Living Matter-Nexus of Physics and Biology in The 21st Century

MBoC | PERSPECTIVE
Living matter—nexus of physics and biology

in the 21st century
Margaret L. Gardel
Institute for Biophysical Dynamics, James Franck Institute, and Department of Physics, University of Chicago,
Chicago, IL, 60637
ABSTRACT Cells are made up of complex assemblies of cytoskeletal proteins that facilitate Monitoring Editor
force transmission from the molecular to cellular scale to regulate cell shape and force gen- William Bement
University of Wisconsin
eration. The “living matter” formed by the cytoskeleton facilitates versatile and robust be-
haviors of cells, including their migration, adhesion, division, and morphology, that ultimately Received: Aug 24, 2012
determine tissue architecture and mechanics. Elucidating the underlying physical principles of Revised: Sep 19, 2012
such living matter provides great opportunities in both biology and physics. For physicists, Accepted: Sep 19, 2012
the cytoskeleton provides an exceptional toolbox to study materials far from equilibrium. For
biologists, these studies will provide new understanding of how molecular-scale processes
determine cell morphological changes.
The distinction between being “alive” or “not alive” has been a developed to trap and cool atoms enabled precise force spectros-
long-standing question for those interested in our natural world. In copy measurements of single molecular motors. We now know that
many ancient cultures, the difference between liv- biological molecules, while more complicated than
ing organisms and inorganic matter was thought to their inorganic counterparts, must obey the rules of
be due to innate differences arising from a “vital physics and chemistry.
force,” such that biology operated with different This wealth of molecular-scale information does
fundamental properties than the physical world. not directly inform the behaviors of living cells. The
The ability to disprove such theories came about organelles within cells are made up of complex and
over the course of the 17th to the 19th centuries, dynamic assemblies of proteins, lipids, and nucleic
as scientists developed theories of atoms and were acids, all immersed within an aqueous environ-
able to synthesize organic matter from inorganic ment. These assemblies are somehow able to build
constituents. Over the past 100 years, develop- materials that can robustly facilitate the plethora
ments in molecular biology and biochemistry have of morphological and physical behaviors of cells
provided a wealth of information on the structure at the subcellular (intracellular transport), cellular
and function of biological molecules, much of (division, adhesion, migration), and multicellular
which was acquired in collaborations between (tissue morphogenesis, wound healing) length
physical and biological scientists. Application of X- scales. The dynamic cytoskeleton transmits infor-
ray–scattering techniques first developed to study mation and forces from the molecular to the cellu-
metals enabled discovery of the structure of com- lar length scales. But what is it about the behaviors
plicated biological molecules ranging from DNA to of biological molecules that endow cells with the
ion channels. Use of laser trapping techniques first Margaret L. Gardel ability to respirate, move, and replicate themselves
robustly—all qualities we consider essential to
“life”? For these questions, understanding of the physics and chem-
istry of systems of biological molecules is needed. Interactions that
DOI: 10.1091/mbc.E12-05-0353
Address correspondence to: Margaret L. Gardel ([email protected]). occur within ensembles of molecules lead to emergent properties
© 2012 Gardel. This article is distributed by The American Society for Cell Biology and behaviors that cannot be predicted at the single-molecule level.
under license from the author(s). Two months after publication it is available to These emergent chemical and physical properties of living matter
the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Cre-
ative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
are likely fundamentally different from inorganic or “dead” materi-
“ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of als. Discovering the underlying principles of living matter provides
the Cell®” are registered trademarks of The American Society of Cell Biology. fantastic opportunities to learn new physics and biology.
Volume 23 November 1, 2012 4165

The fields of condensed matter physics and materials science response to fluctuating and changing environments. These prop-
study the physical properties that emerge when objects (e.g., atoms, erties make living cells exquisite materials that cannot be cap-
molecules, grains of sand, or soap bubbles) are placed in sufficiently tured by existing frameworks of physical matter. I suspect that we
close proximity, such that interactions between them cannot be have not yet identified the important parameters needed to char-
ignored. Interatomic or intermolecular interactions give rise to emer- acterize their properties. The rich dynamics created by active bio-
gent properties that are not seen in isolated species. Familiar logical matter present a formidable challenge in the area of ma-
examples involve electron transport across a material or a material’s terials science.
response to externally applied magnetic fields or mechanical forces. How do we hope to understand the properties of these complex
These emergent properties, such as conductivity, elasticity, and cytoskeletal assemblies and materials? It may seem as though
viscosity, enable us to predict the behavior of a collection of objects understanding cytoskeletal machinery is an insurmountable feat,
in these condensed phases. In this paper, I will focus on my perspec- the approaches that have been successful for physical materials will
tive of how approaches to understanding the mechanical properties not work, and we must rely on complex simulations that require
of physical materials can inform understanding of the mechanical modeling of all individual components. This may be true. However,
properties of living matter found within cells. I think that this is a pessimistic view. Just consider how complicated
In a crystal of metal, precisely organized atoms are located physical materials would be if we did not have the appropriate
nanometers apart, and the energies of their interactions are on the parameters to describe the macroscopic responses and had instead
scale of an electron volt (40-fold larger than thermal energy became obsessed about knowing the details of all the interactions
or twice the energy released on the hydrolysis of a single ATP between underlying atoms and molecules? In the same vein, I
molecule). These give rise to an energy density, or elastic modu- believe that predictive insights into biological matter will emerge
lus, on the order of gigapascals, which underlies the rigidity of through development of new physical theories that use mean-field
metals. For small deformations, the restoring force between atoms approaches to understanding materials that contain active compo-
means that this metal behaves like an elastic spring: after a force is nents and are driven far from equilibrium. The burgeoning field of
applied, the metal returns to its original shape. Understanding active-matter physics is currently considering these questions
force transmission through crystalline metals was facilitated by the (Ramaswamy, 2010). However, these theoretical approaches require
development of elasticity theory in the 16th and 17th centuries. physical measurements of cells and cellular proteins that may not be
Fluids, such as water, lack crystalline order, but predictive under- clearly linked to a physiological process or have a clear biological
standing of fluid flows and forces was captured through develop- context. Materials built from cytoskeletal proteins in vitro should
ment of theories of fluid dynamics. Now think of another material, also provide an excellent source of experimental measurements,
Silly Putty, which behaves elastically at short timescales (it bounces but closer collaboration with theorists working in this field and
like a rubber ball) but then oozes and flows at long timescales, act- collaboration between biochemists and experimental physical sci-
ing like a viscous fluid. Silly Putty is made of long polymers that are entists is needed to develop control over such materials. Develop-
trapped by one another at short timescales, but thermal energy is ing predictive physical theories of the cytoskeleton will elucidate
sufficient to allow them to diffuse and translocate at long times- principles of why “the whole is more than the sum of its parts” that
cales. Silly Putty is also a “soft material,” in that the polymer’s in- will provide greater control and design over living matter, in the
teraction energies are at the thermal energy level, and its length same way that engineering has provided great advances in applica-
scale is at the micrometer level. Materials like Silly Putty were tions of materials from the physical world.
thought to be too complicated for analytical theory. It was only in What do biologists gain from theories of living matter? These
the middle of the 20th century that the theoretical framework to theories will provide a crucial link between molecular and cellular
understand these “messy” and “disorganized” polymer-based length scale behaviors and will provide insight into the mecha-
materials was developed. nisms of why specific molecular perturbations alter cell behavior.
The most powerful theories for understanding these vastly differ- Moreover, they should provide us with general design principles
ent forms of physical matter were developed in the absence of even of living matter. What are the basic aspects of a machine needed
the simplest of computers. The theories relied on developing physi- to separate chromosomes, establish polarity, or generate con-
cal properties or parameters to describe the material with a “mean tractile forces that is utilized across different cell types? Can
field,” a type of coarse-graining that identifies the essential proper- knowing these aspects provide insight into the evolution of
ties of individual constituents and interactions but ignores many cellular machines and the robustness of cell behavior? Thus,
other details. These mean fields give us new intuitions concerning study of cellular materials both provides new opportunities for
the origin of material properties and give rise to definitions of physi- physicists and will provide crucial predictive understanding of cell
cal parameters, such as elasticity and viscosity. However, these theo- physiology.
ries also require materials that do not jostle around a lot and remain
close to equilibrium. In fact, understanding materials “far from equi- ACKNOWLEDGMENTS
librium” has been identified as a major challenge in physics for the I thank David A. Weitz, who instilled in me a passion for soft-matter
next century (National Research Council, 2007). physics; Clare Waterman, who enabled me to see the materials
Materials formed by dynamic protein assemblies in the inside cells; and Rob Phillips, who carefully read this essay. M.L.G.
cytoskeleton are disorganized, heterogeneous, and driven far is funded by a Packard Foundation Fellowship, the Burroughs
from equilibrium. Motor proteins generate local stresses, and Wellcome Fund, and the National Institutes of Health (DP10D00354).
their activity is spatially modulated. The polymerization and de-
polymerization of cytoskeletal polymers is controlled by a myriad REFERENCES
of regulatory proteins. All these dynamic molecular processes National Research Council (2007). Condensed-Matter and Materials
Physics: The Science of the World Around Us, Washington, DC:
endow the cytoskeletal assemblies with unique behaviors that National Academies Press.
enable them to support complex physiological tasks. It is likely Ramaswamy S (2010). The mechanics and statistics of active matter. Annu
these dynamics also provide underlying robustness of the cells in Rev Condens Matt Phys 1, 323–345.
4166 | M. L. Gardel Molecular Biology of the Cell

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MBoC | PERSPECTIVE

Living matter—nexus of physics and biology

Volume 23 November 1, 2012 4165

4166 | M. L. Gardel Molecular Biology of the Cell

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