January 7, 2014: Of Snakes and Men -- Polymer Physics and the stuff of life

At some point in my life DNA transitioned from the arcane to the ubiquitous. The word passed from being solely the subject of scientific discourse to use in daily life. And in the process of becoming quotidian, it acquired a new meaning, rather divorced from its original biological one. Today “DNA” has become synonymous with one’s fundamental essence or make-up. The Rogers Automotive Family in Shelby, NC tells us that “you’ll do better” is not just a slogan, “it’s our DNA.”  Perhaps.

Whatever we mean by DNA today, we discuss it with surprising frequency in scientific articles, popular accounts of science, and, apparently even in the used car business.  Google books will let you track the frequency of
various words and phrases used in its massive (and ever expanding) data base of digitized texts by employing its Ngram viewer^[1]. Let’s track the growth of  “DNA” in the google books data base and compare it to other scientific terms. To make things interesting, we can compare its frequency of use to that of the entire fields that lead to its discovery and characterization: biology, chemistry, and physics. The result shows the inexorable growth of the “DNA” surpassing the reference to “biology” in 1960,  “chemistry” in 1965, and “physics” in 1969. By this measure at least, fascination with DNA has clearly outstripped interest in the physical and life sciences, reaching a plateau in 2000. We live in a linguistic sea of DNA.

Why has DNA become such a cultural touchstone? What is it really, and what does it tell us about physics and about life? We will find that, just as Sherlock Holmes observed that “there’s a scarlet thread of murder running through the colorless skein of life^[2]...,” there’s an intriguing thread of DNA running through much of the history of biological physics in the twentieth century. Let’s follow it.

Again and again and again... The story of polymers - Before we come to the details of DNA, it is worthwhile noting that DNA is an example of a polymer. A molecule of enormous dimensions but built out of just a few subunits repeated over and over again in chain like boxcars linked to each other to form a long train. This DNA is stored in the nucleus of our cells, not as a single molecule but rather in twenty-three molecules, each comprised of tens or hundreds of millions of subunits^[3], or boxcars in our train analogy. These filamentous molecules are about a few inches long and only about twenty atoms wide. Because we have almost a ten thousand trillion (10¹³) cells, you and I have a literally astronomical length of DNA in our bodies. All the DNA in your body, if it were linked end to end, could reach from the earth to the sun and back about seventy times. To me what is a more impressive measure is that each of our cells contains about four feet of DNA wound up in a space a few thousand times smaller than the period at the end of this sentence. We will come to how this is possible later. Before we do, it is worthwhile to reflect more generally on the existence of these gargantuan molecules. For quite some time, their existence was a matter of acrimonious debate.

            Mr. Staudinger and the four hundred meter zebra - Hermann Staudinger had a problem. Or, at least his colleagues thought he did.  In what I can only describe as a Beaux Arts period intervention, a colleague wrote to him  “Dear colleague, abandon your idea of large molecules, organic molecules with molecular weights exceeding 5000 do not exist…”  His colleagues noted Hermann’s stellar work and meteoric rise in the field of organic chemistry working on small molecules. Later in life, Hermann recalled that they asked him why he had  “quit these beautiful fields of research” to chase after “the disgusting and ill-defined compounds such as rubber,” work which they derisively called Schmierenchemie — grease chemistry^[4].

            Why indeed?  And why the dismay at a colleague switching from one area of research to another? At the time, the very idea of massive molecules containing thousands of atoms chemically bonded together was an absurdity. As one chemist said, finding giant molecules was as likely as an explorer returning from the African veldt with descriptions of a four hundred meter long zebra. Today, we have lived with the notion of gigantic molecules for so long that it may be hard to imagine otherwise. Having absorbed this lesson, it is easy to cast Mr. Staudinger as the hero and his detractors as the villains of the story, but I think this misses the more interesting point. The intrigue of these scientific controversies is not in assigning scores to the winners and losers based on our current understanding, but rather in seeing how reasonable people could be on both sides of the debate. To do that, we need to explore, at least briefly, the landscape of chemistry at the turn of the last century.

            It is also interesting (to me at least!) to consider the parallels between this story and the modern development of biological physics. At least some of my colleagues are still convinced that biological problems are too messy and too poorly defined to hold the attention of true physicists. Are we pursuing the “grease chemistry” of our day? It must also be noted that bucking the current trends and popular scientific opinion is no foolproof method of new discovery. Heros and fools are not easily distinguished. For every Staudinger, there are hundreds of others forging new scientific paths that prove to be misguided (Mr. Mesmer and his theories of animal magnetism are only one rather famous example), and a call back to the fold in many cases should be heeded, or at least strongly considered. Even (especially?) smart people can fool themselves and the collective body of scientific thought and opinion is dismissed only at one’s peril. Of course, tenure provides a great deal of protection for those of us holding contrarian or at least idiosyncratic views, but I think we should admire difficulty of the balance between bravery and foolhardiness associated with the scientific choices we make. Even with job security, we cast our lot with our limited time and energy; it is only long after the choice is made that one finds any validations of his/her choices: “For now we see through a glass, darkly…”

            Turning back to our story, Hermann was something of a chemical wunderkind — after studying botany under Professor Klebs at the University of Halle in 1899, he fell in love with chemistry, particularly the field of organic chemistry. As an organic chemist, he studied the various reactions and molecular structures associated with compounds consisting solely or mostly of the elements carbon and hydrogen. He was very good at it, and was appointed a professor at ETH in Zurich by the time he was 31. Much of the work of organic chemists then (as now) has a strong technological or engineering focus: how can we make useful synthetic materials?         At the end of the nineteenth century, chemists were learning to synthesize and isolate a number of useful organic molecules. In the years immediately preceding the First World War, Hermann had turned his attention to making small biofunctional organic molecules, containing tens of atoms each. These compounds found uses as drugs, flavoring, and insecticides^[5]. As an example, Staudinger isolated about seventy different organic molecules that together give coffee its flavor. Working with a Swiss company, he created a mixture of some forty synthetic molecules that approximated coffee flavor. The maritime blockade of Germany by the Allies during WWI had created a market for such synthetic replacements for coffee and, in fact, for pepper as well. Not one to miss an opportunity, Staudinger created a synthetic pepper flavor too.

            The opening of the 20th century also saw a board effort to find synthetic substitutes for a variety of other naturally occurring materials.  The demand for silk, ivory, and rubber had lead europeans on a world-wide hunt. As a consequence, the  rubber boom in Brazil brought railroads to the hinterlands, and the enslavement of the Amazonian natives. Untold rivers of blood had been and split (human and otherwise) in quest for these biomaterials, and the economic and humanitarian rewards associated with replacing this expensive and malevolent rubber, ivory, and silk pipeline drove a concerted effort either to synthesize surrogate materials from scratch, or, at least, to learn to modify more easily obtained natural materials to mimic these special ones. For example, it was discovered that one could produce a silk-like fiber from the nitration of cellulose, which is obtainable from plants. The original nitrocellulose proved to be highly unstable. Today, we know it as “guncotton” or smokeless gunpowder. But, when some of the high-energy nitro groups were tamed, and the resulting material mixed with camphor (a compound from evergreen trees which also gives plants in the mint family their characteristic odor), one could produce a moldable plastic — celluloid, or “man-made ivory.” Billiard balls, once only made of ivory, could now be made of this more easily obtainable material. Alas, this artificial ivory retained some memory of its more unruly past: nitrocellulose billiard balls explode went touched off by a lit cigar!  I suspect this new danger to the drawing rooms of the well heeled was considered to be but a small price to pay by the narwals of boreal seas and the elephants of the tropics. But, I digress.

            In such an environment, it is not surprising that many chemists attempted to understand the chemical structure of silk and rubber. The prevailing notion at the time was that these materials we “colloidal aggregates” of small organic molecules. In essence, they were thought to be ill-defined agglomerations of well-defined small molecules (i.e., those having fixed ratios of constituent atomic elements and a fixed geometry of bonds between those elements) held together in some jumble — a large number of well-defined snowflakes making up a messy snowball. The lines of evidence leading to this view are somewhat complex, but it is interesting to recall a couple of them.

            X-ray crystallography of samples of cellulose and rubber convinced people that the underlying structure of their constitutes was small. You might imagine the molecules as oranges packed in a grocer’s display. It turned out that these basic subunits (making of the unit cell of the crystal) were, in turn, chemically linked, one to the next, like identical boxcars on a train. Turning back to our oranges, you could imagine passing a needle and thread though all of them in the store’s display while they were packed. Observing only the oranges and not the thread, you wouldn’t be able to say if they were connected into one giant string of oranges or not. Thus, the x-ray data were correct, but their interpretation was flawed.

            A theoretical argument was presented against long chain molecules as well.  If the small constituents reacted to form a long line, how would this process ever end?  The ends of the line would always present reactive groups waiting to grab another subunit. The string of oranges, if it were to exist, should grow forever!  Actually there is a subtle balance between energy and entropy that controls the length of the polymer strings and, in fact, their distribution of lengths. Polymeric solutions like natural rubber (but not DNA!) contain a broad mixture of different polymer lengths, just like different trains can have different numbers of boxcars, even though those boxcars are identical to each other. The idea that a substance might not have a specific and fixed number of atoms seems to have been a major stumbling block for scientists of the time.

            Working with polymers of formaldehyde, Stuadinger showed that one could understand the long chains as the limit of chemically well-defined short chains containing only a few basic chemical units. In crystals the ends of these chains were randomly distributed and the packing reflected the size of the underlying chemical units — called monomers today — like the oranges in our example. The x-ray experiments tell us much about the monomers, but not about the length of their polymers. Staudinger went on to show that one could use the measurements of the viscosity of polymeric solutions to develop a reasonable, but imperfect, measure of their length, or molecular weight. It was soon found that not only was rubber a polymer, but so were cellulose, silk, and other proteins, like chitin, which forms the shells and wings of various insects. In fact, the living world runs on the repeated motif of polymers. Stuadinger had been instrument in putting the field of “high polymer chemistry,” the study of such long molecules on the map. For this he received the noble prize in chemistry in 1953.  It turns out that physicists had much to say about the properties of polymers based not so much on the details of their chemical constituents, but rather on their topology as long linked chains. The fact that they are long trains and not the contents of their boxcars controls many of the physical properties of polymers in networks and in solutions. That is a story for another day, and, in our next post, we will turn to the polymer that attracts the most attention — DNA.

December 15, 2013: The living world – physics under your finger tips

            To the reader: Some years ago I was walking with a colleague along the river Cam in the “backs” of Cambridge University. It was already late in the day, but sun still shone bright over the well manicured lawns behind Trinity college, the former home of Isaac Newton and the birthplace of modern physics. The oddly long day and cool pale light of late spring in the far northern latitudes was reminding me, a southern californian, that I was a long way from home.  I had just given a lecture on how one can use the thermal fluctuations of very soft and fragile materials to measure their mechanical properties. During a typical day of meeting the local faculty, I had met Sir Sam Edwards, a leading light in applying field theoretic techniques to the study of polymers, seen Cavendish lab for the first time, and been shown what was said to be the distant descendant of the apple tree that Newton had sat under during his storied moment of inspiration. Apparently, everyone likes to have a bit of fun at the expense of foreign visitors. At least no one had claimed to have been the fifth Beatle.

            After my talk and some polite discussion accompanied by tea and cookies, my host and I were wandering the backs, slowly meandering towards a dinner in town.  He was telling me that on the next night there was going to be an exciting and very well-attended public lecture by a famous astronomer. The press had been alerted and a large lecture hall prepared in case of an overflow crowd.  I casually remarked such preparations would never be necessary for lecture on condensed matter physics, soft condensed matter physics or biological physics. In other words, my areas of study. My host replied, “Well Alex: You know they have beautiful pictures and can talk about looking for the face of God.” He was and is right. Astronomy and high energy particle physics do have an interesting and important story to tell. Their stories rightly capture the attention of general public, since they address deep questions that have been asked in various guises throughout recorded history. What is the universe made of and what is our place in it?  What are the fundamental rules by which the world is constructed?  Is there actually a deep and hidden order to our world and can we understand it? These questions are compelling, thought-provoking, and allow us to transcend our daily life and touch the profound, enigmatic, and beautiful, to extend our horizons to worlds never visited and survey seemingly infinite vistas in time from the moment of creation to the ultimate fate of the universe. 

            But there is more - more to physics and more and different stories to tell that, in my view,  have not been adequately discussed in popular accounts of the subject. I am starting this blog to bring some of these stories to your attention. In particular, I would like to entertain you with the ideas, people, and history of what today we call biological and soft condensed matter physics. Why?  It might appear from the above reminiscence that I am tired of those high energy physicists and astronomers getting all the public adulation. Sure. But frankly, there is very little public adulation of science (and scientists) to go around, and I do not expect even a thin slice of that rather small pie to come my way based on the stories I have in mind. Rather, I think intelligent people of all educational backgrounds have a genuine interest in science in general, and physics in particular. After all, astronomers can fill a lecture hall in Cambridge, and experts like Stephan Hawking can write a best-selling book on black holes and the large scale structure of the universe. As any trip to the science section of your local book store will show you, these areas, along with the foundations of quantum mechanics, have become well trodden ground in that particular genre of popular accounts of physics. I think the same public that gravitates to these accounts will be as fascinated by research into the physical processes by which order emerges from chaos, how complex spatial patterns can form in chemical reactions, and in turbulent fluids, and how, at least in our particular corner of the universe, life can emerge, sustain and reproduce itself over eons.

            If you think that physics is only about worm holes and super springs, then you might be missing something equally fantastic, thought-provoking, and beautiful.  If you think the frontiers of physics can be found only in the tunnels of a Swiss supercollider, you might be surprised to learn they are also lurking in how drops run down a window pane, how rubber cement changes from liquid to solid as it dries, or how the complex machinery of life is right now transcribing your genetic code as you read this sentence. If you would like to understand how the murky edges of our knowledge hide literally in your finger tips, how the life sciences are changing in response to modern physics, and how physics is evolving through its interaction with biology, read on. This is my manifesto and my underlying rationale for writing this blog. That rationale stands or falls on a few underlying assumptions regarding how I think science ought to be done. For you to judge the validity of these assumptions, it is only fair that I make them explicit.

            First, the goal of physics cannot be solely to understand the fundamental constituents and forces of nature. It includes understanding the collective properties of matter that arise from the interaction of billions of fundamental particles. Democratis was right: stuff is made out of atoms^[1]. Atoms themselves are composed of electrons and nuclei. It appears that electrons are structureless point-like particles, but nuclei are composed of protons and neutrons, which themselves have internal structure as assemblages of quarks. All these particles (and actually a number of others that are not immediately relevant to the current topic) interact with each other through essentially three fundamental forces. This is the outcome of the reductionist approach to physics progressing over a hundred years of discoveries that unlocked the structure of matter on ever finer scales as one might imagine opening a sequence of Russian nesting dolls. One might think that this is raison d’etre of physics; all other investigations are, at best, the application of these ideas for technological advancements or the applications of fundamental physics to other fields of study. In short, the only true frontier of physics is found by stripping away the complexity of the natural world to reveal its most fundamental laws and constituents. In contrast to this view, a nobel laureate in condensed matter physics Philip Anderson published a short note entitled “More is Different.” In it he addressed the point that, while the collective properties of billions of atoms must arise from their fundamental particles and interactions between them, this sort of thinking is not generally helpful for understanding these collective properties and how it arises from the intricate organization of those atoms.  It is the same sodium atom that can exist as part of a crystal where all the atoms are arrayed in stately rows like soldiers on parade, or in a liquid surrounded by a jumble of other sodium atoms having a much weaker and more subtle spatial organization. Where in the electrons and quarks of the sodium atom lies this ability to make a collective transition from the rigid spatial organization of the crystal to the relative disorder of the liquid?  Does one even need to think of sodium atoms (or any other element) to understand the transition from liquids to crystals, since all atoms and many molecules have the same sort of phase transition from liquid to crystal?  Does nature admit more complex forms of collective spatial organization and, if so, how can they be described?  All these are questions that arise only when one realizes that more is truly different and that absolute adherence to reductionism prevents us from asking interesting questions about nature.

            In fairness, these views on the beauty and intellectual challenge of the physics of condensed phases of matter (what was once called solid state physics) are not universally shared. A famous physicists and mordant wit at one of our neighboring universities in the southern California referred this sort of work as “squalid state” physics. Perhaps as a consequence of that sort of thinking, the physics of the solid state was studied only in their applied physics/engineering departments at his institution. If one is, however, willing to accept that understanding these collective properties of atoms requires new ways of thinking distinct from the exploring the fundamental constituents of matter and their interactions, the question still remains: Is there still something else to be learned from studying the organization and properties of living matter?  Is the organization of life so fundamentally different from that of a simple crystal that these ideas from solid state physics play no role at all? Alternatively, is biology “merely” the result of the application of these ideas from solid state physics so that the living world has nothing new to teach us as physicists?  The answer, I believe, lies between these two extremes, and provides the rationale for biological physics and for claiming that the living world has much to teach us as physicists.

            Second, biological physics provides a new way to think and is not merely rogue physicists encroaching on the life sciences.  Perhaps a less incendiary way to express the same point is to ask, If one accepts the premise that more is truly different so that there is new physics in complex aggregations of matter, are there yet other physical principles to be learnt from the study of living things? And, conversely, can the physical principles that we already understand shed new light on biology?  These questions are at the very heart of biological physics, and yet they seem to blur the lines between the disciplines of science, with which we are all familiar.  You might be prompted to wonder: why should physicists try to work on the turf of biologists? 

            Of course, the boundaries of the disciplines are neither eternal nor immutable. When the founders of the Royal Society meet in Gresham College in 1660 for the promotion of “experimental philosophy,” they had the most broad interpretation of the range of applicability of the idea that one can learn about nature through experimental tests. Their range of interests encompassed everything!  They discussed whether a pendulum clock would run faster or slower on a mountain top, whether the tides were caused by changes in air pressure (an idea of Descrates), the appearance of an odd “monstrous” calf born in Hampshire, and examined notes on the autopsy of the Earl of Balcarres. As it turned out, the Earl’s liver was unusually large. Robert Boyle also doubted Descrates’ explanation of the tides based on his measurements of the variations in the air pressure, a point of perhaps more lasting impact. My point is that these men saw no particular reason to limit their thinking to one particular class of questions about nature. Unfortunately, as the shear quantity of knowledge grew, it become increasingly difficult to converse meaningfully about absolutely everything; people with a common set of interests and a common knowledge base can more profitably exchange new ideas and information, leading to the growth of what we now see as the traditional disciplines. Today, even within the traditional disciplines there is fragmentation. The Physical Review, our main journal is published today in six (mainly virtual or online) “phone books” separated by subspecialty. A researcher in atomic molecular optical physics is unlikely to look up articles published in the section on, say, nuclear physics.

            But are these dividing lines within and between disciplines meaningful as they currently stand? Should we attempt to return to a time without them?  On the one hand, some of my colleagues think that, since we have draw the boundaries poorly, or, at least in a way that can inhibit current thinking, we should try to do away with them.  On the other hand, scientific disciplines in general and physics in particular represent a coherent approach to the study of nature and influence how we frame our questions. Without this framework, will we become aimless and lose sight of the “bigger picture?” These are important questions under much discussion in academia under the guise of interdisciplinary science. There are no easy answers, but I have come to at least a couple of conclusions. The practice of biological physics as a specialization within the physical as opposed to the life sciences is predicated on how we address this idea of interdisciplinary science. I hope to convince you that this is not just a matter of academic tribal warfare, but rather a question of style of thought and content of investigation. In short: we, as biological physicists (as opposed to life scientists) do not necessarily intend to answer questions in the life sciences differently, but rather to ask different questions.

            In this blog I hope to bring you a mixture of reports from the scientific frontiers, some interesting stories from the history of our field, and some thoughts on the culture of academic science and particularly how it affects those working at the boundaries of the traditional disciplines. Finally, I hope you will join me in these musings by sending questions, comments, and suggestions to me at directorcbp.physics.ucla.edu. I look forward to hearing from you.

Sincerely,

Alex Levine