Linhong Deng talks with
ScienceWatch.com and answers a few questions about
this month's Fast Breaking Paper in the field of Materials
Science. The author has also sent along images of
Article Title: Fast and slow dynamics of the
LH;Trepat, X;Butler, JP;Millet, E;Morgan, KG;Weitz,
Journal: NAT MATER
Year: AUG 2006
* Harvard Univ, Sch Publ Hlth, Program Mol & Integrat
Physiol Sci, Boston, MA 02115 USA.
* Harvard Univ, Sch Publ Hlth, Program Mol & Integrat
Physiol Sci, Boston, MA 02115 USA.
(addresses have been truncated)
Why do you think your paper is highly cited?
Dynamics of the cytoskeleton largely determine the mechanical properties of
the living cell that influence a variety of important cellular behaviors
such as migration, proliferation, and intercellular communication. Despite
extensive studies, however, the dynamics of the cytoskeleton have not been
fully understood, due in part to lack of a generally agreed upon physical
model that can explain its complex nature and underlying mechanisms.
Recently, increasing evidence from studies on adherent cells in culture
demonstrates that the cytoskeleton behaves much like soft glassy materials
such as foam, slurry, and colloids. Although the physics underlying the
behaviors of such materials remains largely elusive, they are generally
regarded as slow dynamics not driven by thermal energy. (Ben Fabry et
al., "Scaling the Microrheology of Living Cells," Physical Review
Letters 87, : 2001; Predrag Bursac et al.
"Cytoskeletal remodelling and slow dynamics in the living cell" Nature
Materials 4: 557-61, 2005).
These findings seem to contradict what has long been known in filamentous
systems formed by reconstituted cytoskeletal protein polymers in
vitro—that is, that the dynamics of such cytoskeleton-mimicking
systems is driven by the thermal fluctuation of semiflexible filaments made
of the cytoskeletal protein (Frederick C. MacKintosh et al., "Elasticity of
Semiflexible Biopolymer Networks," Physical Review Letters 75:
4425-28, 1995; Margaret L. Gardel et al., "Elastic Behavior of
Cross-Linked and Bundled Actin Networks," Science 304 : 1301-05, 28
May 2004). This contradiction has been a hot debate with regard to whether
each type of the observed dynamics is only true to the specific subject
under study, and neither represents the behavior of real cells in
In this paper, we examined the material properties of the cytoskeleton of
freshly isolated airway smooth muscle cells, using the same approach as
with cultured adherent cells. These freshly isolated cells are one step
closer to cells in vivo in terms of their structure and biological
properties. But, how would they behave mechanically? As we characterized
the material moduli of theses cells as we did with the adherent cells in
culture, we found that at low (strain) frequencies (<100 Hz) the
cytoskeleton still behaves like a soft glass material as those cultured
cells, although softer and more elastic.
However, at high frequencies (>100 Hz), we observed a deviation from
glassy behavior towards the elastic behavior associated with a semiflexible
filament network. This finding was quite a surprise, and demonstrated for
the first time the existence of the semiflexible filament dynamics commonly
observed in vitro. Thus, our work has the potential to reconcile
observations made in reconstituted cytoskeletal protein filament networks
(which are usually characterized as elastic bodies) and in living cells
(which behave non-elastically).
Furthermore, the finding that the elastic behavior of the cytoskeleton is
observed only at high frequencies (near 1 kHz) suggests that cells may be
more appropriately characterized as non-elastic bodies because
physiological functions (which require deformation of the cytoskeleton)
carried out by the cells normally occur at frequencies much lower than 1
kHz. This is an important conclusion. Taken together, this paper may have
provided a more appropriate perspective when we treat the living cell as a
complex material. I think this is why our paper is highly cited.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This paper does describe a new finding that the response of the cell to
oscillatory strain (0.1-1k Hz) is characterized by two distinct power-law
regimes: from 0.1 to 100 Hz a very weak dependence (power-law exponent
alpha = 0.05) and from 100-1000 Hz a stronger dependence (power-law
exponent beta = 0.75). These are novel findings; in previous rheological
studies of cells only one power-law regime had been observed over a very
wide range of frequencies/times, with a power-law exponent of 0.1-0.3, and
the other power-law regime with a constant power-law exponent of 0.75 had
only been observed in reconstituted actin gels. Consequently, these results
unify, within a single cell, two rheological models which had been used
independently in the past to describe and interpret data from rheological
measurements on cells.
paper may help us better understand
how cells behavior both in health
From a biological point of view, however, these findings suggest that the
semi-flexible polymer dynamics are irrelevant for cellular functions since
their influence becomes important at high frequencies (>100 Hz) which
are outside of the normal physiological range. This, in turn, implies that
the focus of the research in cellular rheology should be shifted from the
dynamics of semi-flexible polymer networks, which had been a common
approach in the past, to the soft glass rheology that is yet to be fully
understood. An important by-product of this new finding is that the
observed regime of entropic dynamics in the cell indirectly proved that the
magnetic bead-twisting technique we used does probe the actin cytoskeleton.
Would you summarize the significance of your paper in
This paper may be significant because it demonstrates, for the first time,
that the living cell can behave either like a soft glassy material such as
Ketchup and soft dough, or like a network system composed of semiflexible
filaments, depending on how fast the cell is changing its shape. Although a
filamentous network may look like the structure formed by cytoskeletal
proteins both in vivo and in vitro, the mechanical
behavior of such systems can be elegantly explained in terms of thermal
dynamics, and only at a fast rate of shape change can the semiflexible
filamentous network account for the mechanical behavior of the living cell.
Within the range of the physiological rate of shape change, the cell
behaves, instead, rather like Ketchup or soft dough. In other words, the
cell is neither a solid nor a fluid, but something between. What’s
more important is that the cell can alter its property from solid-like to
fluid-like or vice versa in response to both physical and chemical changes
in its environment, much like what glass does when subjected to temperature
change. All together, this paper may help us better understand how cells
behave both in conditions of health and of disease.
How did you become involved in this research, and were
there any problems along the way?
I become involved in this research when I joined the laboratory of
Professor Jeffrey Fredberg at the Harvard School of Public Health. The
group led by Dr. Fredberg had been studying the mechanical behavior of
human airway smooth muscle cells in an attempt to understand its role in
pathobiology of asthma. Over the years, the group gradually came to
establish that adherent cells passaged in culture resemble soft glassy
materials as far as the cell mechanics are concerned. Although soft glassy
behavior of the cell has been replicated in other labs using other or
similar techniques, the concept that cells are soft glassy materials seems
contradictory to what has been learned from gel systems of reconstituted
cytoskeletal protein filaments in vitro.
As usual suspects, the cultured cells were blamed for bringing about the
peculiar soft glassy behavior that might not portray the true picture of
cell mechanics in vivo. Such blame is reasonable due to the
apparent structural difference between cultured cells and those observed in
tissue or freshly isolated. In order to settle the discrepancy, Dr.
Fredberg’s group decided to study the mechanics of the freshly
isolated cells using the same technique as with the cultured cells.
The freshly isolated cells are the closest possible to those in
vivo, and should more closely represent the cells in vivo
with regard to the cell mechanics. However, it proved to be a major
challenge to do such studies. The first problem was that it is extremely
difficult to prepare freshly isolated cells in a state of attachment to the
substrate in the culture dish in order to make mechanical measurement of
these cells. There had been unsuccessful attempts to tackle this problem
for about two years before I took up the task.
Then I spent about a year solving all aspects of this problem before the
first good experiment was achieved. After the initial success in making the
measurement, other problems soon followed, including complex issues of
statistical analysis and interpretation of the experimental data.
Fortunately, I was surrounded by several geniuses to whom I could turn
whenever I encountered a problem. Some of them are my coauthors on this
paper. With the help of this resourceful team, all problems were eventually
solved, one after another, with each of these individuals contributing an
equal effort toward the solution.
Where do you see your research leading in the
There are still numerous unknowns regarding cell mechanics and rheology.
For example, the physics underlying the soft glass rheology is not fully
elucidated; the molecular pathways that regulate the cell’s physical
state, whether it is more solid or more fluid, are not clear; how
pathological factors affect the soft glassy rheology of the cells; whether
there are more regimes of cytoskeleton dynamics, and whether the dynamic
regimes are fixed or shiftable, etc. These are primarily the future topics
which shall lead my research.
Do you foresee any social or political implications for
My research involves basic sciences only. I don’t see that it has any
social or political implications.
Dr. Linhong Deng
Professor and Director
Institute of National 985 Project on Biorheology and Gene Regulations
College of Bioengineering
Molecular and Integrative Physiological Sciences Program
Department of Environmental Health
Harvard School of Public Health
Boston, MA, USA