Abstract

This volume brings together a number of perspectives on how certain physical phenomena contribute to the functional design and operation of the nucleus. This collection could not be more timely, resonating with an increasing awareness of the opportunities that lie at the interface of cell biology and the physical sciences. For example, this was a major theme in the 2012 and 2013 annual meetings of the American Society for Cell Biology, and one that the Society aims to emphasize even further going forward. In addition, the emerging canonical relevance of the physical sciences to cell biology has in recent summers made a most conspicuous appearance in the curriculum (lectures and intense labs) of the famed Physiology Course at the Marine Biological Laboratory in Woods Hole. So, much credit is due to Ronald Hancock and Kwang Jeon, the coeditors of this volume, and all the authors for creating a work that is so au courant.

It all started with the Big Bang

Robertson (2007)

Keywords

Nucleus; Nuclear organization; Biophysics; Physical cell biology

1 Introduction: A Brief History of Biophysics

The English word “physics” deerives, as the plural, from the Greek noun “physic” (Φζικ) and has historically been applied to both medicine (the practice of “physik”) and, more durably, natural phenomena (excluding life). The former term is no longer used in medicine except on occasion when one sees that a professor at some venerable medical school holds a title such as “The (insert an august name here, such as Vesalius or Paracelsus) Professor of Physik.” No one can quite be sure when the prefix “bio” was first attached to physics. The combined word does not appear in any of Aristotle’s brilliant essays on either physics or natural history, for example, though his treatise “Movement of Animals” (translated by Farquharson, 1984) makes for fascinating reading, particularly bearing in mind that he wrote more than two millenia before the time of Newton.

In the mid-eighteenth century, the Italian physician and physicist Luigi Galvani (1737–1798) discovered that the leg muscle of a recently sacrificed frog could conduct static electricity from a piece of metal, resulting in a twitch. This allowed him to make the leap that electricity is related to muscle activity in the living animal. The subsequent discovery by the German physician and physiologist Emil du Bois-Reymound (1818–1896) of what came to be known as the nerve action potential paved the way for what could be called the “pre-biophysics era.” In due course, as the field of biochemistry evolved, a parallel line of thinking arose that “mechanical” and indeed even “engineering” principles were as much at play in living systems as chemistry—a doctrine promoted particularly by the German–American biologist Jacques Loeb (1859–1924).

By the 1920s, the arrival of biophysics was at hand, at least in a form that took up that name. It was both an approach (particular equipment) and a discipline (a vision of mechanism) and was driven, at least to a considerable degree by physiologists continuing to bump into physical underpinnings of biological processes. But there was a second, portentous domain of biophysics in the wind.

Back in 1912, the German physicist, Max von Laue (1879–1960), had discovered the diffraction of X-rays by crystalline materials, and subsequently he and others realized that this diffraction from the lattice would allow the crystal’s structure to be deduced by calculating the pattern back through reciprocal space. In due course, it occurred to several people that such an approach might be applied to more complex molecules than crystalline minerals. The undisputed leader of this movement was the Irish physicist John Desmond Bernal (1901–1971). He was a formidable genius who, even as an undergraduate at Cambridge, presented one of his professors with a penetrating mathematical analysis of the 230 crystal space groups, an achievement even more striking given that he had not done well on the mathematics tripos, leading him to turn to the natural sciences curriculum (Brown, 2005). Later, having become a leading crystallographer, arguably the leading one, Bernal encouraged his former student Dorothy Crowfoot Hodgkin (1910–1994) to take up the larger task (as both the size of the unit cell and magnitude of the achievement, if reached) of tackling biological molecules. By the age of 35, Hodgkin had got the structure of penicillin before it had been determined by chemical means. This was a monumental achievement, and she followed it in due course by solving the structures of vitamin B12 and insulin.

In parallel with these triumphs, there arrived the era of X-ray diffraction analysis of both crystalline proteins and (wet or dry) biological fibers as in the case of collagen, wool, and DNA, and these endeavors, in particular in the X-ray crystallography field, increasingly took on the name “biophysics” in many venues. Thus, for example, the laboratory at King’s College, London, where Maurice Wilkins and, later, Rosalind Franklin undertook X-ray diffraction of DNA had long been named the Biophysics Unit of the Medical Research Council. The term biophysics had become, by the end of the war, part of the scientific lexicon. The crystallographic axis of biophysics soon reached its first “post-Hodgkin” pinnacle in the DNA work of Wilkins and Franklin at King’s, and of Watson and Crick at the University of Cambridge Department of Physics’ Cavendish Laboratory, and, subsequently, in the structural solutions of myoglobin and hemoglobin by John Kendrew and Max Perutz, respectively, at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge. Despite the name of this latter institute, its founding was a direct result of the biophysics era that Bernal and Hodgkin had pioneered, and which England so proudly led for more than three decades.

In the 1950s, another dimension of biophysics coming to fruition was the study of cell structure. Phase contrast microscopy, a major advance in light microscopy, had been discovered in 1930 by the Dutch physicist Frits Zernike (1888–1966), for which he received the 1953 Nobel Prize in Physics, unshared. Meanwhile, also in the early 1930s, the German physicist Ernst Ruska (1906–1988) had developed the principles and prototypes of the electron microscope, for which he received the 1988 Nobel Prize in Physics, shared with Gerd Binning and Heinrich Rohrer for their invention of the scanning tunneling microscope. By the time phase-contrast and electron microscopy arrived, many cytologists, biochemists, and even physcicts (vide infra) were trying to define “protoplasm.” Rivals seemed ready to bet their first-born children on “gel” versus “sol” models of protoplasm. In his very first work with live material, Francis Crick measured the recoil of intracellular iron particles when subjected to a magnetic field, as a probe of the rheological and, thus, cross-sectional density of cytoplasm (Crick, 1950; Crick and Hughes, 1950). I recently reread the first paper (the second is beyond my expertise in the physics required) and would recommend it to all cell biologists as a model of experimental elegance for its time, as well as a marvelous example of fine writing.

Except for the obvious risk of confusing (or annoying) readers, this chapter might have been titled “Nuclear Physics” and this point reminds us, of course, of another major development in biology that sprang from pure physics, namely, the codiscovery of radioactivity by Marie Curie and Henri Becquerel. The subsequent understanding of this phenomenon (i.e., “nuclear physics,” literally) led to the use of unstable isotopes by the Hungarian chemist George de Hevesy (1885–1966; Nobel Prize in Chemistry, 1943) and Rudolf Schőnheimer (1898–1941) as tracers to pursue the biosynthesis and flux of molecules in living systems. Later, the stable isotope nitrogen-15 was the key to the Meselson–Stahl experiment demonstrating the semiconservative replication of DNA, dubbed “the most beautiful experiment in biology” (Holmes, 2001). The entry of radioisotopes to biological research was pure biophysics, although they became such standard tools that their use was not labeled as biophysics per se. So too was the allied field of radiation biology.

Coming to the modern era (1975–present), biophysics might be defined by what is published in the Biophysical Journal (reminding me of a professor who told the class that lipids are defined as substances that are soluble in a lipid solvent). Huge advances have taken place in our ability to measure things such as the diffusion-based transport of molecules in cells—thanks mainly to the advent of fluorescent dyes and proteins. More recently, in just the last decade, advances have cracked the Abbé limit (~ 200 nm) for spatial resolution in diffraction-limited optical microscopy. And meanwhile, the introduction of...