neuron. If you want a muscle to contract with a small force, you activate one motor unit. If you want a muscle to contract more forcefully, you activate many motor units. Motor unit recruitment, plus changes in nerve firing rate, explains the smooth operation of muscles. 

3. Becker didn’t believe that nerves worked using ionic currents, meaning the movement of ions like sodium, potassium, and chloride dissolved in the salt water that makes up our tissues (page 92).

“At that earlier time, there had been only two known modes of current conduction, ionic and metallic. Metallic conduction can be visualized as a cloud of electrons moving along the surface of metal, usually a wire. It can be automatically excluded from living creatures because no one has ever found any wires in them. Ionic current is conducted in solutions by the movement of ions—atoms or molecules charged by having more or fewer than the number of electrons needed to balance their protons’ positive charges. Since ions are much bigger than electrons, they move more laboriously through the conducting medium, and ionic currents die out after short distances. They work fine across the thin membrane of the nerve fiber, but it would be impossible to sustain an ionic current down the length of even the shortest nerve.”

Regular readers of this blog will recall my post about Baker, Hodgkin and Shaw’s experiment in which they squeezed the axoplasm out of a squid nerve axon and replaced it with salt water. The nerve worked just fine. 

Some individual molecules work by transfer of electrons (for instance, the electron transport chain in mitochondria), but currents flowing through tissue are produced by ions. Ionic currents don’t “die out” after short distances.
 

4. Instead of ionic conduction, Becker believed that nerves conducted electricity by semiconduction (page 94).

“I postulated a primitive, analog-coded information system that was closely related to the nerves but not necessarily located in the nerve fibers themselves. I theorized that this system used semiconducting direct currents and that, either alone or in concert with the nerve impulse system, it regulated growth, healing, and perhaps other basic processes.”

Later, he performed measurements of the Hall effect (a voltage induced by current flowing in a magnetic field) and wrote (page 102):

“The experiment demonstrated unequivocally that there was a real electric current flowing along the salamander’s foreleg, and it virtually proved that the current was semiconducting. In fact, the half-dozen tests I’d performed supported every point of my hypothesis.”

Scientists have made semiconductors based on biological ideas: organic semiconductors and semiconductors based on synthetic biology. But there’s no evidence that semiconductors play a role in our normal physiology. Our bodies are basically all salt water. Ionic conduction is the way currents flow through our tissue.
 

5. Becker declared he had discovered the mechanism of acupuncture (page 234).

“The acupuncture meridians, I suggested, were electrical conductors that carried an injury message to the brain, which responded by sending back the appropriate level of direct current to stimulate healing in the troubled area…. If the lines and points [corresponding to acupuncture meridians] really were conductors and amplifiers, the skin above them would show specific electrical differences compared to the surrounding skin.”

Acupuncture is based on pseudoscience; No anatomical structures such as “meridians” exist, and the vital force “qi” has never been observed. Listen to Harriet Hall describe acupuncture. Read what Edzard Ernst says.

6. Becker asserted that static magnetic fields could act as an anesthetic (page 238).

“A strong enough magnetic field oriented at right angles to a current magnetically ‘clamped it’, stopping the flow [of current]. By placing frogs and salamanders between the poles of an electromagnet so that the back-to-front current in their heads was perpendicular to the magnetic lines of force, we could anesthetize the animals just as well as we could with chemicals.”

Such neurological effects are not caused by static magnetic fields. Patients have undergone magnetic resonance imaging in static magnetic fields far larger than what Becker used, and no one has been anesthetized, regardless of the orientation of their head. Using magnets for pain has been discredited.

7. Becker thought that the cells forming the myelin sheaths surrounding myelinated nerve axons carried their own electric current that could have biological effects (page 239).

“Electron microscope work has shown that the cytoplasm of all Schwann cells is linked together through holes in the adjacent membranes, forming a syncytium that could provide the uninterrupted pathway needed by the current.”

The Schwann cells make up the myelin sheath. Myelin consists of layers of fat with little cytoplasm between the layers. Its purpose is to insulate a nerve between openings called nodes of Ranvier. There is no evidence myelin carries significant current, but even if it did carry current along a nerve through the myelin, it would be interrupted ever millimeter or so by a node. 
 

8. Becker believed that magnetoencephalography confirmed his claim that DC current existed in the brain (page 241)

“The MEG research so far seems to be establishing that every electrical evoked potential is accompanied by a magnetic evoked potential. This would mean that the evoked potentials and the EEG of which they’re a part reflect true electrical activity, not some artifact of nerve impulses being discharged in unison, as was earlier theorized. Some of the MEG’s components could come from such additive nerve impulses, but other aspects of it clearly indicate direct currents in the brain.”

DC currents in the brain are uncommon, and primarily associated with brain injury or migraines. Researchers in biomagnetism interpret their results as arising from additive nerve impulses, discharged in unison.

9. Becker promoted the idea that extrasensory perception was a result of DC or extremely low frequency (ELF) electromagnetic fields (page 267).

“At this time the DC perineural system [myelin sheaths around nerves] and its electromagnetic fields provide the only theory of parapsychology that’s amenable to direct experiment. And it yields hypotheses for almost all such phenomena except precognition. Telepathy may be transmission and reception via a biologically programmed channel of ELF vibrations in the perineural system’s electromagnetic field.”

What can I say? I don’t believe in extrasensory perception.
 

10. Becker suggested electromagnetic effects could explain psychokinesis, such as spoon-bending by pure thought (page 269).

“Once we admit the idea of this kind of influence, then the same kind of willed action of biofields on the electromagnetic structure of inanimate matter becomes a possibility. This encompasses all forms of psychokinesis, from metal-bending experiments in which trickery has been excluded to more rigidly controlled tests with interferometers, strain gauges, and random number generators.”

I don’t believe in psychokinesis either.  Neither did James Randi, who died just a year ago.

11. Becker claimed that weak magnetic fields could affect cognitive ability in humans (page 276).

“We exposed volunteers to magnetic fields placed so the lines of force passed through the brain from ear to ear, cutting across the brainstem-frontal current. The fields were 5 to 11 gauss [0.0005 to 0.0011 tesla], not much compared with the 3,000 gauss needed to put a salamander to sleep, but ten to twenty times earth’s background and well above the level of most magnetic storms. We measured their influence on a standard test of reaction time—having subjects press a button as fast as possible in response to a red light. Steady fields produced no effect, but when we modulated the field with a slow pulse of a cycle every five seconds (one of the delta-wave frequencies we’d observed in salamander brains during a change from one level of consciousness to another), people’s reaction slowed down.”

Many reviews of the biological effects of magnetic fields conclude there are no such effects.
 

12. Becker championed the idea that 60-Hz, power line magnetic fields could cause cancer. But he went even further, saying the such “electropollution” could threaten human existence (page 327).

“Everyone worries about nuclear weapons as the most serious threat to our survival. Their danger is indeed immediate and overwhelming. In the long run, however, I believe the ultimate weapon is manipulation of our electromagnetic environment, because it’s imperceptibility subtle and strikes at the core of life itself. We’re dealing here with the most important scientific discovery ever—the nature of life. Even if we survive the chemical and atomic threats to our existence, there’s a strong possibility that increasing electropollution could set in motion irreversible changes leading to our extinction before we’re even aware of them.” 

The “electropollution” Becker speaks of is weak electric and magnetic fields, such as produced by power lines. Power line magnetic fields are safe, and earlier claims that they are not have been shown to be false (see my previous post). “Electropollution” is closer to an imaginary threat than an existential one.

What do I make of all this? Becker’s book is full of nonsense. Moreover, I know little about some of the topics in the book, such as regeneration, bone growth, and injury currents. There could well be more mistakes than just those I’ve caught.

Becker died almost twelve years ago. Am I beating a dead horse? No. According to Google Scholar, The Body Electric has been cited more than 1000 times in the scientific literature (twice as many times as Intermediate Physics for Medicine and Biology), including over 25 times in 2021 already. It’s cited by the supporters of the worst kind of alternative medicine foolishness. The 5G opponents quote him. The power lines and cancer folks quote him. The magnets for pain promoters quote him.

You might wonder: am I upset just because The Body Electric gets more sales and citations than IPMB? Well, maybe that’s part of it. But I believe debunking Becker’s book is a public service. People need to learn real science.

My favorite story in The Body Electric is the time a bigwig physiologist visited Becker’s lab, and told him outright that his results were “artifact, all artifact” (page 106). Thereafter, Becker and his colleagues referred to this fellow derisively as “Artifact Man” and held him up as a symbol for dogmatism. I love Artifact Man.

Chapter 1 sums up Becker’s view of medicine with a defense of “faith healing, magic healing, psychic healing, and spontaneous healing” (page 25). He goes on to say (page 29) 

“The more I consider the origins of medicine, the more I’m convinced that all true physicians seek the same thing. The gulf between folk therapy and our own stainless-steel version is illusory. Western medicine springs from the same roots and, in the final analysis, acts through the same little-understood forces as its country cousins. Our doctors ignore this kinship at their—and worse, their patients’—peril. All worthwhile medical research and every medicine man’s intuition is part of the same quest for knowledge of the same elusive healing energy.”

No, No, No. The origins of medicine should be science. The gulf between folk therapy and modern medicine is wide and must get wider. Our doctors ignore science at their—and worse, their patients’—peril.

Okay, I’m done now. I realize this post is more of a rant than is usual for me. Sorry about that, but there’s something about The Body Electric that really gets my goat.

Bidomain Modeling of Electrical and Mechanical Properties of Cardiac Tissue

This week Biophysics Reviews published my article “Bidomain Modeling of Electrical and Mechanical Properties of Cardiac Tissue” (Volume 2, Article Number 041301, 2021). The introduction states

This review discusses the bidomain model, a mathematical description of cardiac tissue. Most of the review covers the electrical bidomain model, used to study pacing and defibrillation of the heart. For a book-length analysis of this topic, consult the recently published second edition of Cardiac Bioelectric Therapy. In particular, one chapter in that book complements this review: it contains a table listing many bidomain predictions and their experimental confirmation, includes many original figures from earlier publications, and cites additional references. Near the end, the review covers the mechanical bidomain model, which describes mechanotransduction and the resulting growth and remodeling of cardiac tissue.

The review has several aims: to (1) introduce the bidomain model to younger investigators who are bringing new technologies from outside biophysics into cardiac physiology; (2) examine the interaction of theory and experiment in biological physics; (3) emphasize intuitive understanding by focusing on simple models and qualitative explanations of mechanisms; and (4) highlight unresolved controversies and open questions. The overall goal is to enable technologists entering the field to more effectively contribute to some of the pressing scientific questions facing physiologists.

My manuscript traveled a long and winding road. The initial version was a personal account of my career as I worked on the bidomain model (Russ Hobbie and I discuss the bidomain concept in Chapter 7 of Intermediate Physics for Medicine and Biology), and was organized around ten papers I published between 1986 and 2010, with an emphasis on the 1990s. My first draft (and all subsequent ones) benefited from thoughtful comments by my former graduate student, Dilmini Wijesinghe. After I fixed all the problems Dilmini found, I sent the initial version to the editor. He responded that the journal board wanted a more traditional, authoritative review article. That was fine, so I transformed the paper from a memoir into a review, and submitted it officially to the journal. Then the reviewers had a couple rounds of helpful comments, leading to more revisions. Next, there were changes in the page proofs to fulfill all the journal editorial rules. At last, it was published.

The final version is unlike the initial one. I changed the perspective from first person to third; added figures; increased the number of references by almost 50%; and deleted all the reminiscences, colorful anecdotes, and old war stories. 

I hope you enjoy the peer-reviewed, published article. If you want to read the original version (the one with the war stories), you can find it here.  

I made a word cloud based on the article. The giant “Roth” is embarrassing, but otherwise it provides a nice summary of what the paper is about.

Biophysics Reviews is a new journal, edited by my old friend Kit Parker. Long-time readers of this blog may remember Parker as the guy who said “our job is to find stupid and get rid of it.” Listen to him describe his goals as Editor-in-Chief.

Kit Parker, Editor-in-Chief of Biophysics Reviews, introduces the journal.

https://www.youtube.com/watch?v=2V1fpskjJtM

Electroreception

Suppose you’re reading Homework Problem 4 in Chapter 8 of Intermediate Physics for Medicine and Biology, and you run across the phrase “If a shark can detect an electric field strength of 0.5 μV m⁻¹…”. What’s your first reaction? Probably you suspect a typo (it isn’t). An electric field with a strength of 0.5 μV m⁻¹ is tiny. By comparison, you need a field of about 10 V m⁻¹ to stimulate a neuron in the brain. How can a shark detect a field of only 0.0000005 V m⁻¹? The answer makes for an interesting story.

Some of the first studies of electroreception—the ability of some animals, such as sharks, to sense weak electric fields—were performed by a biophysicist at Woods Hole Oceanographic Institute named Adrianus Kalmijn. He observed dogfish sharks while sitting in an inflatable rubber raft in the ten-foot deep water of the Atlantic Ocean near Martha’s Vineyard. Kalmijn attracted the sharks using liquified herring placed on the ocean floor. On either side of the herring was a pair of electrodes that could be used to pass current. The dogfish were initially attracted by the smell of the herring, and “began frantically searching over the sand, apparently trying to locate the odor source” (Kalmijn, 1977). But when current was turned on, the dogfish stopped searching for the herring and “viciously attacked” the electrodes! Using experiments like these, Kalmijn was able to characterize how sharks respond to electric fields. 

Spiny dogfish (Squalus acanthias) at the Josephine Marie shipwreck, Stellwagen National Marine Laboratory. From Wikipedia.

Sharks detect weak electric fields using sensory organs called the ampullae of Lorenzini. The ampullae consist of highly conducting jelly-filled tubes about 30 cm long (a little more than a foot). The shark detects the voltage across the length of the tube, and then places that entire voltage difference across a single cell membrane. An electric field of 0.5 μV m⁻¹ multiplied by a distance of 0.3 m gives you a voltage of 0.15 μV. There’s an extra factor of three arising from the distortion of the field by the shark, so you end up with a transmembrane voltage of about half a microvolt.

A membrane voltage of 0.5 μV is minuscule. The typical resting membrane voltage of a cell is approximately 70 mV, so half a microvolt is less than ten parts per million. How can such a small voltage change be detected? To answer this question, William Pickard, an engineer at Washington University in St. Louis, assumed that this membrane voltage does not cause a neuron to fire (it’s far too weak for that), but instead modulates its spontaneous firing rate. The neuron normally operates in a regime where this rate is very sensitive to the membrane voltage, which has the effect of magnifying a small change in voltage into a large change in rate (Pickard, 1988).

Many ampullae of Lorenzini influence a single neuron. Their summation has the effect of averaging out any background noise. The size of thermal voltage fluctuations across a neuron’s membrane were estimated by Yale physicist Robert Adair to be about 1 μV (Adair, 1991), which is twice as large as the membrane voltage produced by the smallest electric field a shark can detect. Integrating the signal over hundreds of ampullae suppresses these fluctuations, allowing the system to pick a signal out of the thermal background. This sensory mechanism has been honed by evolution to be about as sensitive as it can be without detecting the constant roar of random noise. 

To learn more about electroreception, see Section 9.9 of Intermediate Physics for Medicine and Biology.

1. Kalmijn, A. J. (1977) “The electric and magnetic sense of sharks, skates, and rays.” Oceanus Volume 20, Pages 45-52.
2. Pickard, W. F. (1988) “A model for the acute electrosensitivity of cartilaginous fishes.” IEEE Transactions on Biomedical Engineering Volume 35, Pages 243-249. 
3. Adair, R. K. (1991) “Constraints on biological effects of weak extremely low-frequency electromagnetic fields.” Physical Review A Volume 43, Pages 1039-1048. 
   
   

The ampullae of Lorenzini. https://www.youtube.com/watch?v=9S8a5hSc22s

The 10-20 System

In Chapter 7 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss the 10-20 system of electrodes on the scalp used to record the electroencephalogram.

Much can be learned about the brain by measuring the electric potential on the scalp surface. Such data are called the electroencephalogram (EEG)… Typically, the EEG is measured from 21 electrodes attached to the scalp according to the 10-20 system (Fig. 7.34).

Fig. 7.34. The standard 10-20 system of electrodes to record the EEG.

Why is this placement of electrodes called the “10-20” system? Consider the path starting at the nasion (between the eyes, just above the bridge of the nose), passing over the top of the head, and ending at the inion (a small protuberance at the lower back of the skull). This path is shown as the vertical dashed line in the top view of the head in Fig. 7.34. Five electrodes (O_z, P_z, C_z, F_z, and F_pz) are placed 10, 20, 20, 20, 20, and 10% of the distance along the path. All those 10s and 20s give rise to the name “10-20 system.” The electrodes O_z and F_pz aren’t part of the 10-20 system, so they’re not shown in Fig. 7.34, but their positions are used to properly place the other electrodes.

Now, consider the path starting just behind the left ear (auricle, A₁, sometimes known as the mastoid), passing over the top of the head through C_z, and ending just behind the right ear (A₂); the horizontal dashed line in Fig. 7.34. Five electrodes (T₃, C₃, C_z, C₄, and T₄) are placed 10, 20, 20, 20, 20, and 10% of the distance along the path.

Next, examine the dashed circle in Fig. 7.34, which represents a circumference of the head through O_z, T₃, F_pz, and T₄. Ten electrodes (O₁, T₅, T₃, F₇, F_p1, F_p2, F₈, T₄, T₆, and O₂) are equally spaced along this circumference, each 10% of the way around the circle.

Finally, consider a great circle path passing from F_p1 through C₃ to O₁. The electrode F₃ is halfway between F_p1 and C₃. Similar reasoning gets you the positions of P₃, F₄ and P₄.

How do these electrodes get their funny names? The first letter indicates the region of the brain: F for frontal (front), T for temporal (side, named for your temples), P for parietal (center-back), O for occipital (lower back), Fp for pre-frontal, and C for central. A subscript z means along the midline. Even numbers are used for the right of the head, and odd numbers for the left.

The 10-20 system was proposed by a committee of the International Federation of Clinical Neurophysiology, in order to standardize EEG recordings among different laboratories. 

Measurement of the 10-20 system of electrodes (part 1).
https://www.youtube.com/watch?v=ciGgCoPpPFY

Measurement of the 10-20 system of electrodes (part 2).

https://www.youtube.com/watch?v=Qd4kIvPOQM8

MRI Safety

Will Morton, a staff writer for AuntMinnie.com, published an article about safety issues during magnetic resonance imaging. It begins

As the push toward stronger and faster MRI scanners continues, so does concern over magnet safety, according to Filiz Yetisir, who discussed the potential effects MRI has on patients at the recent International Society for Magnetic Resonance in Medicine virtual meeting (ISMRM 2021).

Main Magnet

An MRI device creates a magnetic field having a strength of several tesla. Any magnetic objects near the device can be sucked into the main field, becoming dangerous projectiles. For instance, in 2001 a six-year-old was killed by an oxygen cylinder. Yetisir warns: “Remember, the magnet’s always on.”

Gradient Coils

The gradient coils used during imaging produce magnetic fields much weaker than the dc main field, but they are turned on and off throughout the imaging pulse sequence. This causes two safety concerns. 1) The changing magnetic field induces eddy currents in the patient, which can stimulate nerves—an effect similar to transcranial magnetic simulation. 2) The switching of current in the gradient coils creates mechanical vibrations, leading to noise so loud that ear plugs may be needed to prevent hearing loss.

Radiofrequency Fields

A radiofrequency magnetic field—which rotates the spins into the plane perpendicular to the main magnet—is an essential part of any MRI pulse sequence. This field can induce eddy currents that heat the tissue. Generally the field isn’t strong enough to cause significant heating, but if a person has metal implants or tattoos, the heating may be increased locally. Any implanted medical device, such as a pacemaker, can interact with all three types of magnetic fields.

Gadolinium

One issue Morton’s article doesn’t discuss is the toxicity of contrast agents such as gadolinium used in some MRI studies.

AuntMinnie.com is one of those websites that’s valuable for readers of Intermediate Physics for Medicine and Biology.

Screenshot of AuntMinnie.com

AuntMinnie.com provides the first comprehensive community internet site for radiologists and related professionals in the medical imaging industry.

We provide a forum for radiologists, business managers, technologists, members of organized medicine, and industry to meet, transact, research, and collaborate on topics within the field of radiology with the ease and speed that only the internet can provide.

AuntMinnie features the latest news and information about medical imaging. Staff members include executives, editors, and software engineers with years of experience in the radiology industry.

AuntMinnie.com reminds me of the Physicsworld medical physics website. Physicsworld is associated with the Institute of Physics, the main physics professional society in the United Kingdom. AuntMinnie is run by a consulting firm, the Science and Medicine Group of Arlington, Virginia. Both websites provide useful information about innovations and news in medical physics. 

Screenshot of MRISafety.com

For more information about MRI safety, see MRIsafety.com. For more information about the physics underlying these safety issues, see Chapter 18 of IPMB.

Photodynamic Therapy

In Chapter 14 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss photodynamic therapy.

Photodynamic therapy (PDT) uses a drug called a photosensitizer that is activated by light (Zhu and Finlay 2008; Wilson and Patterson 2008). PDT can treat accessible solid tumors such as basal cell carcinoma, a type of skin cancer (see Sect. 14.10.4). An example of PDT is the surface application of 5-aminolevulinic acid, which is absorbed by the tumor cells and is transformed metabolically into the photosensitizer protoporphyrin IX. When this molecule interacts with light in the 600–800-nm range (red and near infrared), often delivered with a diode laser, it converts molecular oxygen into a highly reactive singlet state that causes necrosis, apoptosis (programmed cell death), or damage to the vasculature that can make the tumor ischemic. Some internal tumors can be treated using light carried by optical fibers introduced through an endoscope.

The photosensitizer molecule interacts with near infrared light to damage tissue, kill cells, and harm blood vessels. A photon of infrared light doesn’t have much energy, and I’m surprised it can trigger all this destruction. What’s the structure of this molecule that causes so much carnage?

Let’s start with 5-aminolevulinic acid, which is an endogenous nonproteinogenic amino acid. By “endogenous” I mean it occurs naturally in the body. It’s part of the biochemical pathway that leads to the production of heme in animals, and chlorophyll in plants. By “amino acid” I mean it has an amine group (-NH₂) on one end and a carboxylic acid group (-COOH) on the other end. The amino acids that make up proteins have a single carbon atom connecting the amine to the carboxylic acid, like in glycine. 5-aminolevulinic acid, on the other hand, has several carbons linking the two groups. By “nonproteinogenic” I mean that this amino acid is not one that is encoded by our genome, and therefore it never occurs in proteins. Below is a drawing of the structure of 5-aminolevulinic acid.

The chemical structure of 5-aminolevulinic acid. From Wikipedia.

Protoporphyrin IX is a complicated molecule that appears in those same pathways leading to heme and chlorophyll. It contains four pyrrole subunits, each of which is a five-membered ring composed of four carbon atoms and one nitrogen atom. It is nearly planar, and has its four nitrogen atoms facing a central hole. I show its structure below. 

The chemical structure of protoporphyrin IX. From Wikipedia.

In heme, an iron atom occupies the central hole, and is where oxygen binds in the protein hemoglobin found in red blood cells. In chlorophyll, a magnesium atom sits in the central hole.

Most molecules (for instance, water, carbon dioxide, methane, ammonia, urea, and glucose) don’t react when exposed to visible or infrared light, but protoporphyrin IX does. It’s closely related to chlorophyll, which is a key molecule in photosynthesis. When sunlight interacts with chlorophyll, it triggers a series of chemical reactions that leads to the production of carbohydrates from water and carbon dioxide.

I guess I’m not so surprised after all that protoporphyrin IX can wreak so much havoc when exposed to light.

Electroporation

In Chapter 9 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I mention electroporation.

Electrical burns, cardiac pacing, and nerve and muscle stimulation are produced by electric or rapidly changing magnetic fields. Even stronger electric fields increase membrane permeability. This is believed to be due to the transient formation of pores (electroporation). Pores can be formed, for example, by microsecond-length pulses with a field strength in the membrane of about 10⁸ V m⁻¹ (Weaver 2000).

Weaver (2000)
IEEE Trans Plasma Sci,
28: 24–33.

The citation is to an article by James Weaver

Weaver, J. C. (2000) “Electroporation of Cells and Tissues,” IEEE Transactions on Plasma Science, Volume 28, Pages 24–33.

The abstract to the paper is given below.

Electrical pulses that cause the transmembrane voltage of fluid lipid bilayer membranes to reach at least U_m ≈ 0.2 V, usually 0.5–1 V, are hypothesized to create primary membrane “pores” with a minimum radius of ~1 nm. Transport of small ions such as Na⁺ and Cl⁻ through a dynamic pore population discharges the membrane even while an external pulse tends to increase U_m, leading to dramatic electrical behavior. Molecular transport through primary pores and pores enlarged by secondary processes provides the basis for transporting molecules into and out of biological cells. Cell electroporation in vitro is used mainly for transfection by DNA introduction, but many other interventions are possible, including microbial killing. Ex vivo electroporation provides manipulation of cells that are reintroduced into the body to provide therapy. In vivo electroporation of tissues enhances molecular transport through tissues and into their constituative cells. Tissue electroporation, by longer, large pulses, is involved in electrocution injury. Tissue electroporation by shorter, smaller pulses is under investigation for biomedical engineering applications of medical therapy aimed at cancer treatment, gene therapy, and transdermal drug delivery. The latter involves a complex barrier containing both high electrical resistance, multilamellar lipid bilayer membranes and a tough, electrically invisible protein matrix.

Electroporation occurs for transmembrane potentials of a few hundred millivolts, which is only a few times the normal resting potential. I find it amazing that normal resting cells can are so precariously close to electroporating spontaneously. 

One of the most interesting uses of electroporation is transfection: the process of introducing DNA into a cell using a method other than viral infection. This could be used in an experiment in which DNA for a particular gene is transfected into many host cells. If an electric shock is not too violent, the pores created during electroporation will close over several seconds, allowing the cell to then continue its normal function while containing a foreign strand of DNA.

During defibrillation of the heart, the shock can be strong enough to damage or kill cardiac cells. One mechanism for cell injury during electrocution is electroporation followed by entry of extracellular ions such as Ca⁺⁺ that can kill a cell. This raises the possibility of using electroporation to treat cancer by irreversibly killing tumor cells.

Electroporation-based technologies and treatments. https://www.youtube.com/watch?v=u8IeoTg_wTE