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Physics of Life (2022)

Chapter: 1 What Physics Problems Do Organisms Need to Solve?

« Previous: PART I: EXPLORING BIG QUESTIONS
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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1

What Physics Problems Do Organisms Need to Solve?

In order to survive in the world, organisms have to accomplish various tasks. They have to move toward sources of food, sometimes over long distances, guided only by weak cues about the location of the source. They have to sense useful signals in the environment, and internal signals that guide the control of their own state. They often need to generate dynamics on time scales, which are not the natural scales given by the underlying mechanisms. All of these tasks consume energy, and hence require the organism to extract this energy from the environment. These various tasks of the organism often are described as “functions,” and this notion of function is an essential part of what sets living matter apart from non-living matter. To a remarkable extent, carrying out these functions requires the organism to solve physics problems (see Box 1.1), although it is more precise to say that evolution has selected organisms that achieve effective solutions to these problems. One of the central problems in biological physics is to turn qualitative notions of function into precise physical concepts. Along the way, we will see that these physical concepts often give us absolute notions of performance, such as the efficiency of energy conversion or the precision of chemical sensing in relation to the limits set by random arrival of molecules at their targets. It is a remarkable fact about living systems that evolution can in some cases select for mechanisms that approach the bounds of what is allowed by the laws of physics. In many cases what is understood are just the first steps in how these functions are achieved, and new and open physics problems emerge as one pushes beyond these. The list of physics problems that organisms must solve is far from exhausted by the examples in this chapter, and this emphasis on function will carry through all of the subsequent discussion. A sampling of the issues that we encounter is provided in Table 1.1.

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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TABLE 1.1 Physics Problems in the Life of the Organism

Physics Problems Page Number Broad Description of Problems Frontier of New Physics in the “Physics of Life” Potential Application Areas
Energy conversion 49 Living systems harness classical and quantum dynamics to achieve efficient energy conversion; nanoscale linear and rotary motors. New methods for single molecule measurement and manipulation; new theoretical ideas on thermodynamics and information on small scales and away from equilibrium. Photosynthesis, batteries, solar panels.
Mechanics, movement, and the physics of behavior 61 Finding simplicity in movements through complex, natural environments; mechanics and hydrodynamics in novel regimes. Long time scales and hidden symmetries; optimal flow networks. High throughput analysis of behavior; robotics.
Sensing the environment 70 Counting photons and molecules; sensing small forces and displacements; signal processing. Physical limits to sensing and signaling; molecular mechanisms of amplification; separating signal from noise. Bio-inspired sensors and signal processing strategies.
Structures in space and time 80 Emergence and control of structure on scales far removed from microscopic mechanisms. Self-assembly; scaling; molecular clocks. New materials and synthesis methods.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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ENERGY CONVERSION

In the physicists’ view of life, equilibrium is death. To maintain life, organisms capture energy from the environment and use this energy to keep themselves away from equilibrium, creating locally ordered states of matter and carrying out all the other functions crucial for survival. Starting with 19th-century concerns about the laws of thermodynamics, energy conversion in biological systems has been a continuous source of fascination for physicists. These problems range from quantum dynamics in the first steps of photosynthesis to the classical mechanics of swimming and flying.

Photosynthesis

Much of the energy that supports life on Earth comes from the sun, and photosynthetic organisms capture the energy of sunlight directly. This initial energy capture ultimately drives a chain of chemical reactions that convert carbon dioxide into the stuff of life, with spectacular efficiency. Along the way, many photosynthetic organisms emit oxygen as a waste product, and this is the source of almost all the oxygen in our atmosphere, making it possible for us to breathe. It is difficult to overstate the importance of photosynthesis to our lives, and to the health of the planet as a whole. In addition, photosynthesis provides inspiration for the design of artificial systems that capture solar energy.

Physicists have been fascinated by photosynthesis for nearly a century. These explorations have generated the remarkable result that photosynthetic organisms harness a subtle interplay of classical and quantum physics to achieve extraordinary efficiency. Parts of this understanding now are well established, providing a solid foundation for exploration of quantum effects in other biological processes. From a historical perspective, the emergence of this understanding straddles the emergence of biological physics as a part of physics, and thus some of the crucial insights are seen now as part of mainstream biology, or perhaps part of biophysics as a biological science. Many of the conceptual problems arise also in the behavior of large molecules more generally, and thus have strong connections to chemistry. The problem of categorizing these developments is highlighted by the fact that there are subjects (with specialized journals) called physical chemistry and chemical physics. In surveying the physics of living systems, what seems important here is that many crucial questions about photosynthesis came out of the physics community, along with methods—both theoretical and experimental—to address these questions. In this section, as in the rest of the report, the committee takes this broad view of biological physics as the engagement of physicists with the phenomena of life, even at moments when the field did not have a name.

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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The basic processes of photosynthesis are associated with chlorophyll molecules, but photons can be absorbed by other pigment molecules and drive these processes with nearly equal efficiency. Hints of this possibility date back into the 1800s, but conclusive evidence came only in the 1930s, and this triggered, in the theoretical physics community, the first discussions of what now is called fluorescence energy transfer. More generally, photosynthetic organisms contain many more chlorophyll molecules than those involved directly in the chemical reactions driven by light, leading to the picture of a large “antenna” composed of many chlorophylls, absorbing light and funneling energy to a “reaction center” that contains only a handful of these molecules.

The problem of energy transfer in the photosynthetic antenna would recapture the attention of the physics community in the 21st century, with the first direct evidence that the process involves quantum mechanical coherence. But effort first would be focused on the isolation of the reaction center. A crucial observation was that the initial events following photon absorption involved the transfer of an electron, and that this could happen even at very low temperatures. The fact that electron transfer continues at low temperature implied that it was happening not between two separate molecules that had to find one another in solution, but inside a single large molecule or molecular complex, the reaction center (see Figure 1.1).

Electron transfer was detected first by the presence of an electron paramagnetic resonance (EPR) signal from the resulting unpaired electron(s). This pointed the way to the use of sophisticated spectroscopic methods, such as electron-nuclear double resonance, to characterize the dynamics of the reaction center, and this was parallel to the development of these methods to characterize impurities in semiconductors. Furthermore, movement of electrons in large organic molecules is associated with changes in their optical properties. With the continuing development of faster pulsed lasers, it became possible to resolve photon-driven electron transfer in the reaction center on the microsecond time scale, then nanoseconds, then picoseconds. All of these spectroscopic experiments resulted in a picture of the reaction center as a large protein complex that holds several organic molecules, including chlorophylls, which act as electron donors and acceptors, summarized in Figure 1.1A and 1.1B. The reaction center was known to be embedded in a membrane, so that the net result of photon absorption is to separate charge across the membrane, and this provides the “battery” that drives all subsequent chemical reactions. This picture was confirmed, beautifully, when it became possible to crystallize the reactions centers and solve their structures by X-ray diffraction, shown in Figure 1.1B.

Careful investigation of the photon-driven electron transfer events in the photosynthetic reaction center revealed that these reactions not only happen at low temperatures, but the rates of these reactions are in many cases nearly independent of temperature. In the first example, a microsecond reaction time slowed to mil-

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.1 Photon-driven electron transfer in the photosynthetic reaction center. (A) Schematic of photon absorption by a dimer of bacteriochlorophyll [(BChl)2] followed by electron transfer to a bacteriopheophytin (BPh) and then quinones (QA,B), with reaction time scales indicated; when the reaction center is isolated the electron eventually returns to (BChl)2, but slowly. (B) The electron donor and acceptors in the three-dimensional structure of the reaction center. DA and DB form (BChl)2; B is bacteriochlorophyll that acts as a virtual intermediate in the transfer to BPh (ϕ). The symmetry in arrangement of these components is broken by the dielectric properties of the protein, channeling electron transfer to one side. SOURCE: Reprinted by permission from Springer: G. Feher, J.P. Allen, M.Y. Okamura, and D.C. Rees, 1989, Structure and function of bacterial photosynthetic reaction centres, Nature 339:111, copyright 1989.

liseconds as the system was cooled, but then the time became temperature independent below an absolute temperature of around 100 K. To begin, it is astonishing that the mechanisms of life “work” at these low temperatures. As the faster reactions were resolved, it was found that these are nearly temperature independent at room temperature, in some cases even becoming slightly faster as the system is cooled. These results are in marked contrast to typical chemical reactions, where rates are exponentially sensitive to temperature changes, following the Arrhenius law. This is a sign that quantum mechanical effects are important, and through the 1970s and 1980s, the biological physics community reached a relatively complete understanding of this.

In the classical picture of chemical reactions, molecules have two possible structures, each of which is locally stable, being at a minimum of the energy, and there is an energy barrier between them. Thermal fluctuations cause random motions around these minima, and with some small probability these fluctuations have a large enough amplitude to allow escape over the barrier. The typical energy of the thermal fluctuations is kBT, and the height of the barrier is called the activation energy Eact; the rate of the chemical reaction is kAeEact/kBT, where the factor A is related to the time scales of random vibration around the local minima. But quantum mechanics has the possibility of systems visiting states which would be

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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forbidden by classical physics, such as positions under the barrier when the molecule does not have enough energy to go over the barrier. This is called tunneling through the barrier, and will be the dominant reaction mechanism at sufficiently low temperatures. In another view, as the temperature is lowered the random thermal motion is frozen out, and all that remains is the quantum zero-point motion that is required by the uncertainty principle.

Electron transfer reactions, as in photosynthesis, have an additional feature, because the two possible structures of the relevant molecules are associated with distinct states of the electrons. Because of the large distances over which electrons are transferred, these states are very different and the “mixing” of the states is weak. The transferred electron itself always passes through a region of the molecule that would be forbidden by classical physics, and across the relevant range of temperatures there is never enough energy for the electron to go over these barriers. Thus, electron transfer always proceeds by electron tunneling. At high temperatures the prediction is that that the changes in molecular structure occur by thermal activation, but at lower temperatures there will be tunneling from one structure to the other. The crossover temperature is such that the thermal energy is comparable to the energy for one quantum of vibrational motion, and this is consistent with what is seen in the photosynthetic examples. The chemical reaction can be seen as converting the energy released by electron transfer into multiple quanta of vibrational energy, or phonons, which then relax into the surrounding medium. In large molecules such as the photosynthetic reaction center, there is a mix of high frequency and low frequency vibrations, and this can lead to the anomalous patterns of temperature dependence seen in this system. Thus, electron transfer in photosynthesis depends on an interplay of classical and quantum dynamics, at biologically relevant temperatures. This understanding provides a foundation for thinking about quantum effects in biological molecules more generally (see Box 1.2).

Reactions can release energy, and it takes time for the molecule to dissipate this energy, coming to internal equilibrium and to equilibrium with its surroundings. Our usual ideas about chemical reactions are based on a separation of time scales, in which this equilibration is understood to happen fast, much faster than the rate of the reaction, so that it makes sense, for example, to say that the molecule is at the temperature of its environment. However, the very first photon-driven electron transfer in the reaction center happens so quickly that one might worry whether this approximation is valid. More subtly, in a quantum mechanical description, the states where the electron is localized on the donor or acceptor mix coherently, and it takes time for this coherence to be destroyed; again, conventional ideas about chemical reactions assume that the time for loss of quantum coherence is much shorter than the reaction time.

Very careful fast pulse laser spectroscopy on the reaction center reveals oscillations reflecting the persistence of coherence in molecular vibrations on time

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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scales comparable to the initial electron transfer rate. It is important that truly irreversible reactions cannot happen faster than the loss of coherence. The reaction center seems to be in a regime such that the mixing of electronic states, the loss of coherence, and the reaction rate all are on similar time scales. This generates the fastest possible rate given the structure of the relevant electronic states, and pushes us to think about the physics of quantum transitions in a new regime.

The question of quantum coherence was revitalized by observations on components of the photosynthetic antenna. As with chemical reactions, the usual regime for energy transfer between molecules is one in which the transfer rate is much slower than internal rates for the dissipation of energy and the destruction of coherence. Sophisticated spectroscopic experiments in the late 2000s showed that coherence in energy transfer through photosynthetic antenna complexes persists for surprisingly long time scales. The result is that transfer rates are comparable to the rate at which coherence is lost. Exploring these dynamics, and understanding their implications for the efficiency of energy harvesting, are topics of current research.

In the physics laboratory, the search for direct manifestations of quantum coherence often drives us to very low temperatures, and to settings in which the system of interest can be isolated from its surroundings. But life operates (primarily) in a narrow range of temperatures near room temperature, and biological mol-

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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ecules interact strongly with a surrounding bath of water molecules. These warm and wet conditions are not those under which quantum coherence is expected to survive, so the results of these experiments and the subsequent theoretical analysis were unexpected. It was discovered that spectrally tuned “noise” from the real world could in fact enhance both quantum coherence and energy transfer; they can be turned to advantage but are required together, and it seems that living systems have discovered this path and evolved molecular structures that execute this effectively. These analyses connect to ideas about coherence and dissipation in quantum measurement and quantum computing, part of a broader rethinking of how quantum systems couple to the macroscopic world.

The photosynthetic reaction center traps the energy of light by separating electronic charge across a membrane. In the intact system, this electronic charge is compensated by the movement of protons, so that energy is stored in a concentration difference, or chemical potential difference for protons. This chemical potential difference turns out to be a universal intermediary in how cells handle their energy supply. There are even bacteria that have direct light-driven proton pumps as an alternative to the more complex photosynthetic reaction center. In our cells, as in those of other eukaryotes, specialized structures called mitochondria extract energy from many different chemical sources, and then use this energy to pump protons across their membranes. A different protein in the membrane provides a channel for these protons to flow back along the gradient in their chemical potential and harnesses the energy that is released to synthesize the adenosine triphosphate (ATP) molecule; see Figure 1.5. ATP is the classical “energy currency” of biochemistry, and provides the direct fuel for processes ranging from the contraction of our muscles to the correction of errors in reading and copying genetically encoded information. In contrast, bacteria swim by rotating their flagella, and this rotation is powered directly by protons rather than ATP (see Figure 1.4). Even beyond its intrinsic importance, the physics of how the photosynthetic reaction center captures the energy of sunlight thus provides an entrance point for studying mechanisms of energy conversion that are shared across all forms of life on Earth.

Motors

Photosynthesis converts the energy of sunlight into chemical form. When organisms move, they (we!) convert energy from chemical form into mechanical form—forces and displacements. Careful measurements on mechanics and energy dissipation in muscle have their roots in 19th-century experiments that were instrumental in establishing the laws of thermodynamics and banishing ideas of vitalism. In the mid-20th century, X-ray diffraction and optical microscopy methods were developed to visualize the relative sliding of actin and myosin protein filaments, which provides the microscopic basis for muscle contraction. Today, these X-ray

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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measurements can even be done in an insect flight muscle while the insect is flying, directly connecting nanometer scale filament movements to the macroscopic dynamics of force production and movement (see Figure 1.2).

Biochemists and cell biologists discovered that the same proteins, actin and myosin, are present not just in muscle but in all eukaryotic cells. Actin is a key component of the cellular cytoskeleton, which provides a cell with structural support, and myosin is a “motor protein,” or a mechanoenzyme, which converts chemical energy into mechanical work. In muscle fibers, myosin motor proteins are assembled into filaments, responsible for force generation and sliding along

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FIGURE 1.2 X-ray diffraction can be used to visualize microscopic-level muscle contraction, or the relative sliding of actin and myosin protein filaments. Here, synchrotron X-ray diffraction is used to image molecular-scale changes in muscle during flapping flight in a fly. (A) Experimental apparatus showing flight musculature in the tethered fly Drosophila scattering-ray radiation from the small angle instrument on the BioCAT undulator-based beamline 18-ID at the Advanced Photon Source, Argonne National Laboratory. (B) Sample diffraction patterns from live flies at rest (left) and at two phases in a wingbeat cycle. SOURCE: Reprinted by permission from Springer: M. Dickinson, G. Farman, M. Frye, T. Bekyarova, D. Gore, D. Maughn, and T. Irving, 2005, Molecular dynamics of cyclically contracting insect flight muscle in vivo, Nature 433:330, copyright 2005.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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actin filaments. In addition, cells have other motor proteins, such as the kinesin molecules that transport intracellular cargo along microtubules, another structural element of cells. For example, the axons of nerve cells can reach one meter in length, from our spinal cord to our toes, and kinesin motor proteins haul cargo vesicles from the neuronal cell bodies in the spinal column to the tip of the big toe. As described in Chapter 3, the collective behavior of these motor molecules and filaments in living cells provides a prototypical example of active matter.

Analysis of macroscopic measurements on forces and displacements of single muscle fibers suggested that individual protein molecules produce forces on the scale of picoNewtons, and that the elementary molecular events involve displacements on the scale of nanometers. This means that the energy used in the elementary steps of movement is on the order of the thermal kinetic energy of single molecules, far from our usual intuition about macroscopic motors and engines. These basic facts about biological motors provided crucial motivation for new theoretical ideas about non-equilibrium statistical physics and thermodynamics in the stochastic regime. From the experimental side, the exploration of movements in cells and organisms was revolutionized by the realization that controlled forces on this scale could be applied by the interaction of light with matter, in optical traps or “tweezers” (see Box 1.3). The biological physics community made a major effort to develop these single molecule manipulation experiments, which have now been exported to the broader community of biologists. Figure 1.3 shows early measurements on single molecules of the proteins actin and myosin, which generate the force in our muscles. By holding a single actin filament between a pair of optical traps and bringing it into contact with myosin molecules attached to a plastic bead (Figure 1.3A), it was possible to see hints of stepwise motion as the myosin molecule “walks” from one actin monomer to the next along the filament. At low concentration of the fuel for these reactions (ATP), force generating

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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interactions are rare and there are signs of quantization (Figure 1.3B), as expected if these result from discrete molecular interactions. In subsequent data, all of these results have become sharper, and similar results have been found for other motors such as kinesin and dynein.

Myosin, kinesin, and dynein are linear motors. These linear motors power muscles, cell movements, and intracellular transport. They also power the whip-like motions of the cilia that, for example, move fluids and debris along the airways leading to our lungs, and the flagella that allow many single celled organisms to swim. It thus came as a huge surprise that the flagella which power the motion of bacteria are not waving, as they seem to be, but rather rotating. They are driven by the world’s smallest rotary engine, as schematized in Figure 1.4. As noted above, this motor is powered directly by the difference in chemical potential for protons

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FIGURE 1.3 Single molecule experiments help us to understand molecular motors, including force generation in muscle. Optical trapping reveals molecular-scale forces and displacements generated by muscle proteins. (A) A single actin filament is stretched between two beads, each of which is held in an optical trap. The filament is brought into contact with a third bead, which is coated with myosin molecular motors. (B) Force exerted by myosin motors over time under (isometric) conditions of zero displacement; upper trace is force along the filament, lower trace perpendicular to the filament. At these low concentrations of ATP, force generating interactions between myosin and actin are rare, and discrete, suggestive of individual molecular events. SOURCE: Reprinted by permission from Springer: J.T. Finer, R.M. Simmons, and J.A. Spudich, 1994, Single myosin molecule mechanics: Piconewton forces and nanometre steps, Nature 368:113, copyright 1994.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.4 While myosin, kinesin, and dynein are linear motors that power muscles, cell movement, and intracellular transport, the flagella, which power the motion of bacteria, are powered by rotary motors. Schematic (top left) showing the protein components of the motor and its anchoring in the cell membranes. Structure of core components (top right) reconstructed from electron microscopes images. Cells that do not make the MotA protein cannot rotate their flagella. As they make more of the protein, the rotation rate (bottom, for a cell tethered to a glass slide) increases in steps as individual proteins are inserted into the structure, each contributing a discrete unit of torque. SOURCE: H.C. Berg, 2003, The rotary motor of bacterial flagella, Annual Review of Biochemistry 72:19.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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between the inside and outside of the cell. A steady stream of mechanical measurements on single motors has led to very well developed theoretical ideas, which have been invigorated in the last 2 years by two major developments. First, there is a previously undetected feedback from the mechanical load on these motors to their internal dynamics, which has implications for how bacteria control their movements. Second, developments in cryogenic electron microscopy have delivered a structure of almost the entire motor in full atomic detail (see Figure 6.2), which will provide a literal scaffolding for understanding how the flow of protons is coupled to molecular rotation.

An important result of measurements on single motor molecules is the clear demonstration that these systems are engines in which a single working cycle delivers an energy that is larger than the thermal energy, but not by a very large factor. They thus operate in a regime where randomness is not negligible, and consequently the engine cycle has a stochastic duration. Such engines are bound by the same laws of thermodynamics as are the more familiar engines in our engineered, industrial world. But this regime of “Brownian motors” is very different, and this raises new and fundamental questions in statistical physics. On this small scale, for example, is the second law of thermodynamics only true on average? These questions have given rise to a new field of stochastic thermodynamics, and connects to a renaissance in non-equilibrium statistical mechanics. In return, optical trapping and the manipulation of single molecules have provided some of the most important experimental tests of emerging theoretical ideas. These connections are described in more detail in Chapter 5.

Movement Beyond Motors

Many molecules that are not functioning primarily as motors in fact generate forces and movements as an essential part of their function, and can thus be studied using the same methods developed for studying single motor molecules. Indeed, this is true for some of the most crucial molecules of life. As noted above, much of the ATP in all eukaryotic cells is synthesized by a membrane protein, called the F0F1-ATP synthase, that uses the chemical potential difference of protons across the membrane as an energy source. As with the proton-driven motor of bacterial flagella, this molecule rotates as it carries out its chemical function. This rotation is visible in single molecules that are fixed to a glass slide and running “backward,” degrading ATP molecules to pump protons, as in Figure 1.5. Strikingly, unlike the linear motors myosin and kinesin, which have irreversible cycles and convert only a fraction of the energy from ATP into mechanical work, the ATP synthases are nearly 100 percent efficient; they are thus reversible and can be run in either direction (i.e., to consume or to produce ATP). In eukaryotic cells there are additional V-ATPases, rotary motor enzymes that create proton gradients using the

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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energy stored in ATP. These molecules provide important motivating examples for stochastic thermodynamics.

Another crucial class of molecules that move as they carry out their function are those involved in copying, reading, and translating the information encoded in DNA and RNA. These include polymerases, ribosomes, helicases, gyrases, and topoisomerases. Single molecule measurements have provided an extraordinarily direct and precise view of this information processing, as discussed in Chapter 2. As explained there, an important function for many of these molecules is “proofreading,” whereby the cell expends energy to achieve fidelity of information transmission beyond what would be possible from the equilibrium thermodynamic specificity of molecular interactions alone. In the same way the operation of biological motors with cycles that generate near-thermal energies provides motivation for the more general problems of stochastic thermodynamics, the interplay of energy

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FIGURE 1.5 Many molecules that are not functioning primarily as motors generate forces and movements that allow them to be studied using the same methods developed for studying single motor molecules. The F0F1-ATP synthase, a membrane protein that synthesizes much of the ATP in all eukaryotic cells, is an example of a non-motor molecule that rotates to carry out its chemical function. At left, a schematic of the experiment shows the many protein subunits of the molecule assembled and bound to a glass slide at one side and a plastic bead (not to scale) at the other. At right, the angular position of the bead (measured by the number of rotations) versus time is shown. It is clear that movement pauses three times per full rotation. Insets show the distribution of pause lengths and the distribution of bead positions. SOURCE: H. Ueno, T. Suzuki, K. Kinosita, Jr., and M. Yoshida, 2005, ATP-driven stepwise rotation of F0F1-ATP synthase, Proceedings of the National Academy of Sciences U.S.A. 102:1333, Creative Commons License CC BY-NC-ND 4.0.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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dissipation and fidelity in proofreading provided important motivation for deeper understanding of the connections between thermodynamics and information. These ideas continue to develop, and it is reasonable to expect that we will see the emergence of some deeper principles about how life harnesses non-equilibrium statistical physics to generate precise functions at minimal energy cost.

Perspective

The phenomena of energy conversion in living systems have inspired the development of new physics for more than a century, dating back to the origins of thermodynamics, and this continues to the present day. At one extreme, living systems have harnessed a subtle combination of classical and quantum dynamics to achieve efficient energy conversion in photosynthesis. This runs counter to the common intuition that quantum mechanics connects to the phenomena of life only by determining the rules of chemical bonding, highlights new physics in regimes not commonly encountered in the inanimate world, and points to new opportunities for engineered devices and molecular design (Chapter 7). In a different regime, linear and rotary motors provide examples of efficient energy conversion in non-equilibrium systems at fixed temperature. The effort to explore these nanomachines has led to the development of new methods for single molecule measurement and manipulation, and to sharp new theoretical ideas about the relations between thermodynamics and information on small scales and away from equilibrium. These developments in biological physics are continuous with a broader renaissance in non-equilibrium statistical mechanics (Chapter 5). The scarcity of resources places enormous pressure on living systems to be energy efficient, and clear articulation of the physical principles that underlie this efficiency will provide paths for engineering and synthesis (Chapter 7) that will surely help us rise to our global challenges in sustainability and climate change. While we understand much about individual processes, how these processes fit together in whole organisms, and in communities of organisms, is as yet only faintly sketched.

MECHANICS, MOVEMENT, AND THE PHYSICS OF BEHAVIOR

Humans have long been inspired by the soaring flight of birds and the elegant swimming of fish. Children are charmed by the dispersing seeds of a dandelion, and fascinated by columns of ants. The movements of fluid through the stems and leaves of plants are hidden from us, but no less vital. To be alive is to be in motion.

Organisms do not move in isolation. Swimming and flying depend in an essential way on interactions with the surrounding water and air, and have been the source of important problems in the development of fluid mechanics. Many organisms propel themselves through sand or soil, and our growing understand-

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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ing of these movements is linked to current physics problems in the description of granular materials (Chapter 5); there is growing appreciation that similar problems arise for cells moving through tissues, including tumors. Our own interactions with the hard ground while walking seem simpler, but the persistent challenge of building robots that can walk on rough terrain suggests that the underlying dynamics are subtler than they first appear (Chapter 7).

Life at Low Reynolds Number

Most of the organisms on Earth experience moving through the world in a regime very different from what humans experience moving through air or water. A human swimmer, for example, can push off the wall of a swimming pool and move forward for a significant distance with no additional effort. Similarly, if swimmers stop moving their arms and legs, their whole bodies continue to move forward. These are manifestations of inertia. Eventually the drag or viscosity of the surrounding fluid wins out, but not before the swimmer has “coasted” a distance comparable to their own body length, or more. Life is very different for bacteria and other microorganisms.

As always in physics, when writing the equations of fluid flow—in air or water—there is freedom to choose the units of measurements. There are “natural” choices, for example using the typical swimming speed as a unit of velocity, and the size of an organism as the unit of length. In these natural units, the equations describing different organisms in different environments depend only on some unit-less combinations, or ratios. Perhaps the most important of these is the Reynolds number, which is the ratio of inertial to viscous forces (see Figure 1.6). At very large Reynolds number fluid flows become turbulent; at very small Reynolds number inertia is negligible and organisms need to work constantly against the viscosity of the surrounding fluid in order to keep moving.

For a human swimming in water, a typical Reynolds number is 10,000. For a bacterium, a typical Reynolds number is 100 million times smaller, roughly 0.0001. When humans stop swimming they can coast for several feet. If a bacterium stops rotating its flagella, it will coast only for a distance comparable to the diameter of an atom.

Life at low Reynolds number has many consequences. As an example, nutrient molecules arrive at the surface of a bacterium as a result of their random motion, or diffusion, and no reasonable expenditure of energy by the cell could stir the fluid enough to increase this flux. More profoundly, at very low Reynolds number, the viscous forces from the surrounding fluid balance the active forces that an organism generates in order to move, and this balance is enforced moment by moment. As a consequence, as the organism goes through one cycle of movement—one rotation of a bacterial flagellum, one beat of a eukaryotic cilium, one full squirm or writhe

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.6 One can make a rough estimate of the inertial and viscous forces involved when an object of size a moves at speed ν through a fluid with density ρ and viscosity η. The ratio of inertial to viscous forces is the Reynolds number R = avρ/η; it is convenient to define the kinematic viscosity ν = η/ρ. The sketches at the right indicate typical Reynolds numbers for swimming humans, fish, and bacteria. SOURCE: Reproduced from E.M. Purcell, 1977, Life at low Reynolds number, American Journal of Physics 45:3, https://doi.org/10.1119/1.10903, with the permission of the American Association of Physics Teachers.

of a more complex but still microscopic creature—the amount by which it moves forward depends on the sequence of movements and not on the speed with which these movements are executed. In particular, if the sequence looks the same when played forward and backward in time, the net displacement will be zero.

A fluid without viscosity obeys time-reversal invariance, so that a movie of the flow can be run in reverse and still be a solution of the underlying equations. With a little bit of viscosity, this time-reversal invariance is broken, and movies running backward are easily recognized as impossible. But in the limit that viscosity is large—the limit of low Reynolds number—time-reversal invariance is restored. To move through the world, microorganisms must wriggle and writhe in ways that actively break this symmetry on the macroscopic scale.

Bacteria swim by rotating their flagella (see Figure 1.4). The flagella themselves are helical, and thus have a handedness, twisting clockwise or counterclockwise when viewed from the cell body. The combination of rotational direction and helical handedness serves to break time-reversal invariance, and this is what allows the bacterium to propel itself. Similar symmetry breaking can be found in cilia (eukaryotic flagella). Thus, it is not enough to say that these organisms swim because they have motor proteins that generate forces. These forces need to be organized in ways to solve the underlying physics problem. It remains a challenging problem to

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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link what is being learned about molecular motors (e.g., through single molecule experiments as in Figure 1.3) to macroscopic, functional movements.

Abstracting away from the details of particular movements is useful, and generates surprises. Self-propulsion is a process in which organisms change their shape periodically, as with the rhythmic strokes of a swimmer or the rotation of the bacterial flagellum. At low Reynolds number all that matters is the trajectory through this “space of shapes.” But in describing the space of shapes, there is an arbitrariness in the choice of coordinates; any physical quantity, such as the actual movement of the organism as it swims, must be invariant to these choices. This kind of “gauge invariance” has a long history in physics, starting with the theory of the electromagnetic field, and continuing into the theories of the strong and weak forces among elementary particles. In the 1980s, it was realized that much of the beautiful mathematical structure of gauge theories can be translated into this new context, and turned into practical tools for calculation.

The first applications of the gauge theory approach focused on swimming by small deformations of the organism’s surface. This is relevant for single celled organisms such as paramecia that are covered by a dense array of cilia that beat in coordinated patterns, approximating an undulating surface. In this regime it becomes possible to calculate the maximally efficient deformations, and the important lesson is that even the optimal energetic efficiency is very low—a physical rather than biological limitation. More recently, largely through the efforts of control theorists, the gauge theory formulation has been applied to larger amplitude motions, relevant for a much wider range of organisms. In parallel, it has come to be appreciated that organisms that slither and crawl over and through granular materials, such as snakes on the sand, also live at effectively low Reynolds number. Analyses of the movements of these organisms, coupled with gauge theory ideas, have been central to the emergence of new kinds of robots, as described in Chapter 7.

Flow Networks

Fluids flow not only outside the organism, but also inside. In humans and many other animals, life depends on the circulation of blood. This is exquisitely well controlled, especially in the brain. Magnetic resonance imaging allows us to visualize these flows directly and see how they are modulated by demands on brain activity as people interpret what they see, plan movements, recall memories, and so forth (Chapter 6). In plant leaves, a similarly complex network of veins effectively connects every cell to the source of water in the stem (see Figure 1.7, left). Both brains and leaves devote considerable resources to their vasculature, and the biological physics community has explored whether there might be general physical principles governing the distribution of these resources. For example, are there networks that minimize (in the leaf) the pressure drop from the stem to the tips, or

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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equivalently the power dissipation in the flow, on the assumption that segments of veins have a cost related to their conductance? An idealized version of this problem would predict that the network has no loops, but if we search for a network that functions in the presence of fluctuating loads or occasional damage, the optimal networks have loops, as do the real networks (see Figure 1.7, right). This theoretical work raises questions about how to characterize the “loopiness” of flow networks, and how such networks could develop.

Each leaf can have a different vascular structure, so structure is not specified by genetics. Rather, it has been suggested that the structure is determined by the

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FIGURE 1.7 Fluids flow inside of organisms as well as outside. Plant leaves contain a complex network of veins that connects every cell to the source of water in the stem. (A) Visualization of fluid flow through the veins of a leaf, with a fluorescent dye. Fluid coming from the stem (at bottom) reroutes through loops in leaf’s veins, avoiding the damage (black circle) to the main vein, and eventually arriving at the leaf tip. (B) Models of vascular networks that minimize power dissipation develop loops when random links are damaged (left column) or when there is water loss at a varying location in the leaf (right column). The thickness of each vein indicates its conductance. Models with different costs for vein conductance (top to bottom) show that the development of loops is robust. SOURCE: Reprinted with permission from E. Katifori, G.J. Szöll´ósi, and M.O. Magnasco, 2010, Damage and fluctuations induce loops in optimal transport networks, Physical Review Letters 104:048704, copyright 2010 by the American Physical Society.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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process of growth of the leaf combined with biochemical cues that can, for example, impose the rule that each channel in the network grows according to the amount of fluid passing through it—the higher the flux, the more the channel widens. This rule leads to vascular structures “designed” for low dissipation, enhancing the function of the vasculature. In this view what is encoded genetically, and thus subject to selection, are the rules of growth, which ultimately determine the functional performance of the system. Closely related ideas about the interaction of flow and growth have arisen in thinking about the remarkable coordination of behavior over long distances in acellular slime molds.

Toward the Physics of Behavior

The interaction of organisms with their surroundings defines what is necessary for movement, and also sets the context within which this movement is controlled. A moth hovering near a flower to extract nectar, for example, confronts a collection of problems. Hovering near the flower requires seeing the flower itself and compensating for the wind, and it is surprising how well this works even as a bright blustery day turns into dusk, connecting to the problems of sensing (Chapter 1). Notably, visual responses slow down as light levels drop (Chapter 4), increasing integration times to reduce noise, but this is constrained by the speed needed to control the mechanics of flight itself. The wing beats are generated by nonlinear dynamics of neural circuits and muscles, with connections to nonlinear dynamics more generally (Chapter 5), while rhythm-generating circuits in other systems have been important testing grounds for ideas about how organisms navigate the high-dimensional parameter space of possible circuits (Chapter 4). Describing the aerodynamics of the flight itself is a challenging problem, as is defining the algorithm that the moth uses to stabilize itself. In moths it is possible to monitor almost all the neural signals that control the flight muscles, providing an opportunity to test ideas about how information is represented (Chapter 2). This gives a sense for how just one seemingly simple pattern of movement provides paths into many questions in the physics of life. This example also illustrates how the questions asked by the biological physics community connect to questions asked by neurobiologists, engineers, control theorists, and others, as explored more fully in Part II of this report.

Faced with the wide range of questions associated even with one movement, many physicists and biologists have made progress by constraining animal behavior so that some more limited set of movements could be studied more precisely. This is in the reductionist spirit (noted in the “Introduction and Overview” chapter), and has been extremely productive. But there is the worry that constraining movements misses something that is essential to the organism. Within the broad biological community, this point has been emphasized by ethologists, who are interested in

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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the often complex behaviors exhibited by organisms in their natural environments, such as the dance that bees use to communicate to their hive about the location of food sources. In many ways, the challenge ethologists raise is paradigmatic for modern biological physics: Can the complexity of a living system be tamed in its functional context? In the spirit of physicists’ approaches to other complex problems, the goal is not just to build better tools for characterizing behavior, but to discover some underlying principles that govern these complex dynamics. In recent years, the community has taken up this challenge, and many biological physicists now describe themselves as working on the physics of behavior. Over the course a decade these efforts have laid a foundation for a vastly more complete view of naturalistic behaviors, with the discovery that these behaviors themselves are more structured and hence simpler than they might have been. In some cases, we see the emergence of the next generation of physics questions about how these dynamics are organized on longer time scales.

The starting point for work on the physics of behavior is the effort to collect more complete data on what organisms are doing in more complex contexts. Classical approaches to this involve attaching large numbers of probes to the animal, for example, lights to track the angles of joints as people walk through the world. A more modern approach is to start with high-resolution, high-bandwidth video. One can search these high-dimensional data in an unsupervised way, looking for low-dimensional structure, or provide hand-labeled examples of the locations of cardinal points, which can then be used to train an artificial neural network (Chapter 7) to find these points efficiently in the video stream (pose estimation). These methods can be used when observing small organisms under a microscope, large animals in the wild, or interactions among individuals in small groups (see Figure 1.8).

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FIGURE 1.8 High-resolution, high-bandwidth video is a modern approach to collecting more complete data on what organisms are doing in more complex contexts, informing our understanding on the physics of behavior. Combining high-resolution video imaging with machine learning extracts the posture of animals during natural movements. Deep networks are trained to identify cardinal points on the body, including joint positions and angles, reducing images with tens of thousands of pixels to a handful of intrinsic coordinates. (A) Flies during courtship. (B) A giraffe. (C) Mice in a social interaction. SOURCE: Reprinted from S.R. Datta, D.J. Anderson, K. Branson, P. Perona, and A. Leifer, 2019, Computational neuroethology: A call to action, Neuron 104:11, copyright 2019 with permission from Elsevier.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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The combination of video and machine learning has created the opportunity to study more complex, naturalistic behaviors in many systems, and generated considerable excitement, but this is only a start. It is an accomplishment to reduce high-resolution videos of walking flies automatically to more than 40 coordinates describing the movements of relatively rigid body parts, as in Figure 1.8A, but surely flies do not wander randomly in this 40+ dimensional space. Many groups are searching, with different methods, for further simplification; examples include the projection onto lower dimensional spaces that still capture most of the variability in movements, and the discovery of stereotyped segments of the organism’s trajectory through the high-dimensional space that can be identified as behavioral states. With this further reduction, it becomes possible to reconstruct the dynamics of movements. This is a literal “physics of behavior,” because it results in equations of motion for the organism, an analog of Newton’s equations.

A recent example shows that apparently random components of the crawling behavior of the worm Caenorhabditis elegans can be traced to deterministic chaos in the underlying dynamics (see Figure 1.9A and 1.9B). More detailed analysis shows that each mode of behavioral variation that grows in time is paired with a mode along which variability decreases, quantitatively, so that the dynamics exhibit a symmetry analogous to the symplectic symmetry of Hamiltonian mechanics (see Figure 1.9C). Efforts along these lines are developing rapidly, in many different systems, from the simple and slow movements of plants to the rapid transitions among multiple gaits as animals move over complex terrains. The example of C. elegans illustrates how raw movies of unconstrained animal movements can lead to discoveries of hidden symmetry principles.

Beyond observing complex movements and trying to infer the underlying dynamics, it is possible to perturb these movements and study how the system responds. In thermal equilibrium, spontaneous fluctuations are related precisely to the respond functions, but of course this is not true in actively moving systems. Indeed perturbation experiments connect to very different points of view on animal movement, notably ideas from control theory. An example that brings physics and control together is the response of fly flight to mechanical perturbations (see Figure 1.10). By attaching small ferromagnetic pins to the fly, one can apply forces during free flight and observe the responses with multiple high-speed cameras to allow three-dimensional reconstruction of body and wing movements. These measurements reveal highly stereotyped responses on time scales of tens of milliseconds, which can be understood in terms of feedback from gyroscopic sensors called halteres.

Perspective

The motion of organisms through fluids—from swimming bacteria to soaring birds—has long provided inspiration for the physics community, pushing our

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.9 The worm Caenorhabditis elegans is a widely used model organism, shown at bottom. Recent work has uncovered chaos and hidden symmetries in the worm’s crawling movements. (A) Measurement of the worm’s shape can be projected into lower dimensional spaces. As the worm crawls forward, a wave passes along its body, and this oscillation corresponds to the counterclockwise rotations in the two-dimensional projection at left. Two trajectories (red and blue), which begin close together, both correspond to forward crawling, but gradually diverge. This can be seen in the full images of the worm, evolving in time at right: Although starting in almost identical configurations, the red and blue worm go their separate ways. (B) Embedded in slightly higher dimensional space, one can find all the trajectories that start within a ball B0 and then follow the stretching or compression of this ball along different dimensions, defining the Lyapunov exponents λi. (C) The distribution of Lyapunov exponents from multiple experiments, illustrating the near symmetry around a central negative value. SOURCES: (A–C) Reprinted by permission from Springer: T. Ahamed, A.C. Costa, and G.J. Stephens, 2020, Capturing the continuous complexity of behaviour in Caenorhabditis elegans, Nature Physics 17:275, copyright 2020. Image of Caenorhabditis elegans from Zeynep F. Altun, editor of www.wormatlas.org, https://en.wikipedia.org/wiki/Caenorhabditis_elegans, Creative Commons license CC BY-SA 2.5.

understanding into new regimes and far eclipsing what human-made machines can accomplish. Conversely, insights from physics are indispensable for understanding the mechanics of movement and the special requirements that must be met in movement through fluctuating environments. The transport of fluids by and within organisms has likewise challenged us; for example, problems posed by vascular networks can be mapped in their simplest incarnation into electrical resistor networks, but the latter networks traditionally studied by physicists are not

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.10 Fly flight control in response to controlled perturbations is an example of physics an control theory working together. (A) Three-dimensional reconstruction of the fly (Drosophila) bod (2.5 mm long) and wing kinematics during an aerial “stumble” during transit through a Helmholtz coil the perturbation is induced by a brief magnetic field pulse which couples to a small ferromagnetic pi attached to the fly’s thorax. Images are captured 35 times per wing beat cycle, but shown only ever four beats. (B) Top view images of the fly before, during, and after the perturbation, beneath whic are shown body yaw (heading), wing relative attack angle over time (normalized by wingbeat period T = 4.5 milliseconds), and aerodynamic/control model estimated torque. SOURCE: L. Ristroph, A.J Bergou, G. Ristroph, K. Coumes, G.J. Berman, J. Guckenheimer, Z.J. Wang, and I. Cohen, 2010, Dis covering the flight autostabilizer of fruit flies by inducing aerial stumbles, Proceedings of the Nationa Academy of Sciences U.S.A. 107:4830, Creative Commons License CC BY-NC-ND 4.0.

required to adapt to minimize dissipation, remain robust to enormous damage, or send extra current to different locations on demand. In the last decade, physicists have confronted animal behavior in its full complexity, showing, for example, that one can reconstruct the effective equations of motion for naturalistic movements, even to the point of discovering underlying symmetries hidden in these dynamics. There are many frontiers where progress is expected in the coming decade: better connections of microscopic with macroscopic understanding; better understanding of movements through materials that can behave either as fluids or solids such as sand and soil, where our understanding of the materials themselves is still evolving; and the search for physical principles governing more complex movements in their natural context. The beautiful collective motions of flocks and swarms are discussed in Chapter 3.

SENSING THE ENVIRONMENT

In order to do the right thing, organisms must sense their environment. Sense organs are the instruments that organisms, including humans, use in making measurements on the world, and perceptions are the inferences that we draw from

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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these data. As such, physicists have been especially fascinated by sensation and perception at least since the 19th century. Organisms and even single cells also sense their internal states, and generate signals. Physical principles that govern sensing the environment thus should also govern much of the everyday business of all cells as they exchange and process information, as described in Chapter 2.

Photon Counting

Thinking about the nature of light has been bound up with our understanding of vision for millennia. By the late 1800s it was understood that light was an electromagnetic wave, and the new unification of electricity, magnetism, and optics explained many important aspects of vision, including the irreducible level of blur that comes from diffraction. But in 1900, the quantum revolution began, and by 1905 it was proposed that the interaction of light with matter is described by the absorption and emission of discrete particles of light, called photons. Just a few years later, it was suggested that the dimmest lights humans can see, on a dark night, deliver just a handful of photons to our retina. The idea that the limit to vision is set by the quantum nature of light set an agenda that would unfold over the course of a century, with broad implications.

It now is established that, even under controlled conditions, our perception of very dim lights fluctuates, not because our attention is wandering but because normal sources of light deliver photons at random. Only recently has the full power of quantum optics been used to make light sources that eliminate much of this randomness, and our perception of these light sources is more reliable and deterministic, as predicted. There was a decades-long march from observations on human behavior to recording the electrical responses of receptor cells to single photons (see Figure 1.11A and 1.11B), and these now have been seen in animals across the tree of life—from butterflies to mice, and from horseshoe crabs to monkeys whose visual systems are very much like our own.

Inside the receptor cell, photons are absorbed by the rhodopsin molecule. A typical receptor has roughly 1 billion of these molecules, packed so densely that the cell is almost black. The absorption of one photon triggers a change in the structure of one rhodopsin molecule. As in photosynthesis, the first molecular events that follow photon absorption happen within trillionths of a second, so fast that these events compete with the loss of quantum mechanical coherence. Subsequent structural changes unfold on longer times scales, until the rhodopsin molecule reaches a metastable state that can trigger biochemical events through interactions with other molecules. These events form a cascade that serves as an amplifier, so that one rhodopsin molecule at the start of the cascade results in the degradation of many thousands of cyclic guanosine monophosphate (cGMP) molecules at the end of the cascade (see Figure 1.11C). The cGMP molecules in turn bind to ion

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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channel proteins in the receptor cell membrane, regulating the flow of electrical current into the cell. Arrival of a single photon results in a pulse of current roughly one picoAmpere in size, well above the background of random fluctuations.

Although details vary, the molecular components of the amplification cascade that enables photon counting have direct analogs in a wide variety of processes throughout the living world. When a hormone molecule circulating in our blood binds to a cell surface receptor, this receptor interacts with a protein that belongs to the same “G-protein” family as the transducin (T) molecule in the visual cascade of Figure 1.11C. Following the hormonal response through its cascade, the G-protein activates an enzyme that changes the concentration of a different cyclic nucleotide, playing the role of cGMP in Figure 1.11C. These mechanisms are so widespread that it was possible to find the receptor molecules in our sense of smell by searching for G-protein coupled receptors encoded in the genome. Different parts of the amplification cascade have been discovered first in different systems,

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FIGURE 1.11 Normal sources of light deliver photons at random, causing our perception of very dim light to fluctuate. This is demonstrated by photon counting in single rod cells from the eye. (A) A single rod cell is drawn into a pipette and stimulated by light. A tight seal insures that current flowing across the cell membrane flows up the pipette, where it is measured. (B) Current trace (top) in response to a series of dim, brief flashes of light (below). Responses are quantized and probabilistic, as expected in the regime where individual photons are being counted. (C) Absorption of one photon by a single molecule of rhodopsin (Rh) triggers a molecular cascade. One molecule at the input results in the degradation of many molecules of cGMP at the output, which in turns changes the number of open ion channels in the membrane, producing the currents in (B). SOURCE: Reprinted with permission from F. Rieke and D.A. Baylor, 1998, Single-photon detection by rod cells of the retina, Reviews of Modern Physics 70:1027, copyright 1998 by the American Physical Society.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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with the universality of the mechanisms emerging only gradually. Some measure of the importance of these mechanisms is their recognition in multiple Nobel Prizes: the discovery of rhodopsin itself (1967); the discovery of cyclic nucleotides as internal signaling molecules (1971); the discovery of G-proteins (1994) and olfactory receptors (2004); and the elucidation of the structural basis for the interaction between the receptors and G-proteins (2012). Photon counting is the example in which our understanding can be tested in the greatest quantitative detail, in the physics tradition, and has provided a touchstone throughout these developments.

Despite its importance, the amplification cascade is not enough to explain the ability of the visual system to count photons. A single rhodopsin molecule will continue to drive changes in the cGMP concentration so long as it is in its active state. But a single molecule makes transitions between states at random times, and this randomness would be passed through the cascade, ultimately resulting in a highly variable current across the cell membrane. Such variability would make it impossible for cells to report reliably that different numbers of photons had been counted; in fact the current pulses in response to single photons are stereotyped and reproducible. Part of the answer to this problem is that the active rhodopsin molecule does not just spontaneously switch off; rather, it is actively turned off by another protein that attaches multiple phosphate groups to the rhodopsin. Experimentalists can manipulate the genome so that cells produce rhodopsin molecules that are missing the sites at which these phosphate groups are added, and even deleting one out of six sites results in noticeably more variable responses to single photons; variability increases as more sites are deleted, and this pattern follows theoretical predictions. This is an inspiring example of how the complexity of biological molecules can be understood, quantitatively, as a response to the physics problems that organisms must solve.

More subtly, the multiple steps involved in turning off the activity of rhodopsin all dissipate energy, and this is essential. If no energy were dissipated, each step would be reversible and the molecule would take a random walk from its active to inactive state, restoring the original randomness of the transition. Simple models show that there is a tradeoff between energy dissipation and the reduction of variance in the time the molecules spend in the active state, anticipating the “thermodynamic uncertainty relations” that are part of recent progress in non-equilibrium statistical mechanics.

Looking carefully at Figure 1.11B, there is one example of a single photon response that seems to come before the flash of light. This is not a violation of causality, but an example of the “dark noise” that one finds in all photodetectors. In this case, there is some probability that rhodopsin will change its structure as the result of a thermal fluctuation rather than the absorption of a photon. In a single molecule this transition occurs roughly once every thousand years. But a

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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single photoreceptor cell is packed with 1 billion rhodopsins, so there is one event per minute. Remarkably, these random events provide a dominant source of noise, limiting the organism’s ability to be sure it has seen very dim flashes of light. In cold-blooded animals, one can lower the temperature, reducing the dark noise and increasing the reliability of seeing, just as is done with photodetectors in the physics lab.

The problem of photon counting in vision does not end with a current pulse in the photoreceptor cell. This current drives a change in voltage across the cell membrane, which in turn drives the flow of current carried by calcium ions, and increases in calcium concentration trigger the release of vesicles into the synapse onto cells in the next layer of the retina. Vesicle release is a central feature of signaling between cells, not just in the retina but throughout the brain and at the connection between nerve and muscle. Indeed, the phenomenon is much more general, encompassing many processes where cells need to export materials, from hormones to waste products. The idea that transmission across a synapse involves discrete vesicles, each containing thousands of neurotransmitter molecules, emerged from the discovery of quantization in high-resolution recordings of the electrical signals at the neuromuscular junction, and eventually it was possible to measure directly the added capacitance of the cell membrane as single vesicles fuse with it; this classical chapter in the interaction between physics and biology was recognized with a Nobel Prize in 1970. The commonality of vesicle release mechanisms was crucial in the identification of the key protein molecules involved in the process, which was recognized by a Nobel Prize in 2013. Today, vesicle release is studied with the full range of experimental methods from the biological physics community, down to the single molecule level. Variations in molecular properties tune different vesicle release systems to different requirements, from the slow release of hormones to the transmission of signals with near microsecond precision in the auditory system. A major theoretical question is whether there are unifying principles that govern the molecular events across these many orders of magnitude in time scale.

The synapse connecting the photoreceptor to the next layer of the retina has been an important example of how sensory signals are processed. In the fly, this synapse holds the record for the highest rates of information transmission seen in neurons, approaching the physical limit set by counting every single vesicle with millisecond resolution. In animals more like us, the synapse acts as a filter, helping to separate the single photon responses from the background of dark noise. The synapse also is nonlinear in its response, further enhancing this separation and making it possible for individual neurons to sum the signals from many receptor cells without being swamped by summed noise. The structure of this filtering and nonlinearity can be derived, quantitatively, from a common principle of maximizing the signal-to-noise ratio for detecting these dim flashes of light, and in this way aspects of these first steps in visual signal processing can be understood as

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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solutions to the underlying physics problem. A challenge for the coming decade is to determine whether these physical principles can predict the dynamics of signal processing at synapses in the retina more generally.

Molecule Counting

Photon counting is not the only example where biological signaling systems encounter fundamental physical limits to performance. As bacteria swim, propelled by the rotation of their flagella (see Figure 1.4), they move toward sources of food and away from noxious chemicals. A breakthrough came in the early 1970s, with the construction of a tracking microscope that could follow the trajectories of single bacteria, demonstrating that their motion consists of relatively straight “runs” interrupted by “tumbles” that select a new direction almost at random; illustrations related to these measurements are shown in Figure 1.12. Runs correspond to counterclockwise rotation of the cell’s multiple flagella, which allows them to come together in a bundle, while clockwise rotation causes tumbles as the bundle flies apart. Runs typically last for a few seconds, but in mutant bacteria that are incapable of chemical navigation, runs last much longer. Experiments show that when cells are swimming up toward increasing concentrations of attractive molecules, runs are prolonged, and this is the basis of navigation: These bacteria do not “steer” toward a source of food, but rather take a random walk that is biased toward the source. This is an algorithm for finding the maximum concentration that is similar to Monte Carlo optimization.

The chemical navigation system of bacteria is called chemotaxis, and it is extraordinarily sensitive: Significant changes in run length occur when the concentration changes by just a few parts in a million across the length of the cell. But molecules arrive at the cell surface by random motion, and this randomness obscures the small differences between the front and back of the cell. The only possibility is that cells monitor how concentrations change as they move, integrating over the several seconds of a run which carries them dozens of body lengths through their surroundings. Even so, they must effectively count every single molecule that arrives at their surface. These theoretical inferences from the sensitivity of chemotaxis were confirmed, for example in experiments where a bacterium is tethered to a glass slide by a single flagellum and then the rotation of the motor causes the whole cell to rotate; changes in the probability of clockwise versus counterclockwise rotation can then be monitored in response to brief pulses of attractive or noxious molecules. These and other experiments show that cells are responding to changes of concentration over time, not space; that there are significant responses when one extra molecule is bound to a receptor on the cell surface; that the cell can ignore the overall concentration of molecules and respond only to changes; and that the response averages these changes over times long enough to suppress noise but not

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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FIGURE 1.12 Bacteria swim toward sources of food and away from noxious chemicals, their motion characterized by relatively straight “runs” interrupted by “tumbles” that select a new direction almost at random. (A) Chemotaxis in the bacterium Escherichia coli. Three-dimensional trajectory of a single cell, with velocity coded by color. Runs with high, relatively constant velocity are interrupted by tumbles with low velocity. (B) A modern schematic of chemotaxis system, showing the flow of information from ligand molecules outside the cell through receptors, the addition of phosphate groups to proteins, and finally control of the flagellar motor’s rotation. The label X marks the key proteins CheA, CheB, CheR, CheW, CheY, and CheZ, and the phosphate group is represented by the purple circle labeled P. SOURCES: (A) N. Figueroa-Morales, R. Soto, G. Junot, T. Darnige, C. Dourache, V.A. Martinez, A. Lindner, and É. Clément, 2020, 3D spatial exploration by E. coli echoes motor temporal variability, Physical Review X 10:021004, Creative Commons License Attribution 4.0 International (CC BY 4.0). (B) Y. Tu, 2013, Quantitative modeling of bacterial chemotaxis: Signal amplification and accurate adaptation, Annual Review of Biophysics 42:337.

so long that cells would be disoriented by their own rotational Brownian motion. In this way, much of the chemotactic behavior of bacteria can be understood as solutions to the underlying physics problems.

Ideas about the physical limits to molecular signaling that have their roots in thinking about chemotaxis have reappeared in connection with experiments on many different systems, from the control of gene expression to axon guidance during the development of the brain. The problem also continues to inspire new theoretical developments, notably generalizations to dynamic signals and to the

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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case where there are many species of molecules to be detected and many different kinds of receptors. It is encouraging to see how the scientific community takes these steps toward more complex and biologically realistic formulations while remaining grounded in general physical principles.

In the case of chemotaxis, generations of scientists have connected the overall strategies for solving the underlying physics problems to detailed molecular mechanisms (see Figure 1.12). The enormous sensitivity of the system has contributions from multiple components: cooperative interactions among neighboring receptor molecules in the cell membrane; a cascade of molecule multiplication not unlike that found in photon counting; and cooperative interactions of the final signaling molecule in controlling the direction of the flagellar motor. This detailed mechanistic understanding was built using a combination of experimental methods from biology and physics, for example using genetic engineering to make fluorescent analogs of crucial molecular components and monitoring their interaction through measurements of energy transfer. These developments have gone hand in hand with increasingly precisely theoretical descriptions of the system, which have been used, for example, to address questions about the relations between energy dissipation and signal-to-noise ratio, which are much more general. Nearly 50 years after the first tracking microscope measurements, this system continues to inspire new developments.

Mechanical Sensing

Cells that move along solid surfaces or through the spaces of porous materials can sense and respond to the mechanical properties of their surroundings. Cells crawl using molecular motors (Chapter 1) and exert forces on their substrates via adhesive connections. The same mechanisms of force transduction are at play in the differentiation of stem cells placed on substrates of varying rigidity; stem cells placed on soft gels differentiate into cells belonging to soft tissues such as the brain, while those placed on very stiff gels differentiate into cells belonging to bone. These phenomena illustrate that mechanical cues can play as strong a role as chemical ones in biological processes, and can often work in tandem with chemical cues to influence behavior. Another example of this interplay occurs at the organ level in the early embryonic heart. The heart is the first organ to function, beating and pumping fluid, in animals. Each heartbeat consists of a wavefront of cell contraction that traverses the heart from one end to the other. The mechanism for cell signaling that coordinates the heartbeat has long been understood to be electrical—hence electrical defibrillators. It was recently shown, however, that the early embryonic heart does not use electrical signaling to coordinate its heartbeat. Rather, the mechanical strain that contracting cells exert on other cells is instrumental in signaling them to contract.

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Mechanical sensing and extraordinary sensitivity come together in the specialized cells of the inner ear. In a quiet room, we can hear sounds that cause our eardrums to vibrate by less than the diameter of an atom. Several different mechanical sensors are embedded in the bones behind the human ear—the cochlea, which responds to sounds that move the eardrum; the semicircular canals, which respond to fluid motions caused by the rotation of our head; and otoliths, which respond to movements of tiny calcium carbonate crystals caused by linear accelerations, including gravity. At the heart of all these organs are the hair cells, which generate electrical signals in response to displacement of their “hairs” or stereocilia (see Figure 1.13). To be clear, these “hairs” are quite different from the hairs on our head at the molecular scale, but early microscopists were struck by the appearance of these cells, and the name persists. Mechanical sense organs with hair cells are found in all animals with backbones, including the lateral line in fish, which senses motion of the water as the fish swims, and the frog sacculus, which senses ground vibration. In one species of tropical frog, ground vibrations of just 10 trillionths of a meter are sufficient to trigger responses.

Image
FIGURE 1.13 The hair cells of the inner ear generate electrical signals in response to displacement of their “hairs” or stereocilia. (A) Schematic of a hair cell surrounded by supporting cells. A ribbon synapse at the base of the cell releases vesicles that drive electrical activity of the afferent neuron, which carries information to the brain. The efferent neuron carries signals from the brain that modulate the sensitivity of the hair cell. Stereocilia vary systematically in length across each hair bundle and are connected by “tip links” that transmit forces to ion channels in the membrane. In many hair cells, there is a true cilium, the kinocilium, which has a role in organizing and orienting the bundle. (B) A scanning electron micrograph shows an individual hair bundle from the frog’s sacculus, an organ that detects gravity and ground-borne vibration. (C) A scanning electron micrograph shows the specialized hair bundle of an outer hair cell from the bat’s cochlea, which is V-shaped and has only three ranks of stereocilia. SOURCE: Reprinted by permission from Springer: A.J. Hudspeth, 2014, Integrating the active process of hair cells with cochlear function, Nature Reviews Neuroscience 15:600, copyright 2014.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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A dramatic development in our understanding of mechanical sensing in living systems is the realization that hair cells are not just sensors, but active sensors, so that the inner ear—and presumably most other systems based on hair cells—are mechanically active. Dramatic qualitative evidence for this comes from the fact that ears can emit sound. These acoustic emissions are very pure tones, unique to each individual, and quite common. Presumably, these result from minor pathologies that allow too much of the mechanical activity to couple back into the macroscopic mechanics of the ear, much as in the instability of a microphone pointed at a loudspeaker. Quantitative evidence is based on interferometric measurements of the spontaneous hair bundle movements, and the demonstration that these violate the fluctuation-dissipation theorem.

These observations suggest a model in which elements of the inner ear are active filters, poised close to their instability. As this critical point or bifurcation is approached, the frequency range of the mechanical response narrows, suppressing the effects of thermal noise, and the magnitude of the response to external forces increases. Independent of the underlying mechanism, the behavior in the neighborhood of the bifurcation is universal. An example of this universal behavior is nonlinear mixing of nearby frequencies, with a strength that is nearly independent of amplitude. These essentially parameter-free predictions are consistent with classical perceptual observations on “combination tones,” and with direct measurements on hair cells.

Perspective

This discussion of just three of the very many sensing systems that organisms possess has revealed deep principles. Sensors in living systems are precise despite having to function with signals that can vary by many orders of magnitude. This precision in many cases approaches fundamental physical limits to their performance, which belies the commonly repeated claim that living systems are irreducibly noisy and messy. In some cases the observation of near-optimal performance can be turned into a theoretical principle, from which aspects of system function and mechanism can be derived, following the classic example of the insect eye. Molecular components that implement these mechanisms have a surprising universality, and sensing itself plays a role in the behavior of all cells. The physics of sensing continues beyond the receptor cell into signal processing within the sensory organs and then on into the brain. A growing understanding of these architectures is blurring the distinction between sensing, filtering, and de-noising so that an organism can extract the most useful signals from the environment, which will be discussed further in Chapter 2.

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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STRUCTURES IN SPACE AND TIME

Organisms act on spatial and temporal scales that are removed by orders of magnitude from the natural scales of their molecular components. These phenomena are reminiscent of many pattern-forming systems in the inanimate world, and this connection has provided a path for many physicists to begin their exploration of the living world. At the same time, pattern formation in living systems poses qualitatively new challenges, driving the search for new physical principles that can explain these beautiful phenomena.

Allometry

The first spatial structures of plants and animals that attracted human attention were the most macroscopic, and it would take into the 20th century to state the problem of how these are encoded by the underlying molecules. The macroscopic structures have a logic of their own, often grounded quite directly in physical principles: The cross-sections of bones scale with overall body size so that animals do not collapse under their own weight, stems and roots scale with plant size to be sure that water and nutrients can be transported to the leaves, and so on. The study of such scaling or allometric relationships has a long history in the biological literature, and extends to the scaling of metabolic rates, lifespan, population density, and even brain size with body size.

Allometric scaling defines power-law dependences, for example of metabolic rate on body mass across species. These relations often are quite precise, and extend over many decades for each variable. In many cases, the scaling exponents are simple rational numbers, but not what would be expected from dimensional analysis. For example, animals should lose heat at a rate proportional to their surface area, while body mass is proportional to volume and area ∼(volume)2/3, suggesting that to keep constant temperature requires heat production scaling with the 2/3 power of body mass. In fact mammalian heat production scales as the 3/4 power of body mass, across a factor of 100,000 from mice to elephants. Theory, in a similar spirit to ideas about fluid flow in leaf vein networks (see Figure 1.7), predicts that this scaling emerges from the properties of resource distribution networks that carry nutrients through the body. As usual in physics, the leading scaling behavior is derived for systems that are asymptotically large, and more recent work emphasizes how finite size correction can lead to observed departures from simple scaling. It remains to be discovered whether any allometric relations exhibit anomalous scaling dimensions, as in more familiar physics problems.

Self-Assembly and Physical Virology

At the opposite extreme, an important example of structure formation is the assembly of viruses. Viruses typically consist of a protein shell, the capsid, which

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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in the simplest case is made up of many copies of a single protein, which envelopes the viral genome in the form of either single- or double-stranded DNA or RNA. For viruses that infect mammalian cells, there is generally also a lipid bilayer coat. It is an extraordinary fact that viruses often will reassemble in a test tube from purified protein and nucleic components. Historically, this was important in convincing the scientific community as a whole that one could, in practice, study the building blocks of life with concepts and methods from physics and chemistry. In modern times, the self-assembly of viruses has emerged as a physics problem, and the interplay between the biological physics community and the larger biology community interested in viruses has led to a field called physical virology, now the subject of regular conferences.

X-ray diffraction images of crystals of viruses revealed, long ago, that many of them have icosahedral symmetry. More recently, electron microscopy has provided high-resolution reconstructions of viral capsids. An icosahedron can be folded from a flat sheet of hexagons by replacing some 6-fold vertices by 5-fold defects; this realization led to the classification in the 1960s of icosahedral virus shells (capsids) in terms of triangulation numbers, which characterize the distances between neighboring 5-fold defects—a classification still used today. While isolated 5-fold defects lead to icosahedral viruses, it is now understood that a line of 5-fold defects is responsible for conical capsids, as in the HIV virus. A modern example of these ideas is from recent work on the Brome Mosaic Virus (BMV), shown in Figure 1.14. In this system the nearly spherical capsid shell, composed of 180 identical proteins, has axes of 5-, 3-, and 2-fold symmetry. The BMV virus packages three different RNA molecules separately into different virions that are all present during an infection. Because it needs to package all genomes separately but simultaneously, it uses non-specific electrostatic interactions between the RNA and the capsid, resulting in much more disordered RNA in the interior. This is in contrast to other viruses in which the RNA acts as a template for assembly of the protein components and can serve as a “molecular ruler” to set the size of the virus as a whole.

Studies of viral self-assembly have been pushed forward by observations and manipulation of single viruses. This approach from the biological physics community parallels single molecule experiments aimed at understanding force generation in muscle (see Figure 1.3), the synthesis of ATP from the flux of protons across a membrane (see Figure 1.5), the readout of information encoded in the genome (see Figure 2.1), and the flow of electrical current through ion channels (see Figure 2.8). These methods reveal how the mechanisms of self-assembly address the physics problems that arise: Weak interactions among small numbers of capsid proteins allow the system to avoid kinetic traps, while the fully assembled structure is strong enough to resist the osmotic pressure generated by the long polymer of the genome packed inside. In bacteriophages—viruses that infect bacteria—direct measurements show that these pressures are on the order of 10 atmospheres, and special packaging motors are required to stuff the genome into the capsid; this pressure

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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in turn drives the genome into the host cell during infection. Viruses thus provide examples of both spontaneous self-assembly and the active construction of stable far-from-equilibrium structures.

Image
FIGURE 1.14 The Brome Mosaic Virus (BMV) is a modern example of the 1960s classification of icosahedral virus shells in terms of triangulation numbers characterizing the distance between neighboring 5-fold defects. The BMV system has axes of 5-, 3-, and 2-fold symmetry. (A) and (B) Interior view of the virus, reconstructed from electron microscope images, showing the back half of the capsid protein (CP) shell and either the entire (A) or the back half of (B) the RNA genome. Protein components are color-coded based on their radius from the center of the virus, and symmetry axes are shown as a guide. RNA sits near the 2- and 3-fold axes but not near the 5-fold; no RNA density is resolved at the center. (C) and (D) Slices through the reconstruction without (C) and with (D) low-pass filtering to 10 Å. The symmetry axes have been indicated, and it is clear that the RNA is situated preferentially near the 2- and 3-fold axes and away from the 5-fold axes. SOURCE: C. Beren, Y. Cui, A. Chakravarty, X. Yang, A.L.N. Rao, C.M. Knobler, Z.H. Zhou, and W.M. Gelbart, 2020, Genome organization and interaction with capsid protein in a multipartite RNA virus, Proceedings of the National Academy of Sciences U.S.A. 117:10673, Creative Commons License CC BY-NC-ND 4.0.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Bacterial Growth, Shape, and Division

Bacteria are larger than viruses, typically several microns in length. In many cases, including the well-studied Escherichia coli, the overall structure of the cell is supported in part by a polymer of protein molecules that wraps the cell, underneath its membrane, with a helical structure. This helix has a radius essentially equal to the radius of the cell itself, many hundreds of times larger than the diameter of the constituent protein molecules. As in the assembly of viruses, this long length scale results from a small angle between proteins along the polymer, and this small angle is determined by the structure of the protein–protein interfacial surface, pointing toward a more general physical principle in the construction of living systems. The possibility of creating structures with long internal length scales by assembly of microscopic components inspires a broader exploration of self-assembly, as discussed in Chapter 5.

Many important examples of structure formation are connected with cell division. In many bacteria, the process is triggered by polymerization of a single protein in a belt or ring around the middle of the cell. But this middle position is determined by a surprisingly dynamic process. It had been known for some time that a set of proteins called “Min” were essential for division; the name derives from the fact that mutations in these proteins cause the appearance of miniature cells. The surprise was that dynamic measurements on the concentration of these proteins inside the cell revealed an oscillation, with protein accumulating at one end of the cell and then the other, periodically, with a cycle of less than a minute (see Figure 1.15); the middle of the cell is where concentrations are persistently low, and this is consistent with the role of Min proteins as an inhibitor of ring formation. Theory suggested that these oscillations could arise if ATP binds to one protein (MinD) and increases its affinity for the membrane, then a second protein (MinE) binds to the first and triggers ATP hydrolysis. Diffusion, coupled with these reactions, is enough to generate the observed spatiotemporal oscillations. If this is correct, it should be possible to reproduce the essential behavior in a purified system. Indeed, this works, but it is essential to mimic the geometry of the cell (see Figure 1.15E and 1.15F). In different geometries, this simple system can produce many different patterns, consistent with theoretical predictions. Also consistent with theory, in cells where cell division is blocked the pattern of oscillations includes several periods along the length of the cell.

The simple picture of Min oscillations as the mechanism by which cells define their middle is incomplete. In some species of bacteria, the division ring can be placed precisely in the middle even in the absence of Min proteins. In other species, the formation of miniature cells is inhibited by Min, but the patterns are static, and targeting of the protein to the ends of the cell requires other factors. It has never been clear whether Min is sufficient, even in Escherichia coli, to explain the preci-

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Image
FIGURE 1.15 In many bacteria, a set of “min” proteins are essential for cell division. The concentrations of these proteins oscillate, accumulating first at one end of the cell then the other. Min protein oscillations, in cells and in a reconstituted system. (A) Time-lapse images of MinD protein, fused with green fluorescent protein (GFP), in live Escherichia coli cells. Time is noted in seconds and scale bar is 1 µm. DM Raskin and PAJ de Boer, Rapid pole-to-pole oscillation of a protein required for directing division to the middle of Escherichia coli. (B) MinD oscillations in a purified system containing only two proteins, MinD and MinE, with a supply of ATP. The solution containing the proteins is confined in a chamber (C) that is lined with lipids to mimic the cell membrane. SOURCES: (A) D.M. Raskin and P.A.J. de Boer, 1999, Rapid pole-to-pole oscillation of a protein required for directing division to the middle of Escherichia coli, Proceedings of the National Academy of Sciences U.S.A. 96:4971, Creative Commons License CC BY-NC-ND 4.0. (B–C) Adapted from B. Ramm, P. Glock, and P. Schwille, 2018, In vitro reconstitution of self-organizing protein patterns on supported lipid bilayers, Journal of Visualized Experiments 137:e58139, https://doi.org/10.3791/58139.

sion with which cells divide in half. What certainly is missing is an understanding of what physical principles determine the advantages and disadvantages of these different molecular mechanisms.

Reactions, Diffusion, Scaling, and Size Regulation

Despite open questions, the Min system illustrates the power of coupling reactions and diffusion to generate patterns. The general mathematical structure of such systems allows for different kinds of patterns that can be fully classified. These patterns have been recognized in many different living systems (e.g., Figure 1.16), even if it can be difficult to identify the particular molecular components that implement these dynamics. The study of reaction–diffusion systems has a remarkable history (see Box 1.4).

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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In coupled reaction–diffusion systems, there are characteristic length scales that correspond, roughly, to the distance that a molecule can diffuse before it reacts. These length scales are intrinsic to the dynamics, and set the size of pattern elements, such as the width of stripes or the distance between spots. In a larger system, there would be more stripes or spots. While this happens, there also are systems where the patterns scale to the size of the organism. An example is the segmented body plan of a caterpillar or maggot, where individuals of different size have the same number of segments and the segment size or spacing changes in proportion to overall body size; in maggots (larval flies) this can be traced to scaling in the patterns of gene expression that drive these patterns (as in Figure 2.7). It seems fair to say that there is no general understanding of how this scaling is achieved. While the inanimate world provides many examples of pattern formation, some of which may remind us of patterns in living systems, these patterns do not scale. Perhaps this is one more example of life finding new physics.

Related to the problem of scaling is the problem of size regulation. What sets the size of an organism? What sets the size of an organ, or a single cell? Which of these are tightly regulated, and which are fluctuating widely across individuals? Within a single cell, what sets the size of organelles? There is a classical example of size regulation in the algal cell Chlamydomonas reinhardtii, which has two flagella of equal length, and this is crucial for its swimming. If one flagellum is broken or removed, the other will shorten, and the two flagella will lengthen together only once they are of equal length. This problem has come back into focus because of a new generation of quantitative experiments and mathematical analyses that exclude many classical models. The problems of size regulation and scaling are simple to state, but may provide hints of deeper principles.

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FIGURE 1.16 Patterns in reaction-diffusion models and in animal skin coloration. (A) Two molecular species diffuse and react. Increased concentrations of the activator promote its own (auto-catalytic) synthesis, and the synthesis of an inhibitor. (B) Patterns formed with different parameter settings of the model in (A). (C) Patterns in nature, left to right: hybrid fish (Salvelinus leucomaenis x Oncorhynchus masou masou); marine beta (Calloplesiops altivelis); cheetah (Acinonyx jubatus); bengal cat (Felis catus); and giraffe (Giraffa camelopardalis reticulate). SOURCE: H.C. Metz, M. Manceau, and H.E. Hoekstra, 2010, Turing patterns: How the fish got its spots, Pigment Cell and Melanoma Research 24:12, © 2010 John Wiley & Sons A/S.
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Perspective

As with energy conversion, the building of structures in space and time is a prerequisite for many other functions of living systems. There has been a very productive exchange between the exploration of particular living systems and the synthesis of artificial systems that operate under similar or perhaps even the same principles of pattern formation and self-assembly. At the same time, there is something different about the living systems, and the community has struggled to articulate this difference. There is tension, for example, between the idea of patterns emerging spontaneously out of homogeneous backgrounds and the idea that information about position in a developing embryo is passed through a cascade of molecular signals, starting with some initial symmetry-breaking event (Chapter 2). In a different direction, we have the idea that information for self-assembly is encoded in molecular structures and especially in the energetics of contacts between the assembling subunits, but we do not really know how to measure this information or relate it to the matrix of contact energies. As in many examples of

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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biological function, an essential part of the problem is not just to stabilize the correct outcome, but to avoid the vastly more numerous incorrect outcomes. It will be exciting to see how the examples of self-assembly and pattern formation guide the search for more general physical principles that address this challenge.

Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Page 86
Suggested Citation:"1 What Physics Problems Do Organisms Need to Solve?." National Academies of Sciences, Engineering, and Medicine. 2022. Physics of Life. Washington, DC: The National Academies Press. doi: 10.17226/26403.
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Page 87
Next: 2 How Do Living Systems Represent and Process Information? »
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Biological physics, or the physics of living systems, has emerged fully as a field of physics, alongside more traditional fields of astrophysics and cosmology, atomic, molecular and optical physics, condensed matter physics, nuclear physics, particle physics, and plasma physics. This new field brings the physicist's style of inquiry to bear on the beautiful phenomena of life. The enormous range of phenomena encountered in living systems - phenomena that often have no analog or precedent in the inanimate world - means that the intellectual agenda of biological physics is exceptionally broad, even by the ambitious standards of physics.

Physics of Life is the first decadal survey of this field, as part of a broader decadal survey of physics. This report communicates the importance of biological physics research; addresses what must be done to realize the promise of this new field; and provides guidance for informed decisions about funding, workforce, and research directions.

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