Francis Crick, Biological Physicist

I'm fascinated by scientists who straddle physics and biology. In particular, I'm curious how a scientist trained in one field switches to another. The quintessential physicist-turned-biologist is Francis Crick. Yes, I mean Crick of “Watson and Crick," the team who discovered the structure of DNA.

Asimov's Biographical
Encyclopedia of Science
and Technology

To start learning about the education of Francis Crick, consider his entry in Asimov’s Biographical Encyclopedia of Science and Technology.

CRICK, Francis Harry Compton

English biochemist

Born: Northampton, June 8, 1916

Crick was educated at University College in London and went on to obtain his Ph.D. at Cambridge University in 1953. He was a physicist to begin with and worked in the field during World War II, when he was involved in radar research and in magnetic mine development…

At the time, under the leadership of [Max] Perutz, a veritable galaxy of physics-minded scientists was turning to biochemistry at Cambridge and their refined probings established the science of molecular biology, as fusion of biology, chemistry, and physics…

Crick was one of the physicists who turned to biochemistry or, rather, to molecular biology, and with him was a young American, James Dewey Watson…

The Eighth Day of Creation,
by Horace Freeland Judson.

To explore in more detail how Crick changed from physics to biology, let’s turn to the definitive history of modern biology: Horace Freeland Judson’s masterpiece The Eighth Day of Creation.

Crick is to an unusual extent self-educated in biology. He went to a minor English public school, Mill Hill, in northern London; his interest in science was already so single-minded that his family thought him odd. At University College, London, he read physics and had nearly finished his doctorate when the war broke out and a German bomb destroyed his laboratory and gear. When Crick left the Admiralty and physics in 1947, he set out to master the literature of biology, reading with an appetite that has slackened, if at all, only in the last few years [Judson published The Eighth Day of Creation in 1979]. His peers concede without question his astonishing reach. Perutz, whose knowledge is encyclopedic in scope and order: “Francis of course reads more widely than the rest of us.” Jacques Monod, the science’s other great theorist: “No one man discovered or created molecular biology. But one man dominates intellectually the whole field, because he knows the most and understands the most. Francis Crick.”

This idea that you have to read the literature resonates with me. I spent the first months of graduate school at Vanderbilt reading research articles about how nerves worked. I took no classes in neurobiology. I didn’t have a biological mentor (my PhD advisor, John Wikswo, was a physicist). I just read. That's the way many physicists learn biology.

Judson humorously tells of Crick's introduction to Perutz's laboratory:

"The first thing Francis did was to read everything we had done," Perutz said. "Then he started criticizing."

Why did Crick change to biology? Judson explains

“An important reason Crick changed to biology, he said to me, was that he is an atheist, and was impatient to throw light into the remaining shadowy sanctuaries of vitalistic illusions. ‘I had read [Erwin] Schrodinger’s little book [What is Life?], too [According to Judson, "everyone read Schrodinger."]. Essentially, if you read that book critically, the main import is very peculiar; for one thing, it’s a book written by a physicist who doesn’t know any chemistry! But the impact—there’s no doubt that Schrodinger wrote it in a compelling style, not like the junk that most people write, and it was imaginative. It suggested that biological problems could be thought about, in physical terms—and thus gave the impression that exciting things in this field were not far off. My own motives I never had any doubt about; I was very clear in my mind. Because when I decided to leave the Admiralty, when I was about thirty, then on the grounds that I knew so little anyway I might just as well go into anything I liked, I looked around for fields which would illuminate this particular point of view, against vitalism. And the two fields I chose were what we would now call molecular biology, though the term wasn’t common then, certainly I didn’t know it—but I would have said the borderline between the living and nonliving. That was the phrase I had in my mind, on the one hand. And on the other, the higher nervous system and this problem of consciousness...”

What Mad Pursuit:
A Personal View
of Scientific Discovery,
by Francis Crick.

Crick reminisces about his shift from physics to biology in his autobiography What Mad Pursuit.

"By the time most scientists have reached age thirty they are trapped by their own expertise. They have invested so much effort in one particular field that it is often extremely difficult, at that time in their careers, to make a radical change. I, on the other hand, knew nothing, except for a basic training in somewhat old-fashioned physics and mathematics and an ability to turn my hand to new things. I was sure in my mind that I wanted to do fundamental research rather than going into applied research...

Since I essentially knew nothing, I had an almost completely free choice...Working in the Admiralty, I had several friends among the naval officers. They were interested in science but knew even less about it than I did. One day I noticed that I was telling them, with some enthusiasm, about recent advances in antibiotics—penicillin and such. Only that evening did it occur to me that I myself really knew almost nothing about these topics...It came to me that I was not really telling them about science. I was gossiping about it.

This insight was a revelation to me. I had discovered the gossip test—what you are really interested in is what you gossip about. Without hesitation, I applied it to my recent conversations. Quickly I narrowed down my interests to two main areas: the borderline between the living and nonliving, and the workings of the brain..."

I'm not sure Crick's reflections can be generalized. To me, they imply that the choice of a research topic can be haphazard and personal.

Four good books.

Perhaps more useful is Crick's thoughts about theory in biology, which appear in the conclusion of What Mad Pursuit.

"Physicists are all too apt to look for the wrong sorts of generalizations, to concoct theoretical models that are too neat, too powerful, and too clean. Not surprisingly, these seldom fit well with the data. To produce a really good biological theory one must try to see through the clutter produced by evolution to the basic mechanisms lying beneath them, realizing that they are likely to be overlaid by other, secondary mechanisms. What seems to physicists to be a hopelessly complicated process may have been what nature found simplest, because nature could only build on what was already there...

The job of theorists, especially in biology, is to suggest new experiments. A good theory makes not only predictions, but surprising predictions that then turn out to be true. (If its predictions appear obvious to experimentalists, why would they need a theorist?) ... If this book helps anyone to produce good biological theories, it will have performed one of its main functions."

Crick is a case study into how and why a physicist switches to studying biology. Readers of Intermediate Physics for Medicine and Biology who are contemplating such a switch may benefit from his story.

Want to learn more? Listen to Crick himself discuss how he became interested in science.

 Listen to Francis Crick talking about how he became interested in science.

Harry Pennes, Biological Physicist

First page of Pennes (1948) J Appl Physiol 1:93-122.

I admire scientists who straddle the divide between physics and physiology, and who are comfortable with both mathematics and medicine. In particular, I am interested in how such interdisciplinary scientists are trained. Many, like myself, are educated in physics and subsequently shift focus to biology. But more remarkable are those (such as Helmholtz and Einthoven) who begin in biology and later contribute to physics.

Obituary of Harry H. Pennes.

Which brings me to Harry Pennes. Below I reproduce his obituary published in the April 1964 issue of the American Journal of Psychiatry (Volume 120, Page 1030).

Dr. Harry H. Pennes.—Dr. Harry H. Pennes [born 1918], who had been active in clinical work and research in psychiatry and neurology died in November, 1963, at his home in New York City at the age of 45. Dr. Pennes had worked with Dr. Paul H. Hoch and Dr. James Cattell at the Psychiatric Institute of New York Columbia-Presbyterian Medical Center on new techniques of research and medical experimentation.

Dr. Pennes was born in Philadelphia and studied medicine at the University of Pennsylvania where he received a degree in 1942. In 1944 he came to New York to do research at the Neurological Institute. Soon afterward he took a two-year residency at the New York State Psychiatric Institute, and he later joined the staff as Senior Research Psychiatrist. He was also the Research Associate in Psychiatry at Columbia University. At Morris Plains, N. J., Dr. Pennes participated in intensive studies in the Columbia-Greystone Brain Research Project. He did research into chemical warfare from 1953 to 1955 at the Army Chemical Center in Maryland. Later, in Philadelphia, he was Director of Clinical Research for the Eastern Pennsylvania Psychiatric Institute for several years. He subsequently returned to New York a few years ago and resumed private practice.

First page of Wissler (1998).

Before we discuss what’s in his obituary, consider what’s not in it: physics, mathematics, or engineering. Yet, today Pennes is remembered primarily for his landmark contribution to biological physics: the bioheat equation. Russ Hobbie and I analyze this equation in Section 14.11 of Intermediate Physics for Medicine and Biology. In an article titled “Pennes’ 1948 Paper Revisited” (Journal of Applied Physiology, Volume 85, Pages 35-41, 1998), Eugene Wissler wrote:

It can be argued that one of the most influential articles ever published in the Journal of Applied Physiology is the “Analysis of tissue and arterial blood temperatures in the resting human forearm” by Harry H. Pennes, which appeared in Volume 1, No. 2, published in August, 1948. Pennes measured the radial temperature distribution in the forearm by pulling fine thermocouples through the arms of nine recumbent subjects. He also conducted an extensive survey of forearm skin temperature and measured rectal and brachial arterial temperatures. The purpose of Pennes’ study was “to evaluate the applicability of heat flow theory to the forearm in basic terms of the local rate of tissue heat production and volume flow of blood.” An important feature of Pennes’ approach is that his microscopic thermal energy balance for perfused tissue is linear, which means that the equation is amenable to analysis by various methods commonly used to solve the heat-conduction equation. Consequently, it has been adopted by many authors who have developed mathematical models of heat transfer in the human. For example, I used the Pennes equation to analyze digital cooling in 1958 and developed a whole body human thermal model in 1961. The equation proposed by Pennes is now generally known either as the bioheat equation or as the Pennes equation.

So, how did a psychiatrist make a fundamental contribution to physics? I don’t know. Indeed, I have many questions about this fascinating man.

1. Did he work together with a mathematician? No. Pennes was the sole author on the paper. There was no acknowledgment thanking a physicist friend or an engineer buddy. The evidence suggests the work was done by Pennes alone.
2. Did he merely apply an existing model? No. He was the first to include a term in the heat equation to account for convection by flowing blood. He cited a previous study by Gagge et al., but their model was far simpler than his. He didn’t just adopt an existing equation, but rather developed a new and powerful mathematical model. 
3. Was the mathematics elementary? No. He solved the heat equation in cylindrical coordinates. The solution of this partial differential equation included Bessel functions with imaginary arguments (aka modified Bessel functions). He didn’t cite a reference about these functions, but introduced them as if they were obvious.
4. Was his paper entirely theoretical? No. The paper was primarily experimental and the math appeared late in the article when interpreting the results. 
5. Were the experiments easy? No, but they were a little gross. They required threading thermocouples through the arm with no anesthesia. Pennes claimed the “phlegmatic subjects occasionally reported no unusual pain.” I wonder what the nonphlegmatic subjects reported?
6. Was Pennes’s undergraduate degree in physics? I don’t know.
7. Did Pennes’s interest in math arise late in his career? No. His famous 1948 paper was submitted a few weeks before his 30th birthday.
8. Did Pennes work at an institution out of the mainstream that might promote unusual or quirky career paths? No. Pennes worked at Columbia University’s College of Physicians and Surgeons, one of the oldest and most respected medical schools in the country.
9. Did Pennes pick up new skills while in the military? Probably not. He was 23 years old when the Japanese attacked Pearl Harbor, but I can’t find any evidence he served in the military during World War II. He earned his medical degree in 1942 and arrived at Columbia in 1944.  
10. Do other papers published by Pennes suggest an expertise in math? I doubt it. I haven’t read them all, but most study how drugs affect the brain. In fact, his derivation of the bioheat equation seems so out-of-place that I’ve entertained the notion there were two researchers named Harry H. Pennes at Columbia University.
11. Did Pennes’ subsequent career take advantage of his math skills? Again, I am not sure but my guess is no. The Columbia-Greystone Brain Project is famous for demonstrating that lobotomies are not an effective treatment of brain disorders. Research on chemical warfare should require expertise in toxicology. 
12. How did Pennes die? According to Wikipedia he committed suicide. What a tragic loss of a still-young scientist!

I fear my analysis of Harry Pennes provides little insight into how biologists or medical doctors can contribute to physics, mathematics, or engineering. If you know more about Pennes’s life and career, please contact me (roth@oakland.edu).

Even though Harry Pennes’s legacy is the bioheat equation, my guess is that he would’ve been shocked that we now think of him as a biological physicist.

Venkataranan Ramakrishna, Biological Physicist

Failed physicist?

I was reading the November issue of APS News (A publication of the American Physical Society) when I noticed an article titled “Failed Physicist? From Biologist Turned Nobel Laureate to Author.” The article was about Venkataraman Ramakrishnan, winner of the 2009 Nobel Prize in Chemistry for “studies of the structure and function of the ribosome.” He received a PhD in physics before switching to biology. In the article, he calls himself a “failed physicist.”

Many readers of Intermediate Physics for Medicine and Biology may be in a similar position of having been trained in physics but now learning biology. Ramakrishnan provides an interesting case study in how to make such a transition. I looked up his biographical statement on the Nobel Prize website, and I reproduce excerpts below. Changing fields is not easy, but it is possible, and can ultimately lead to groundbreaking research.

Choosing Basic Science

[When Ramakrishna was growing up in India, he was looking for a university for his undergraduate studies.] A faculty member in the physics department in [the University of] Baroda, S.K. Shah, told me about a brand new curriculum they were introducing for their undergraduate course. It began with the Berkeley Physics Course, and was supplemented by the Feynman Lectures on Physics before moving on to more specialized areas. I therefore decided to enroll in the B.Sc. course in physics in Baroda, my hometown. Since I was only 16 when I began this course, I sensed that my parents, especially my father, were relieved that I was not leaving home….

I found myself tremendously interested by the articles in biology in Scientific American, to which I have subscribed off and on through the years. It appeared that hardly a month went by without a major breakthrough in the life sciences, whereas physics was having a hard time making any fundamental progress. Certainly I felt that if I continued in physics, I would be doing boring and tedious calculations rather than making really interesting advances. The result was that I felt so frustrated that I withdrew from my thesis work and spent an inordinate amount of time on extracurricular activities….

[Ramakrishna eventually finished his BS in physics, and then obtained a PhD in Physics at Ohio University]…. By that time I had already decided I was going to switch to biology.

Transition to Biology

Since I hardly knew any biology, I felt I needed formal training of some sort. I could go to graduate school again, with the option of getting a second Ph.D. or go to medical school, which was ironic since I had turned down the opportunity to do precisely that when I was younger. I took the MCAT …. but despite scoring in the 99th percentile in all the subjects, I only got one interview (at Yale) because I was not a U.S. citizen or even a permanent resident at that point…. However, I had also written to a number of graduate programs. Many of them said that they would not accept someone who already had a Ph.D. The chairman of the Molecular Biophysics and Biochemistry ... department at Yale, Franklin Hutchinson, wrote to me saying that while they could not take me as a graduate student, he would circulate my CV to faculty members for a potential postdoctoral position. Two of them responded: One was Don Engelman, and the other, ironically, was Tom Steitz, with whom I shared the Nobel Prize. Although I found their work very interesting, I thought doing a postdoc directly from a degree in physics would leave me with too narrow a background in biology to be an effective scientist. So when three schools accepted me into their graduate program, I chose to go to the University of California, San Diego (UCSD)…. During the first year, I did several lab rotations in biology and took as many undergraduate courses as I could possibly manage, including genetics, taught by Dan Lindsley, a well-known Drosophila geneticist, and biochemistry, where I was inspired by the brilliant and enthusiastic lectures of Paul Price.

In my second year [at UCSD], I settled down to do research in Mauricio Montal's lab. Mauricio had developed an ingenious method of incorporating conducting channels into lipid bilayers formed by bringing together two defined monolayers, and was thus doing single molecule biophysics at a time when nobody called it that. Around this time, however, I read an article in Scientific American by Don Engelman and Peter Moore about their ribosome work, and became interested in it. It also struck me that there was no longer any reason to continue on to obtain a second Ph.D. because I felt I had acquired the background I needed. I therefore wrote to Don Engelman, one of the two people from Yale who had responded to me earlier. Don was interested in membrane proteins, a subject I was already working on in Mauricio's lab. Don wrote back and said that he and Peter had a position open on their ribosome project, and I could always work on membrane-related projects once I got there. Peter arranged to meet me in San Diego in early 1978 and offered me a postdoctoral position soon afterwards. Thus began my lifelong interest in ribosomes….

In the APS News article, Ramakrishnan said something that could be the motto for IPMB.

Physics is a great training for every science because it teaches you quantitative and mathematical thinking, and that way of approaching problems is becoming increasingly important in every field, including biology.

Want to learn more? Ramakrishna has a new book out: Gene Machine: The Race to Dicipher the Secrets of the Ribosome. It's on my list of books to read. Below are a couple videos in which you can hear from Ramakrishna himself. Enjoy!

Gopalasamudram Narayanan Ramachandran, Biological Physicist

Many followers of the Intermediate Physics for Medicine and Biology Facebook page are from India, and I would like to somehow thank them for their interest in our book. The only way I can express my appreciation is by writing in this blog. So, today’s post is about the great Indian physicist Gopalasamudram Narayanan Ramachandran (1922-2001).

In an obituary published in the Biographical Memoirs of Fellows of the Royal Society (Volume 51, Pages 367–377, 2005), Vijayan and Johnson write

G. N. Ramachandran has been among the most outstanding crystallographers and structural biologists of our times. He is considered by many to be the best scientist to have worked in independent India. The model of collagen developed by him has stood the test of time and has contributed greatly to understanding the role of this important fibrous protein. His pioneering contributions in crystallography, particularly in relation to methods of structure analysis using Fourier techniques and anomalous dispersion, are well recognized. A somewhat less widely recognized contribution of his is concerned with three-dimensional image reconstruction. Much of the foundation of the currently thriving field of molecular modelling was laid by him. The Ramachandran plot remains the simplest and the most commonly used descriptor and tool for the validation of protein structures.

Ramachandran appears in Intermediate Physics for Medicine and Biology in Chapter 12, when Russ Hobbie and I discuss computed tomography. He and A. V. Lakshminarayanan developed one of the two man main tomographic techniques: filtered back projection. We write

Filtered back projection is more difficult to understand than the direct Fourier technique. It is easy to see that every point in the object contributes to some point in each projection. The converse is also true. In a back projection every point in each projection contributes to some point in the reconstructed image…A very simple procedure would be to construct an image by back-projecting every projection…We will now show that the image f_b(x,y) obtained by taking projections of the object F(θ,x') and then backprojecting them is equivalent to taking the convolution of the object with the function h.

h(x) is

Unfortunately, this function does not exist; the integral doesn’t converge. The factor |k| diverges as k goes to ±∞. But Ramachandran and Lakshminarayanan realized that you don’t need to integrate to infinity. In the above integral, k is the spatial frequency. He suggested there should be an upper limit on the spatial frequency, k_max. What should the upper limit be? The measured projection F(θ,x') is not a continuous function of position x'. The data is discrete, measured at a finite number of points. The largest spatial frequency is that given by the Nyquist sampling criterion: there should be at least two points per wavelength. Using this upper limit for k_max, Ramachandran and Lakshminarayanan were able to solve the integral for h(x) analytically, and found that

where i denotes the ith discrete value of x. This result looks slightly different than Eq. 12.44 in IPMB; Here I factored N²/16 out of each term, and I use i for the integer instead of k, because I don’t want to use k for both spatial frequency and an integer. Below is a plot of h(i).

Convolution with function h(i) corresponds to a passing the signal through a high pass filter (often called the "Ram-Lak filter"). Therefore, the convolution of a constant should vanish, implying that all the values of h(i) should add to zero. In fact, this is true. The infinite series
 

 is exactly what is needed to ensure this.

At the end of their obituary, Vijayan and Johnson discuss Ramachandran’s impact on science and India.

To more than a generation of scientists in India, and some abroad, Ramachandran was a source of scientific and personal inspiration. Many of his contributions were based on simple but striking ideas. He demonstrated how international science could be influenced, even from less well-endowed neighbourhoods, through ingenuity and imagination. It is remarkable that although Ramachandran left structural biology and mainstream research about a quarter of century ago, his presence in the field remains as vibrant as ever. Indeed, Ramachandran established a great scientific tradition. That tradition lives on and thrives in the world, in India, and in the two research schools he founded.

Thanks to all the Indian readers of IPMB. I’m glad you like the book.

Charles Bean, Biological Physicist

I’ve always been fascinated by physicists who move into biology, and I collect stories about scientists who have made this transition successfully. Today let me share one example: Charles Bean (1923–1996). Bean spent much of his career studying solid state physics, especially magnetism and superconductivity. He worked for more than 30 years at the General Electric Research and Development Center in Schenectady, New York. You can read about his research for GE in a biographical memoir published by the National Academy of Sciences. I want to focus on his work in biological physics.

Relatively early in his career, Bean expanded his scientific interests beyond magnetism and superconductivity. He also studied biophysics, and he encouraged colleagues to consider the field as well. In an invited talk to the American Physical Society on how to change from physics to biology, one of his recommendations was straightforward: “Start to eat lunch with biologists.” In 1960 Bean managed to convince the now-renowned biophysicist Carl Woese to join the General Electric Research and Development Center in Schenectady, where he stayed for three years before joining the University of Illinois in 1970. And Charlie took his own advice and ate with Carl every day.

Bean was elected the first Coolidge Fellow at the GE laboratory. The Coolidge Fellowship program was a way to recognize the company’s most valuable scientists, and its main advantage was that the recipient could go on sabbatical leave to any another institution with full pay. Charlie decided to go to Rockefeller University, where he stayed (not full time) from 1973 to 1978. There he was exposed to neurophysiology, and he eventually wrote a theory of stimulation of myelinated fibers that was published in the British Journal of Physiology (1974).

At about this time Bean had started to spend his summers in Woods Hole, MA, which he enjoyed enormously, both for its outdoor activities and its laboratories. When asked why, he said, “I like to be at a place where the library is open 24 hours a day.” Here he became interested in sea urchin sperm, and he invented a clever method to determine the average velocity and length they can swim. He did this by having a dilute concentration of sperm in a solution above a clean gold surface, and each time a sperm hit the gold it stuck.

Very soon Bean’s research papers began to be published in biophysics journals rather than physics journals. He first became interested in membranes, for example, and wrote a long treatise for the U.S. Department of the Interior on reverse osmosis (1969). Taking advantage of GE’s Nuclepore membranes, he developed, together with Ralph DeBlois, a virus counter—a variant of the famous Coulter counter (1970). Later he developed a seminal theory of neutral porous membranes (1972). On the basis of this paper he was offered a professorship, which tempted him, though eventually he turned it down.

… Bean also continued more serious research while at RPI [Rensselaer Polytechnic Institute]. For example, being a good friend of French biophysicist P. G. de Gennes, through him Bean became fascinated by electrophoresis—in particular the way a strand of DNA twists through a gel, like a snake through grass. He analyzed and modeled the process, and in 1987 wrote a paper on the subject with H. Hervet.

Bean spent much of his later time looking for the elusive magnetic bacteria, which were rediscovered by R. P. Blakemore at Woods Hole in 1975 (they had been seen in 1963 in Italy by Salvatore Bellini but thereafter largely forgotten). The reason why these bacteria are guided by a magnetic field is that they have small internal magnets corresponding to the chain-of-spheres model. Bean developed simple equipment that enabled him to seek such magnetotactic bacteria virtually everywhere. He thought he had found some in a pothole right outside RPI, but before verifying and publishing his findings Bean died of heart failure.

Bean appears often in Intermediate Physics for Medicine and Biology. In Section 5.9, Russ Hobbie and I describe a continuum model for volume and solute transport in a pore. We cite his Department of the Interior report and his model of neutral pores repeatedly.

Bean CP (1969) Characterization of cellulose acetate membranes andultrathin films for reverse osmosis. Research and Development Progress Report No. 465 to the U.S. Department of Interior, Office of Saline Water. Contract No. 14-01-001-1480. Washington, Superintendent of Documents, October 1969.

Bean CP (1972) The physics of porous membranes—neutral pores. In: Eisenman G (ed) Membranes, vol 1. Dekker, New York, pp 1–55.

The description of his work in this field is even more extensive in earlier editions of IPMB (see, for example, the third edition which Russ authored before I came along and ruined it). In the fifth edition, we added a homework problem about the Coulter counter, in which we cite another publication by Bean.

DeBlois RW, Bean CP (1970) Counting and sizing of submicron particlesby the resistive pulse technique. Rev Sci Inst 41:909–916.

Given my interest in neural stimulation, I was particularly curious about Bean’s theory of microstimulation of myelinated nerve axons. I had trouble finding his paper on this topic, until I realized that it’s an appendix of a paper by Abzug, Maeda, Peterson and Wilson (“Cervical branching of lumbar vestibulospinal axons”). Bean develops a theory of neural stimulation very similar to that of the activating function introduced in Homework Problem 38 of Chapter 7 in IPMB. Bean assumed a myelinated axon with discrete nodes of Ranvier rather than a continuous cable. This assumption makes little difference if the stimulating electrode is far from the nerve, but if it is closer to the nerve than one internodal space, the discrete model is more appropriate.

Figure 8.25 in IPMB shows a magnetotactic bacterium containing a chain of small particles of magnetite. Bean developed a theory for the magnetic properties of such a “chain-of-spheres” before they were known to occur in bacteria.

In summary, Charles Bean is a fine example of a physicist who moved from physics to biology, and was able to contribute a unique perspective on important biological problems. In my experience, such physicists can contribute to a wide variety of biological topics. Often their insights ignore much of biology’s complexity, but they are based on universal physical principles that may be unfamiliar to many biologists.

Now, I need to go find a biologist to have lunch with.

Alan Turing, Biological Physicist

Recently, my wife and I went to the theater to see The Imitation Game, about Alan Turing and the breaking of the enigma code during World War II. It is a fascinating movie. I’m a big fan of Benedict Cumberbatch, who played Turing (I particularly enjoy his portrayal of Sherlock Holmes in the TV series Sherlock), and I always enjoy performances by Keira Knightly.

Turing was primarily a mathematician, but he did publish one paper that straddled the disciplines of mathematical biology and biological physics: A. M. Turing, 1952, “Chemical Basis of Morphogenesis.” Philosophical Transactions of the Royal Society of London. Series B, Volume 237, Pages 37–72. The abstract is reproduced below.

It is suggested that a system of chemical substances, called morphogens, reacting together and diffusing through a tissue, is adequate to account for the main phenomena of morphogenesis. Such a system, although it may originally be quite homogeneous, may later develop a pattern or structure due to an instability of the homogeneous equilibrium, which is triggered off by random disturbances. Such reaction-diffusion systems are considered in some detail in the case of an isolated ring of cells, a mathematically convenient, though biologically unusual system. The investigation is chiefly concerned with the onset of instability. It is found that there are six essentially different forms which this may take. In the most interesting form stationary waves appear on the ring. It is suggested that this might account, for instance, for the tentacle patterns on Hydra and for whorled leaves. A system of reactions and diffusion on a sphere is also considered. Such a system appears to account for gastrulation. Another reaction system in two dimensions gives rise to patterns reminiscent of dappling. It is also suggested that stationary waves in two dimensions could account for the phenomena of phyllotaxis. The purpose of this paper is to discuss a possible mechanism by which the genes of a zygote may determine the anatomical structure of the resulting organism. The theory does not make any new hypotheses; it merely suggests that certain well-known physical laws are sufficient to account for many of the facts. The full understanding of the paper requires a good knowledge of mathematics, some biology, and some elementary chemistry. Since readers cannot be expected to be experts in all of these subjects, a number of elementary facts are explained, which can be found in text-books, but whose omission would make the paper difficult reading.

Mathematical Biology,
by James Murray.

You can learn more about Turing’s theory in James Murray’s book Mathematical Biology (I am basing my comments on the edition in the Oakland University library: the Second, Corrected Edition, 1993). Murray writes

Turing’s (1952) idea is a simple but profound one. He said that if, in the absence of diffusion….[two chemicals] A and B tend to a linearly stable uniform steady state then, under certain conditions, which we shall derive, spatially inhomogeneous patterns can evolve by diffusion driven instability… Diffusion is usually considered a stabalising process which is why this was such a novel concept. To see intuitively how diffusion can be destabilizing consider the following, albeit unrealistic, but informative analogy.

Consider a field of dry grass in which there is a large number of grasshoppers…

I don’t know about you, but I gotta love someone who explains mathematics using dry grass and grasshoppers.

Diffusion is a key concept underlying Turing’s work. Russ Hobbie and I discussion diffusion in Chapter 4 of the 4th edition of Intermediate Physics for Medicine and Biology, and it is one of the central ideas in all of biological physics. Diffusion-driven instabilities play a role when analyzing the Belousov-Zhabotinsky oscillating chemical reaction, and are relevant to explaining how leopards get their spots (a spotted leopard graces the cover of Murray’s book; whenever I search for his book in the stacks of the OU library, I just look for the leopard).

Murray continues

A reaction diffusion system exhibits diffusion-driven instability or Turing instability if the homogeneous stead state is stable to small perturbations in the absence of diffusion but unstable to small spatial perturbations when diffusion is present. The usual concept of instability in biology is in the context of ecology, where a uniform steady state becomes unstable to small perturbations and the populations typically exhibit some temporal oscillatory behaviour. The instability we are concerned with here is of a quite different kind. The mechanism driving the spatially inhomogeneous instability is diffusion: the mechanism determines the spatial pattern that evolves. How the pattern or mode is selected is an important aspect of the analysis.

Not only did Turing make a monumental contribution to deciphering the enigma code, but also he helped to develop the field of mathematical biology. In my book, that makes him a biological physicist.

Willem Einthoven, Biological Physicist

In Chapter 7 of the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I mention Einthoven’s triangle. This triangle is formed by three electrodes used to measure the electrocardiogram: one on the right arm, one on the left arm, and one on the left leg. Who is this Einthoven of Einthoven’s triangle? He is an excellent example of a scientist well versed in both physics and physiology.

Asimov's Biographical
Encyclopedia.

Asimov’s Biographical Encyclopedia of Science and Technology describes Einthoven in this way:

Einthoven, Willem (eyent’-hoh-ven)
Dutch physiologist
Born: Semarang, Java (now part of Indonesia), May 22, 1860
Died: Leiden, September 29, 1927

Einthoven’s father was a practicing physician serving in the East Indies, which was then a Dutch colony. The father died in 1866, and in 1870 the family returned to the Netherlands and settled in Utrecht. In 1878 Einthoven entered the University of Utrecht and began the study of medicine, although always with considerable interest in physics. He obtained his medical degree in 1885 and was at once appointed to a professorship of physiology at the University of Leiden, serving there the remainder of his life.

The physicist in him provoked his interest in the tiny electric potentials produced in the human body…. In 1903 Einthoven developed the first string galvanometer. This consisted of a delicate conducting thread stretched across a magnetic field. A current flowing through the thread would cause it to deviate at right angles to the direction of the magnetic field lines of force, the extent of the deviation being proportional to the strength of the current. The delicacy of the device was sufficient to make it possible to record the varying electrical potentials of the heart.

Einthoven continually improved his device and worked out the significance of the rises and falls in potential. By 1906 he was correlating the recordings of these peaks and troughs (the result being what he called the electrocardiogram) with various types of heart disorders….For the development of electrocardiography Einthoven was awarded the 1924 Nobel Prize in medicine and physiology.

Willem Einthoven (1860-1927):
Father of Electrocardiology.

I became intrigued by Einthoven’s skill at both mathematics and medicine, so I decided to explore deeper into how he straddled these two fields. The book Willem Einthoven (1860-1927): Father of Electrocardiography, by H. A. Snellen, provided these insights:

[Einthoven’s work] demanded more knowledge of mathematics than Einthoven’s high school and medical training had provided. He supplemented this mainly through self-study; learning differential and integral calculus from Lorentz’ book on the subject in the early 1890’s.

30 Years later he presented a copy of this book to Frank Wilson with the words: “May I send you the excellent book of Lorentz’ Differential- und Integralrechnung? I have learned my mathematics from it after my nomination as a professor in this University and I hope you will have as much pleasure and profit by it as I have had myself.”

In physical matters he was aided by his correspondence and talks with his friend (and later brother-in-law) Julius, who became extra-ordinary professor of physics at Amsterdam and subsequently full professor at Utrecht, where they had studied together.

Einthoven profited also from written and personal contact with the somewhat older and already famous Lorentz, professor of theoretical physics at Leiden….

Einthoven the physiologist with a marked general concern about patients and general medicine was at heart a physicist though not by training and office…

Most of the important topics in the correspondence [between Einthoven and English physiologist A. V. Hill] are reflected in Hill’s obituary of Einthoven in Nature. I quote a few lines, which bear testimony to Hill’s keen observation and his sincere admiration of Einthoven: “Einthoven’s investigations cover a wide range, but they are all notable for the same characteristic—the mastery of physical technique which they show. Einthoven, in spite of his medical training and his office, was essentially a physicist, and the extraordinary value of his contributions to physiology, and therewith indirectly to medicine, emphasizes the way in which an aptitude—in Einthoven’s case a genius—for physical methods can aid in the solution of physiological problems.”

Many scientists have made the leap from physics to biology (see my blog entry of a few weeks ago for examples). Einthoven did the opposite: going from biology to physics. I’ve always suspected this is the more difficult path, and it certainly seems to be the less common one. Yet, he appears to have made the journey successfully. Snellen’s book provides no anecdotes about how Einthoven picked up his mathematics and physics, but I imagine he must of spent many a night slogging through Lorentz’s book, painstakingly teaching himself the subject.

I suspect IPMB can aid physicists moving into biology and medicine. I wonder how useful it is for someone like Einthoven, travelling in the other direction?

George Ralph Mines, Biological Physicist

In Chapter 10 of the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss the contribution of George Ralph Mines to cardiac electrophysiology.

The propagation of an action potential is one example of the propagation of a wave in excitable media. We saw in Chap. 7 that waves of depolarization sweep through cardiac tissue. The circulation of a wave of contraction in a ring of cardiac tissue was demonstrated by Mines in 1914. It was first thought that such a wave had to circulate around an anatomic obstacle, but it is now recognized that no obstacle is needed.

This year marks the 100th anniversary of Mines’ landmark work. Regis DeSilva, in an article titled “George Ralph Mines, Ventricular Fibrillation and the Discovery of the Vulnerable Period” (Journal of the American College of Cardiology, Volume 29, Pages 1397–1402, 1997) describes Mines’ work in more detail.

George Ralph Mines … made two major contributions to electrophysiology. His scientific legacy includes elucidating the theoretical basis for the occurrence of reentrant arrhythmias and the discovery of the vulnerable period of the ventricle.

First, DeSilva discusses Mines’ analysis of reentry in cardiac tissue.

Mines applied his concept of reentry to myocardial tissue and suggested that closed circuits may also exist within heart muscle. Under normal conditions, these circuits are uniformly excited, and an excitatory wave dies out. He suggested that the twin conditions of unidirectional block and slow conduction may occur in abnormal myocardial tissue. Thus, tissue in a reentrant circuit may allow a circulating wavefront to be sustained by virtue of conductive tissue being always available for excitation. In this paper, he also published a now classic figure by illustrating the concept of circus movement in such small myocardial circuits, and this diagram is still used unchanged today in teaching this mechanism to students of electrocardiography (14)

Reference 14 (Mines GR, “On Dynamic Equilibrium in the Heart, Journal of Physiology,” Volume 46, Pages 349–383, 1913) is not cited in IPMB.

DeSilva then addresses Mines identification of a “vulnerable period” in the heart.

Mines’ second major contribution was also his most important discovery. It was published … in 1914, entitled “On Circulating Excitations in Heart Muscles and Their Possible Relation to Tachycardia and Fibrillation” [Transactions of the Royal Society of Canada, Volume 8, Pages 43–52, 1914] (15).…[Before 1914] the most common method of inducing fibrillation was by the application of repeated electrical shocks to the heart through an induction coil. Mines’ innovation in studying the onset of fibrillation was to modify the method by applying single shocks to the rabbit heart, and by timing them precisely at various periods during the cardiac cycle.… Stimuli were delivered by single taps of a Morse key, and the moment of application of the stimulus was signaled by the use of a sparking coil connected to an insulated pointer that produced dots on the kymographic trace. Correlation of the position of the dots on the mechanical trace with the electrocardiogram provided an indication of its timing in electrical diastole…. By so doing, ‘it was found in a number of experiments that a single tap of the Morse key if properly timed [his italics] would start fibrillation which would persist for a time. . . . The point of interest is that the stimulus employed would never cause fibrillation unless it was set in at a certain critical instant’ (15)…. The importance of this work lies in the fact that Mines identified for the first time a narrow zone fixed within electrical diastole during which the heart was extremely vulnerable to fibrillation. An external stimulus, or a stimulus generated from within the heart, if properly timed to fall within this zone, could trigger a fatal arrhythmia and cause death. This observation has spurred three generations of scientists to study the factors which cause death by disruption of what Mines called 'the dynamic equilibrium of the heart' (14).

Clearly Mines made landmark contributions to our understanding of the heart. But perhaps the most intriguing aspect of Mines’ life was the unusual circumstances of his untimely death. DeSilva writes

On the evening of Saturday November 7, 1914, the night janitor entered Mines’ laboratory and found him lying unconscious with equipment attached, apparently for the recording of respiration (25). He was taken immediately to the Royal Victoria Hospital where he regained consciousness only briefly. Shortly before midnight, he developed seizures and died without regaining consciousness. A complete autopsy was performed, including examination of all the abdominal and thoracic viscera and the brain, but no final diagnosis was rendered (26). The presumption was that death resulted from self-experimentation.

Here is how Art Winfree describes the same event, in his Scientific American article “Sudden Cardiac Death: A Problem in Topology”

Mines had been trying to determine whether relatively small, brief electrical stimuli can cause fibrillation. For this work he had constructed a device to deliver electrical impulses to the heart with a magnitude and timing that could be precisely controlled. The device had been employed in preliminary work with animals. When Mines decided it was time to begin work with human beings, he chose the most readily available experimental subject: himself. At about six o’clock that evening a janitor, thinking it was unusually quiet in the laboratory, entered the room. Mines was lying under the laboratory bench surrounded by twisted electrical equipment. A broken mechanism was attached to his chest over the heart and a piece of apparatus nearby was still recording the faltering heartbeat. He died without recovering consciousness.

Winfree notes in the 2nd edition of his book The Geometry of Biological Time that there is still some controversy about if Mines' death was truly from self experimentation. The circumstances of his death are certainly suggestive of this, even if we lack definitive proof.

I can't help but notice the similarities between George Ralph Mines and Henry Moseley. Both were Englishmen whose last name started with "M". Both were born at about the same time (Mines in 1886, Moseley in 1887). Both made fundamental contributions to science at an early age (Mines to cardiac electrophysiology, and Moseley to our understanding of the atomic number and the periodic table). Both are probably underappreciated in the history of science, and neither won the Nobel Prize. And both died before reaching the age of 30 (Mines in 1914, Moseley in 1915). Mines died in the mysterious accident in his lab described above, and Moseley died in the Battle of Gallipoli during World War I. And, of course, both are mentioned in the 4th edition of Intermediate Physics for Medicine and Biology.

Hermann von Helmholtz, Biological Physicist

Who was the greatest biological physicist ever? That’s a difficult question, but one candidate is the German scientist Hermann von Helmholtz (1821–1894). Helmholtz was both a physician and physicist who made important contributions to physiology. Russ Hobbie and I mention him briefly in the 4th edition of Intermediate Physics for Medicine and Biology. In Chapter 6 on Impulses in Nerve and Muscle Cells, we write

The action potential was first measured by Helmholtz around 1850.

Asimov's Biographical Encyclopedia
of Science and Technology,
by Isaac Asimov.

That is true, but he made many other contributions to biological physics. To highlight some of these, I turn to Asimov’s Biographical Encyclopedia of Science and Technology. Asimov first describes Helmholtz’s work on vision (some of which I have described previously in this blog).

Like [Thomas] Young, Helmholtz made a close study of the function of the eye, and in 1851 he invented an ophthalmoscope, with which one could peer into the eye’s interior—an instrument without which the modern eye specialist would be all but helpless…In addition he revived Young’s theory of three-color vision and expanded it, so that it is now known as the Young-Helmholtz theory.

He also studied sound, the ear, and music (he was a fine musician).

Helmholtz studied that other sense organ, the ear, as well. He advanced the theory that the ear detected differences in pitch through the action of the cochlea, a spiral organ in the inner ear. It contained, he explained, a series of progressively smaller resonators, each of which responded to a sound wave of progressively higher frequency. The pitch we detected depended on which resonator responded.

And as Russ and I noted, he made pioneering measurements in nerve electrophysiology.

Helmholtz was the first to measure the speed of the nerve impulse. His teacher, Muller, was fond of presenting this as an example of something science could never accomplish because the impulse moved so quickly over so short a path. In 1852, however, Helmholtz stimulated a nerve connected to a frog muscle, stimulating it first near the muscle, then farther away. He managed to measure the added time required for the muscle to respond in the latter case.

He also helped formulate the principle of the conservation of energy, an idea he came upon when studying the behavior of muscle.

But he is best known for his contributions to physics and in particular for his treatment of the conservation of energy, something to which he was led by his studies of muscle action. He was the first to show that animal heat was produced chiefly by contracting muscle and that an acid—which we now know to be lactic acid—was formed in the working muscle.

Given my admiration for 19th century physicists, I’m a little surprised that I don’t know more about Helmholtz. This is probably because I am more familiar with the great British physicists—Faraday, Maxwell, Kelvin—than with the Germans of that era (this is odd, given that I am half German). I wouldn’t go so far as to claim Helmholtz was as great a physicist as my Victorian heroes, but I do suggest that he was a greater biological physicist. I think a good argument could be made that he is the greatest of all biological physicists.

Lord Rayleigh, Biological Physicist

Theory of Sound,
by Lord Rayleigh.

I am a big fan of Victorian physicists. Among my heroes are Faraday, Maxwell, and Kelvin. Another leading Victorian was John William Strutt, also known as Lord Rayleigh (1842–1919). Russ Hobbie and I mention Rayleigh in the 4th edition of Intermediate Physics for Medicine and Biology, in the context of Rayleigh Scattering. In Chapter 15 on the interaction of x-rays with matter, we write

A photon can also scatter elastically from an atom, with none of the electrons leaving their energy levels. This (γ, γ) process is called coherent scattering (sometimes called Rayleigh scattering), and its cross section is σ_coh. The entire atom recoils; if one substitutes the atomic mass in Eqs. 15.15 and 15.16, one finds that the atomic recoil kinetic energy is negligible.

In Rayleigh scattering, the oscillating electric field in an electromagnetic wave exerts a force on electrons. These electrons are displaced by this force, and therefore oscillate at the same frequency as the wave. An oscillating charge emits electromagnetic radiation. The net result is scattering of the incident wave. If the electrons are free, this is known as Thomson scattering. If the electrons are bound to an atom, and the frequency of the light is less than the natural frequency of oscillation of the bound electrons, then it is known as Rayleigh scattering. Light scattering is complicated when the wavelength is similar to or smaller than the size of the scatterer, because light scattered from different regions within the particle interfere. However, Rayleigh scattering assumes that the wavelength is large compared to the size of the scatterer, so interference is not important.

Rayleigh scattering not only plays a role in the scattering of x-rays, but also is responsible for the scattering of visible light. The Rayleigh scattering cross section varies as the 4th power of the frequency, or inversely with the 4th power of the wavelength. When we look at the sky, we see the scattered light. Since the short wavelength blue light is scattered much more than the long wavelength red light, the sky appears blue.

Lord Rayleigh made other important contributions to physics. For example, he wrote an influential book on the Theory of Sound, and he won the Nobel Prize in 1904 for his discovery of the element argon. He succeeded Maxwell as the Cavendish Professor of Physics (see this video: https://www.youtube.com/watch?v=tkwLavjqsBI to learn more).

Was Rayleigh a biological physicist? Yes! Rayleigh was one of the first to explain how we localize sound. His Duplex Theory suggests that we can determine the direction a sound came by sensing the arrival time difference at each of our two ears for low frequencies, and sensing the intensity difference between the ears for high frequencies.

Lord Rayleigh was born 170 years ago this fall (November 12, 1842). J. J. Thomson studied under Rayleigh, and Ernest Rutherford studied under Thomson. Previously in this blog, I described how I am descended, academically speaking, from Rutherford. This means Lord Rayleigh is, again academically speaking, my great-great-great-great-great-great grandfather.

Charles Dickens: Medical Physicist?

The 200th anniversary of the birth of Charles Dickens occurs this week (he was born February 7, 1812). I am a big Dickens fan, so I had to fit him into this week’s blog entry somehow. It is not easy, since there is little overlap between Dickens’ novels and the 4th edition of Intermediate Physics for Medicine and Biology. But let us try.

Great Expectations,
by Charles Dickens.

Dickens’ life spanned an incredibly productive era of Victorian science in England. He was born the same year as English Chemist Humphry Davy published his Elements of Chemical Philosophy. Dickens’ birth fell almost exactly halfway between the births of the two greatest of 19th century British physicists: Michael Faraday (September 1791) and James Maxwell (November 1831). Just as Maxwell was publishing his eponymous Maxwell’s equations, Dickens was publishing Great Expectations. The physician John Snow was born one year after Dickens. It was Snow who famously traced the source of the 1854 cholera epidemic to the Broad Street pump in London (read more about this story in The Ghost Map by Steven Johnson). Dickens was born just two years after the birth of Charles Darwin, and On The Origin of Species appeared almost simultaneously with Dickens’ masterpiece A Tale of Two Cities. William Thomson (Lord Kelvin) was 12 years younger than Dickens. He formulated his version of the second law of thermodynamics in 1851, soon after Dickens published David Copperfield.

David Copperfield,
by Charles Dickens.

A young Charles was working long hours at Warren’s Blacking Warehouse when the first issue of the British medical journal The Lancet appeared in 1823. Dickens published his first story the year after Faraday proposed his vision of electric and magnetic fields, and he got married and published his first novel (The Pickwick Papers) in 1836, the year Darwin returned from his voyage on the Beagle. Martin Chuzzlewit came out in 1843, the same year James Joule determined the mechanical equivalent of heat. Dickens traveled to France and Italy the year that the prominent English chemist John Dalton died in England. His last complete novel, Our Mutual Friend, appeared in 1865, the year before the first transatlantic telegraph cable was laid (for more about this fascinating story, read A Thread Across the Ocean by John Gordon). Kelvin developed the cable equation to govern the transmission of signals over this telegraph line, and the same equation is used nowadays to describe nerve axons. An elderly Dickens came to the United States for a reading tour in 1867, the year English surgeon Joseph Lister pioneered the use of antiseptic to sterilize surgical instruments. Charles Dickens died of a stroke in 1870—leaving the Mystery of Edwin Drood unfinished—just a few months before the birth of the greatest experimental physicist since Faraday, Ernest Rutherford.

A Tale of Two Cities,
by Charles Dickens.

The medical literature contains several studies of how medicine was portrayed in Dickens’ books. Howard Markel writes about “Charles Dickens and the Art of Medicine” in the Annals of Internal Medicine (Volume 101, Pages 408–411, 1984).

Charles Dickens, the novelist, humanist, and social reformer, was a keen observer of all the characteristics of the people in his novels. Dickens observed physicians and visited hospitals so that he could record various illnesses and diseases of people he met during his life. Dickens also worked for many public health reforms in Victorian England. The author used his observations of sick people in many of his novels and produced several accurate descriptions of disease, including Ménière's disorder and acute leukemia.

Bleak House,
by Charles Dickens.

The article analyzes how, in Bleak House, Phil Squod (who was always “shoulding his way along walls”) demonstrated symptoms consistent with “dysfunction of the vestibular nerve…most likely Meniere’s disorder.” In Dombey and Son, the symptoms of young Paul Dombey “resemble those of a child with an acute form of leukemia.”

Kerrie Schoffer and John O’Sullivan focus on movement disorders in their study of Charles Dickens in the Journal of Clinical Neuroscience (Volume 13, Pages 898–901, 2006)

Nineteenth-century Victorian novelists played an important role in developing our understanding of medicine and illness. With the eye of an expert clinician, Charles Dickens provided several detailed accounts of movement disorders in his literary works, many of which predated medical descriptions. His gift for eloquence, imagery, and precision attest not only to the importance of careful clinical observation, but also provide an insightful and entertaining perspective on movement disorders for modern students of neuroscience.

Pickwick Papers,
by Charles Dickens.

So is Dickens a medical physicist? I guess not. But he was a great writer. My favorite Dickens book is A Christmas Carol; I read it every Christmas. I reread A Tale of Two Cities during my Paris trip two years ago (“…It is a far, far better thing that I do, than I have ever done; it is a far, far better rest that I go to than I have ever known.”). I enjoyed Bleak House a few years ago, although it took me a long time to plow through that 818 page tome. I love Dickens’ characters, like the Artful Dodger in Oliver Twist, and Wilkins Micawber in David Copperfield. What will be my next Dickens book? I haven’t read Nicholas Nickleby yet; I think it will be next.