Citation Classic Commentaries

From 1977 to 1993, thousands of Citation Classic Commentaries appeared in Current Contents, a database of journal tables of contents originally published by the Institute of Scientific Information. The full texts of these mostly one-page articles are now available at http://garfield.library.upenn.edu/classics.html. In each article, the author of a highly-cited paper tells the story behind the research and describes how the paper came to be published. I find that these commentaries provide a glimpse into the human side of science. They offer insight into what an author thinks about his own work years after it is completed. I always enjoyed reading them, and wish they were still being written.

Many of these commentaries are related to medical and biological physics. Below I list a dozen that readers of the 4th edition of Intermediate Physics for Medicine and Biology might enjoy. Each link will download a pdf of the commentary.

N Bloembergen, EM Purcell, and RV Pound (1948) “Relaxation Effects in Nuclear Magnetic Resonance Absorption,” Physical Review, Volume 73, Pages 679–712.

EL Hahn (1950 “Spin Echoes,” Physical Review, Volume 80, Pages 580–594.

B Lown, R Amarasingham, and I Neumann (1962) “A New Method for Terminating Cardiac Arrhythmias,” Journal of the American Medical Association, Volume 182, Pages 548–555.

S Meiboom and D Gill (1958) “Modified Spin-Echo Method for Measuring Nuclear Relaxation Times,” Review of Scientific Instruments, Volume 29, Pages 688–691.

AL Hodgkin and AF Huxley (1952) “A Quantitative Description of Membrane Current and its Application to Conduction and Excitation in Nerve,” Journal of Physiology, Volume 117, Pages 500–544.

JH Hubbell (1969) “Photon Cross Sections, Attenuation Coefficients, and Energy Absorption Coefficients From 10 keV to 100 GeV,” Washington, DC: US Government Printing Office, August 1969. National Standard Reference Data Series Report No. NSRDS-NBS 29. 8Op.

ME Phelps, EJ Hoffman, S-C Huang and DE Kuhl (1978) “ECAT: A New Computerized Tomographic Imaging System for Positron-Emitting Radiopharmaceuticals,” Journal of Nuclear Medicine, Volume 19, Pages 635–647.

FJ Bonte, RW Parkey, KD Graham, J Moore and EM Stokely (1974) “A New Method for Radionuclide Imaging of Myocardial Infarcts,” Radiology, Volume 110, Pages 473– 474.

IR Young, DR Bailes, M Burl, AG Collins, DT Smith, MJ McDonnell, JS Orr, LM Banks, GM Bydder, RH Greenspan and RE Steiner (1982) “Initial Clinical Evaluation of a Whole Body Nuclear Magnetic Resonance (NMR) Tomograph,” Journal of Computer Assisted Tomography, Volume 6, Pages 1–18.

JH Hubbell (1982) “Photon Mass Attenuation and Energy-Absorption Coefficients from 1 keV to 20 MeV,” Internatonal Journal of Applied Radiation and Isotopes, Volume 33, Pages 1269–1290.

PA Bottomley and ER Andrew (1978) “Magnetic Field Penetration, Phase Shift and Power Dissipation in Biological Tissue: Implications for NMR Imaging,” Physics in Medicine and Biology, Volume 23, Pages 630–643.

JW Cooley and JW Tukey (1965) “An Algorithm for the Machine Calculation of Complex Fourier Series,” Mathematics of Computation, Volume 19, Pages 297–301.

Cardiac Bioelectric Therapy

Cardiac Bioelectric Therapy:
Mechanisms and Practical Implications,
Edited by Efimov, Kroll, and Tchou.

In the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I introduce some fundamental concepts about the electrical properties of the heart (see, for example, Chapters 7 and 10). A new multi-author book, Cardiac Bioelectric Therapy: Mechanisms and Practical Implications, provides an in depth examination of this topic. In a foreword to the book, Ray Ideker writes

Since pacemakers and defibrillators were developed a little more than 50 years ago, their usage has grown rapidly, so that over 900,000 pacemakers and 200,000 defibrillators are implanted every year throughout the world. During this half century there have been astonishing advances in the efficacy and sophistication of these devices. Yet the devices still have major limitations...

Although there are many books that deal with the practical aspects of pacing and defibrillation, there is a pressing need for a single source that presents current knowledge about the basic mechanisms of cardiac bioelectric theory. This book, edited by Efimov, Kroll, and Tchou [admirably] fulfills this need. The chapters thoroughly and masterfully cover all aspects of this subject and are written by experts in the field... I predict this book will be the standard source that will be consulted both by experienced workers in this area as well as by students and others who wish to learn more about this subject.

I have two chapters in this book: “The Bidomain Theory of Pacing” written with my former graduate student Debbie Janks, now at the University of Vermont College of Medicine, and “Virtual Electrode Theory of Pacing” coauthored with John Wikswo of Vanderbilt University, a long-time collaborator and my PhD dissertation advisor. Other chapters that I find particularly useful are “Bidomain Model of Defibrillation” by Natalia Trayanova and Gernot Plank, “The Generalized Activating Function” by Leslie Tung (who invented the bidomain model of cardiac tissue in his PhD dissertation), “Critical Points and the Upper Limit of Vulnerability for Defibrillation” by Raymond Ideker and Derek Dosdall, and “The Virtual Electrode Hypothesis of Defibrillation” by Crystal Ripplinger and Igor Efimov. This is only a partial list; other excellent chapters are written by a Who’s Who of leaders in the field, such as Craig Henriquez, Steve Knisley, Vladimir Fast, Hrayr Karagueuzian, Niels Otani, Alain Karma, Shiien-Fong Lin, and Wanda Krassowska, among others.

The book covers two topics in detail: the bidomain, a mathematical model of the heart’s electrical properties that I have worked on much in my career, and optical mapping of transmembrane potential. This second topic is an experimental technique that involves a fluorescent dye that is bound to the cell membrane. This amount the dye fluoresces depends on the transmembrane potential, which allows researchers to record an electrical quantity using optical methods.

I can think of only one problem with the book: at $199 it’s expensive (you could get two copies of the 4th edition of Intermediate Physics for Medicine and Biology for that price and still have money left over). But for students and researchers serious about understanding pacemakers and defibrillators, this book is worth the money. For students interested in browsing the book to expand their knowledge, all I can say is try your library, and there’s always interlibrary loan.

The National Institutes of Health

The National Institutes of Health.

About now, you undergraduate students studying from the 4th edition of Intermediate Physics for Medicine and Biology are probably starting to wonder what you’ll be doing this summer. I suggest you consider an internship to do biomedical research at the National Institutes of Health (application deadline: March 1). I can’t think of a better first step toward a career applying physics to medicine and biology.

For seven years (1988–1995), I had the privilege of working at the National Institutes of Health in Bethesda, Maryland. According to Wikipedia:

The National Institutes of Health (NIH) is an agency of the United States Department of Health and Human Services and is the primary agency of the United States government responsible for biomedical and health-related research. The Institutes are responsible for 28%—about $28 billion—of the total biomedical research funding spent annually in the U.S., with most of the rest coming from industry. The NIH is divided into two parts: the “Extramural” parts of NIH are responsible for the funding of biomedical research outside of NIH, while the “Intramural” parts of NIH conduct research. Intramural research is primarily conducted at the main campus in Bethesda.

I was part of the intramural Biomedical Engineering and Instrumentation Program, which no longer exists. (Now Bioengineering has an entire institute, the National Institute of Biomedical Imaging and Bioengineering.) The mission of our group was to provide expertise in physics, engineering, and mathematics, and to collaborate with NIH’s biologists and medical doctors. I learned much during my stay at NIH about how physics is applied to biomedicine. It was the ideal preparation for working on a book like Intermediate Physics for Medicine and Biology.

Doing research at NIH was a joy and an honor, and I highly recommend it to any physicist (or physics student) interested in biomedical applications. Apply for an internship today.

Isaac Asimov

I, Robot, by Isaac Asimov.

Isaac Asimov (1920–1992) was born 89 years ago today. He is best known as a science fiction writer, and is considered one of the “big three” of science fiction (along with Robert Heinlein and Arthur C. Clarke). He was also a great author of science popularizations, and wrote or edited over 500 books.

I started reading Asimov’s nonfiction when in high school, and it had a big influence on me. One of the main reasons I decided to study science in college was because of his books. I particularly enjoyed his collections of essays originally published in The Magazine of Fantasy and Science Fiction. Asimov’s writing covered all areas of science: biology, chemistry, physics, geology, astronomy, and medicine. My personal intellectual journey—from physics to biological physics to coauthor of the 4th edition of Intermediate Physics for Medicine and Biology—began with the scientific liberal education he provided. When I was young, my goal was to read every book Asimov had ever written. I read scores of them, but soon I realized that he was writing them faster than I could read them.

The Foundation Trilogy,
by Isaac Asimov.

Which of Asimov’s books do I recommend? Among his fiction, I suggest  I, Robot and the The Foundation Trilogy. Unfortunately, his science popularizations are a bit dated now, but you might still enjoy many of his books, including his three-volume Understanding Physics, The Genetic Code, The Wellsprings of Life, The Human Body, and The Human Brain. For those wanting an Asimov sampler, try Opus 100, Opus 200, or Opus 300. Asimov aficionados will enjoy his two-volume autobiography In Memory Yet Green and In Joy Still Felt. The Isaac Asimov Home Page has much information including a complete list of his books. One obsessive Asimov fan provides summaries and reviews of all his work.

Readers of Intermediate Physics for Medicine and Biology may sometimes wonder how they will ever obtain the prerequisite background in physics, chemistry, biology and medicine necessary for such an interdisciplinary field of study. My solution was to start by reading Isaac Asimov. I don’t know of any single author who could provide a better introduction to these topics.

Happy Birthday, Dr. Asimov. You left us too soon.

Asimov’s Autobiographies.

Part of my Asimov collection.

 Listen to an interview with Isaac Asimov.
https://www.youtube.com/embed/4gn3MyTE80A 

A Gift For the Readers of Intermediate Physics for Medicine and Biology

The holiday season is a time when we often exchange gifts. My gift to the readers of the 4th edition of Intermediate Physics for Medicine and Biology is a new homework problem. It belongs to the chapter on magnetic resonance imaging, and specifically to Section 18.12 (this section about functional MRI has no homework problems associated with it, so the new one fills the gap), but it also draws heavily on Section 8.1 about the magnetic force on a current, sometimes called the Lorentz force. The purpose of the problem is to determine if you can use MRI and the Lorentz force to detect nerve activation.

Section 18.12

Problem 37 1/2 Suppose your median nerve, having a radius of 2 mm, carries a current density of 10 Amps per square meter over a length of 10 millimeters. (Assume all the axons are simultaneously active, so the current density is uniformly distributed throughout the nerve).

a) You are having a magnetic resonance image taken, and the steady uniform magnetic field has a strength of 4 Tesla and is directed perpendicular to the nerve. Calculate the magnitude and direction of the magnetic force on the nerve.

b) Assume the nerve is held in position by an elastic force equal to the product of k and s, where k is the spring constant of 400 Newtons per meter and s is the distance the nerve is displaced from its equilibrium position. Calculate the displacement of the nerve experiencing the force found in part a.

c) Finally, assume that a magnetic field gradient of 36 milliTesla per meter is present, so that when the nerve moves the distance calculated in part b, it enters a region of different magnetic field strength. Calculate the change in magnetic field that the nerve experiences because of its motion. Calculate the change in resonance angular frequency (assuming you are imaging protons). If the gradient and current last for 15 milliseconds, what is the change in phase of the MRI signal?

Where did I come up with this problem? It is based on a paper that Peter Basser and I recently published, titled “Mechanical Model of Neural Tissue Displacement During Lortenz Effect Imaging,” which appeared in the January 2009 issue of the journal Magnetic Resonance in Medicine (Volume 61, Pages 59–64). The mechanical problem is somewhat more complicated than described in part b of the above problem, but the calculated displacement is similar to what Basser and I find for the more accurate calculation. If you solve the new homework problem correctly, you should obtain a very small displacement, implying a phase shift too small to measure with current technology. The conclusion is that nerve action currents are unlikely to be measurable using this method.

Do you want the solution to the problem? Send me an email (roth@oakland.edu) and I will be happy to supply it.

Happy Holidays!

Benjamin Franklin, Biological Physicist

The First American:
The Life and Times of
Benjamin Franklin,
by Henry Brands.

I recently finished reading H. W. Brands’ biography The First American: The Life and Times of Benjamin Franklin. (Actually, I listened to the book on tape while walking my dog Suki each evening.) I enjoy history and biography, but was not expecting to find any biological physics in the book.

Wrong. Late in Franklin’s life, during his years in France, he played a role in a bizarre episode related to biomagnetism. Brands writes

“Friedrich Anton Mesmer had studied medicine at Vienna during the period when Franklin’s electrical experiments were becoming known on the European continent. Like many of Franklin’s readers from the Poor Richard days, Mesmer believed in astrology; having learned from Franklin how lightning carried celestial energy to earth, he easily concluded that electricity provided an invisible but pervasive fluid that linked the stars to human lives. Unfortunately for both his scientific theory and his medical practice, electricity was unpleasant to patients, sometimes violently so. But Mesmer was resourceful, and substituting magnetism for electricity as the invisible transmitter, he developed a flourishing practice stroking patients with magnets. In time he dispensed with the magnets, replying simply on his own powers of persuasion to release the therapeutic effects of “animal magnetism”...

In March 1784 King Louis appointed a committee of the Paris faculty of medicine to investigate; the distinguished members included Joseph Ignace Guillotin, who would add a word to several languages by his advocacy of the use of a swift and thereby comparatively humane decapitation machine. The doctors decided they needed help from the Academy of Sciences, whereupon Louis added five members, including the great chemist Lavoisier—who would meet his end at the device endorsed by Dr. Guillotin—and the eminent American, Dr. Franklin...

Franklin and the commissioners filed their report [on Mesmer’s activities], with his name heading the list of signatures. A public version was hurried into print, and twenty thousand copies were snatched up. The report declared the claims of animal magnetism unproven; such mitigation of symptoms as appeared were due to the customary causes of self-delusion and ordinary remission.

Voodoo Science,
by Robert Park.

I am not too surprised that Mesmer was able to fool so many for so long in the 1700s, long before Faraday, Maxwell, and others provided a complete understanding of electricity and magnetism, and well before the importance of well controlled, double-blind medical studies was appreciated. What’s disturbing about this tale is that similar hoaxes go on today, at a time when we know so much more about bioelectricity and biomagnetism, and put much more effort into conducting careful clinical trials (for specific examples, see Bob Park’s book Voodoo Science). Such non-scientific activities have a striking similarity to Mesmer’s claims.

How do we combat such nonsense? Knowledge and education is the only way I know. Hopefully readers of the 4th edition of Intermediate Physics for Medicine and Biology will be in position to more effectively detect and expose non-scientific claims. Like Franklin, we must encourage educational and civic measures designed to separate exciting and important scientific developments from unfortunate and unsupportable scientific frauds.

The FDA Approves Transcranial Magnetic Stimulation for Treatment of Depression

In Chapter 8 of the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I describe transcranial magnetic stimulation. This technique is a classic example of how fundamental physics can be applied to solve a medical problem. A pulse of current is passed through a coil held near the head. The changing magnetic field produced by this current induces an electric field that excites neurons, thus allowing noninvasive, painless stimulation of the brain. Magnetic simulation was invented in the 1980s by Tony Barker and his colleagues in Great Britain. One of my projects when I worked at the National Institutes of Health in the late 1980s and early 1990s was to calculate the electric field induced in the head by different coil geometries. I had the pleasure of working with leading neurologists like Mark Hallett, Leo Cohen, and others in the intramural program of the National Institute of Neurological Disorders and Stroke, and with engineer Peter Basser (my May 30, 2008 entry to this blog tells the story of how Basser subsequently developed magnetic resonance diffusion tensor imaging).

For many years the main use of magnetic stimulation was as a diagnostic tool to assess diseases of the central nervous system, or as a research method to study how the brain changes over time. But another less well understood use of this technique is for therapy. Transcranial magnetic stimulation made news this fall when the Food and Drug Administration approved its use for treating depression (for more information about this decision, see the brain stimulant: stimulation blog or an article in IEEE Spectrum Online). Magnetic stimulation was first applied as a psychiatric treatment with the goal of improving on or replacing electroconvulsive therapy. The gist of both methods is to stimulate neurons in the brain, and thereby affect brain function. One major difference between electroconvulsive therapy and transcranial magnetic stimulation is that magnetic stimulation does not require a siezure. Electroconvulsive therapy is performed under sedation because in that case the brain must undergo a siezure in order to benefit the patient. The method is effective, but has severe side effects. Magnetic stimulation, on the other hand, is safe but less effective.

On October 8 of this year Neuronetics, a medical device company in Malvern, Pennsylvania, obtained FDA clearance for its Neurostar TMS Therapy for the Treatment of Depression. A recent double blind multisite study, whose results were published in the journal Biological Psychiatry (Volume 62, Pages 1208–1216, 2007), showed a statistically significant improvement in symptoms in patients treated with transcranial magnetic stimulation who had not responded to more traditional treatments for depression, compared to a control group. Despite these promising results, I think the effectiveness of magnetic stimulation as a psychiatric therapy is still an open question. I hope it proves successful, because it would be gratifying to me personally to have worked on a technique that could benefit so many people, but I’ll need to see some confirmation of the initial success before I consider it as a proven treatment. Nevertheless, it certainly makes an interesting case study in the application of physics to medicine and biology.

Is Cell Phone Electromagnetic Radiation Dangerous?

Is electromagnetic radiation from cell phones dangerous? This point is debated in a point/counterpoint article in the December, 2008 issue of the journal Medical Physics. (See my January 11, 2008 entry to this blog for more about point/counterpoint articles). This readable, if somewhat testy, exchange between scientists highlights many of the crucial issues in this debate.

Arguing for the proposition that cell phones are dangerous is Dr. Vini Khurana, a neurosurgeon at the Canberra Hospital in Australia. Khurana appeared on Larry King Live (May 27, 2008) and claimed that cell phones could cause cancer. He writes that “there is a statistically significant elevated odds (about twofold) of developing a glioma or acoustic neuroma on the same side of the head preferred for cell phone use over a duration of exposure [greater than or equal to] 10 years.” He cites the BioInitiative Report: A Rationale for a Biologically-based Public Exposure Standard for Electromagnetic Fields to support his claim.

Arguing against the proposition is Dr. John Moulder of the Medical College of Wisconsin. Moulder, an expert on the biological effects of exposure to non-ionizing radiation, contends that “the current evidence for a causal association between cancer and exposure to radiofrequency (RF) energy is weak and unconvincing.” He cites a study published in the New England Journal of Medicine titled “Cellular-Telephone Use and Brain Tumors” (Volume 344, Pages 79–86, 2001) to support his claim.

Readers of the 4th edition of Intermediate Physics for Medicine and Biology will be familiar with this topic from Chapter 9, Section 10: Possible Effects of Weak External Electric and Magnetic Fields. Our discussion there was centered on the question of 60 Hz power line fields and health hazards, but these considerations also apply to cell phone frequencies.

Where do I stand on this issue? I am skeptical of these claims of cell-phone-induced brain cancer. The key point is that these fields are non-ionizing. Cell phones operate at a frequency of about 850 MHz. The energy of a photon of that frequency is 3.5 millionths of an electron volt (0.0000035 eV). Energies of an electron volt or more are needed to break most chemical bonds. X-ray photons, and even ultraviolet photons, have that much energy, but photons at cell phone frequencies do not have nearly enough energy to break bonds, and most cancers are caused by the breaking of bonds in a DNA molecule. Moreover, the thermal energy of particles at body temperature is about 0.03 electron volts, which is roughly ten thousand times more energy than an 850 MHz photon has. In other words, all the molecules in your body are bouncing around and colliding with your DNA molecules with energies vastly larger than the energy of a cell phone photon. Perhaps there are a whole lot of photons, what then? That is another way of saying that the electromagnetic radiation heats the tissue (like in a microwave oven). Strong electric fields in the MHz and GHz range can heat tissue, that is the main way they can interact with your body, but slight heating doesn’t cause cancer.

Physicist Bob Park, author of the weekly newsletter What’s New, makes a similar case against the danger of biological effects of nonionizing radiation in an editorial published by the Journal of the National Cancer Institute. Khurana’s response to these arguments is that “no known mechanism does not equate to no mechanism.” Perhaps. But without a plausible mechanism, one expects the epidemiological evidence to be compelling and unambiguous. I suggest you read the point/counterpoint article and cited references, and then decide for yourself. One point I am certain about: you need a good understanding of basic physics and its application to medicine and biology in order to sort out complex issues such as these. The 4th edition of Intermediate Physics for Medicine and Biology is one place to gain that knowledge.

Adrian Kantrowitz (1918-2008)

Last week heart surgeon and pacemaker pioneer Andrian Kantrowitz died in Ann Arbor, Michigan. Among his many roles, Kantrowitz was an Adjunct Professor in the Department of Physics here at Oakland University where I work. Soon after I arrived at OU in 1998, Emeritus Professor Norm Tepley and I visited Kantrowitz’s company L.VAD Technology in Detroit, which makes a left ventricular assist device that helps the heart pump blood. In February 2005 I invited Kantrowitz to give our weekly physics colloquium. At the time his health was already fragile and he gave his lecture sitting down. But it was an excellent talk to one of the largest crowds we ever had at our colloquium series.

Machines in Our Hearts: The Cardiac Pacemaker,
the Implantable Defibrillator, and American Health Care,
by Kirk Jeffrey.

Kantrowitz had an inspirational life story. As a young man, he served as a battalion surgeon in World War Two. He later performed the first heart transplant in the United States. He also played a role in the early development of the pacemaker, a topic discussed in Chapter 7 of the 4th edition of Intermediate Physics for Medicine and Biology. Kirk Jeffrey, in his book  Machines in Our Hearts: The Cardiac Pacemaker, the Implantable Defibrillator, and American Health Care, wrote

GE [General Electric] had developed an implantable pacemaker in its electronics laboratory in cooperation with heart surgeon Adrian Kantrowitz of Maimonides Hospital in Brooklyn. This project began in 1960, apparently in response to the announcement of the Chardack-Greatbatch pacemaker. The initial model was implanted in May 1961 and, as was common with these early devices, the designers made improvements based on the experience of the early patients.

The GE pacemakers had one remarkable technological feature—an external control unit that communicated with the implanted generator by magnetic induction. When taped to the skin on the patient's abdomen, the controller enabled the physician to set the pacing rate anywhere between 64 and 120 beats per minute. Kantrowitz viewed rate control as a means to safeguard the elderly patient.

You can learn more about Adrian Kantrowitz from obituaries in the New York Times, the Washington Post and the Los Angeles Times.

Howard Hughes Medical Institute Holiday Lectures on Science

Each year in early December the Howard Hughes Medical Institute presents their Holiday Lectures on Science. Not sure you can make it to Chevy Chase, Maryland for this year’s lectures? Don’t worry, all the lectures are webcast live, and then are available as on-demand webcasts and on DVD.

This year the live webcast is December 4 and 5, starting at 10:00 A.M. each day. The topic is “Making Your Mind: Molecules, Motion, and Memory,” presented by Eric Kandel and Thomas Jessell.

Eric R. Kandel, M.D. and Thomas M. Jessell, Ph.D. of Columbia University will help us understand how the nervous system turns an idea into action—from the complex processing that takes place in the brain to the direct marching orders the spinal cord gives to the muscles. Modern neuroscience equates mind with the organ we call the brain, an astounding network more than 100 billion neurons connected in a vast complicated web. The presenters will help us puzzle out how the brain is organized and identify the seat of human memory. The question of understanding how the brain functions is rivaled by the question of how such a complex network of cells develops in the first place.

I have watched these Holiday Lectures the last couple years, and they are extremely well done. They are aimed at high school students interested in careers in science or medicine. I think that readers of the 4th edition of Intermediate Physics for Medicine and Biology will find them very informative and inspirational.

Topics from previous years (all available as free on-demand webcasts) are

• 2007 AIDS: Evolution of an Epidemic
• 2006 Potent Biology: Stem Cells, Cloning, and Regeneration
• 2005 Evolution: Constant Change and Common Threads

plus many others. Also at the HHMI website are other lectures, animations, videos, virtual labs, and a virtual museum. It is all cool science. The website is ideal for someone trying to get up-to-date on hot topics in medicine and biology. Enjoy.