Friday, August 16, 2019

This View of Life

What’s the biggest idea in science that’s not mentioned in Intermediate Physics for Medicine and Biology? Most of the grand principles of physics appear: quantum mechanics, special relativity, the second law of thermodynamics. The foundations of chemistry are included, such as atomic theory and radioactive decay. Many basic concepts from mathematics are discussed, like calculus and chaos theory. Fundamentals of biology are also present, like the structure of DNA.

In my opinion, the biggest scientific idea never mentioned in Intermediate Physics for Medicine and Biology, not even once, is evolution. As Theodosius Dobzhansky said, “nothing in biology makes sense except in the light of evolution.” So why is evolution absent from IPMB?

A simple, if not altogether satisfactory, answer is that no single book can cover everything. As Russ Hobbie and I write in the preface to IPMB, “This book has become long enough.”

At a deeper level, however, physicists focus on principles that are common to all organisms; which unify our view of life. Evolutionary biologists, on the other hand, delight in explaining how diverse organisms come about through the quirks and accidents of history. Russ and I come from physics, and emphasize unity over diversity.

Ever Since Darwin, by Stephen Jay Gould, superimposed on Intermediate Physics for Medicine and Biology.
Ever Since Darwin,
by Stephen Jay Gould.
Suppose you want to learn more about evolution; how would you do it? I suggest reading books by Stephen Jay Gould (1941-2002), and in particular his collections of essays. I read these years ago and loved them, both for the insights into evolution and for the beauty of the writing. In the prologue of Gould’s first collection—Ever Since Darwin—he says
These essays, written from 1974-1977, originally appeared in my monthly column for Natural History Magazine, entitled “This View of Life.” They range broadly from planetary and geological to social and political history, but they are united (in my mind at least) by the common thread of evolutionary theory—Darwin’s version. I am a tradesman, not a polymath; what I know of planets and politics lies at their intersection with biological evolution.
Is evolution truly missing from Intermediate Physics for Medicine and Biology? Although it’s not discussed explicitly, ideas about how physics constrains evolution are implicit. For instance, one homework problem in Chapter 4 instructs the student to “estimate how large a cell …can be before it is limited by oxygen transport.” Doesn’t this problem really analyze how diffusion impacts natural selection? Another problem in Chapter 3 asks “could a fish be warm blooded and still breathe water [through gills]?” Isn’t this really asking why mammals such as dolphins and whales, which have evolved to live in the water, must nevertheless come to the surface to breathe air? Indeed, many ideas analyzed in IPMB are relevant to evolution.

In Ever Since Darwin, Gould dedicates an essay (Chapter 21, “Size and Shape”) to scaling. Russ and I discuss scaling in Chapter 1 of IPMB. Gould explains that
Animals are physical objects. They are shaped to their advantage by natural selection. Consequently, they must assume forms best adapted to their size. The relative strength of many fundamental forces (gravity, for example) varies with size in a regular way, and animals respond by systematically altering their shapes.
The Panda's Thumb, by Stephen Jay Gould, superimposed on Intermediate Physics for Medicine and Biology.
The Panda's Thumb,
by Stephen Jay Gould.
Gould returns to the topic of scaling in an essay on “Our Allotted Lifetimes,” Chapter 29 in his collection titled The Panda’s Thumb. This chapter contains mathematical expressions (rare in Gould’s essays but common in IPMB) analyzing how breathing rate, heart rate and lifetime scale with size. In his next essay (Chapter 30, “Natural Attraction: Bacteria, the Birds and the Bees”), Gould addresses another topic covered in IPMB: magnetotactic bacteria. He writes
In the standard examples of nature’s beauty—the cheetah running, the gazelle escaping, the eagle soaring, the tuna coursing, and even the snake slithering or the inchworm inching—what we perceive as graceful form also represents an excellent solution to a problem in physics. When we wish to illustrate the concept of adaptation in evolutionary biology, we often try to show that organisms “know” physics—that they have evolved remarkably efficient machines for eating and moving.
Gould knew one of my heroes, Isaac Asimov. In his essay on magnetotactic bacteria, Gould describes how he and Asimov discussed topics similar to those in Edward Purcell’s article “Life at Low Reynolds Number” cited in IPMB.
The world of a bacterium is so unlike our own that we must abandon all our certainties about the way things are and start from scratch. Next time you see Fantastic Voyage... ponder how the miniaturized adventurers would really fare as microscopic objects within a human body... As Isaac Asimov pointed out to me, their ship could not run on its propeller, since blood is too viscous at such a scale. It should have, he said, a flagellum—like a bacterium.
I’m fond of essays, which often provide more insight than journal articles and textbooks. Gould’s 300 essays appeared in every issue of Natural History between 1974 and 2001; he never missed a month. Asimov also had a monthly essay in The Magazine of Fantasy and Science Fiction, and his streak lasted over thirty years, from 1959 to 1992. My twelve-year streak in this blog seems puny compared to these ironmen. Had Gould and Asimov been born a half century later, I wonder if they’d be bloggers?

Gould ends his prologue to The Panda’s Thumb by quoting The Origin of Species, written by his hero Charles Darwin. There in the final paragraph of this landmark book we find a juxtaposition of physics and biology.
Charles Darwin chose to close his great book with a striking comparison that expresses this richness. He contrasted the simpler system of planetary motion, and its result of endless, static cycling, with the complexity of life and its wondrous and unpredictable change through the ages:
There is a grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.

Listen to Stephen Jay Gould talk about evolution.
https://www.youtube.com/embed/049WuppYa20

 National Public Radio remembers Stephen Jay Gould (May 22, 2002).
https://www.youtube.com/embed/7mTirfwTMsU

Friday, August 9, 2019

Arthur Sherman wins the Winfree Prize

A photo of Arthur Sherman, winner of the Arthur T. Winfree Prize from the Society of Mathematical Biology.
Arthur Sherman
My friend Arthur Sherman—who I knew when I worked at the National Institutes of Health in the 1990s—has won the Arthur T. Winfree Prize from the Society of Mathematical Biology. The SMB website states
Arthur Sherman, National Institute of Diabetes and Digestive and Kidney Diseases, will receive the Arthur T. Winfree Prize for his work on biophysical mechanisms underlying insulin secretion from pancreatic beta-cells. Since insulin plays a key role in maintaining blood glucose, this is of basic physiological interest and is also important for understanding the causes and treatment of type 2 diabetes, which arises from a combination of defects in insulin secretion and insulin action. The Arthur T. Winfree Prize was established in memory of Arthur T. Winfree’s contributions to mathematical biology. This prize is to honor a theoretician whose research has inspired significant new biology. The Winfree Prize consists of a cash prize of $500 and a certificate given to the recipient. The winner is expected to give a talk at the Annual Meeting of the Society for Mathematical Biology (Montreal 2019).
Russ Hobbie and I discuss the glucose-insulin negative feedback loop in Chapter 10 of Intermediate Physics for Medicine and Biology. I’ve written previously in this blog about Winfree.

Read how Sherman explains his research in lay language on a NIDDK website.
Insulin is a hormone that allows the body to use carbohydrates for quick energy. This spares fat for long-term energy storage and protein for building muscle and regulating cellular processes. Without sufficient insulin many tissues, such as muscle, cannot use glucose, the product of digestion of carbohydrates, as a fuel. This leads to diabetes, a rise in blood sugar that damages organs. It also leads to heart disease, kidney failure, blindness, and finally, premature death. We use mathematics to study how the beta cells of the pancreas know how much glucose is available and how much insulin to secrete, as well as how failure of various components of insulin secretion contributes to the development of diabetes.
When I was at NIH, Sherman worked with John Rinzel studying bursting. Here’s a page from my research notebook, showing my notes from a talk that Artie (as we called him then) gave thirty years ago. A sketch of a bursting pancreatic beta cell is in the bottom right corner.

A photo of my notes from my NIH Research Notebook 1, March 30, 1989, taken during a talk by Arthur Sherman.
From my NIH Research Notebook 1, March 30, 1989.
I recommend the video of a talk by Sherman that you can view at https://video.mbi.ohio-state.edu/video/player/?id=338. His abstract says
I will trace the history of models for bursting, concentrating on square-wave bursters descended from the Chay-Keizer model for pancreatic beta cells. The model was originally developed on a biophysical and intutive basis but was put into a mathematical context by John Rinzel's fast-slow analysis. Rinzel also began the process of classifying bursting oscillations based on the bifurcations undergone by the fast subsystem, which led to important mathematical generalization by others. Further mathematical work, notably by Terman, Mosekilde and others, focused rather on bifurcations of the full bursting system, which showed a fundamental role for chaos in mediating transitions between bursting and spiking and between bursts with different numbers of spikes. The development of mathematical theory was in turn both a blessing and a curse for those interested in modeling the biological phenomena⁠—having a template of what to expect made it easy to construct a plethora of models that were superficially different but mathematically redundant. This may also have steered modelers away from alternative ways of achieving bursting, but instructive examples exist in which unbiased adherence to the data led to discovery of new bursting patterns. Some of these had been anticipated by the general theory but not previously instantiated by Hodgkin-Huxley-based examples. A final level of generalization has been the addition of multiple slow variables. While often mathematically reducible to models with a one-variable slow subsystem, such models also exhibit novel resetting properties and enhanced dynamic range. Analysis of the dynamics of such models remains a current challenge for mathematicians.
Congratulations to Arthur Sherman, for this well-deserved honor.

Arthur Sherman giving a talk at the  Colorado School of Mines, October 2017.

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

Friday, August 2, 2019

Can Magnetic Resonance Imaging Detect Electrical Activity in Your Brain?

Can magnetic resonance imaging detect electrical activity in your brain? If so, it would be a breakthrough in neural recording, providing better spatial resolution than electroencephalography or magnetoencephalography. Functional magnetic resonance imaging (fMRI) already is used to detect brain activity, but it records changes in blood flow (BOLD, or blood-oxygen-level-dependent, imaging), which is an indirect measure of electrical signaling. MRI ought to be able to detect brain function directly; bioelectric currents produce their own biomagnetic fields that should affect a magnetic resonance image. Russ Hobbie and I discuss this possibility in Section 18.12 of Intermediate Physics for Medicine and Biology.

The magnetic field produced in the brain is tiny; a nanotesla or less. In an article I wrote with my friend Ranjith Wijesinghe of Ball State University and his students (Medical and Biological Engineering and Computing, Volume 50, Pages 651‐657, 2012), we concluded
MRI measurements of neural currents in dendrites [of neurons] may be barely detectable using current technology in extreme cases such as seizures, but the chance of detecting normal brain function is very small. Nevertheless, MRI researchers continue to develop clever new imaging methods, using either sophisticated pulse sequences or data processing. Hopefully, this paper will outline the challenges that must be overcome in order to image dendritic activity using MRI.
Toward Direct MRI of Neuro-Electro-Magnetic Oscillations in the Human Brain, Truong et al., Magn. Reson. Med. 81:3462-3475, 2019, superimposed on Intermediate Physics for Medicine and Biology.
Truong et al. (2019) “Toward Direct
MRI of Neuro-Electro-Magnetic
Oscillations in the Human Brain,”
Magn. Reson. Med.
81:3462-3475.
Since we published those words seven years ago, has anyone developed a clever pulse sequence or a fancy data processing method that allows imaging of biomagnetic fields in the brain? Yes! Or, at least, maybe. Researchers in Allen Song’s laboratory published a paper titled “Toward Direct MRI of Neuro-Electro-Magnetic Oscillations in the Human Brain” in the June 2019 issue of Magnetic Resonance in Medicine. I reproduce the abstract below.
Purpose: Neuroimaging techniques are widely used to investigate the function of the human brain, but none are currently able to accurately localize neuronal activity with both high spatial and temporal specificity. Here, a new in vivo MRI acquisition and analysis technique based on the spin-lock mechanism is developed to noninvasively image local magnetic field oscillations resulting from neuroelectric activity in specifiable frequency bands.

Methods: Simulations, phantom experiments, and in vivo experiments using an eyes-open/eyes-closed task in 8 healthy volunteers were performed to demonstrate its sensitivity and specificity for detecting oscillatory neuroelectric activity in the alpha‐band (8‐12 Hz). A comprehensive postprocessing procedure was designed to enhance the neuroelectric signal, while minimizing any residual hemodynamic and physiological confounds.

Results: The phantom results show that this technique can detect 0.06-nT magnetic field oscillations, while the in vivo results demonstrate that it can image task-based modulations of neuroelectric oscillatory activity in the alpha-band. Multiple control experiments and a comparison with conventional BOLD functional MRI suggest that the activation was likely not due to any residual hemodynamic or physiological confounds.

Conclusion: These initial results provide evidence suggesting that this new technique has the potential to noninvasively and directly image neuroelectric activity in the human brain in vivo. With further development, this approach offers the promise of being able to do so with a combination of spatial and temporal specificity that is beyond what can be achieved with existing neuroimaging methods, which can advance our ability to study the functions and dysfunctions of the human brain.
I’ve been skeptical of work by Song and his team in the past; see for instance my article with Peter Basser  (Magn. Reson. Med. 61:59‐64, 2009) critiquing their “Lorentz Effect Imaging” idea. However, I’m optimistic about this recent work. I’m not expert enough in MRI to judge all the technical details—and there are lots of technical details—but the work appears sound.

The key to their method is “spin-lock,” which I discussed before in this blog. To understand spin-lock, let’s compare it to a typical MRI π/2 pulse (see Section 18.5 in IPMB). Initially, the spins lie at equilibrium along a static magnetic field Bz (blue in the left panel of the figure below). To be useful for imaging, you must rotate the spins into the x-y plane so they precess about the z axis at the Larmor frequency (typically a radio frequency of many Megahertz, with the exact frequency depending on Bz). If you apply an oscillating magnetic field Bx (red) perpendicular to Bz, with a frequency equal to the Larmor frequency and for just the right duration, you will rotate all the spins into the x-y plane (green). The behavior is simpler if instead of viewing it from the static laboratory frame of reference (x, y, z) we view it from a frame of reference rotating at the Larmor frequency (x', y', z'). At the end of the π/2 pulse the spins point in the y' direction and appear static (they will eventually relax back to equilibrium, but we ignore that slow process in this discussion). If you’re having trouble visualizing the rotating frame, see Fig. 18.7 in IPMB; the z and z' axes are the same and it’s the x-y plane that’s rotating.

After the π/2 pulse, you would normally continue your pulse sequence by measuring the free induction decay or creating an echo. In a spin-lock experiment, however, after the π/2 pulse ends you apply a circularly polarized magnetic field By' (blue in the right panel) at the Larmor frequency. In the rotating frame, By' appears static along the y' direction. Now you have a situation in the rotating frame that’s similar to the situation you had originally in the laboratory frame: a static magnetic field and spins aligned with it seemingly in equilibrium. What magnetic field during the spin-lock plays the role of the radiofrequency field during the π/2 pulse? You need a magnetic field in the z' direction that oscillates at the spin-lock frequency; the frequency that spins precess about By'. An oscillating neural magnetic field Bneural (red) would do the job. It must oscillate at the spin-lock frequency, which depends on the strength of the circularly polarized magnetic field By'. Song and his team adjusted the magnitude of By' so the spin-lock frequency matched the frequency of alpha waves in the brain (about 10 Hz). This causes the spins to rotate from y' to z' (green). Once you accumulate spins in the z' direction, turn off the spin lock and you are back to where you started (spins in the z direction in a static field Bz), except that the number of these spins depends on the strength of the neural magnetic field and the duration of the spin-lock. A neural magnetic field not at resonance⁠—that is, at any other frequency besides the spin-lock frequency⁠—will not rotate spins to the z' axis. You now have an exquisitely sensitive method of detecting an oscillating biomagnetic field, analogous to using a lock-in amplifier to isolate a particular frequency in a signal.

Comparison of a π/2 pulse and spin-lock during magnetic resonance imaging.
Comparison of a π/2 pulse and spin-lock.
There’s a lot more to Song’s method than I’ve described, including complicated techniques to eliminate any contaminating BOLD signal. But it seems to work.

Will this method revolutionize neural imaging? Time will tell. I worry about how well it can detect neural fields that are not oscillating at a single frequency. Nevertheless, Song’s experiment—together with the work from Okada’s lab that I discussed three years ago—may mean we’re on the verge of something big: using MRI to directly measure neural magnetic fields.

In the conclusion of their article, Song and his coworkers strike an appropriate balance between acknowledging the limitations of their method and speculating about its potential. Let’s hope their final sentence comes true.
Our initial results provide evidence suggesting that MRI can be used to noninvasively and directly image neuroelectric oscillations in the human brain in vivo. This new technique should not be viewed as being aimed at replacing existing neuroimaging techniques, which can address a wide range of questions, but it is expected to be able to image functionally important neural activity in ways that no other technique can currently achieve. Specifically, it is designed to directly image neuroelectric activity, and in particular oscillatory neuroelectric activity, which BOLD fMRI cannot directly sample, because it is intrinsically limited by the temporal smear and temporal delay of the hemodynamic response. Furthermore, it has the potential to do so with a high and unambiguous spatial specificity, which EEG/MEG cannot achieve, because of the limitations of the inverse problem. We expect that our technique can be extended and optimized to directly image a broad range of intrinsic and driven neuronal oscillations, thereby advancing our ability to study neuronal processes, both functional and dysfunctional, in the human brain.

Friday, July 26, 2019

The Oxford English Dictionary

The Meaning of Everything: The Story of the Oxford English Dictionary, by Simon Winchester, superimposed on Intermediate Physics for Medicine and Biology.
The Meaning of Everything,
by Simon Winchester.
I’m a fan of Simon Winchester, and I recently finished his book The Meaning of Everything: The Story of the Oxford English Dictionary. I enjoyed it immensely, and it motivated me to spend a morning browsing through the OED in the Oakland University library, which owns the 1989 twenty-volume second edition.

Rather than describe a typical OED entry, I’ll show ten examples using words drawn from Intermediate Physics for Medicine and Biology.

bremsstrahlung

The entry for bremsstrahlung in the Oxford English Dictionary.

In OED entries, the information right after the word in parentheses is the pronunciation based on the International Phonetic Alphabet, and the text within brackets is the etymology. Bremsstrahlung is German (G.; the OED uses lots of abbreviations). It has its own OED entry, so I guess it’s considered part of the English language too. The entry spans two columns, so I had to cut and paste photos of it. To my ear, bremsstrahlung is the oddest sounding word in IPMB.

candela

The entry for candela in the Oxford English Dictionary.

The origin of candela is from Latin (L.). IPMB and Wikipedia define the candela as lumen per steradian. I don’t see the solid angle connection listed in the OED.

chronaxie

The entry for chronaxie in the Oxford English Dictionary.

Russ Hobbie and I spell chronaxie ending in -ie, which is the most common spelling, although some end it in -y. Chronaxie is from a French (F.) term that appeared in an 1909 article by Louis Lapicque, cited in IPMB.

cyclotron

The entry for cyclotron in the Oxford English Dictionary.

My favorite part of an OED entry are the quotations illustrating usage. Several quotes are provided for cyclotron. The first is from a 1935 Physical Review article by Ernest Lawrence, the cyclotron’s inventor. XLVIII is the volume number in Roman numerals, and 495/2 means the quote can be found on page 495, column 2.

defibrillation

The entry for defibrillation in the Oxford English Dictionary.

Two definitions of defibrillation exist. IPMB uses the word in the second sense: the stopping of fibrillation of the heart. Other forms of this medical (Med.) term are listed, with defibrillating being the participial adjective (ppl. a.) and defibrillator the noun. Carl Wiggers is a giant in cardiac electrophysiology, and the Lancet is one of the world’s leading medical journals.

electrotonus 

The OED’s definition of electrotonus is different from mine.

The entry for electrotonus in the Oxford English Dictionary.

In IPMB, Russ and I write
The simplest membrane model is one that obeys Ohm’s law. This approximation is valid if the voltage changes are small enough so the membrane conductance does not change, or if something is done to inactivate the normal changes of membrane conductance with voltage. It is also useful for myelinated nerves between the nodes of Ranvier. This is called electrotonus or passive spread.
IPMB says nothing about a constant current stimulus, and the OED says nothing about passive spread. I wonder if I’ve been using the word correctly? Wikipedia agrees with me.

The two vertical lines in the top left corner on the entry indicate an alien word (used in English, but from another language). I would have thought bremsstrahlung more deserving of this designation than electrotonus.

fluoroscope

The entry for fluoroscope in the Oxford English Dictionary.

Wilhelm Röntgen discovered x-rays in late 1895, so I’m surprised to see the term fluoroscope used only one year later. X-rays caught on fast. Nature is one of the best-known scientific journals.

leibniz

My PhD advisor John Wikswo and I are engaged in a quixotic attempt to introduce a new unit, the leibniz.

The entry for leibniz in the Oxford English Dictionary.

If I were going to append a new definition, it would look something like this:
2. A unit corresponding to a mole of differential equations. 2006 HUANG et al. Rev. Physiol. Biochem. Pharmacol. CLVII. 98 Avogadro’s number of differential equations may be defined as one Leibnitz. 2006 WIKSWO et al. IEE P-Nanobiotechnol. CLIII. 84 It is conceivable that the ultimate models for systems biology might require a mole of differential equations (called a Leibnitz). 2015 HOBBIE and ROTH Intermediate Physics for Medicine and Biology 53 In computational biology, a mole of differential equations is sometimes called a leibniz.

quatrefoil

The entry for quatrefoil in the Oxford English Dictionary.

Wikswo coined the term quatrefoil for four-fold symmetric reentry in cardiac tissue. Quatrefoil appears in the OED, but its definition is focused on foliage rather than heart arrhythmias. I guess Wikswo didn’t invent the word but he did propose a new meaning. I can’t complain that this sense of the word is missing from the OED, because quatrefoil reentry wasn’t discovered until after the second edition went to press. My proposed addition is:
3. A four-fold symmetric cardiac arrhythmia. 1999 LIN et al. J. Cardiovasc. Electrophysiol. X. 574 A novel quatrefoil-shaped reentry pattern consisting of two pairs of opposing rotors was created by delivering long stimuli during the vulnerable phase.

 tomography 

The entry for tomography in the Oxford English Dictionary.

Godfrey Hounsfield built the first computed tomography machine in 1971. I didn’t realize that tomography had such a rich history before then. I don’t like the OED’s definition of tomography. I prefer something closer to IPMB’s: “reconstructing, for fixed z, a map of some function f(x,y) from a set of projections F(θ,x').”

Missing Words

Some words from IPMB are not in the OED; for example chemostat, electroporation, and magnetosome. Kerma is absent, but it’s an acronym and they aren’t included. Brachytherapy is absent, even from the long entry for the prefix brachy-. Sphygmomanometer doesn’t have its own entry, although it’s listed among the surprisingly large number of words starting with the prefix sphygmo-. Magnetocardiogram is included under the prefix magneto-, but the more important magnetoencephalogram is not. I was hoping to find the definition of bidomain, but alas it’s not there. Here’s my version.
bidomain (ˌbaɪdəʊ'meɪn). Phys. [f. BI- + -DOMAIN.] A mathematical description of the electrical behavior of syncytial tissue such as cardiac muscle. 1978 TUNG A Bi-domain Model for Describing Ischemic Myocardial D-C Potentials (Dissertation) 2 Bi-domain, volume-conductive structures differ from classical volume conductors (mono-domain structures) in that a distinction is made between current flow in the extracellular space and current flow in the intracellular space. 1983 GESELOWITZ and MILLER Ann. Biomed. Eng. XI. 200  The equations of the bidomain model are a three-dimensional version of the cable equations.

The OED took decades to complete, mostly during the Victorian era. The effort was led by James Murray, the hero of Winchester’s book. He supervised a small group of assistants, plus a motley crew of contributors whose job was to search English literature for examples of word use. Winchester’s stories about this collection of oddballs and misfits is engrossing; they volunteered countless hours with little recognition, some contributing tens of thousands of quotations, each submitted on a slip of paper during those years before computers. I can think of only one modern parallel: those unsung heroes who labor over Wikipedia.

The Professor and the Madman: A Tale of Murder, Insanity, and the Making of the Oxford English Dictionary, by Simon Winchester, superimposed on Intermediate Physics for Medicine and Biology.
The Professor and the Madman,
by Simon Winchester.
If you like The Meaning of Everything, you’ll love Winchester’s The Professor and the Madman, also about the Oxford English Dictionary. In addition, Winchester has written several fine books about geology; my favorites are Krakatoa and The Map That Changed the World.

To close, I’ll quote the final paragraph of a speech that Prime Minister Stanley Baldwin gave in 1928 at a dinner celebrating the completion of the OED, which appears at the end of Winchester's Prologue to The Meaning of Everything.
It is in that grand spirit of devotion to our language as the great and noble instrument of our national life and literature that the editors and the staff of the Oxford Dictionary have laboured. They have laboured so well that, so far from lowering the standard with which the work began, they have sought to raise it as the work advanced. They have given us of their best. There can be no worldly recompense—expect that every man and woman in this country whose gratitude and respect is worth having, will rise up and call you blessed for this great work. The Oxford English Dictionary is the greatest enterprise of its kind in history.
Intermediate Physics for Medicine and Biology nestled among volumes of the Oxford English Dictionary.
Intermediate Physics for Medicine and Biology
nestled among volumes of the Oxford English Dictionary.

Friday, July 19, 2019

The 5G Health Hazard That Isn’t

Screenshot of the start of the article "The 5G Health Hazard That Isn't" by William Broad in the New York Times.
Screenshot of the start of the article
"The 5G Health Hazard That Isn’t"
by William Broad in the New York Times.
A recent article by William Broad in the New York Timestitled “The 5G Health Hazard That Isn’ttells the sad story of how unfounded fears of radio-frequency radiation were stoked by one mistaken scientist. Broad begins
In 2000, the Broward County Public Schools in Florida received an alarming report. Like many affluent school districts at the time, Broward was considering laptops and wireless networks for its classrooms and 250,000 students. Were there any health risks to worry about?
The district asked Bill P. Curry, a consultant and physicist, to study the matter. The technology, he reported back, was “likely to be a serious health hazard.” He summarized his most troubling evidence in a large graph labeled “Microwave Absorption in Brain Tissue (Grey Matter).”
The chart showed the dose of radiation received by the brain as rising from left to right, with the increasing frequency of the wireless signal. The slope was gentle at first, but when the line reached the wireless frequencies associated with computer networking, it shot straight up, indicating a dangerous level of exposure.

“This graph shows why I am concerned,” Dr. Curry wrote. The body of his report detailed how the radio waves could sow brain cancer, a terrifying disease that kills most of its victims.
Over the years, Dr. Curry’s warning spread far, resonating with educators, consumers and entire cities as the frequencies of cellphones, cell towers and wireless local networks rose. To no small degree, the blossoming anxiety over the professed health risks of 5G technology can be traced to a single scientist and a single chart.
Except that Dr. Curry and his graph got it wrong.
Russ Hobbie and I describe the possible effects of weak electric and magnetic fields in Section 9.10 of Intermediate Physics for Medicine and Biology. We quote a review by Moulder et al. (2005) that concludes
Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF [radio frequency] energy is weak and unconvincing.
In his New York Times article, Broad goes on to describe how your “skin” blocks the radio waves. That’s not how I would say it. The waves can’t penetrate your body because of “skin depth” (to learn more about skin depth, do Problem 29 in Chapter 8 of IPMB). An electromagnetic wave penetrates a conductor to a distance on the order of the skin depth, which decreases as the frequency increases. A typical 5G frequency is 3 GHz, corresponding to a skin depth of about 30 mm (a little over an inch). Therefore, deep structures in your body are somewhat shielded from this radiation. It has nothing to do with skin itself; the effect works the same when the wave tries to penetrate the surface of the ocean. It depends on the electrical conductivity. Some planned 5G networks will operate at even higher frequencies (up to 300 GHz). In that case, the skin depth would be ten times smaller than for 3 GHz, or 3 mm, similar to the thickness of skin.

If the amplitude of the electromagnetic wave was high enough, it could burn you. Most people who object to radio frequency waves aren’t worried about heating. They’re concerned about hypothetical nonthermal effects, like causing cancer.

I can think of many reasons to ditch your fancy-schmancy 5G cell phone. Cancer isn’t one of them.

Friday, July 12, 2019

The Fifth Solvay Conference

Participants at the Fifth Solvay Conference in 1927.
Participants at the Fifth Solvay Conference in 1927.
This iconic photograph taken at the Fifth Solvay Conference shows the greatest gathering of intelligence ever. Physicists met in October 1927 in Brussels to discuss the then-new theory of quantum mechanics. Russ Hobbie and I mention several of the conference participants in Intermediate Physics for Medicine and Biology.
Niels Bohr
Niels Bohr (Copenhagen, Denmark). The Bohr model of the hydrogen atom and its energy levels is dealt with in Chapter 14 about Atoms and Light, and Bohr’s work on stopping power—how a charged particle loses energy as it passes through tissue—is discussed in Chapter 15 about the Interaction of Photons and Charged Particles with Matter.
Max Born
Max Born (Göttingen, Germany). The Born charging energy appears in Chapter 6 about Impulses in Nerve and Muscle Cells.
William Lawrence Bragg
William Lawrence Bragg (Manchester, England). Chapter 16 about the Medical Uses of X-Rays contains the Bragg-Gray relationship, specifying the absorbed dose in a cavity. The Bragg peak was discovered by Lawrence's father William Henry Bragg (invited to the conference but could not attend).
Arthur Compton
Arthur Compton (Chicago, United States). Compton scattering—the dominant mechanism by which x-rays interact with electrons in tissue at energies around 1 MeV—plays a central roll in Chapter 15. Compton’s name is associated with the Compton wavelength and the Compton cross section.
Marie Curie
Marie Curie (Paris, France). The curie—a unit of radioactivity equal to 37,000,000,000 decays per second—appears in Chapter 17 about Nuclear Physics and Nuclear Medicine. The Curie temperature, discussed in Chapter 8 on Biomagnetism, is named after Marie Curie’s husband Pierre Curie, who died two decades before the Fifth Solvay conference.
Louis de Broglie
Louis de Broglie (Paris, France). de Broglie and his discovery, the relationship between an electron’s momentum and wavelength, is considered when discussing the electron microscope in Chapter 14.
Peter Debye
Peter Debye (Leipzig, Germany). Debye appears in IPMB three times: The debye unit for dipole moment is discussed in Chapter 6, and the Debye length and the Debye-Huckel model are analyzed in Chapter 9 about Electricity and Magnetism at the Cellular Level.
Paul Dirac
Paul Dirac (Cambridge, England). Dirac is most famous for contributing to quantum mechanics, but he is remembered also for the Dirac delta function, which is developed in Chapter 11 about the Method of Least Squares and Signal Analysis.
Albert Einstein
Albert Einstein (Berlin, Germany). The Einstein relationship between diffusion and viscosity is studied in Chapter 4 about Transport in an Infinite Medium, and the unit of the einstein—a mole of photons—appears in Chapter 14. Throughout IPMB, we use Einstein’s ideas about the special theory of relativity and the quantum theory of light, although we rarely mention him by name.
Paul Langevin
Paul Langevin (Paris, France). The Langevin equation is used in Chapter 4 to model the random motion of a particle in a viscous liquid.
Hendrik Lorentz
Hendrik Lorentz (Haarlem, the Netherlands). The Lorentz force exerted on a charge by electric and magnetic fields is a central concept in Chapter 8.
Wolfgang Pauli
Wolfgang Pauli (Hamburg, Germany). The Pauli exclusion principle—no two electrons in an atom can have the same values for all their quantum numbers—is introduced in Chapter 14.
Max Planck
Max Planck (Berlin, Germany). The Nernst-Planck equation is introduced in Chapter 9, Planck’s blackbody radiation formula is analyzed in Chapter 14, and Planck’s constant appears throughout IPMB.
Erwin Schrodinger
Erwin Schrodinger (Zurich, Switzerland). The Schrodinger equation is mentioned in passing at the start of Chapter 3 about Systems of Many Particles.


Watch this fascinating movie taken at the conference.

The Fifth Solvay Conference, 1927.

The greatest physicist of the early 20th century who did not attend the Fifth Solvay Conference was Ernest Rutherford, whose gold foil experiment proved that the atom contains a massive nucleus. Rutherford—who is my academic great-great-great-great-grandfather—was at the Seventh Solvay Conference in 1933 (see photograph below; Rutherford is sitting, sixth form the right), which is probably the second greatest gathering of intelligence ever (Einstein did not attend).

Participants at the Seventh Solvay Conference, 1933.
Participants at the Seventh Solvay Conference, 1933.
One little known fact about the Fifth Solvay Conference is that several of the participants brought their copy of Intermediate Physics for Medicine and Biology.

Participants at the Fifth Solvay Conference, holding copies of Intermediate Physics for Medicine and Biology.

Friday, July 5, 2019

The Biophysics and Pathophysiology of Lesion Formation During Radiofrequency Catheter Ablation

This week I went with a group of Oakland University undergraduates—part of an American Heart Association-funded summer research program—to Beaumont Hospital in Royal Oak, Michigan to visit Dr. David Haines. Haines is the director of the Heart Rhythm Center, and an expert in using radiofrequency catheter ablation to treat cardiac arrhythmias such as atrial fibrillation.

During the visit, I noticed how physics underlies most of Haines’s work in the clinic. Much of this physics is described in Intermediate Physics for Medicine and Biology. Russ Hobbie and I discuss the electrical behavior of the heart and the electrocardiogram in Chapter 7, arrhythmias such as fibrillation in Chapter 10, and the bioheat equation governing the tissue temperature in Chapter 14.

Cardiac Electrophysiology: From Cell to Bedside, 4th Ed., Edited by Zipes and Jalife, superimposed on Intermediate Physics for Medicine and Biology.
Cardiac Electrophysiology:
From Cell to Bedside
, 4th Ed.,
Edited by Zipes and Jalife.
Haines wrote a chapter about “The Biophysics and Pathophysiology of Lesion Formation during Radiofrequency Catheter Ablation” that appeared in Cardiac Electrophysiology: From Cell to Bedside, a book often cited in IPMB. He begins
The rationale of ablation is that, for every arrhythmia, there is a critical region of abnormal impulse generation or propagation that is required for that arrhythmia to be sustained clinically. If that substrate is irreversibly altered or destroyed, then the arrhythmia should not occur spontaneously or with provocation. To accomplish this with a catheter, several criteria must be met. The technology needs to be controllable: Big enough to incorporate the target but small enough to minimize collateral damage. It needs to be affordable and adaptable to equipment conventionally found in the electrophysiology (EP) suite. Despite considerable experience and experimentation with a variety of catheter ablation technologies, ablation with radiofrequency (RF) electrical energy emerged and has persisted as the favored modality. The study of the mechanisms of RF energy heating and the tissue’s response to this injury will give insight into these and other phenomena and should allow the operator to optimize procedure outcome.
Let me describe some of the physics of catheter ablation.
  • The Catheter. A catheter is used to place the lead used for ablation into the heart. Usually it’s inserted into a vein in the leg, and then snaked through the vessels into the right atrium. (Ablating tissue in the left atrium is trickier; you may have to create a small hole between the atria by doing a transseptal puncture.) Catheterization is less invasive than open heart surgery, so some patients can avoid even a single night in the hospital after treatment.
  • Radiofrequency Energy. Ablation is performed using electrical energy with a frequency between 0.3 and 1 MHz (in the frequency band of AM radio). These frequencies are too high to cause direct electrical stimulation of muscles or nerves. The mechanism of ablation is Joule heating, like in your toaster, which raises the temperature of the tissue within a few millimeters of the lead tip.
  • Lesion Formation. Cells become irreversibly damaged at temperatures on the order of 50° C. The temperature of the lead tip is kept below 100° C to avoid boiling the plasma and coagulating proteins.
  • Atrial Fibrillation. Atrial fibrillation is the most common arrhythmia treated with ablation. Fibrillation means that the electrical wave fronts propagate in a irregular and chaotic way, so the mechanical contraction is unorganized and ineffective. Unlike ventricular fibrillation, which is lethal in minutes if not defibrillated, a person can live with atrial fibrillation, but the heart won’t pump efficiently causing fatigue, the backup of fluid into the lungs, and an increased risk of stroke.
  • Electrical Mapping. The first part of the clinical procedure is to map the arrhythmia. Multiple electrodes on the catheter record the electrocardiogram throughout the atrium, locating the reentrant pathway or the focus (an isolated spot that initiates a wave front). If the arrhythmia is intermittent, then it may need to be triggered by electrical stimulation in order to map it.
  • Ablation Sites. Once the arrhythmia is mapped, the doctor can determine where to ablate the tissue. Usually many isolated spots will be ablated to create a large lesion, often located around the pulmonary veins where many reentrant pathways occur.
While visiting Beaumont, the students and I talked with Haines about his career, and watched him perform a procedure. The team of specialists and their high-tech equipment were impressive; an example of physics and engineering intersecting physiology and medicine.

Cardiac Electrophysiology: From Cell to Bedside alongside Intermediate Physics for Medicine and Biology.
My copy of Cardiac Electrophysiology:
From Cell to Bedside
, alongside IPMB.
I’ll end by quoting Haine’s chapter summary in Cardiac Electrophysiology: From Cell to Bedside.
During RF catheter ablation, RF current passes through the tissue in close contact with the electrode and is resistively heated. The temperature of the tissue at the border of the lesion is reproducible in the 50°C to 55°C range. It is likely that the dominant model of myocardial injury is thermal, although electrical fields have been demonstrated to stun and kill cells depending on the field intensity. On inspection of the myocardial lesions, the tissue shows evidence of desiccation, inflammation, and microvascular injury, which certainly leads to ischemia. Late injury or recovery of the tissue at the lesion border zone may occur as a result of progression or resolution of inflammatory response or endothelial injury. On the cellular level, many possible mechanisms of myocyte damage exist, but membrane injury probably dominates. This may lead to cellular depolarization, intracellular Ca2+ overload, and cell death. Further damage to the cytoskeleton, cellular metabolism, and nucleus may occur at lower temperatures with more prolonged hyperthermia exposure. RF catheter ablation has been proven to be an effective clinical modality for the treatment of arrhythmias, but many of the basic pathophysiologic effects of this empirical procedure on the tissue and cellular level remain to be determined.

Dr. David Haines of Beaumont Hospital.
https://www.youtube.com/watch?v=FZdHk2dznWk

An interview with Dr. David Haines to discuss radiofrequency ablation.

Friday, June 28, 2019

The Innovators

The Innovators: How a Group of Hackers, Geniuses, and Geeks Created the Digital Revolution, by Walter Isaacson, superimposed on Intermediate Physics for Medicine and Biology.
The Innovators: How a Group
of Hackers, Geniuses, and Geeks
Created the Digital Revolution
,
by Walter Isaacson.
Computers play a large and growing role in biomedical research. Intermediate Physics for Medicine and Biology contains four computer programs that illustrate the computations behind topics such as the Hodgkin-Huxley model and computed tomography. To learn more about the history of computers, I read The Innovators: How a Group of Hackers, Geniuses, and Geeks Created the Digital Revolution, by Walter Isaacson. The introduction begins
The computer and the Internet are among the most important inventions of our era, but few people know who created them. They were not conjured up in a garret or garage by solo inventors suitable to be singled out on magazine covers or put into a pantheon with Edison, Bell, and Morse. Instead, most of the innovations of the digital age were done collaboratively. There were a lot of fascinating people involved, some ingenious and a few even geniuses. This is the story of these pioneers, hackers, inventors, and entrepreneurs—who they were, how their minds worked, and what made them so creative. It’s also a narrative of how they collaborated and why their ability to work as teams made them even more creative.
Mr. Ray Dennis,
my FORTRAN teacher at
Shawnee Mission South High School.
From the 1977-1978 school yearbook.
Transistors, microchips and computers were invented before I was born, but I witnessed the rise of personal computers and the creation of the Internet in the 70s, 80s. and 90s. My first experience with computers was during my senior year of high school (1978), when I took a programming class based on the computer language FORTRAN. It was the most useful class I ever took; I programmed in FORTRAN almost every day for decades. At that time, many computers used punch cards to input programs. I remember typing up a stack of cards during class and giving them to my teacher, Ray Dennis, who ran them on an off-site computer after school. The next day he would return our cards along with our output on folded, perforated paper. Mistype one comma and you lost a day. I learned to program with care.

The next year I attended the University of Kansas, where they were phasing out punch cards and replacing them with time-sharing terminals. I thought it was the greatest advance ever. During my freshmen year, my roommate was an engineering graduate student from California who owned an Apple II, and he let me use it to play a primitive Star Trek video game. The Physics Department purchased a Vax mainframe computer that I used for undergraduate research analyzing light scattering data.

At Vanderbilt, my advisor John Wikswo made sure each of his graduate students had their own computer (an IBM clone), which I thought was amazing. I also got my first email account. During my grad school years I followed the rivalry between Bill Gates and Steve Jobs. After starting as a PC guy,  I moved to the National Institutes of Health in 1988 and switched over to an Apple Macintosh, and have been a loyal Mac man ever since. I remember going to a lecture at NIH about something called the World Wide Web, and thinking that it sounded silly. Since then, I’ve seen the rise of Yahoo!, Google, and Wikipedia, and I write these posts ever week using blogger. All these developments and more are described in The Innovators

I’m a fan of Walter Isaacson. He’s written several “genius biographies (Steve Jobs, Leonardo da Vinci, Albert Einstein, Ben Franklin), but my favorite of his books is The Wise Men, the story of six influential leaders—Averell Harriman, Dean Acheson, George Kennan, Robert Lovett, John McCloy, and Charles Bohlen—during the cold war. The Innovators reminds me of The Wise Men in that it focuses on the interactions among a group, rather than the contributions of an individual.

For readers of IPMB who use computers for biomedical research, I recommend The Innovators. It provides insight into how the digital world was invented, and the role of collaboration in science and technology. Enjoy!