Perspectives on Working at the Physics-Biology Interface

Physical Biology.

A few weeks ago, I wrote that “I’ve always been fascinated by physicists who move into biology, and I collect stories about scientists who have made this transition successfully.” Imagine my delight when I discovered a special issue of the journal Physical Biology about “Perspectives on Working at the Physics-Biology Interface.” Howard Berg and Krastan Blagoev collected many stories about physicists working in biology. In their introductory editorial, they write

Physics is analytical, heavily dependent on mathematical equations; biology is more descriptive, heavily dependent on historical facts. There is a cultural gap. In physics, a theorist who can interpret others' experimental results is revered. In biology, such a person is suspect: ideas are thought cheap, facts dear.

But cultures can change. As problems in physics have become more difficult and more expensive to solve, or have been solved and thus are less interesting, physicists have begun to explore more complex areas of endeavor, including biology. Biologists, on the other hand, have begun to appreciate the benefits of thinking more quantitatively about their data. We thought it would be of interest to hear from physicists who have negotiated this cultural gap. What did they find challenging about biology, and how did they manage to begin work in such a different field? What advice might they have for younger practitioners of the art? One of us (HCB) moved long ago from work on hydrogen masers to studies of the motile behavior of bacteria. His trajectory is given in an interview published in Current Biology [1].

Some of our contributors have been involved with biophysics since their PhD, several were trained in condensed-matter theory, and others in nuclear or high-energy particle physics. Their interests range from the structure of proteins, RNA, or natural products, to cognitive or social abilities of bacteria, to emergent properties of complex or active media, or to the behavior of immune systems or neural networks. They all have interesting points of view, some subdued, others outspoken. We hope you enjoy the mix. Our hope is that with this issue we are able to capture the situation at the beginning of the 21st Century and to follow with another issue of this kind in ten years time.

Below I list all the papers in this special issue, along with their abstracts. I hope readers of Intermediate Physics for Medicine and Biology will find them as inspiring as I did.

The emergence of a new kind of biology by Harold J Morowitz

“It is happily no longer axiomatic that a biophysicist is a physiologist who can fix his own amplifier. Fortunately, physicists are still drifting into biology and bringing new ideas. Please dear colleagues, do take the time to learn biochemistry.” Harold Morowitz provides a personal perspective on working at the interface between the physical and biological sciences.

Two cultures? Experiences at the physics-biology interface by John J Hopfield

“I didn’t really think of this as moving into biology, but rather as exploring another venue in which to do physics.” John Hopfield provides a personal perspective on working on the border between physical and biological sciences.

A Perspective: Robert B Laughlin by Robert B Laughlin

Despite their cultural differences, physics and biology are destined to interact with each other more in the future. The reason is that modern physics is fundamentally about codification of emergent law, and life is the greatest of all emergent phenomena.

Ask not what physics can do for biology—ask what biology can do for physics by Hans Frauenfelder

Stan Ulam, the famous mathematician, said once to Hans Frauenfelder: “Ask not what Physics can do for biology, ask what biology can do for physics.” The interaction between biologists and physicists is a two-way street. Biology reveals the secrets of complex systems, physics provides the physical tools and the theoretical concepts to understand the complexity. The perspective gives a personal view of the path to some of the physical concepts that are relevant for biology and physics (Frauenfelder et al 1999 Rev. Mod. Phys. 71 S419–S442). Schrödinger's book (Schrödinger 1944 What is Life? (Cambridge: Cambridge University Press)), loved by physicists and hated by eminent biologists (Dronamraju 1999 Genetics 153 1071–6), still shows how a great physicist looked at biology well before the first protein structure was known.

Universal relations in the self-assembly of proteins and RNA by D Thirumalai

Concepts rooted in physics are becoming increasingly important in biology as we transition to an era in which quantitative descriptions of all processes from molecular to cellular level are needed. In this perspective I discuss two unexpected findings of universal behavior, uncommon in biology, in the self-assembly of proteins and RNA. These findings, which are surprising, reveal that physics ideas applied to biological problems, ranging from folding to gene expression to cellular movement and communication between cells, might lead to discovery of universal principles operating in adoptable living systems.

Physics transforming the life sciences by José N Onuchic

Biological physics is clearly becoming one of the leading sciences of the 21st century. This field involves the cross-fertilization of ideas and methods from biology and biochemistry on the one hand and the physics of complex and far from equilibrium systems on the other. Here I want to discuss how biological physics is a new area of physics and not simply applications of known physics to biological problems. I will focus in particular on the new advances in theoretical physics that are already flourishing today. They will become central pieces in the creation of this new frontier of science.

Research at the interface of physics and biology: bridging the two fields by Kamal Shukla

I firmly believe that interaction between physics and biology is not only natural, but inevitable. Kamal Shukla provides a personal perspective on working at the interface between the physical and biological sciences.

Let’s not forget plants by Athene Donald

“Many physicists see the interface with biology as an exciting place to be.” Athene Donald provides a personal perspective on working at the interface between the physical and biological sciences.

My encounters with bacteria—learning about communication, cooperation and choice by Eshel Ben-Jacob

My journey into the physics of living systems began with the most fundamental organisms on Earth, bacteria, that three decades ago were perceived as solitary, primitive creatures of limited capabilities. A decade later this notion had faded away and bacteria came to be recognized as the smart beasts they are, engaging in intricate social life through a sophisticated chemical language. Acting jointly, these tiny organisms can sense the environment, process information, solve problems and make decisions so as to thrive in harsh environments. The bacterial power of cooperation manifests in their ability to develop large colonies of astonishing complexity. The number of bacteria in a colony can amount to many billions, yet they exchange 'chemical tweets' that reach each and every one of them so they all know what they're all doing, each cell being both actor and spectator in the bacterial Game of Life. I share my encounters with bacteria, what I learned about the secrets of their social life and wisdom of the crowd, and why and how, starting as a theoretical physicist, I found myself studying social intelligence of bacteria. The story ends with a bacteria guide to cyber-war on cancer.

Working together at the interface of physics and biology by Bonnie L Bassler and Ned S Wingreen

Good communication, whether it is between quorum-sensing bacteria or the different scientists studying those critters, is the key to a successful interdisciplinary collaboration, Bonnie Bassler and Ned Wingreen provide a personal perspective on working at the interface between the physical and biological sciences.

Learning physics of living systems from Dictyostelium by Herbert Levine

Unlike a new generation of scientists that are being trained directly to work on the physics of living systems, most of us more senior members of the community had to find our way from other research areas. We all have our own stories as to how we made this transition. Here, I describe how a chance encounter with the eukaryotic microorganism Dictyostelium discoideum led to a decades-long research project and taught me valuable lessons about how physics and biology can be mutually supportive disciplines.

Letting the cat out of the bag: a personal journey in Biophysics by Carlos J Bustamante

When the author arrived in Berkeley, in the mid 1970s, to study Biophysics he soon felt as if he was engaging himself in a somewhat marginal activity. Biology was then entering another of its cyclical periods of annotation that was to culminate with the human genome project. Two decades later, however, at the end of this process, it had become clear that two main tasks were acquiring a central importance in biological research: a renewed push for a quantitative, precise description of biological systems at the molecular level, and efforts towards an integrated understanding of the operation, control, and coordination of cellular processes. Today, these have become two of the most fertile research areas in Biophysics.

A theoretical physicist’s journey into biology: from quarks and strings to cells and whales by Geoffrey B West

Biology will almost certainly be the predominant science of the twenty-first century but, for it to become successfully so, it will need to embrace some of the quantitative, analytic, predictive culture that has made physics so successful. This includes the search for underlying principles, systemic thinking at all scales, the development of coarse-grained models, and closer ongoing collaboration between theorists and experimentalists. This article presents a personal, slightly provocative, perspective of a theoretical physicist working in close collaboration with biologists at the interface between the physical and biological sciences.

Understanding immunology: fun at an intersection of the physical, life, and clinical sciences by Arup K Chakraborty

Understanding how the immune system works is a grand challenge in science with myriad direct implications for improving human health. The immune system protects us from infectious pathogens and cancer, and maintains a harmonious steady state with essential microbiota in our gut. Vaccination, the medical procedure that has saved more lives than any other, involves manipulating the immune system. Unfortunately, the immune system can also go awry to cause autoimmune diseases. Immune responses are the product of stochastic collective dynamic processes involving many interacting components. These processes span multiple scales of length and time. Thus, statistical mechanics has much to contribute to immunology, and the oeuvre of biological physics will be further enriched if the number of physical scientists interested in immunology continues to increase. I describe how I got interested in immunology and provide a glimpse of my experiences working on immunology using approaches from statistical mechanics and collaborating closely with immunologists.

Rejoice in the hubris: useful things biologists could do for physicists by Robert H Austin

Political correctness urges us to state how wonderful it is to work with biologists and how, just as the lion will someday lie down with the lamb, so will interdisciplinary work, where biologists and physicists are mixed together in light, airy buildings designed to force socialization, give rise to wonderful new science. But it has been said that the only drive in human nature stronger than the sex drive is the drive to censor and suppress, and so I claim that it is OK for physicists and biologists to maintain a wary distance from each other, so that neither one censors or suppresses the wild ideas of the other.

One of my favorite quotes is from Morowitz’s paper: “Like many physicists, Gamov was impatient with biochemical nomenclature and for adenine, thymine, guanine, and cytosine he substituted hearts, spades, clubs, and diamonds.” Many of the papers reinforce the need for tight collaborations with biologists, and the need to learn some biology. I agree with that view, but it was nevertheless a guilty delight to read Robert Austin’s article, in which the old physics hubris takes center stage. Read it, but don’t tell anyone that you did.

The Rest of the Story

Alan was born 102 years ago today in Banbury, England. He was descended from a long line of Quakers. Quakers are often pacifists, so Alan’s dad George didn’t fight in World War I. Instead, he took part in a relief effort in the Middle East. But war is dangerous even if you are not in the line of fire, and George died of dysentery in Baghdad when Alan was only four.

Alan’s mom was left to raise him and his two brothers alone. She encouraged Alan’s interest in science, and so did his eccentric Aunt Katie who took him bird watching. When he was 15, Alan was hired by a ornithologist to survey rookeries and heronries. He spent hours searching for rare birds in salt marshes. All this kindled his passion for learning.

Based on his strong academic record, Alan won a scholarship to study botony, zoology, and chemistry at Trinity College, part of the University of Cambridge. One of Cambridge’s distinguished zoologists gave Alan some good advice: study as much physics and mathematics as you can! So he did. He also did what all undergraduates should do: research. He was good at it; so good that he was awarded a Rockefeller Fellowship to go to New York for a year. He kept at his research, and traveled around to other parts of the United States, such as Massachusetts and Saint Louis, to learn more.

When he got back to Cambridge, Alan’s knowledge of physics allowed him to build his own equipment, enabling him to move his research in exciting directions. He and his collaborators began to get dramatic results. Just when he was on the verge of making decisive discoveries, Hitler marched into Poland and the world was at war again.

Page 2

Alan suspended his own research and dedicated his talents to defeating the Germans. The Battle of Britain was won, in part, by the development of radar. Alan worked on a special type of radar that was installed in airplanes and used by RAF fighter pilots to locate and intercept Luftwaffe bombers. Alan and a small group of scientists toiled frantically, working seven days a week. They risked their lives on test flights in planes fitted with the new radar. For six years, during what should have been a young scientist’s most productive period, Alan set aside his own interests to help the Allies win the war.

Once World War II ended, Alan returned to Cambridge. After all this time, had science passed him by? No! He took up his research where he had left off, and started making groundbreaking discoveries in electrophysiology. With his coworkers, Alan figured out how nerves send signals down their axons, first passing sodium ions through the cell membrane and then passing potassium ions.

In 1963, Alan Hodgkin received the 1963 Noble Prize for Physiology or Medicine for discovering the ionic mechanism of nerve excitation.

And now you know THE REST OF THE STORY. Good day!

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This blog post was written in the style of Paul Harvey’s wonderful “The Rest of the Story” radio program. The content is based on Hodgkin’s autobiography Chance and Design: Reminiscences of Science in Peace and War. You can read about Hodgkin's work on electrophysiology—including Hodgkin and Huxley’s famous mathematical model of the nerve action potential—in Chapter 6 of Intermediate Physics for Medicine and Biology.

Happy birthday, Alan Hodgkin!

The Number and Distribution of Capillaries in Muscles with Calculations of the Oxygen Pressure Head Necessary for Supplying the Tissue

Oxygen diffuses from capillaries into tissue where it is used for metabolism. Russ Hobbie and I discuss diffusion in Chapter 4 of Intermediate Physics for Medicine and Biology. Below is a new homework problem on this topic.

Section 4.11

Problem 37 ½. Consider a cylindrical capillary of radius a, containing blood having an oxygen concentration C_o (molecules/m³). The capillary is surrounded by a cylinder of tissue of radius b that has an oxygen concentration C(r), consumes oxygen at a rate per unit volume Q (molecules/m³s), and has a diffusion constant D (m²/s). At r = a, C = C_o and at r = b, dC/dr = 0. Within the tissue, C(r) obeys the steady-state diffusion equation

(a) Calculate C(r). Hint: guess a solution of the form C(r) = A + B r² + E ln(r), and determine values for the constants A, B, and E.

(b) Plot C(r) versus r assuming b = 10a and Qb²/(C_oD) = 1

(c) Determine the minimum value of C_o as a function of a, b, D, and Q, assuming the oxygen concentration is nowhere negative.

(d) Describe what assumptions underlie this model.

This problem plays an important role in the history of physiology. August Krogh used the model to infer that when Q increased during exercise, b must decrease (by additional vessels opening that were closed when the muscle was at rest) in order to supply the tissue with sufficient oxygen. For “his discovery of the capillary motor regulating mechanism,” he was awarded the Nobel Prize. Krogh’s model also represents an early contribution of mathematical modeling to medicine and biology. He presented his model in the paper:

Krogh, A. (1919) The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J. Physiol., 52: 409–415.

He acknowledges mathematician K. Erlang for deriving the mathematical formula for C(r).

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

Isaac Asimov includes an entry for Krogh in Asimov’s Biographical Encyclopedia of Science and Technology (Second Revised Edition).

KROGH, Schack August Steenberg (krawg)

Danish physiologist

Born: Grena, Jutland, November 15, 1874

Died: Copenhagen, September 13, 1949

Krogh, the son of a brewer, was educated at the University of Copenhagen, where he intended to study medicine but shifted his interest to physiology. He obtained his master’s degree in 1899.

He was particularly involved in respiration, following the path of oxygen, nitrogen, and carbon dioxide in and out of the body. In 1908 he gained a professorial position at the University of Copenhagen and there his studies of respiration led him to suggest that the capillaries (the tiniest blood vessels) of the muscles were open during muscular work and partially closed during rest. He went on to demonstrate this and to show the importance of such capillary control to the economy of the body.

For this work, he was awarded the Nobel Prize in Physiology and Medicine in 1920. He went on thereafter to show that this capillary control was brought about by the action of both muscles and hormones.

After Denmark was occupied by Nazi Germany in 1940, Krogh was forced to go underground and then to escape to Sweden. He remained there till the end of the war, then returned to liberated Denmark.

A Brief History of Human Functional Brain Mapping

In Chapter 18 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I describe functional magnetic resonance imaging.

The term functional magnetic resonance imaging (fMRI) usually refers to a technique developed in the 1990s that allows one to study structure and function simultaneously. The basis for fMRI is inhomogeneities in the magnetic field caused by the differences in the magnetic properties of oxygenated and deoxygenated hemoglobin. No external contrast agent is required. Oxygenated hemoglobin is less paramagnetic than deoxyhemoglobin. If we make images before and after a change in the blood flow to a small region of tissue (perhaps caused by a change in its metabolic activity), the difference between the two images is due mainly to changes in the blood oxygenation. One usually sees an increase in blood flow to a region of the brain when that region is active. This BOLD contrast in the two images provides information about the metabolic state of the tissue, and therefore about the tissue function.

Brain Mapping: The Systems.

The amazing story of how, 25 years ago, two competing teams developed fMRI simultaneously is told by Marcus Raichle in his chapter “A Brief History of Human Functional Brain Mapping,” published in the book Brain Mapping: The Systems. Below I provide excerpts.

A race was on to produce the first human functional images with MRI even though the participants were unaware of the activities of each other! Who were the participants? [Seiji] Ogawa and his colleagues working with Kamil Ugurbil and friends at the University of Minnesota and a group at the Massachusetts General Hospital led by Ken Kwong...

Ugurbil turned to a new postdoctoral fellow in the laboratory, Ravi Menon, to help in the effort to obtain the first functional MRI BOLD images in humans...He was joined by Ogawa and [David] Tank from Bell Labs along with members of the Ugurbil lab and a pair of Grass Goggles for visual stimulation!….It was early summer of 1991 that believable results were finally obtained. This was obviously too late to submit an abstract to the upcoming Society of Magnetic Resonance Conference to be held in San Francisco in August. Members of the laboratory, nevertheless, left for the meeting with slides in their pockets hopeful that they would have a chance to show some of their new results.

Meanwhile, a very parallel but completely independent set of events was unfolding in Boston. Ken Kwong, a member of the group at the Massachusetts General Hospital, was anxious to develop a method for measuring blood flow with MRI….Kwong saw a poster by Bob Turner, another MR physicist working at the NIH, which was of related interest. Turner had been studying hypoxia/ischemia in cats produced by brief periods of ventilatory arrest….They choose a visual activation paradigm. A pair of well-known Grass Goggles resided in the lab to support the function activation work using contrast agents….

Buoyed by the results obtained with the goggles and BOLD imaging, the MGH group rushed to submit a “Works in Progress” abstract to the Society of Magnetic Resonance Conference… Much to the MGH group’s dismay and to this day unexplained, this particular abstract failed to reach those putting the program together…. Recognizing by this time the significance of their results, they persuaded Tom Brady to include their results in his plenary lecture. The group from Minneapolis had no such opportunity! Not only did the scientific world get its first glimpse of fMRI, but the two groups working on the concept also realized for the first time who the competition was!

By the early fall of 1991 both the Minneapolis and the Boston groups had publishable results. With great anticipation, papers were submitted to Nature (Minneapolis) and Science (Boston) and summarily rejected. The basic judgment of both journals was that they contained nothing new! It is fitting that the work of the two groups appeared together in the Proceedings of the National Academy of Science (Kwong et al., 1992; Ogawa et al., 1992). A new and very important chapter on functional brain imaging had begun.

Functional MRI has since been used for many studies of how the brain works. I consider it one of the best examples of physics applied to medicine in the last 25 years. Raichle not only tells the story of fMRI’s development well (but perhaps with too many exclamation points for my taste), but also reviews the long history of mapping brain function, dating back into the 19th century. The chapter is well worth a read. Enjoy!

You Can Hear About a Nickel’s Worth of Difference

In Chapter 13 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I describe a logarithmic scale for sound intensity: the decibel. In general, an increase in intensity is perceived as a greater loudness (although this relationship is surprisingly complex). Is there an analogous relationship between frequency and pitch? Yes! Loudness is determined using a logarithmic scale with a base of ten, whereas pitch is measured using a logarithmic scale of base two, because a doubling of the frequency corresponds to raising the pitch by one octave. Those familiar with music are accustomed to associating different pitches with different notes in a musical scale. Most instruments are tuned using the equal tempered scale, dividing an octave into twelve equal logarithmic steps. One step, called a semitone, corresponds to the difference in pitch between, say, F and F-sharp. The fractional change of one semitone is 2^1/12 = 1.0595, or an increase in frequency of roughly 6%. This frequency shift is so important that it is expressed by a special unit: one semitone is equal to 100 cents. The cent is to pitch as the decibel is to loudness. Doubling the intensity corresponds to an increase of 3 dB, whereas doubling the frequency corresponds to an increase of 1200 cents.

How finely can the human ear resolve pitch? In other words, if you play two pure tones one right after the other, by how much must their frequency differ for you to notice that they are indeed different? A typical listener can detect a change of about 5 cents, leading to the rule of thumb that you can hear about a nickel’s worth of difference. Try testing your own pitch perception online here. When I tried, I could always detect a difference of 50 cents (tones of 440 and 453 Hz, presented one after another; I assume this is a control used by the testing software, because the difference is obvious). I could never detect a difference of 4 or 6 cents (440 compared to 441 or 441.5 Hz). I had inconsistent results with 8 and 11 cents (440 compared to 442 or 443 Hz); sometimes I perceived slightly different tones, and sometimes I didn’t. Ten cents is a reasonable approximation to my just noticeable difference, which confirms what I have always suspected: I have poor but not pathological pitch perception. When playing the tuba in my high school band, the director often had us “tune up” relative to a standard note, typically played by the first clarinet. I always had trouble with this task; he had to tell me if I was sharp or flat. Poor pitch perception has its advantages: you don’t need to hire a piano tuner! Pity my poor wife—my only audience, other than my dog Suki—but my wrong notes are probably more bothersome than the out-of-tune piano, so spending for a piano tuner would not help.

Humans can hear pitches from roughly 20 to 20,000 Hz. Because 2¹⁰ is about 1000, humans can hear frequencies that range over roughly ten octaves, or 12,000 cents, and therefore you (but not I) can distinguish about 2400 different tones. A piano keyboard plays notes 28 to 4186 Hz, which is a little more than seven octaves, or roughly 8700 cents (87 semitones between the 88 keys). Sometimes changes in frequency are measured in millioctaves: 1 mO = 1.2 cents. Although the cent is not a metric unit, I still worry that the SI police, who insist that all things centi- are going out of fashion compared to all things milli-, will demand we start using the millioctave. I hope not.

If two tones are played at the same time, rather than one after another, you can perceive small differences in pitch using beats. Consider the triginometric identity

If frequencies A and B are similar, then their sum consists of a carrier frequency equal to the average of the two original frequencies modulated by the difference of the two frequencies. For instance, if you have a tone corresponding to concert A (440.00 Hz) and another tone out of tune with concert A by 3 cents (440.78 Hz), when played together the sound consists of a tone having frequency 440.39 Hz modulated by a sinusoid that gets louder and softer with a frequency of 0.78 Hz (or a period of 1.3 seconds). Your ear can’t tell that the pitch of the carrier tone is different from concert A, but it can detect the variation in loudness caused by the beats. You can hear beats generated online here.

If several tones have widely separated frequencies, your ear (or more properly, your brain) detects distinct notes played together; a chord. If two tones have nearly the same frequency (like in the example above), you hear a single tone with modulated amplitude; beats. For intermediate frequency differences (say, between a note an octave above concert A, 880 Hz, and a severely out-of-tune A at 897 Hz, a difference of 17 Hz or 33 cents) you hear neither a chord nor beats. Instead, your brain perceives dissonance. A London police whistle generates frequencies of 1904 and 2136 Hz, a difference of 232 Hz or more than 200 cents. It sounds annoying. Try it yourself.

The frequency ratio between a C and G (a perfect fifth) should be 3:2, which is 702 cents. However, in equal tempered tuning the shift between C and G is 700 cents. This difference of 2 cents is indistinguishable to all but the best ears. The major third is more of a problem. It should have a ratio of 5:4, or 386 cents. In the equal tempered scale, a third is 400 cents, off by 14 cents, which a good ear can hear. If all these tonal relations are different than what they would be in just intonation, then why do we use an equal tempered scale? It allows us to change keys without retuning the instrument. But we pay a price in that a major chord does not have precisely the desired 4:5:6 frequency ratio. Pythagoras must be turning over in his grave.

Both pitch perception and color vision arise from the physics of frequency detection. But the tones we hear and colors we see are determined by more than just physics. There is a lot of information processing by the brain, which leads to many fascinating and unexpected results including surprising pathologies. To completely appreciate how we perceive frequency, you also need to understand the brain.

Biomagnetism Therapy: Pseudoscientific Twaddle

Voodoo Science,
by Robert Park.

Ever since Robert Park—author of Voodoo Science and the weekly column What’s New—suffered a stroke in 2013, I have been searching for another debunker of pseudoscience. Finally, I’ve found her! Harriet Hall is a retired physician and former Air Force flight surgeon. Every week she battles nonsense in the blog sciencebasedmedicine.org. In her November 20 entry, she addressed “biomagnetic therapy.”

Biomagnetism Therapy: Pseudoscientific Twaddle

In a television interview, a practitioner of biomagnetic therapy claimed she had cured her own breast lump and the metastatic cancer of another person. I wonder how many viewers believed her. On the “official website” of biomagnetism therapy, http://biomagnetism.net/, they claim it is “the answer to ALL your health problems… an all-natural, non-invasive therapy proven to prevent, diagnose and treat countless diseases, chronic illnesses and degenerative health problems.”

Sound too good to be true? Of course it does! You are already skeptical. If you read further, you will become even more skeptical….”

She concludes

…It pains me to see misinformation such as this fed to gullible patients. Using biomagnetic therapy isn’t likely to harm patients physically, but it’s likely to harm their comprehension of science. It’s likely to waste their money, and it could delay getting treatments that do work. Perhaps the worst thing is that people who practice this therapy are deceiving themselves. They don’t understand science, and they mistake testimonials for evidence of efficacy. They don’t understand the need for controlled studies. They don’t understand placebo effects, suggestion, expectation, regression to the mean, the natural course of illness, and all the other things that can lead people to believe a bogus treatment works. It is particularly tragic that anyone trained as an MD could have such poor critical thinking skills and be misled by such egregious pseudoscience.

Russ Hobbie and I have an entire chapter about biomagnetism in Intermediate Physics for Medicine and Biology. We discuss the measurement of the very small magnetic fields produced by the brain (magnetoencephalography) and the use of rapidly changing magnetic fields to stimulate neurons (transcranial magnetic stimulation). We also devote a chapter to magnetic resonance imaging. These are important topics, but they often get mixed up with phony claims about “biomagnetic therapy.”

If you doubt this is a real problem, go to Google and search for “biomagnetism” (the title of Chapter 8 in IPMB). The first site you get starts “One of the most peculiar therapy systems that FAIM [Foundation for Alternative and Integrative Medicine] is investigating is one that uses ordinary magnets to heal. Although magnets have been used in therapies for a long time, this particular method uses pairs of magnets to neutralize disease-causing pathogens in the body...” The second site begins “Yes! It’s the answer to ALL your health problems…” The third describes “The Revolutionary Therapy based on the Biomagnetic Pairs discovered by Dr. Isaac Goiz Durán, MD in 1988...” The fourth is the “Official website for Biomagnetism classes in the USA with Dr. Isaac Goiz Durán...” Finally, the fifth site in the list is Wikipedia’s entry on biomagnetism (the measurement of weak magnetic fields produced by the body). The first four are twaddle; the fifth is reputable.

Women Aren’t Supposed to Fly,
by Harriet Hall.

If you want to learn more about Harriet Hall, read her autobiography Women Aren’t Supposed to Fly, in which she describes her experiences in medical school and the Air Force. From the Preface:

There’s an old curse “may you live in interesting times.” I lived in an era when society was starting to allow women to enter male-dominated fields, but didn’t yet entirely approve. Someone said, “Whatever women do they must do twice as well as men to be thought half as good. Luckily this is not difficult.” Actually, it was difficult. It was frequently frustrating, sometimes painful, often ridiculously funny, and always interesting. Come with me on a ramble through my education and career and let me tell you what it was like.

What Women Aren’t Supposed to Fly does not explain is how Hall ended up a lampooner of baloney and poppycock. She needs to write a second book, telling that story. I’m sure it would be equally fascinating and amusing.

I’d have preferred another physicist pick up Bob Park’s banner, but I’ll take what I can get. Harriet Hall, keep up the good work and let’s end this “biomagnetic therapy” rubbish.

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.

The Royal Institution's 2015 Christmas Lecutres: How to Survive in Space

Michael Faraday lecturing
at the Royal Institution.

190 years ago at the Royal Institution in London, Michael Faraday presented the first Christmas Lectures. These lectures about science have continued annually except during the worst years of World War II, and are now broadcast on television and online. Each year is a different topic, and this year the topic is How to Survive in Space.

In December 2015, Tim Peake will become the first Briton in space for more than 20 years and a new member of the European Astronaut Corps. As Tim adjusts to life on board the International Space Station (ISS), Kevin Fong’s CHRISTMAS LECTURES will take us on a journey from planet Earth into Low Earth Orbit and beyond. This is the story of human survival against all the odds; the story of how science, medicine and engineering come together to help answer our biggest questions about Life, the Earth, the Universe and our place in it.

From artificial gravity and greenhouses in space to plasma drives and zero-G surgical suits, the Lectures will reveal how what once was the stuff of science fiction is fast becoming today’s science fact.

Throughout the three-part series, Kevin will be accompanied by special guest appearances from ISS astronauts who will reveal what daily life is like 400 kilometres above the Earth, demonstrate the technology and techniques that help them stay safe and healthy, and explain the scientific experiments they are part of that are helping to stretch the limits of our understanding of human physiology and survival in a way that no experiment back on Earth could.

Intermediate Physics for Medicine and Biology does not address space medicine specifically, but many of the topics examined in these Christmas Lectures require a deep understanding of how physics and medicine interact. I plan to watch. The lectures will be first broadcast by the BBC on December 28, 29, and 30. I won’t be able to view them until they are posted afterward (hopefully, soon afterward) on the Ri Channel.

A Christmas Carol,
by Charles Dickens.

Because this year I’m posting on Christmas Day, I’ll conclude with a Christmas present—the final lines of my all-time favorite book (yes, even better that IPMB): A Christmas Carol, by Charles Dickens. I reread it every December.

Scrooge was better than his word. He did it all, and infinitely more; and to Tiny Tim, who did not die, he was a second father. He became as good a friend, as good a master, and as good a man, as the good old city knew, or any other good old city, town, or borough, in the good old world. Some people laughed to see the alteration in him, but he let them laugh, and little heeded them; for he was wise enough to know that nothing ever happened on this globe, for good, at which some people did not have their fill of laughter in the outset; and knowing that such as these would be blind anyway, he thought it quite as well that they should wrinkle up their eyes in grins, as have the malady in less attractive forms. His own heart laughed: and that was quite enough for him.

He had no further intercourse with Spirits, but lived upon the Total Abstinence Principle, ever afterwards; and it was always said of him, that he knew how to keep Christmas well, if any man alive possessed the knowledge. May that be truly said of us, and all of us! And so, as Tiny Tim observed, God bless Us, Every One!

Star Wars

With The Force Awakens opening in theaters, now is the perfect time to answer your questions about how Intermediate Physics for Medicine and Biology relates to Star Wars. (Warning: This post is spoiler laden for Episodes I - VI, but not for Episode VII which I haven’t seen yet.)

1. With so many light saber duels, why is there so little blood? Even blasters kill without gore or carnage. In Section 14.11 of IPMB, Russ Hobbie and I discuss tissue ablation. According to Wookieepedia, ablation cauterizes wounds, preventing bleeding. This is the same reason we use lasers in surgery.

 

2. Why do blaster shots not propagate at the speed of light? Chapter 14 of IPMB gives the speed of light as 3 × 10⁸ m/s. In Star Wars, shots travel not much faster than a hard-thrown fastball, maybe 100 m/s. Apparently this far-away galaxy has a large permeability of free space, μ_o. Next time you view these films, watch for exaggerated magnetic effects.

 3. How did Han Solo freeze so quickly (and reversibly!) in carbonite? The bioheat equation  developed in Chapter 14 of IPMB implies that heat diffuses into tissue, and over long distances diffusion is slow. My guess is that carbonite freezing makes use of the blood flow term in the bioheat equation, perhaps by rapidly injecting cold carbonite intravenously. However, I don’t see any IV tubes coming out of Han. Do you? Carbonite freezing has to be dangerous. But no matter; had Han died during freezing, Chewbacca would have saved Princess Leia.

4. How does Luke Skywalker’s artificial hand work? Chapter 7 of IPMB discusses electrical stimulation of nerves, which is crucial for developing neural prostheses. Luke had such a prosthesis after he lost his hand during his epic duel with Darth Vader (Luke’s FATHER!). Functional neural stimulation is becoming so sophisticated that artificial hands may arrive sooner than you think.

5. How does Darth Vader control his breathing? Chapter 10 in IPMB analyzes feedback loops, and our main example describes how we control the carbon dioxide in our blood by adjusting our ventilation rate. I wonder, does Vader’s mask break that feedback loop? Perhaps a carbon dioxide sensor in the mask adjusts the rate of his slow, heavy breathing. I suspect something is horribly wrong with his physiological control mechanism, because once the mask comes off Vader dies.

6. What determines the anatomy of all those alien life forms? In Chapter 2 of IPMB, Russ and I describe how size impacts the structure of animals: scaling. One famous result involves the strength of bones. Body mass scales as length cubed, but the strength of a bone scales as its radius squared, meaning that bones must get thicker relative to their length in larger animals. This is why Jabba the Hutt has no legs. Yoda lied when he said “size matters not.”

7. How did Luke avoid freezing to death on Hoth? When an animal dies, it loses heat according to Newton’s law of cooling (Chapter 3 in IPMB). After Han killed the tauntaun and shoved Luke into its belly, its temperature began to fall exponentially. Luke must have gotten really cold. What saved him was immersion into a bacta tank, which speeds rewarming by taking advantage of convection as well as conduction. I suspect bacta may also contain suspended stem cells, but who knows? Whatever the mechanism, Luke survived. During his recuperation is the most disturbing event in the entire Star Wars saga: the incestuous kiss. Ewwwwww!

8. What did leaders of the Rebel Alliance say when they realized that Vader knew about their plans to attack the Death Star? One way to measure radiation dose is to use thermoluminescent phosphors, which Russ and I describe in Chapter 16 of IPMB as a “dielectric material that has been doped with impurities or has missing atoms in the crystal lattice to form metastable energy levels or traps.” So, Admiral Ackbar must have just discovered the mechanism of thermoluminescence when he exclaimed “It’s a trap!” 

If you want answers to all of your Star Wars questions, keep a copy of Intermediate Physics for Medicine and Biology handy. Before watching the new film, find time for a Star Wars marathon (with episodes in machete order, thereby avoiding Jar Jar Binks). Finally, don’t miss my favorite version of the Star Wars theme song, performed in the video below by lounge singer Nick Winters. Now, off to the movies. And, May The Force Be With You.

The Art of Insight in Science and Engineering

The Art of Insight
in Science and Engineering,
by Sanjoy Mahajan.

I recently read The Art of Insight in Science and Engineering, by Sanjoy Mahajan (MIT Press, 2014). The Preface begins:

Science and engineering, our modern ways of understanding and altering the world, are said to be about accuracy and precision. Yet we best master the complexity of our world by cultivating insight rather than precision.

We need insight because our minds are but a small part of the world. An insight unifies fragments of knowledge into a compact picture that fits in our minds. But precision can overflow our mental registers, washing away the understanding brought by insight. This book shows you how to build insight and understanding first, so that you do not drown in complexity.

I think that Mahajan makes a good point. I’ve noticed that many of my students can use complicated algorithms to calculate numbers correctly, but often lack the ability to estimate a solution. This leads students to make mistakes in their homework that result in ridiculously wrong results. When this happens, I often print “THINK BEFORE YOU CALCULATE” in big red letters on their paper, and take off more than my normal number of points. On the other hand, when a homework question requires an intricate calculation that the student skips but instead writes down a reasonable estimate for the solution, I take off a few points but give them most of the credit because they actually thought about what they were doing.

Russ Hobbie and I stress estimation in the very first section of Intermediate Physics for Medicine and Biology: “One valuable skill in physics is the ability to make order of-magnitude estimates, meaning to calculate something approximately right.”. We provide several “back-of-the-envelope” homework problems in our book, such as “Estimate the number of hemoglobin molecules in a red blood cell,” “Estimate the size of a box containing one air molecule”, and “Estimate the density of water”. In fact, if you search through our book for the word “estimate” you will find many such questions. Students often object to these problems. When I explore why they are having difficulty, I find that many are reluctant to guess some number. For instance, a homework problem in Chapter 6 says “Suppose that an action potential in a 1-μm diameter unmyelinated fiber has a speed of 1.3 m s⁻¹. Estimate how long it takes a signal to propagate from the brain to a finger.” Some students grind to a halt because the length of the arm is not given (or they use 1 μm for the length, getting a ridiculous result). When I tell them that the word “estimate” means “make a reasonable guess,” they’re not any happier; they think that guessing the length of the arm is cheating. But I’m just asking them to estimate the time to send a signal from the brain to the hand, and then THINK about the result. That’s why the last sentence in the problem says “Speculate on the significance of these results for playing the piano.”

In The Art of Insight, Mahajan also talks about units. In homework assignments, I often ask my students to algebraically solve for some expression; for example a relationship involving a distance x, time t, and speed v. A student will sometimes hand in a result like “v + x t”. Yikes! The units don’t work! (I use a lot of exclamation points when grading assignments.) I am stingy with partial credit when the derived equation is dimensionally incorrect, not because I want to punish a minor error, but because the student didn’t take the time to look at their equation and ask “do the units make sense?”

Another skill Mahajan stresses is proportional reasoning. Russ and I emphasize this in Chapter 2, when we discuss scaling. For instance, here is a question from an exam I gave earlier this semester in my Biological Physics class:

Assume the specific metabolic rate R* scales with mass M as R* = C M^−1/4 , where C is a constant. If an 81 kg person has a specific metabolic rate of 1.5 W/kg, what is the specific metabolic rate of a 1 kg guinea pig?

Some students get stuck because I didn’t give them a value for C. The point is, R* times M^1/4 is a constant, so R*_person M_person^1/4 = R*_{guinea pig} M_{guinea pig}^1/4. You don’t need C. (You don't even need your calculator if you recall that 81 = 3⁴.)

Mahajan talks about examining “easy cases,” which is similar to our emphasis on taking limits of equations. Consider the analysis of Eq. 2.25 in IPMB: dy/dt = a – by. The solution (Eq. 2.26) is y = a/b (1 – e^−bt). When I derive this equation in class, I always stop and ask the students what is the limit when t goes to inifinity? The answer is clearly y = (a/b), which they usually get right. Then I ask what is the limit when t goes to zero? This case requires more thought. A student will often say “zero,” but then I respond “yes, but HOW does it go to zero?” Using the Taylor series e^x = 1 + x gives a limit of y = at. This skill is even more important for more complicated expressions. For instance, Section 4.12 in IPMB compares drift and diffusion. Equation 4.63 gives the concentration of a material that drifts with fluid speed v and diffuses with diffusion constant D through a tube of length x₁. The student gains much insight by taking the limits when x₁v/D is much greater than one and much less than one. If the student doesn’t take these limits, then this example is just a mathematical exercise that provides no insight.

Finally, Mahajan discusses briefly the value of log-log plots when analyzing scaling laws. This is a topic Russ and I emphasize in Chapter 2 of IPMB. It’s amazing how much information you can get from a log-log plot. One little fact I never realized until I read Mahajan’s book is that the geometric mean, √ab, of two numbers a and b is just the half-way point between the two numbers on a logarithmic scale.

A Mind for Numbers,
by Barb Oakley.

I had a chance to offer my views on insight and learning when my Oakland University colleague and friend Barb Oakley published her book A Mind for Numbers: How to Excel at Math and Science (Even if You Flunked Algebra). Barb asked several people, including me, for short “sidebars” to include in her book. Here is mine:

Insights on Learning from Physics Professor Brad Roth, A Fellow of the American Physical Society and Co-Author of Intermediate Physics for Medicine and Biology

One thing I stress in my classes is to think before you calculate. I really hate the ‘plug and chug’ approach that many students use. Also, I find myself constantly reminding students that equations are NOT merely expressions you plug numbers into to get other numbers. Equations tell a story about how the physical world works. For me, the key to understanding an equation in physics is to see the underlying story. A qualitative understanding of an equation is more important than getting quantitatively correct numbers out of it.

Here are a few more tips:

1. Often, it takes way less time to check your work than to solve a problem. It is a pity to spend twenty minutes solving a problem and then get it wrong because you did not spend two minutes checking it.

2. Units of measurement are your friend. If the units don’t match on each side of an equation, your equation is not correct. You can’t add something with units of seconds to something with units of meters. It’s like adding apples and rocks—nothing edible comes of it. You can look back at your work, and if you find the place where the units stop matching, you probably will find your mistake. I have been asked to review research papers that are submitted to professional journals that contain similar errors.

3. You need to think about what the equations means, so that your math result and your intuition match. If they don’t match, then you have either a mistake in your math or a mistake in your intuition. Either way, you win by figuring out why the two don’t match.

4. (Somewhat more advanced) For a complicated expression, take limiting cases where one variable or another goes to zero or infinity, and see if that helps you understand what the equation is saying.

Books like The Art of Insight and A Mind for Numbers reinforce fundamental yet critical skills. I hope IPMB reinforces these skills too.