Theo Odijk: the equations that waited twenty-two years to be confirmed

In 1983, a young theoretical physicist working in the Netherlands published a short paper on what happens to long, slightly stiff molecules when they are forced into channels narrower than their own natural curvature. The prediction contradicted the prevailing intuition of polymer physics and was largely dismissed. Twenty-two years passed before nanofabrication advanced enough to actually build channels small enough to test it. When the experiments were finally performed — on single DNA molecules confined in nanochannels — they confirmed the prediction with striking precision. That paper became the foundation of an entire branch of modern biophysics, and the molecular ruler it described is now used in biomedical instruments capable of detecting structural variants of the human genome that conventional sequencing cannot see.

That young physicist was Theo Odijk. Today he is a member of the Royal Netherlands Academy of Arts and Sciences, Guest Professor at the Lorentz Institute for Theoretical Physics in Leiden, and a longstanding visitor at the Max Planck Institute for Polymer Research in Mainz. Across more than four decades of work he has moved deliberately between physics, chemistry and biology — building the statistical mechanics of supercoiled DNA, working out the thermodynamics of the bacterial nucleoid, modeling surfactant phases for industry, and returning again and again to the nonlinear electrostatics of highly charged biological matter. In this Dialogue he speaks at length, and with rare candor, about how that path was built: from a home laboratory in a primitive Australian suburb at age seven, through a Master’s degree taken simultaneously in experimental chemistry and theoretical physics, to the slow recognition that the science he had been told was rubbish was, in fact, correct.

What first drew you toward science, and at what point did you realize that physics, chemistry, and biology could be connected through deep theoretical ideas?

A) I was 7 years old when my dad brought home from the library a chemistry book (he was already aware that I was a very precocious child). I saw a picture of brown iodine turning into indigo when added to starch. Amazed, I started my home lab and my parents allowed me to do anything. For instance, I was fast letting glycerine burn by adding potassium permanganate gaining insight into oxidation versus a reduction. We were living in Smithfield, Australia at the time which was a very primitive suburb of Sydney adjacent to the outback. Nevertheless, the drugstore sold an advanced mathematical journal which I relished. And I was allowed to borrow books from the adult section of the Smithfield municipal library. Our neighbour was an enlightened guy for he lent me Frontiers of Astronomy by Fred Hoyle. I recall being struck by the red shift of galaxies which showed their velocity of separation.

B) At school I disliked the biology teacher immensely. So I decided to adopt a very sophisticated Bachelor’s without biochemistry!! Namely, N4f plus extra mathematics: it was a terrifying programme: Physics, Chemistry, Mathematics, Crystallography majors. 60 hours crammed into a time interval of 40 hours; 20 hours overlap so lab practice had to be done twice as fast etc. Nobody else ever did this and people thought I was crazy. But I felt that I needed a broad background. Recall that I had a sophisticated home lab for 12 years. Actually, I was bored to tears by the University of Leiden and even thought of quitting. Then I heard a professor quoting Goethe in German: which I had read, so I thought Michel Mandel could be an interesting guy. As it turned out Mandel was both a theoretician and an experimentalist; he actually invented his own devices. His interest was in the spectroscopy of polar liquids and polyelectrolytes like DNA and proteins. He was also the leading editor of Biophysical Chemistry, a journal in which physics and chemistry were applied to elucidate the behaviour of biopolymers. The level was sophisticated. I was a Master’s student in both experimental physical chemistry and theoretical physics. Theories of polyelectrolytes were an utter disaster when compared to experiment. I had already written a huge thesis on rocket motion when I was 16 and had worked through books at the University level at 17, so I believed in myself. I told Mandel that I wanted to work on the characterization of DNA solutions and try to solve the polyelectrolyte enigma via statistical mechanics. And he said okay! You can do whatever you like in my department! Accordingly, it was by chance (Goethe!!) that got me into trying to combine physics, chemistry and biology.

Your career has moved across several scientific territories, including chemistry, soft matter, physics, biology, genetics, and nanotechnology. How did this interdisciplinary way of thinking develop?

In 1985 the preeminent biophysicist John Schellman approached me at a macromolecule conference and insisted that I was the theoretician who could solve the general statistical physics of supercoiled DNA in solution. I had explained the effects of charge, confinement and liquid-crystalline order on linear DNA (in vitro). But at that time supercoiled DNA in bacteria was deemed to be an impossibly complicated object to theorize on because it was solenoidal and wildly fluctuating as a result of thermal fluctuations. That changed in 1990 when Boles and White proved experimentally that supercoiled DNA turned out to be plectonemic: a closed and twisted DNA helix was interwound with manageable fluctuations. In 1990, I was invited to talk at a Biochemistry conference in Cambridge, England. Again, several important biophysicists insisted that I should work on tough DNA problems.

During that period I was formulating models of elongated micelles and coming up with new theories involving charge when Unilever asked me to look into the soap phase. This consisted of surfactant lamellae separated by water layers and stabilized by charges. But thermal undulations renormalized the electrostatic interaction to a higher level. Accordingly, it occurred to me that positionally ordered DNA would bear renormalized interactions of a similar nature: hexagonal phases and plectonemic configurations. Also, at the time, I had an experimental PhD student Petra Wissenberg who started working on polymer liquid crystals. But surface alignment proved very tedious so we switched to concentrated solutions of mononucleosomal DNA (147 basepairs long i.e. well-defined). Everything seemed to be converging.

I wrote a proposal for a PhD student with regard to studying DNA more in a biophysical context in 1993. But people thought this transitioning from physics and physical chemistry to biology was ridiculous. I called up F. Hesselink who was now the director of NWO (our NSF) and had previously headed a committee awarding me a scientific prize. He said, okay, next year you’ll get the money. Next, I was invited to give a talk at the conference Biocomplexity in 1996. The cell biologist Conrad Woldringh asked me to think about E. Coli bacteria: Why did its nucleoid exist as a separate entity in the absence of a membrane? There were very small negatively charged proteins able to enter the very large supercoil (also negatively charged). Hence, there must be an equality of the chemical potentials, inside versus outside. On the other hand, the DNA has an excluded-volume effect pushing it outwards. There must be thermodynamic equilibrium which imposes the nucleoid to have an optimum size. This theory (1998) is in very good agreement with experiment. We set up elaborate experiments to falsify or verify this scenario (1996. – now).

EDITOR'S NOTE — The Odijk deflection length
When a flexible polymer like a piece of cooked spaghetti is dropped into a narrow tube, it coils into a random ball. But DNA is not flexible in that sense. It has an intrinsic stiffness, measured by what physicists call its persistence length: roughly fifty nanometers in physiological conditions, or about 150 base pairs of double-stranded helix. Below that scale, DNA behaves almost like a rigid rod. Above it, it begins to bend.
What Theo Odijk realized in 1983, and what nobody in the polymer physics community wanted to accept at the time, is that when such a semiflexible chain is forced into a channel narrower than its own persistence length, it does not coil at all. Instead, it executes a sequence of gentle wave-like deflections against the channel walls, each separated by a characteristic distance. That distance is now known as the Odijk deflection length and obeys a remarkably simple scaling law:
λ³ ∼ D² · P
where P is the persistence length of the polymer and D is the diameter of the channel. The equation says something counterintuitive: as the channel gets narrower, the chain does not crumple more — it stretches out, with the deflections becoming shorter and more frequent. The DNA molecule effectively unfolds itself by confinement.
For twenty-two years this prediction lived in the literature as an outlier. The mathematics was clean, but the experimental tools needed to test it did not yet exist. In 2005, advances in nanofabrication finally produced channels narrow enough to confine single DNA molecules under controlled conditions. The measurements confirmed Odijk's scaling almost exactly. Today the deflection length is the foundational concept behind optical DNA mapping in nanochannels — a technology used to detect structural variants of the human genome that conventional sequencing cannot see, with direct applications in cancer diagnostics and rare disease research.
A theoretical paper dismissed as nonsense in 1983 became, four decades later, the operating principle of a real biomedical instrument.

In the beginning of the 80’s, polymer chains were being inserted in etched channels experimentally. It took me several years of very hard thinking, that a semiflexible chain would bump against the walls in a wavelike manner determined by a deflection length considerably shorter than the typical step length of the unconfined chain. This paper (1983) was in drastic conflict with the thinking in polymer physics; it was generally regarded as rubbish. Nevertheless, lithography advanced over time. In 2005 it was verified that the deflection concept was correct for DNA within a thin channel! I immediately extended my 1983 paper to analyse the precise conditions that it would hold: entropy is lost as a chain nears a wall – entropic depletion! Purely by accident, David C Schwartz of Madison, Wisconsin wrote to me about the paper concerning electrostatics (1977); I wrote back that I had just been writing a new paper on DNA confinement in nanochannels but his lab was working on this very problem for optical sequencing! So we decided to work together and we have done so ever since (2006 until now). Accordingly, my forays into important problems in structural biology and biophysics happened by sheer accident.

« This paper was in drastic conflict with the thinking in polymer physics; it was generally regarded as rubbish.»

You describe yourself as both a theoretician and an experimentalist developing new concepts in physics, chemistry, and biology. How do theory and experiment interact in your own scientific work?

I had a rather sophisticated home lab for 12 years. On the other hand, I discovered that pure (persistent!) thinking could also lead to a reorganization of one’s outlook. For instance, the Debye-Hückel theory of electrolytes (and plasmas!) led to a screening length which caused the free energy to be nonanalytic i.e. a Taylor series in terms of the concentration was no longer possible. This had a deep impact on me because it was also apparent that experiments proved this. Hence, I did 3 years of experiments using many techniques in Mandel’s lab. He had to close down his instruments concerning polar liquids for political reasons! But he was so energetic that he had a complete array of instruments pertaining to polyelectrolytes within a couple of years! I supervised experiments as a lecturer at Leiden University. Later, in 1987, I became full professor in rheology and materials science at Delft University of Technology. The books on polymer science in the Netherlands were utterly outdated so I wrote a short booklet on polymers. Therein modern theory and practice came together. As I explained earlier, I started dealing with various experimental biophysical phenomena involving DNA so I was forced to extending polymer theory to biopolymers. This often involved heavy mathematics but experimental correspondence had to be found. In this business there was no turning back for the experiments were very high level compared to the more sloppy polymer field.

Much of modern science advances at the boundaries between disciplines. In your experience, what makes interdisciplinary research intellectually powerful, and what makes it difficult?

A monodisciplinary field is self-contained and has its conferences ad nauseum. Anomalies are not actively sought out. In interdisciplinary research, boundaries and concepts collide almost automatically. Hence, thinking anew has to start immediately. But a lazy mistake often made is to not be conversant enough in the field beyond one’s expertise. Just listening to another expert will not do!! The famous applied mathematician Sir James Lighthill who worked on the swimming of fishes, insisted that he had a lot to learn of these animals otherwise his theories would be unrealistic. One need not become a full expert but a working knowledge of the novel field seems essential!

«The most important quality that one needs as a scientist or any other creative person is persistence»

You spent many years as a full professor at Delft University of Technology and later became associated with institutions such as Leiden, the Lorentz Institute for Theoretical Physics, and Johannes Gutenberg University. How did these different scientific environments shape your work?

I had just switched from the Chemical Engineering Department to the Biotechnology Department at Delft University of Technology when I was requested to become a LUF professor at the Chemistry Faculty of Leiden University. I was a sort of trouble shooting professor to help all disciplines. I was rated the top chemist by an external committee of foreign scientists at the time. But I wanted definite changes so my presence was deeply resented. Nevertheless, I did succeed in managing a research project involving the discovery of new edible protein/polysaccharide mixtures funded by the Dutch government and nine food multinationals. The low calorie mixtures would have the texture of fatty emulsions. The formulation of the mixture or depletion rules displaying phase diagrams were a big success. I was affiliated with the physics department of the Johannes Gutenberg Universität in Mainz at first as a visiting professor but lately that has been amended to a visiting professorship at the Max Planck Institute for Polymers at the same University. My contact there is Mischa Bonn who has recently discovered how peculiar water acts near various surfaces. I’ve had a fifty year old interest in water which remains an enigmatic substance even today. The Lorentz Institute for Theoretical Physics is of world class. All disciplines are addressed. It is very lively and closely associated with the Lorentz Centre where workshops on a very broad array of topics are presented weekly. So this keeps me on my toes.

Your profile highlights soft matter, nanotechnology, and biological systems. Why are these systems so rich from a physical point of view?

«Soft matter» is matter that typically deforms at forces of order kT/nm where k is Boltzmann’s constant and T is absolute temperature. «Soft matter physics» was officially launched as a subject in its own right in a two-week symposium organised by Jacob Klein at the Weizmann Institute in Rehovot in 1988. The Who’s Who in soft matter were invited to give presentations of their work on: polymers, colloids, fluid and cellular membranes, interfaces at the nm level, rheology, crystallization, biopolymers, pertinent parts of biophysics and structural biology, complex electrolytes, liquid crystals etc. Statistical physics was the underlying methodology. Soft matter physics started, then, back in the middle of the century, was a full discipline in 1988 and has developed rapidly since. It is apt to compare it to fluid dynamics and astrophysics which are also ramified disciplines with their own methods in applied mathematics.

Many readers are familiar with physics through astronomy, particles, or cosmology, but less through biological and chemical systems. What can the physics of matter, molecules, and biological structures teach us about nature at a fundamental level?

In astrophysics and cosmology, a lot of contingent problems needed to be addressed physically. The subject matter was and is simply there. This is in contrast to physics courses in general where the problems to be solved are idealised. Likewise, the physical problems that need to be solved in soft matter are also contingent. A whole body of applied mathematics has arisen as a result. In fact, some of these results can be applied to other fields in view of possible deep analogies.

You are a member of the Royal Dutch Academy of Sciences. Looking back, what do you consider some of the most important lessons from building a long scientific career?

The most important quality that one needs as a scientist or any other creative person is persistence. Doris Wallace and Howard Gruber have come to this conclusion based on their twelve cognitive case studies in their book «Creative People at Work». The scientists, writers and artists that they studied in detail are: Antoine Lavoisier, Hans Krebs, William Wordsworth, Michael Faraday, Charles Darwin, William James, Dorothy Richardson, Albert Einstein, Jean Piaget, Anaïs Nin, Robert Burns Woodward and Melissa Zink.

«Now is the time to study the anomalies!»

For students and young scientists in Latin America, Spain, and other regions who may see high-level research as distant or difficult to reach, what would you like them to understand about the real path into science?

First of all, read the affordable booklets «Advice to a Young Scientist» by Peter Medawar and «Letters to a Young Scientist» by Edward O. Wilson. Medawar received the Nobel award in Physiology for inventing transplantation and mechanisms of the immune system (1960). Both Medawar and Wilson are fascinating scientists; see their respective Wikipedia entries. Becoming a scientist is a very slow process of self-realisation. One’s heart needs to be in it for the long run. Along the way, all kinds of insight and pertinent information is accumulated: it pays to have a diary. There are two worlds: one formal involving education at a university which is often not very useful for carrying out research, the other private and informal which optimizes for research later on. It is important to seek guidance from people outside of the system. In my case, I learned of Wittgenstein and Freud at the age of 18 which proved very beneficial with regard to my scientific outlook later on. When I had just turned 21, I discovered the Course of Theoretical Physics by Landau and Lifshitz which allowed me to make intuitive sense of a lot of dry formalism. One has to follow one’s own path. At this very moment, we have utterly novel measurements by the James Webb telescope contradicting a lot of conventional paradigms. Now is the time to study the anomalies! This is, of course, easier said than done; but discovering new physical concepts has never been straightforward.

Looking toward the future, which questions at the intersection of physics, chemistry, biology, and theoretical science do you believe remain especially important or promising?

As I’ve stated before, soft matter physics has become a sophisticated field in its own right. In particular, I myself have been confronted by highly nonlinear problems where two phenomena are intertwined. The difficulty is that you cannot «perturb» yourself out of this problem i.e. assume a naive perturbation theory exists. Let me given an example. The double-stranded DNA helix in a NaCl solution may be viewed as a highly negatively charged cylinder surrounded by Na+ ions and Cl- ions. The electrostatic potential Y is basically given by the so-called nonlinear Poisson-Boltzmann equation: ΔY = sinh Y in dimensionless units (lengths are scaled by a Debye screening length). At the cylinder surface at dimensionless radius a, Na+ ions will tend to cluster more and more as a becomes very small. But it turns out that Y tends towards a Schwartz distribution as a -> 0. Moreover, the equation cannot be linearized. Perturbation theory is useless. People have asked me to look into the quantum gravity problem because I’ve managed to solve several intertwined nonlinear problems in soft matter physics.

Chemistry is now undergoing rejuvenation because of AI.

Biology is merely at the beginning stage of being a predictive science. Things are happening concurrently at so many levels. My impression is that deep progress will be slow.

Editorial Reflection

What emerges from this conversation is not a tribute. It is a working portrait of how serious science is actually built: alone, slowly, often against the prevailing taste of one’s own field, and always with the discipline to hold an idea long enough that the rest of the world catches up. Odijk’s career is a sequence of intellectual bets placed before the experimental tools to verify them existed — on confined polymers, on plectonemic DNA, on the thermodynamics of the bacterial nucleoid, on the nonlinear electrostatics of highly charged cylinders. In each case the timing was the same: the prediction came first, and the verification came years or decades later. The deflection length waited twenty-two years. Other ideas in this conversation are still waiting.

What he leaves the reader with, beyond the science itself, is a method of inhabiting the scientific life. Read widely outside your discipline. Keep a private notebook alongside the formal one. Be genuinely conversant in the territory you are crossing into, not merely curious about it. And above all, study the anomalies — the measurements that do not fit, the data the current paradigm cannot accommodate, the conflicts between theory and observation that the field would prefer to ignore. The James Webb Space Telescope is producing such anomalies now, in cosmology. Soft matter physics produces them constantly. Biology has barely begun. For a young scientist in Latin America, Spain, or anywhere else wondering whether a life of this kind is reachable, Theo Odijk’s answer is in this Dialogue, said plainly: it is reachable, but it is slow, and the only requirement that cannot be substituted is persistence.

By Homer Dávila Gutiérrez,FRAS. SKYCR.ORG