Friday, August 28, 2015

Art Winfree and the Bidomain Model of Cardiac Tissue

Art Winfree was a pioneer in applying physics and mathematics to cardiac electrophysiology. Russ Hobbie and I cite him often in the 5th edition of Intermediate Physics for Medicine and Biology. After his untimely death in 2002, I was asked to write an article for a special issue of the Journal of Theoretical Biology published in his honor. My paper, “Art Winfree and the Bidomain Model of Cardiac Tissue,” appeared in 2004.

My original submission for the special issue was a personal tribute to Art. It began
" ‘Spiral waves have become so popular in Tucson they are even sold in hair styling salons (Figure 1)’
Figure 1
I had to laugh as I read the above quote in a preprint Art Winfree sent me. It was to be the opening sentence of a chapter appearing in a prestigious textbook on cardiac electrophysiology. Unfortunately, the sentence and the picture were deleted before the book's publication, although the picture (Fig. 1) did appear eventually in the second edition of Art's The Geometry of Biological Time. For me, the quote captures the essence of Art: his humor, his irreverence, and his uncanny ability to find science in the world around him. I only met Art in person once, but we corresponded often by email, exchanging ideas, frustrations, and gossip. Of all the scientists who have influenced my research career, only my PhD advisor John Wikswo had a greater impact than Art Winfree did. In this paper, I describe several instances where my path crossed Art's as we each attacked related problems in cardiac electrophysiology. In addition, I hope to show that Art made important contributions to what is known as the ‘bidomain model’ of cardiac tissue."
Later in the article is one of my favorite passages.
“I recall vividly a sunny day in April, soon after my second daughter Katherine was born. I was sitting on a rocking chair in the living room of our house in Kensington, Maryland, holding the sleeping infant in one arm and Art's book When Time Breaks Down in the other. Outside I could see our dogwood tree in full blossom. As I read page after page, I remember thinking "life doesn't get any better than this." The book (and the daughter) changed my life.”
Unfortunately, the editors of the special issue didn’t like my paper, saying they wanted a more traditional review article. In particular, they objected to my quoting Art’s emails he had sent me. So, I gave the paper a lobotomy and published a harmless but lifeless review. When the issue came out, I found a wonderful article by George Oster about Winfree, full of personal insights and even the text of one of Art’s emails. I wish now I had pushed harder to get my article published in its original form. The best article in the special issue was “Art Winfree, Artist of Science” by his daughter Rachael Winfree.

In the acknowledgments of my paper is the line “I would like to thank Jesse Malouf for his help editing this paper.” Jesse was a student in my honors college course about Pacemakers and Defibrillators. At Oakland University, Honors College has many of the best students in the university, but they are from all backgrounds and often have weak math skills. Jesse was a mathaphobe, but a wonderful writer. On one of my exams I had a mixture of questions, some requiring mathematical analysis and others needing an essay. Jesse skipped the math questions, but to make up for it he not only answered all the essay questions elegantly but also wrote a “bonus essay”. I never had a student hand in a bonus essay before! The next semester, I hired him to help me write the Winfree article. I fear many of his contributions to the original version were not included in the published one.

In the “olden days” the original draft of my Winfree article would be lost forever, or maybe would sit in some file cabinet unseen for decades. But nowadays, you can find anything on the internet (how did we live without it?). I have posted the original submission on my ResearchGate page. You can find it here.

Friday, August 21, 2015

The Coulter Counter

In Intermediate Physics for Medicine and Biology, Russ Hobbie and I often include applications of important topics in the homework problems. One such problem, new in Chapter 6 of the 5th edition, is an analysis of a Coulter counter.
Problem 23. The Coulter counter or resistive pulse technique is used to count and size particles in a wide variety of applications (Kubitschek 1969; DeBlois and Bean 1970), including the automated counting of blood cells. The cells being counted are assumed to be nonconducting and immersed in a conducting fluid. The fluid is made to flow through a narrow channel. When a suspended particle enters the channel there is a change in resistance. Assume a long channel of radius b with no end effects.
(a) What is the resistance of pure fluid of resistivity ρ = 1/σ in a segment of channel of length 2a?
(b) A cylindrical non-conducting cell of radius a and length 2a is in the channel. Its axis and the axis of the channel coincide. What is the resistance of a segment of channel of length 2a? Ignore end effects.
(c) Show that the resistance change (the difference between these two results) is proportional to the volume of the cell, V=2πa3, and inversely proportional to b4.
In the August issue of Physics Today is an article about extending the Coulter counter to sequencing DNA. Murugappan Muthukumar, Calin Plesa, and Cees Dekker write
“In the 1940s Wallace Coulter set about finding a way to quickly count blood cells, which at the time was a slow and inefficient process. His approach was to pass cells, one by one, through a small hole connecting to compartments filled with electrolyte solution. Simultaneously, he applied a voltage across the compartment and measured the ionic current passed through the hole. As a cell passed through the hole, it would partially block the flow of electric charges, and the current would drop by an amount proportional to the volume of the cell….Coulter’s technique worked out wonderfully and revolutionized cell counting.”
Then, the authors describe how this method can be used to sequence DNA.
“The last two decades have seen a renaissance of the Coulter counter concept. The principle remains essentially the same, but nanopores—holes with a diameter of merely a few nanometers—have shrunk the length scale from that of single cells to that of single molecules. When DNA molecules are added to one side of the pore and an electric field is applied, the resulting electrophoretic force on the negatively charged DNA can pull the molecule through the pore in a head-to-tail fashion, leading to an observable blockade in the ionic current…

In the 1990s several research groups […] began probing whether the different bases on a DNA strand might block measurably different amounts of ionic current as they pass through a nanopore. If so, the pattern of current generated by a DNA strand threaded through a nanopore might provide a linear readout of the strand’s base sequence….Although significant challenges remain to turn that vision into a practical reality, the goal appears to be within reach.”
The authors then describe more details about the technique. Some use transmembrane proteins like the membrane channels described in Chapter 9 of IPMB. Others use tiny holes drilled into sheets of silicon nitride. Still others use a hybrid of these two.

Clearly the method will not work unless the DNA is a single strand. Wanunu (2012) discusses the molecular dynamics involved in unzipping a double strand to obtain two single strands, one of which can then be threaded through the pore to do the sequencing.The nanopores must be very narrow if you are to have any chance of distinguishing different bases attached to the DNA backbone.

Russ and I had no idea about these modern uses of the Coulter counter when we added the homework problem. This new application of the Coulter idea shows how a strong understanding of the fundamentals of physics as applied to medicine and biology can allow one to quickly move to the forefront of cutting-edge new technologies.

Friday, August 14, 2015

The Psychic Probe

In the summer my wife and I sometimes take long car trips, and I often listen to audiobooks while I drive to keep me awake and alert. During a recent trip I listened to Isaac Asimov’s Foundation trilogy. Regular readers of this blog know that I am a huge Asimov fan. I first read the Foundation series about forty years ago, and this was my third or fourth time through these delightful books.

In brief, the Foundation series tells the history of the decaying galactic empire, and describes the work of the psychohistorian Hari Seldon who has calculated mathematically how to reduce the duration of the dark ages following the empire’s fall from 30,000 years to merely 1000. All goes according to plan until the Mule, a mutant who can control other people’s emotions, causes all to go awry.

One of Asimov’s inventions in this future history is a device that can read minds, called the Psychic Probe. He writes in Foundation and Empire,
“The general threw away his shredded, never-lit cigarette, lit another, and shrugged. ‘Well, it is beside the immediate point, this lack of first-class tech-men. Except that I might have made more progress with my prisoner were my Psychic Probe in proper order.’

The secretary's eyebrows lifted. ’You have a Probe?’

‘An old one. A superannuated one which fails me the one time I needed it. I set it up during the prisoner's sleep, and received nothing. So much for the Probe. I have tried it on my own men and the reaction is quite proper, but again there is not one among my staff of tech-men who can tell me why it fails upon the prisoner. Ducem Barr, who is a theoretician of parts, though no mechanic, says the psychic structure of the prisoner may be unaffected by the Probe since from childhood he has been subjected to alien environments and neural stimuli. I don't know. But he may yet be useful. I save him in that hope.’ ”
Of course, Russ Hobbie and I don’t mention the Psychic Probe in the 5th edition of Intermediate Physics for Medicine and Biology….or do we? Asimov didn’t explain the physical mechanism behind the Probe, but I can speculate. Four candidates are:
PET and fMRI are too slow to accurately follow rapid brain activity. PET detects brain metabolism and fMRI detects blood flow, both of which are only indirectly related to neuron firing. My best guess for the Psychic Probe is some combination of MEG and TMS. Apparently the probe can damage the brain when used aggressively, which suggests TMS. But it can also read minds when used more gently, which points toward MEG. A combo TMS/MEG unit could therefore both detect and alter brain function.

While working at NIH in the 1990s, I studied both magnetoencephalography and transcranial magnetic stimulation. Yikes! I may be partially responsible for the invention of the Psychic Probe!

Friday, August 7, 2015

Kramers’ Law

When preparing the 5th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I added a homework problem about Kramers’ Law. (We spelled it Kramer’s, but his name is Kramers with an s, so we should have written Kramers’.) Kramers’ law is Eq. 16.3a, the photon energy fluence dΨ/d() as a function of frequency ν for bremsstrahlung radiation
where Z is the atomic number, h is Planck’s constant, νo is the frequency of a photon having the same energy as the incident electrons, and C is a constant. In his paper “On the Theory of X-ray Absorption and of the Continuous X-ray Spectrum” (Philosophical Magazine, Volume 46, Pages 836-871, 1923), Kramers writes
“The continuous x-ray spectrum has in the course of the last years been investigated by a number of physicists. The problem is here to determine how, for a given tension [voltage] on the tube and a given anticathode material [typically tungsten], the energy in the continuous spectrum is distributed among different frequencies…

The object of the present paper is to show how it is possible to account theoretically for the main features of the phenomena of x-ray absorption and continuous x-ray emission discussed above. The explanation of these phenomena may be traced back to the determination of the radiation processes which may occur when a free electron of given velocity approaches a positive nucleus with given charge.”
Who was Kramers? According to the Dictionary of Scientific Biography, Hendrik Anthony (Hans) Kramers was born in Rotterdam, the Netherlands in 1894. He joined Niels Bohr’s Institute of Theoretical Physics, and in 1934 he moved to Leiden University, where he remained until his death in 1952. He is known for many contributions to physics, including the Kramers-Kronig Relations. The Dictionary of Scientific Biography article concludes
“Kramers’ work, which covers almost the entire field of theoretical physics, is characterized both by outstanding mathematical skill and by careful analysis of physical principles. It also leaves us with the impression that he tackled problems because he found them challenging, not primarily because they afforded chances of easy success. As a consequence his work is somewhat lacking in spectacular results that can be easily explained to a layman; but among fellow theoreticians he was universally recognized as one of the great masters.”
Here is my favorite Kramers story. Jewish physicist Abraham Pais described in his autobiography A Tale of Two Continents how he spent much of World War II in Holland hiding from the Gestapo. Kramers was one of the few people who knew of his hiding place, and would visit him weekly to talk physics. One day when Kramers was there, Gestapo agents knocked at the door and Pais had to hide in a small enclosure behind a panel in the wall. Pais writes
“I kept sitting in the tiny space, practically bent over double, holding onto the panel, when I heard the door to my room, which lay at the other side of my hiding spot, open softly. Someone entered, I did not at first know who. Then that person sat down on a small bench that stood right at the wall behind which I was folded up. The person began to read, not loud but quite softly. It was Kramers. Earlier he had lent me a volume of Bradley’s Lectures on Shakespeare. What this good man was doing now was reading to me from that book, in order to calm my nerves.”