Friday, November 30, 2018

Venkataranan Ramakrishna, Biological Physicist

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

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

Choosing Basic Science

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

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

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

Transition to Biology

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

In my second year [at UCSD], I settled down to do research in Mauricio Montal's lab. Mauricio had developed an ingenious method of incorporating conducting channels into lipid bilayers formed by bringing together two defined monolayers, and was thus doing single molecule biophysics at a time when nobody called it that. Around this time, however, I read an article in Scientific American by Don Engelman and Peter Moore about their ribosome work, and became interested in it. It also struck me that there was no longer any reason to continue on to obtain a second Ph.D. because I felt I had acquired the background I needed. I therefore wrote to Don Engelman, one of the two people from Yale who had responded to me earlier. Don was interested in membrane proteins, a subject I was already working on in Mauricio's lab. Don wrote back and said that he and Peter had a position open on their ribosome project, and I could always work on membrane-related projects once I got there. Peter arranged to meet me in San Diego in early 1978 and offered me a postdoctoral position soon afterwards. Thus began my lifelong interest in ribosomes….
In the APS News article, Ramakrishnan said something that could be the motto for IPMB.
Physics is a great training for every science because it teaches you quantitative and mathematical thinking, and that way of approaching problems is becoming increasingly important in every field, including biology.
Want to learn more? Ramakrishna has a new book out: Gene Machine: The Race to Dicipher the Secrets of the Ribosome. It's on my list of books to read. Below are a couple videos in which you can hear from Ramakrishna himself. Enjoy!

Friday, November 23, 2018

Write Mind

Write Mind, by Eric Maisel
Write Mind, by Eric Maisel.
Every Saturday morning my wife and I visit the Rochester Hills Public Library. I like to browse the stacks, and sometimes I find a gem. Recently, I checked out Write Mind: 299 Things Writers Should Never Say to Themselves (and What They Should Say Instead) by Eric Maisel.

Write Mind contains some cognitive therapy jargon that I don’t care for, but its second sentence quotes Epictetus so it can’t be all bad. Seriously, at its core this delightful book is about attitude. Not all problems can be solved by a positive attitude but some can, whether you are an aspiring writer or a struggling physics student.

Write Mind is aimed at writers. Two hundred and ninety nine times it first states an incorrect, negative attitude (WRONG MIND) and then a better, positive attitude (RIGHT MIND).

To help students of Intermediate Physics for Medicine and Biology I have paraphrased Write Mind, providing 29 pairs of statements about physics applied to medicine and biology. Forgive me if sometimes they are corny; I hope you find them useful.


WRONG MIND: Mathematics and medicine are so different; I can’t learn both so I’ll settle for one or the other.

RIGHT MIND: I can master both mathematics and medicine.


WRONG MIND: Physiology requires so much memorization! I will give up and stick to physics.

RIGHT MIND: I can learn both physics and physiology.


WRONG MIND: I hate toy models because they oversimplify biology.

RIGHT MIND: I will gain insight from a toy model, and then analyze its strengths and weaknesses.


WRONG MIND: I have difficulty understanding what some homework problems are asking; I skip those.

RIGHT MIND: Research problems are often ill-defined. I will try my best to understand the question and then answer it.


WRONG MIND: Robert Plonsey, Art Winfree, and John Wikswo have contributed so much; I can never accomplish that much in my career.

RIGHT MIND: I intend to work hard, and take Plonsey, Winfree, and Wikswo as role models.


WRONG MIND: I’m good at math and I love medicine, but I have trouble connecting the two.

RIGHT MIND: Homework problems let me practice connecting math to medicine. Many students struggle with this difficulty. I am not alone.


WRONG MIND: IPMB and its blog recommend so many books; I don’t have time to read them all, so I won’t read any.

RIGHT MIND: I will find time to read one of the books recommended in IPMB or its blog. Once I have finished it, I will try to find time for another.


WRONG MIND: I like IPMB but I don’t have time to do the homework problems.

RIGHT MIND: Today I’ll make time to solve four homework problems. Tomorrow, four more.


WRONG MIND: You have to be a genius to apply physics and mathematics to biology and medicine; I have no chance.

RIGHT MIND: I can learn to apply physics and math to biology and medicine.


WRONG MIND: I am a biologist, and biologists can’t do math.

RIGHT MIND: I intend to learn math.


WRONG MIND: I love math, but my premed advisor says I don’t need math to become a medical doctor.

RIGHT MIND: I choose to learn math and to become a medical doctor.


WRONG MIND: Some students learn the topics in IPMB easily, but for me they are difficult. I am not meant to understand this subject.

RIGHT MIND: I can understand the topics in IPMB if I work hard.


WRONG MIND: Applying physics and mathematics to medicine and biology is difficult; I need so many skills. It isn’t worth it. I give up.

RIGHT MIND: I am learning how to apply physics and math to medicine and biology. I’m seeing how it all fits together. It’s so cool!


WRONG MIND: I got my homework back and it was covered with red ink. My instructor is an ass.

RIGHT MIND: I got my homework back and my instructor made many corrections. Such valuable feedback!


WRONG MIND: I spent 30 minutes solving a differential equation. After all that effort, I doubt my solution is correct.

RIGHT MIND: I spent 30 minutes solving a differential equation. Now I will spend 3 minutes plugging my solution back into the differential equation to check that it really works.


WRONG MIND: I solved the differential equation. The solution is complicated and I don’t understand what it means physically.

RIGHT MIND: I solved the differential equation. Now I will examine limiting cases to understand what it means physically.


WRONG MIND: My homework is due Friday. I don’t have to start working on it until Thursday night.

RIGHT MIND: My homework is due Friday. I will start working on it on Monday, leaving time to ask questions if I get stuck.


WRONG MIND: I need to read books by Steven Vogel, Mark Denny, and Knut Schmidt-Nielsen before I am ready to begin my homework.

RIGHT MIND: I would love to read books by Vogel, Denny, and Schmidt-Nielsen, but first I really need to start my homework.


WRONG MIND: I know how to compute an answer to the homework, but it doesn’t mean anything.

RIGHT MIND: The purpose of computation is insight. I will think about my answer until I understand it physically.


WRONG MIND: I have taken a calculus course, but I didn't really master the subject. IPMB uses calculus a lot; I shouldn’t take a course based on it.

RIGHT MIND: I will take a course based on IPMB, and use the experience to improve my math skills.


WRONG MIND: Real-world problems are so complicated. The toy models presented in IPMB won’t prepare me for complex real-world problems.

RIGHT MIND: Solving toy models will help me build the skills and intuition I need to successfully attack more complicated real-world problems.


WRONG MIND: To solve a homework problem, I search for an equation to put numbers into: “plug-and-chug.”

RIGHT MIND: I will think before I calculate. After I calculate, I will think if my answer makes sense. I will always think.


WRONG MIND: Some homework problems ask me to “estimate” something, but they don’t give me all the data I need. What a bunch of BS.

RIGHT MIND: Part of learning to estimate is to make reasonable assumptions about data I do not have. I will develop this skill.


WRONG MIND: I derived a complicated equation. I have no idea if it is correct.

RIGHT MIND: I will check my equation by verifying that it has the correct units. This doesn’t prove it’s right, but it could prove it’s wrong. I will practice this skill.


WRONG MIND: Why does IPMB derive so many equations? I don’t need the derivation; I just want to use the equation to calculate numbers.

RIGHT MIND: A derivation is like a story. The derivation explains what is happening physically, and reminds me what assumptions were made.


WRONG MIND: IPMB is always using math to model biological phenomena. This bugs me, and I dislike using “model” as a verb.

RIGHT MIND: I need to be able to build simple mathematical models of biological phenomena. I must learn to model.

WRONG MIND: The computed tomography algorithms that create an image from projections are beautiful. I could never discover something that profound.

RIGHT MIND: With much hard work, I intend to discover something new. I will use those beautiful computed tomography algorithms to motivate me.


WRONG MIND: I received a C- on my first exam, and a D+ on the second. I quit.

RIGHT MIND: I have learned so much from my mistakes on the first two exams. Had I gotten A’s on those exams, I wouldn’t be pushing myself hard enough.


WRONG MIND: The homework is difficult for me, and my exam average is a C+. I will never achieve my goal of making new and valuable contributions to biomedical engineering.

RIGHT MIND: The skills needed in research are not identical to those needed in the classroom. I have as much to contribute on the job as the A student.

WRONG MIND: I would love to write. RIGHT MIND: I intend to write.
WRONG MIND: I would love to write. RIGHT MIND: I intend to write.

Friday, November 16, 2018

Mathematics is Biology’s Next Microscope, Only Better; Biology is Mathematics’ Next Physics, Only Better

Intermediate Physics for Medicine and Biology is full of equations. Equations are on almost every page, and often lots of them. Russ Hobbie and I use calculus without apology, and we discuss differential equations, Fourier analysis, and vector calculus. To understand biology, must we use all this mathematics?

Mathematics is Biology’s Next Microscope, Only Better;
Biology is Mathematics’ Next Physics, Only Better
The answer given by Joel Cohen of Rockefeller University is Yes! In his 2004 article “Mathematics is Biology’s Next Microscope, Only Better; Biology is Mathematics’ Next Physics, Only Better” (PLoS Biol 2:e439), Cohen argues that math skills are crucial for modern biologists. He writes
Although mathematics has long been intertwined with the biological sciences, an explosive synergy between biology and mathematics seems poised to enrich and extend both fields greatly in the coming decades.
The first half of his argument I believe enthusiastically: math has much to offer biology.
Mathematics broadly interpreted is a more general microscope. It can reveal otherwise invisible worlds in all kinds of data... For example, computed tomography can reveal a cross-section of a human head from the density of X-ray beams without ever opening the head, by using the Radon transform [see Chapter 12 of IPMB] ... Charles Darwin was right when he wrote that people with an understanding “of the great leading principles of mathematics… seem to have an extra sense”... Today’s biologists increasingly recognize that appropriate mathematics can help interpret any kind of data. In this sense, mathematics is biology’s next microscope, only better.
In IPMB, Russ and I illustrate how mathematical models can describe biological and medical systems. We don’t use sophisticated or complicated math, but instead focus on toy models that train students to analyze biological problems quantitatively. On the first day of my Biological Physics class, I tell the students that the course is a workshop on applying simple mathematical models to biological phenomena. Mathematics really is biology’s next microscope.

The second half of Cohen’s argument is not as obvious. Will biology lead to new advances in mathematics?
In the coming century, biology will stimulate the creation of entirely new realms of mathematics. In this sense, biology is mathematics’ next physics, only better. Biology will stimulate fundamentally new mathematics because living nature is qualitatively more heterogeneous than non-living nature.
Well, maybe, but I am skeptical. Cohen claims that biology generates large amounts of data, and biological systems are diverse and heterogeneous, which will lead to new math concepts that deal with what we now call Big Data. I hope this is true, but I expect much of the math already exists. Perhaps my skepticism arises because I love simple models, and the new math will certainly be elaborate and abstruse. We will see.

In his article, Cohen does more than make general claims; he gives specific examples. For instance, he tells a lovely story about how simple mathematical reasoning led William Harvey to predict the existence of capillaries
[Harvey’s] theoretical prediction, based on his meticulous anatomical observations and his mathematical calculations, was spectacularly confirmed more than half a century later when Marcello Malpighi (1628–1694) saw the capillaries under a microscope. Harvey’s discovery illustrates the enormous power of simple, off-the-shelf mathematics combined with careful observation and clear reasoning. It set a high standard for all later uses of mathematics in biology.
I encourage you all to read Cohen’s article. It makes a persuasive case that books such as Intermediate Physics for Medicine and Biology are necessary and even essential. Enjoy!

Friday, November 9, 2018

Marie Curie and her X-ray Vehicles’ Contribution to World War I Battlefield Medicine

Sunday is Veterans Day. This year the holiday is particularly significant because it marks the 100th anniversary of the armistice ending World War I.

Marie Curie in a Mobile Military Hospital X-Ray Unit
Marie Curie in a Mobile Military Hospital X-Ray Unit.
Readers of Intermediate Physics for Medicine and Biology might wonder how the Great War influenced the application of physics to medicine. Timothy Jorgensen published a fascinating article on the website The Conversation discussing Nobel Prize-winner Marie Curie’s use of medical x-rays on the battlefield. Below are some annotated excerpts.
[In addition to her discovery of radium and polonium, Curie (1867-1934)] was also a major hero of World War I. In fact, a visitor to her Paris laboratory 100 years ago would not have found either her or her radium on the premises. Her radium was in hiding and she was at war.

The Guns of August,by Barbara Tuchman.
For Curie, the war started in early 1914, as German troops headed toward her hometown of Paris [“early” 1914? Germany declared war against France on August 3; see Guns of August by Barbara Tuchman]…[Curie] gathered her entire stock of radium, put it in a lead-lined container, transported it by train to Bordeaux…and left it in a safety deposit box at a local bank…

With the subject of her life’s work hidden far away…she decided to redirect her scientific skills toward the war effort; not to make weapons, but to save lives.

X-rays...had been discovered in 1895 by Curie’s fellow Nobel laureate, Wilhelm Roentgen.… Almost immediately after their discovery, physicians began using X-rays to image patients’ bones and find foreign objects – like bullets. But at the start of the war, X-ray machines were still found only in city hospitals, far from the battlefields where wounded troops were being treated. Curie’s solution was to invent the first “radiological car” – a vehicle containing an X-ray machine and photographic darkroom equipment – which could be driven right up to the battlefield where army surgeons could use X-rays to guide their surgeries....

[As the war progressed,] more radiological cars were needed. So Curie exploited her scientific clout to ask wealthy Parisian women to donate vehicles. Soon she had 20, which she outfitted with X-ray equipment. But the cars were useless without trained X-ray operators, so Curie started to train women volunteers. She recruited 20 women for the first training course, which she taught along with her daughter Irene [1897-1956, making her a teenager during much of the war], a future Nobel Prize winner herself….

Not content just to send out her trainees to the battlefront, Curie herself had her own “little Curie” [Petites Curies] – as the radiological cars were nicknamed – that she took to the front. This required her to learn to drive, change flat tires and even master some rudimentary auto mechanics, like cleaning carburetors. And she also had to deal with car accidents. When her driver careened into a ditch and overturned the vehicle, they righted the car, fixed the damaged equipment as best they could and got back to work [don’t you just love her?]....

Curie survived the war but was concerned that her intense X-ray work would ultimately cause her demise. Years later, she did contract aplastic anemia, a blood disorder sometimes produced by high radiation exposure. Many assumed that her illness was the result of her decades of radium work – it’s well-established that internalized radium is lethal [see The Radium Girls by Kate Moore]. But Curie was dismissive of that idea. She had always protected herself from ingesting any radium. Rather, she attributed her illness to the high X-ray exposures she had received during the war. (We will likely never know whether the wartime X-rays contributed to her death in 1934, but a sampling of her remains in 1995 showed her body was indeed free of radium.)
To learn more about Marie Curie, I recommend Jorgensen’s fine book Strange Glow: The Story of Radiation, or the article about Marie and her husband Pierre Curie and the discovery of polonium and radium, published by the Nobel Prize website. If you are a child at heart and enjoy Animated Hero Classic videos, watch this tearjerker.

To learn more about x-ray imaging, see Intermediate Physics for Medicine and Biology:
Chapter 16 describes the use of x rays for medical diagnosis and treatment. It moves from production to detection, to the diagnostic radiograph. We discuss image quality and noise, followed by angiography, mammography, fluoroscopy, and computed tomography. After briefly reviewing radiobiology, we discuss therapy and dose measurement. The chapter closes with a section on the risks from radiation.
To learn more about the First World War, visit the National World War I Museum and Memorial in Kansas City (know locally as Liberty Memorial).

National World War I Museum and Memorial in Kansas City
National World War I Museum and Memorial in Kansas City.
Happy Veterans Day all who have defended our country in the military (including my dad and my brother-in-law). Thank you for your service.

Friday, November 2, 2018

Roderick MacKinnon's Nobel Lecture

In Chapter 9 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I write
Roderick MacKinnon and his colleagues determined the three-dimensional structure of a potassium channel using X-ray diffraction (Doyle et al. 1998; Jiang et al. 2003). MacKinnon received the 2003 Nobel Prize in Chemistry for his work on the potassium channel.
When I teach my graduate class on bioelectricity, we read the Doyle et al. article (“The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity,” Science, Volume 280, Pages 69–77, 1998). In my class, usually either my students and I discuss a paper or I explain some aspect of it. However, I’ve not found a better way to describe potassium channels than to watch MacKinnon’s brilliant Nobel lecture. I suggest you watch it too, using the embedded Youtube link below. It's 45 minutes long, but well worth the time.

If you have no time to spare, listen to the much shorter (less than two minute) interview where MacKinnon explains how being a scientist is like being an explorer.


Roderick MacKinnon’s Nobel lecture.

“Being a scientist is like being an explorer.