Welcome to Biophysics! — A “Resource Letter”

Update November 22, 2021: The final, published article is here.

Update June 18, 2021: A preprint of my article is here.

Over a year ago, I was invited to write a “resource letter” on Biological Physics for the American Journal of Physics, a very good education-focused journal. The goal of its resource letters is to provide a collection of books, articles, and other resources that would be a useful introduction for people new to the field. “Biological Physics” is a vast topic, far larger than most things covered in the journal’s resource letters, and so I wondered if this is a hopeless task. If it isn’t hopeless, I can think of people who are more qualified than to write such a list. And finally, I have far too much to do. Nonetheless, I said “yes,” especially since the deadline was far in the future. Now, however, that deadline is approaching! I’ve therefore been working on the article and asking myself: how can I organize biophysics into a set of sub-topics, and what are some useful entry points to learning about each? Thankfully, I’ve thought about these exact questions when designing and teaching (several times) a graduate biophysics course and an undergraduate course, and writing a popular science book. (The book has been far more useful for this task than one might think!)

Here, I’m posting my list of topics and the introductory paragraphs for each topic, but not the resources themselves. The text begins with an introduction to “biological physics.”

What topics, dear reader, am I missing? The major gap at the moment is a section I should probably include on internet resources, rather than books and articles. Suggestions are welcome! Though I’ve completed a draft of the whole article including references, if anyone would like to contribute more substantially, please let me know! (You’ve only got 3 weeks, though.)

Sections (described below)

• Introduction
• General Textbooks
• DNA
• Proteins, Protein Structure, and Protein Folding
• Membranes, Surfaces, and Interfaces
• Motility and Chemotaxis
• Embryos, Tissues, and Other Collections of Cells
• Genetic Networks and Systems Biology
• Ecology and Evolution
• Neuroscience
• Medical Physics
• Physiology and Macroscopic Biophysics
• Internet Resources
• Popular Science Books

Introduction

I comment below on the distinction between biophysics and biological physics, of little importance in practice, but I first note that whatever one calls it, the field is vast, active, and hard to define. One could perhaps consider biophysics as the intersection of biology and physics, containing the systems and approaches of interest to both biologists and physicists, but this simply sidesteps the questions of what occupies that intersection and why. Moreover, since every living system obeys the laws of physics, it is hard to escape the conclusion that all of biology could fall under the umbrella of biological physics. Biophysicists do in fact consider scales ranging from ions to ecosystems; there is no shortage of topics to attract our attention. Nonetheless, one can state a few principles that, even if they don’t quite define biological physics, at least unite many of its inquiries and methods. One such principle is the notion that the physical properties of biological materials are central to their function. It is not surprising that bone strength influences the agility of animals, but this sort of connection extends to all the components of the living world. The mechanical stiffness of DNA governs how each of our cells pack about a meter of this molecule into every cell nucleus, while still managing to read out the code it carries. The nature of cellular membranes as two-dimensional liquids is integral to the activity of membrane-anchored proteins. Tissues and developing embryos can adopt solid- or fluid-like phases with different consequences for their dynamics. Understanding these and countless other systems requires more than information about genes or biochemical interactions; it requires a grasp of the physics at work.

A second principle is the notion that fluctuations, noise, and entropy are central to life. This is in some sense obvious — living things obey laws of physics, and statistical mechanics is central to these laws — but the extent to which it is embedded in the workings of life often comes as a surprise to those new to biophysics. Proteins explore complex free energy landscapes; genes are expressed in stochastic bursts; diffusion dictates the molecular distributions that pattern developing limbs. The tools that help us make sense of randomness give us insights into life, and conversely, life illustrates the potential of guided randomness to generate function.

A third principle is that the living world obeys general laws, transcending often complicated details, that are amenable to quantitative analysis. Making and testing numerical predictions, and assessing the mathematical forms of natural phenomena, have long been hallmarks of physics. Biological data are quantitative and precise in a large and expanding number of contexts, made possible in many cases by new biophysical tools, and in general facilitating the application of biophysical analyses. We can investigate single protein molecules and untangle signatures of active motion and universal diffusive dynamics, observe the stochasticity of gene expression and relate it to dictates of probability theory, map the positions of thousands of cells in an embryo and identify characteristics of collective phases of matter, and more.

Is there a distinction between “biological physics” and “biophysics?” About twenty years ago, Frauenfelder, Wolynes, and Austin identified biological physics as “the field where one extracts interesting physics from biological systems” (“Biological Physics,” H. Frauenfelder, P. G. Wolynes, and R. H. Austin, Rev. Mod. Phys. 71, S419-430 (1999)). Aside from the impossibility of defining “interesting physics,” the authors themselves noted that the differences between biological physics and biophysics “represent only psychological style and current attitude; the same person at different times could be thinking as a biophysicist or as a biological physicist.” There are certainly many areas in which studies of biological phenomena have advanced our understanding of physical concepts, for example in studies of active and non-equilibrium systems and complex networks of various sorts. However, given the principles above, it is hard to imagine “biophysical” topics from which one could not also extract “biological physics.” I believe there is little to gain by thinking about the distinction.

The following list of resources for biological physics is necessarily incomplete and idiosyncratic — it couldn’t be otherwise. It is informed by my experiences in the field, many discussions with colleagues over many years, and biophysics courses I have designed for both graduate students and non-science-major undergraduates. Biophysicists have very diverse perspectives, and I encourage the reader to seek out other views as well.

General Textbooks

Thorough, well-written, and captivating textbooks exist on the topic of biological physics. Each of the books listed below, written by and for physicists, provides biological information, physical insights, abundant examples of contemporary research, and exercises that help build the reader’s skills.

(The books I’m listing here are Nelson’s Biological Physics, Phillips, Kondev, Theriot, and Garcia’s Physical Biology of the Cell, and Bialek’s Biophysics: Searching for Principles.)

DNA

No molecule exemplifies our modern understanding of life as much as DNA. DNA is, of course, the carrier of genetic information. It is also a tangible thing whose physical properties are deeply connected to its function. Physicists have been central to the investigation of DNA for well over half a century, with contributions to our understanding of its structure from well-known names like Erwin Schrodinger [CITE: What is Life?] that even precede the discovery of the double helix. Around the turn of century, methods for manipulating single molecules of DNA and RNA provided unprecedented insights into the interplay between microscopic mechanics, statistical thermodynamics, and function. More recently, the advent of contemporary experimental and theoretical tools to probe the dynamic three-dimensional architecture of DNA in living cells contributes to ongoing excitement about the biophysics of DNA. Basic aspects of DNA mechanics are covered well in the Nelson and Phillips et al. textbooks noted earlier. The following papers are landmarks or good entry points to the biophysics of DNA or entire genomes.

Proteins, Protein Structure, and Protein Folding

Protein molecules shape themselves into particular three-dimensional forms, with form and function intimately connected. The characterization of protein structure via crystallography was one of physics’ most important contributions to biology, and its methods are now well established. Current topics of particular interest to physicists include the challenge of predicting protein structure, known as the “protein folding problem,” understanding the landscape of possible forms, and experimentally probing the paths taken as proteins explore these landscapes.

Membranes, Surfaces, and Interfaces

Much of life takes place at interfaces — gas exchange at the surfaces of leaves and lungs, for example, and cell-cell signaling at the membranes that demarcate cell boundaries. The physics of these environments is fascinating, as their nature as quasi-two-dimensional materials in a three-dimensional world influences how principles of electrostatics, statistical mechanics, and mechanics are manifested.

Motility and Chemotaxis

Motion has always been a central concern of physicists. The motion of living objects provides amazing, beautiful, and important illustrations of how mechanisms for generating movement and directing it to particular ends is governed by physical principles. Notably, physicists explorations of organismal motion span scales from the microscopic behaviors of individual cells to the macroscopic dynamics of flocks, swarms, and schools of animals.

Embryos, Tissues, and Other Collections of Cells

The transformation of a single cell into a complete organism is one of nature’s most stunning feats. Multicellular development has fascinated scientists for centuries, and though it involves considerable biochemical and genetic complexity, it also reflects universal physical principles governing pattern formation and mechanics that are increasingly amenable to quantitative understanding. These issues are also central to other multi-cellular systems such as tissues and organs, either in their natural state or in newly engineered construction such as organoids.

Genetic Networks and Systems Biology

A hallmark of life is adaptability, implemented at all its scales. At the level of DNA, the activation or repression of the expression of individual genes is tied to all sorts of stimuli, including the expression of other genes. Genes thereby form networks of activity, made possibly by the specificity of protein and DNA interactions but also by general principles of dynamical systems that give rise to motifs like feedback loops, oscillations, and memory. The study of genetic networks intersects the broad field of systems biology, which also encompasses the engineering of new genetic circuits.

Ecology and Evolution

The existence of general rules describing collections of species, or whole ecosystems, has long been debated. In influential work, Robert May in the 1970s applied random matrix theory to generic models of inter-species interactions to explore questions of stability. In recent years, a growing number of physicists have examined issues of coexistence and cooperation in strongly interacting living systems. The topic also intersects that of evolutionary dynamics, especially in the interplay between random and non-random processes.

Neuroscience

The understanding that emerged in the mid-twentieth century of how electrical signals propagate along neurons, especially from work by Aaron Lloyd Hodgkin and Andrew Huxley, is one of the great triumphs of biophysics. Neuroscience continues to have considerable intersection with physics, involving mechanisms of cellular activity, means of encoding and decoding information, and techniques for probing and perturbing neural activity. The textbooks noted above provide excellent introductions to the basics of neural function. The articles below touch on a few aspects of a vast field.

Medical Physics

Physics finds many powerful applications in health and medicine, including radiation therapies and many varieties of medical imaging. Medical physics is a large field in itself, with devoted professional organizations and publications.

Physiology and Macroscopic Biophysics

Biophysics and Biological Physics typically focus on microscopic scales. Physics, of course, applies much more broadly, for example to the function of organ systems, whole organisms, and even ecosystems. Much of our study or organism function falls under the classic heading of physiology. The references below give a few examples that may be of particular interest to physicists.

Internet Resources

[I need to write something here. What should I include? …]

Popular Science Books

There are remarkably few popular science books on biological physics (spurring me to write my own, noted below). Nonetheless, a handful of excellent works intersecting topics of biophysical interest exist.

That’s all! What’s missing, that needs to be included?

Update June 18, 2021: A preprint of the article is here; you can see what made the cut, and what has changed since this post.

Today’s illustration.

A mountain — not very good, but I managed to do it quickly, and with just two colors! Based roughly on this.

— Raghuveer Parthasarathy; May 8, 2021