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ScienceWeek
SCIENCE-WEEK - January 18, 2002 - Vol. 6 Number 3
An Email Research Digest Published Weekly Since 1997
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I believe there is no philosophical high-road
in science, with epistemological signposts.
No, we are in a jungle and find our way by
trial and error, building our road behind us
as we proceed.
-- Max Born (1882-1970)
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Section 1
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Contents of this Issue (Full reports in Section 2):
1. Jamming and the Glass State
2. On Molecular Modeling as an Experimental Tool
3. Oceanic Photochemical Recycling of Iron
4. On Experiments with Single Molecules
5. Geophysics: Models of Mantle Convection
6. On Thermodynamics Beyond Local Equilibrium
7. Immunology: On Antibody Alterations
8. DNA Methylation and Epigenetics
9. Fixation of Nitrogen in the Ocean
10. On Tropical Species Diversity
11. On the Measurement of Past Biodiversity
12. On Telomerase and Dyskeratosis Congenita
13. PostDoctoral Fellowship Profile:
Laboratory of Jingwu Xie at University of Texas Medical Branch
14. In Focus: On Empty Space
15. From PRAXIS: On the Globalization of Seismology
16. This Week in PRAXIS
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Section 2
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1. JAMMING AND THE GLASS STATE
G. D'Anna and G. Grimaud (Ecole Polytechnique Lausanne, CH)
discuss jamming and make the following points:
1) It has been suggested that a common conceptual framework
known as "jamming" may be used to classify a wide variety of
physical systems that include granular media, colloidal
suspensions, and glass-forming liquids, all of which display a
critical slowdown in their dynamics before a sudden transition to
an amorphous rigid state. Decreasing the relevant control
parameter (such as temperature, drive, or inverse density) may
cause geometrical constraints to build up progressively and thus
restrict the accessible part of the system's phase space.
2) In glass-forming liquids (thermal molecular systems),
jamming is provided by the classical vitrification process of
supercooling, characterized by a rapidly increasing and
apparently diverging viscosity at sufficiently low temperatures.
In driven (athermal) macroscopic systems, a similar slowdown has
been predicted to occur, notably in sheared foam or vibrated
granular media.
3) The authors report experimental evidence for dynamic
behavior, qualitatively analogous to supercooling, in a driven
granular system of macroscopic millimeter-size particles. The
granular medium is perturbed by isolated tapping or continuous
vibration, with the perturbation intensity serving as a control
parameter. The authors observe the random deflection of an
immersed torsion oscillator that moves each time the grains
rearrange, analogous to a "thermometer" sensing the granular
noise.
4) The authors caution that their granular analogy to
supercooling is based on similarities in the dynamical behavior
rather than on quantitative theory.
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Nature 2001 413:407
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2. ON MOLECULAR MODELING AS AN EXPERIMENTAL TOOL
Romas Kazlauskas (McGill University, CA) discusses molecular
modeling and makes the following points:
1) Molecular modeling is a theoretical method that comprises
a broad range of computer methods that allow chemists to display
molecules, predict their structures, make short movies of their
motions, predict how they bind to each other and react with each
other. As this method becomes more routine and more reliable,
experimentalists are using it more frequently to guide and
improve experiments and to construct solutions to questions that
are impossible to examine experimentally.
2) The simplest application of modeling is molecular
visualization -- the use of computers to display molecular
structures measured experimentally. Not only are computer models
easier to build and store than plastic models, computer models
can both simplify and highlight molecular features. For example,
a schematic tracing of a protein chain simplifies a complex
protein structure, whereas a space-filling representation of the
binding site emphasizes its shape and a stick representation of a
bound molecule emphasizes its chemical structure. Each type of
image serves a different purpose.
3) All modeling involves approximations, and this is true
for even the most advanced theoretical methods. The key to
effective modeling is to include enough detail in the model to
accurately describe the phenomenon in question, but to omit
details that waste computer time or add needless complexity. With
a good model, the simplest questions can be answered by
displaying the structure of the molecules involved. More complex
problems, however, require the simulation of a process, such as
molecular motion. Quantitative predictions of binding or
reactivity usually cannot be obtained from a single structure and
may require examination of hundreds or thousands of low-energy
structures. Furthermore, chemical reactions involve bond-making
or bond-breaking, which can only be modeled using quantum
mechanics.
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Science 2001 293:2277
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3. OCEANIC PHOTOCHEMICAL RECYCLING OF IRON
K. Barbeau et al (University of California Santa Barbara, US)
discuss oceanic iron, the authors making the following points:
1) Iron is a limiting nutrient for primary production in
large areas of the oceans. Dissolved iron(III) in the upper
oceans occurs almost entirely in the form of complexes with
strong organic ligands presumed to be of biological origin.
Although the importance of organic ligands to aquatic iron
cycling is becoming clear, the mechanism by which such ligands
are involved in this process remains uncertain.
2) Siderophores are high-affinity iron(III) ligands produced
by bacteria to facilitate iron acquisition, and siderophores or
their breakdown products probably make up a large component of
the strong iron(III)-binding ligands that dominate iron(III)
speciation in surface ocean waters. Numerous marine cyanobacteria
and heterotrophic bacteria have been demonstrated to produce
siderophores in culture in response to iron stress. Voltammetric
studies have demonstrated that the ferric-ion binding strength of
siderophores is similar to that of the naturally occurring strong
iron(III)-binding ligands in sea water.
3) The authors report observations of photochemical
reactions involving iron(III) bound to siderophores. The authors
demonstrate that photolysis of iron(III)-siderophore complexes
leads to the formation of lower-affinity iron(III) ligands and
the reduction of iron(III), increasing the availability of
siderophore-bound iron for uptake by planktonic assemblages.
These photochemical reactions are mediated by the alpha-hydroxy
acid moiety, a group that has generally been found to be present
in the marine siderophores that have been characterized. The
authors suggest that iron(III)-binding ligands can enhance the
photolytic production of reactive iron species in the euphotic
zone and so influence iron availability in aquatic systems.
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Nature 2001 413:409
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4. ON EXPERIMENTS WITH SINGLE MOLECULES
Th. Basche et al (Johannes Gutenberg University, DE) discuss
research on single molecules, the authors making the following
points:
1) At first an experimental challenge, the ability to
conduct experiments with single molecules has been strongly
connected with progress in experimental techniques and
instrumentation.
2) Scanning probe techniques, such as the scanning tunneling
microscope or the atomic force microscope (AFM), use sharp tips
in close proximity [10^(-9) meters] to a sample to measure
tunneling currents or weak mechanical forces that in turn allow
generation of a real-space "image" of a single atom or molecule.
3) In another approach, macromolecules can be clamped
between an AFM tip and a substrate to determine the forces needed
to stretch a single polymer chain. Similar experiments are
feasible by use of "optical tweezers", where a macromolecule is
attached to a tiny bead and a substrate. The light force acting
on the bead can be used to translate it against a force generated
by the macromolecule.
4) In the optical domain, the fluorescence emission of
single molecules (or more generally, single fluorophores) in some
condensed-phase environments can be imaged by advanced optical
microscopes, such as scanning confocal microscopy or near-field
scanning optical microscopy. At low temperatures, single
fluorophores can also be isolated by a frequency-selective
technique that uses the fact that the sharp optical transition
frequencies of dopant molecules are different because of
imperfections of the environment. These optical techniques permit
detailed spectroscopic investigations at the single-molecule
level, taking advantage of spectral, time-resolved, and
polarization information.
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Proc. Natl. Acad. Sci. 2001 98:10527
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Related Background:
ON FORCES AT THE LEVEL OF SINGLE MOLECULES
T. Strick et al (Cold Spring Harbor Laboratories, US) discuss the
manipulation of single biomolecules and the range of forces at
the level of single molecules. Biophysics is currently undergoing
a transformation due to the development of new tools for
manipulating, visualizing, and studying single molecules and
their interactions. The smallest measurable forces at the
molecular level are the *Langevin forces responsible for the
Brownian motion of bacteria, pollen grains, and other small
objects in water at room temperature. The average force buffeting
a bacterium every second is comparable to its weight and is
approximately 10^(-14) newtons. Almost a thousand times stronger
are the forces typical of molecular motors, which convert
chemical energy from adenosine triphosphate (ATP) into mechanical
work. ATP is the common coin of stored chemical energy in all
life on Earth. The hydrolysis of an ATP molecule yields an energy
of approximately 14 kT, where the thermal energy (kT) at body
temperature is 4 x 10^(-21) joules, and the molecular dimensions
are of the order of 10 nanometers. Thus, the characteristic
forces of such motors are of the order of 10^(-11) newtons. Next
on the way up the force scale are the cohesion forces associated
with hydrophobic interactions and cooperative hydrogen bonding.
Such interactions contribute to the stability of biomolecules and
their native folded configurations. These forces are of the order
of 10^(-10) newtons, the typical force required to break a
noncovalent bond and denature a protein. The strongest forces at
the molecular level are the forces of the order of 10^(-9)
newtons required to break covalent bonds with dimensions of the
order of an angstrom and typical binding energies of 1
electronvolt.
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Physics Today 2001 October
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Notes:
... ... *Langevin forces: Named after Paul Langevin (1872-1946).
In this context, the term "Langevin forces" refers to two forces
appearing in the Langevin equation of random motion. The two
forces are a frictional force resulting from the viscosity of the
surrounding fluid and a random force describing the average
effect of Brownian motion.
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SCIENCE-WEEK 2001 9 Nov
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Related Background:
ON SINGLE MOLECULE PHYSICS AND CHEMISTRY
Only a few decades ago, most scientists believed that individual
molecules would not come within the domain of experimental
observations within their lifetime, if ever, and that the
statistical ensemble properties of molecules were therefore the
only properties of relevance. That view has now undergone a
dramatic alteration as a consequence of technological advances,
and there is much excitement evident in many laboratories over
the prospects of single-molecule explorations in physics,
chemistry, and biology.
... ... C. Bai et al (4 authors at 3 installations, CN US)
present a short review of recent work in single-molecule physics
and chemistry, the authors making the following points:
1) The authors point out that when Richard Feynman (1918-
1988) was bothered while looking through one of the first
*scanning tunneling microscopes, he was upset to have been
interrupted because seeing the images of singe atoms was a
"religious experience". For many generations of scientists, the
molecule was both the concrete ultimate entity upon which our
understanding of the everyday world was based, and at the same
time an elusive intellectual construct whose very existence could
only be inferred circumstantially by experiments on macroscopic
samples. Thus, seeing an individual atom or molecule in motion
brings immediate emotional impact to this central concept of
modern thought.
2) The authors ask: "When is molecular individuality
important?" The new possibility of studying single molecules is
important because molecular individuality does finally come into
play when the molecule is a complex entity. This may occur
because the molecule itself may have an intricate internal
structure -- e.g., a biomolecule -- resulting in a complex energy
landscape. Alternatively, the molecule may be part of a complex
environment that substantially changes the behavior of the
molecule. Here, distinguishing different molecules at different
locales is crucial for understanding the system as a whole.
Biomolecules in living cells are examples of this. Even simple
inorganic molecules on structured surfaces or in disordered
systems such as viscous liquids or glasses provide situations in
which molecular individuality matters. In all of these cases, the
capability of studying an individual molecule over time can
provide new insights unavailable by straightforward experiments
on macroscopic populations of molecules.
3) With the aid of *scanning probe microscopy, direct
observations of entire arrays of atoms, molecules, and the fine
structures of molecular aggregates have become possible. The
ability to precisely control probes permits the study of long-
range structures made by molecules lying on surfaces. However,
although pretty pictures of such systems are easy to construct,
obtaining quantitative characteristics of surface-bound molecules
is not entirely straightforward, and the rigorous interpretation
of scanning probe microscopy images requires substantial
theoretical as well as experimental effort.
4) The authors conclude: "We are only at the beginning, but
it is clear there is much to be discovered of a fundamental
nature about complex molecules viewed as individuals. Perhaps
equally important will be the idea of single molecule control.
Now that experiments interact with molecules at an individual
level, we can try to control them as individuals, not as
populations. A molecule under active control by an adaptive
environment will be a new beast. Such tamed molecules may well
resemble much more the elegant engineered machinery of everyday
experience than the unruly, wild molecules we are used to
studying today."
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Proc. Natl. Acad. Sci. 1999 96:11075
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Notes:
... ... *scanning tunneling microscopes: First available in the
early 1980s, this technique involves an atomically sharp metal
tip brought in atomic proximity (e.g., 0.5 to 1 nanometer) to a
flat surface so that electrons can *tunnel between the two
systems. Recording the atomic modulation of the atomic structure
which scanning the tip across the surface allows one to image
adsorbed species and surface morphologies.
... ... tunnel: Tunneling is a quantum mechanical phenomenon
involving an effective penetration of an energy barrier resulting
from the width of the barrier being less than the wavelength of
the particle.
... ... *scanning probe microscopy: A general term comprising all
atomic-level probe techniques. See background material below.
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SCIENCE-WEEK 1999 3 Dec
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Related Background:
APPLICATIONS OF SINGLE-MOLECULE SPECTROSCOPY
Only a few decades ago, most scientists believed that
individual molecules would not come within the domain of
experimental observations within their lifetime, if ever, and
that the statistical ensemble properties of molecules were
therefore the only properties of relevance. That view has now
undergone a dramatic alteration as a consequence of technological
advances, and there is much excitement evident in many
laboratories over the prospects of single-molecule explorations
in physics, chemistry, and biology.
As an experimental technique, single-molecule spectroscopy
is only a few years old, but already research reports are
appearing in a variety of applications as diverse as low-
temperature dynamics of single dye molecules embedded in
crystals, optical tracking of the entry of individual viruses
into living cells, single photon light sources from single
molecules, polymer conformations and dynamics, the mechanisms of
single enzymatic motors.
In a commentary on new research involving single-molecule
spectroscopy, A.M. Kelley et al point out that one reason for the
burgeoning interest in single-molecule optical techniques is that
photons may be the least perturbing probe of the state of a
molecule. "In combination with single-molecule manipulation,
microfluidics, and microelectromechanical systems, [single-
molecule optical studies] will open up ever more possibilities
for new discoveries."
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Science 2001 292:1671
PRAXIS 2001 6 Aug
SCIENCE-WEEK 2001 9 Nov
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Related Background:
ON THE NANOSCALE SCIENCE OF SINGLE MOLECULES
In recent years, experiments on individual molecules using
scanning probe microscopies [*Note #1] have demonstrated a
diversity of physical, chemical, mechanical, and electronic
phenomena. These techniques have permitted deeper insight into
the quantum electronics of molecular systems and have provided
unique information about the conformational and mechanical
properties of these systems. Concomitant developments in
experimentation and theory have allowed a diverse range of
molecules to be studied, molecules varying in complexity from
simple diatomic systems to biological macromolecular systems.
... ... J.K. Gimzewski and C. Joachim (2 installations, CH FR)
present an extensive review of current single-molecule research,
the authors making the following points: 1) The very nature of
proximal probe methods encourages exploration of the nanoworld
beyond conventional microscopic imaging. Scanning probes now
allow us to perform "engineering" operations on single molecules,
atoms, and bonds, thereby providing a tool that operates at the
ultimate limits of fabrication. These techniques have also
enabled explorations of molecular properties on an individual
basis as opposed to explorations restricted to the statistical
properties of large populations of molecules. 2) The
nanomechanical properties of individual molecules take the form
of vibrations, rotations, conformational changes, and
translations. *Inelastic tunneling processes, probe-tip-induced
forces, and Brownian motion have been found to drive mechanical
responses in individual molecules, and these aspects are the
focus of current research. The important role of thermal noise at
room temperature in nanoscale systems suggests that future
technologies for building small energy-efficient devices will
need to use ambient temperature fluctuations rather than fight
against them. 3) Future developments in single-molecule nanoscale
science call for a close integration of chemistry, biology,
physics, and technology in terms of synthesis, theoretical
modeling, and advanced scanning probe microscope techniques.
Although scanning probe microscopy has been shown to be an
ultimate probe for investigating the properties of individual
molecules, it is still an open question whether these techniques
have the intrinsic capabilities to be useful fabrication tools in
technology. The recent development of massive micromechanical
arrays of thousands of scanning probe microscopy probes suggests
that such a possibility is becoming more real each day.
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Science 1999 283:1683
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Notes:
... ... *Note #1: The general approach in scanning probe
microscopy research is illustrated by consideration of two major
techniques, scanning tunneling microscopy (STM) and atomic force
microscopy (AFM). In scanning tunneling microscopy, an atomically
sharp metal tip is brought in atomic proximity (e.g., 0.5 to 1
nanometer) to a flat surface so that electrons can *tunnel
between the two systems. The probe is slowly moved across the
surface and raised and lowered so as to keep the tunneling
current constant. A computer-generated contour map of the surface
is thus produced. The technique can resolve individual atoms, but
requires electrically conducting materials. In atomic force
microscopy, a tip is fixed to a cantilever whose position is
monitored while the tip scans the surface. The force between the
tip and the surface determines the position of the cantilever.
When recorded in atomic resolution, the image represents a map of
atomic forces at the surface. The advantage of atomic force
microscopy is that the probed surface does not need to be
electrically conducting.
... ... *tunnel: "Tunneling" is a quantum mechanical
phenomenon involving an effective penetration of an energy
barrier resulting from the width of the barrier being less than
the wavelength of the particle.
... ... *Inelastic tunneling processes: In general, an
"inelastic" process is a process which results in a permanent
change in the properties of a system. In this context, the term
"inelastic tunneling process" refers to a technique involving the
input of energy into a single-molecule system to selectively
excite chemical bonds or to perform spectroscopic studies of the
system.
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ScienceWeek 1999 21 May
ScienceWeek 2001 9 Nov
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SCIENCE-WEEK 18 Jan 2002 http://scienceweek.com
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5. GEOPHYSICS: MODELS OF MANTLE CONVECTION
Don L. Anderson (California Institute of Technology, US)
discusses mantle convection, the author making the following
points:
1) There are two competing models for mantle convection. In
the first model, the mantle is stratified into two or more
separate convecting regions. In the second model, the whole
mantle convects as a single unit. Recent progress in plate
tectonics, seismology, solid-state physics, and mantle convection
is providing strong support for the stratified convection model.
The results may also help explain how plate tectonics relate to
mantle convection: upper mantle convection may be driven by plate
tectonics, whereas the deep mantle may convect in a completely
different style.
2) Evidence for whole mantle convection comes primarily from
seismology, and involves high-velocity seismic anomalies that
appear to be slabs traversing the mantle. The evidence for
occasional slab penetration below 650 kilometers is usually
considered sufficient evidence for whole mantle convection. Whole
mantle convection is also the reigning paradigm among geodynamic
modelers because of the seismic evidence and the similarity
between the geoid (the surface of constant gravitational
potential that would represent the sea surface if the oceans were
not in motion) and deep mantle seismic tomography (which works
much like medical x-ray tomography except that seismic velocities
are imaged). Whole mantle convection simulations are also easier
to do.
3) Arguments for stratified convection are more complex and
more difficult to understand. Pressure suppresses the effect of
temperature on density, making it more difficult for the deep
mantle to convect. Pressure also suppresses the effect of
temperature on seismic velocities, which are used by
seismologists to map temperature variations. Ab initio
calculations of mantle minerals indicate that subtle differences
in seismic gradients and velocities may be compositional: even
small changes in chemistry can stratify mantle convection.
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Science 2001 293:2106
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6. ON THERMODYNAMICS BEYOND LOCAL EQUILIBRIUM
J.M. Vilar and J.M. Rubi (Princeton University, US) discuss non-
equilibrium thermodynamics, the authors making the following
points:
1) Concepts in everyday use such as energy, heat, and
temperature acquired a precise meaning after the development of
thermodynamics, which provides us with the basis for
understanding how heat and work are related and with the rules
that the macroscopic properties of systems at equilibrium follow.
Outside equilibrium, most of those rules do not apply and the
mentioned quantities cannot be defined unambiguously.
2) There is, however, a natural extension of thermodynamics
to systems away from but close to equilibrium, the extension
based on the local equilibrium hypothesis, which assumes that a
system can be viewed as formed of subsystems where the rules of
equilibrium thermodynamics apply. Because of the usual disparity
between macroscopic and microscopic scales, most systems fall
into this category. This is the case, for example, of heat
transfer from a flame, flow through a pipe, or electrical
conduction in a wire. Nonequilibrium thermodynamics extracts the
general features, providing laws such as Fourier's law of heat
conduction, Fick's law of diffusion, and Ohm's law of electric
currents, laws which do not depend on the detailed microscopic
nature of the system.
3) In contrast, there are other situations where the local
equilibrium hypothesis does not hold. Many examples are present
in the relaxation of glasses and polymers, in the flow of
granular media, and in the dynamics of colloids. The main
characteristic of such systems is the similarity between
microscopic and macroscopic scales, the systems usually involving
internal variables with "slow" relaxation times. The so-called
inertial effects in diffusion processes are perhaps the simplest
and most illustrative example. In this case, the relaxation of
the velocity distribution and changes in density occur at the
same time, and therefore local equilibrium is never reached. The
authors demonstrate theoretically how nonequilibrium
thermodynamics, as already established in the 1960s, can be
applied to this situation.
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Proc. Natl. Acad. Sci. 2001 98:11081
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Related Background:
THEORETICAL PHYSICS:
ON THE EQUILIBRIUM MECHANICAL PROPERTIES OF INDIVIDUAL MOLECULES
In general, conventional thermodynamics is the systematic
study of the relationship between heat, work, temperature, and
energy, and the relations of these variables to the general
behavior of systems at equilibrium. The term "classical
thermodynamics" usually refers to a phenomenological approach
that does not involve consideration of individual atoms or
molecules. "Statistical thermodynamics" does consider individual
atoms or molecules, in the sense of involving a few elementary
assumptions concerning atoms or molecules, but the focus in
statistical thermodynamics is on the behavior of statistical
populations of atoms or molecules. In general, statistical
thermodynamics attempts to express macroscopic thermodynamic
properties in terms of the statistics of the behavior of
individual particles and their interactions. During the 20th
century, there has emerged the field of "nonequilibrium"
("irreversible") thermodynamics. Unlike classical thermodynamics,
in which it is assumed that the system is at equilibrium,
nonequilibrium thermodynamics investigates systems that are not
at equilibrium. There has been much progress in nonequilibrium
thermodynamics, particularly for systems close to equilibrium,
but in general our understanding of nonequilibrium phenomena is
not comparable to our understanding of equilibrium phenomena.
Now suppose one has an individual molecule isolated and
under control, for example an individual polymer molecule
specifically constrained and contacted so that it can be
stretched, and one wants to describe (and understand) the
behavior of this single molecule, not in terms of electrons and
atomic nuclei and so on, but as a _single system_. A priori, one
can say that if the laws of thermodynamics are not constrained by
scale, they should in principle be applicable to a single
molecule considered as a thermodynamic system. And, in fact, it
should be possible to develop statistical considerations for a
single molecule if we consider the real fluctuating states of the
molecule as a statistical ensemble of states constrained by
thermodynamic parameters. This is the essential basis of research
applying statistical thermodynamics (both equilibrium and
nonequilibrium) to the behavior of individual molecules.
... ... G. Hummer and A. Szabo (National Institutes of Health,
US) present a theoretical analysis of nonequilibrium single-
molecule pulling experiments, the authors making the following
points:
1) The authors point out that recent advances in the
micromanipulation of single molecules have led to new insights
into the dynamics, interactions, structure, and mechanical
properties of individual molecules. Single-molecule manipulation
with an *atomic force microscope, *laser-tweezer stretching, and
analogous computer experiments have revealed details about
unfolding and unbinding events of individual proteins and their
complexes. In an atomic-force-microscope experiment, a single
molecule is subjected to a time-varying external force, e.g., by
pulling on the end of a linear polymer. The applied force is
determined from the time-dependent position of the cantilever tip
with respect to the sample. Thus, one can drive rare molecular
events, determine their force characteristics, and simultaneously
monitor them with atomic resolution. However, both experiments
and simulations actively perturb the system, leading to
hysteresis and nonequilibrium effects.
2) The authors ask: How can one extract equilibrium
properties from such measurements that drive the system away from
equilibrium? From the second law of thermodynamics, we know that
on average the mechanical work of pulling will be larger than the
free energy. Only if the experiment is performed reversibly,
i.e., infinitely slowly, will the work equal the free energy.
Thus, making rigorous thermodynamic measurements by pulling
appears to require an extrapolation to zero pulling speed.
However, C. Jarzynski (1997) recently discovered a remarkable
identity between thermodynamic free energy differences and the
irreversible work. This identity, although not directly
applicable to atomic force measurements, suggests that in
principle one should be able to extract free energy surfaces from
repeated pulling experiments.
3) The authors (Hummer and Szabo) demonstrate, with a
quantitative theoretical analysis, how equilibrium free energy
profiles can be extracted rigorously from repeated non-
equilibrium force measurements on the basis of an extension of
Jarzynski's identity between free energies and irreversible work.
... ... In a commentary on the above study, C. Jarzynski (Los
Alamos National Laboratory, US) makes the following points:
1) Jarzynski points out that what Hummer and Szabo propose
amounts to a distinctive method of deducing the equilibrium
mechanical properties of individual molecules. Hummer and Szabo
provide a prescription for combining the data from [repeated
pulling] experiments, so that what ultimately emerges is the
equilibrium tension as a function of elongation, even if the
molecule was driven away from equilibrium during the pulling
process. Jarzynski states: "Moreover, they make a solid case --
by using simulations as well as analysis of published
micromanipulation data -- that their method is experimentally
feasible."
2) Concerning the theoretical approach of Hummer and Szabo,
Jarzynski points out that when a system is perturbed away from
equilibrium by the arbitrary variation of an external parameter,
then a particular statistical description of its response -- the
description constructed via a weighting procedure involving a
Boltzmann distribution factor [*Note #1] -- behaves with
remarkable simplicity: it exactly follows the instantaneous
equilibrium state associated with the changing value of the
parameter. Jarzynski points out that Hummer and Szabo have
translated this abstract notion into a concrete proposal for an
experimental method of measuring the properties of molecules.
"Not only does their method represent a potentially useful
laboratory technique, but an experiment along these lines would
provide the first direct test of the underlying theory."
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Proc. Natl. Acad. Sci. 2001 98:3636,3658
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Notes:
... ... *atomic force microscope: An atomic force microscope is a
type of microscope in which a small probe is held on a spring-
loaded cantilever in contact with the surface of a sample. In
this context, single polymer molecules are anchored between a
surface and an atomic force microscope tip and then stretched.
until the molecule became detached.
... ... *laser-tweezer stretching: (optical-tweezer stretching)
The term "laser tweezers" refers to a laser trap used to hold and
move microscopic objects. The term "laser trap" refers to a
device for confining atoms, molecules, and neutral particles up
to 10 microns in diameter, the trap consisting of a focused laser
beam tuned to a frequency such that particles are attracted to
regions of high laser intensity.
... ... *Note #1: The weighting factor is e^(-W/kT), where (W) is
the total work performed, (k) is Boltzmann's constant, (T) is
absolute temperature.
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SCIENCE-WEEK 2001 18 May
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Related Background:
STATISTICAL PHYSICS: EQUILIBRIUM STATISTICAL MECHANICS APPLIED
TO NONEQUILIBRIUM SYSTEMS
Statistical mechanics (statistical physics) is a quantitative
approach to the average behavior of a system containing many
particles, the approach derived from first principles and certain
simplifying assumptions concerning the nature and interactions of
the particles in the system. It is the most successful approach
to the behavior of physical systems containing many particles,
but its application has been limited to systems at or near
thermodynamic equilibrium.
... ... David A. Egolf (Los Alamos National Laboratory, US) now
reports on the application of statistical mechanics to systems
far from equilibrium, the author making the following points:
1) The author points out that statistical mechanics
describes the macroscopic physical properties of matter through a
probabilistic rather than a detailed knowledge of microscopic
dynamics, and that the theory has been applied successfully to a
wide variety of equilibrium systems, ranging from simple
molecular gases to *white dwarf stars. Statistical mechanics has
provided a theoretical understanding of the phases of matter, the
transitions between phases, and the deep property of universality
that unifies the descriptions of continuous transitions in
systems physically quite distinct (e.g., magnets and gases). In
nature, however, many systems are not in equilibrium, including,
for example, large-scale flows in the atmosphere, the evolution
of ecological systems, and the transport of energy in biological
cells. None of these situations can presently be understood with
equilibrium statistical mechanics.
2) Although the theory of equilibrium statistical mechanics
has been developed to extend it to systems only slightly
perturbed away from equilibrium (for which a quantitative
description of the evolution of the system is well-approximated
with only linear terms), in deterministic systems driven far from
equilibrium (where nonlinearities are important), theoretical
progress has been limited to relatively simple situations. In
particular, theorists have not yet developed an understanding of
the intriguing phenomenon of spatially extended *chaos, which is
typically characterized by disordered arrays of defects, patches
of uncorrelated regions, and a chaotic dynamics that persists
indefinitely. This remarkable behavior has been found in large,
deterministic, far-from-equilibrium systems as varied as
convecting horizontal fluid layers, chemical reaction-diffusion
systems, colonies of microorganisms, and *fibrillating heart
tissue. These disparate systems often display strikingly similar
macroscopic features and behaviors, which suggests the question
of whether one can construct a statistical predictive theory of
phases and transitions applicable to such chaotic far-from-
equilibrium systems.
3) The author reports that in his own computer-analysis
study, at intermediate coarse-grained scales, of a simple far-
from-equilibrium spatially extended chaotic model system, a
number of equilibrium properties, including *ergodicity and
*detailed balance, were found to be recovered by the system,
which indicates, the author suggests, that the macroscopic
behavior of some far-from-equilibrium systems might be understood
in terms of equilibrium statistical mechanics.
4) The essential idea resulting from this work and proposed
by the author is that simple far-from-equilibrium *dissipative
and extensively chaotic systems "can recover certain equilibrium
properties at coarse-grained scales with the underlying chaotic
dynamics serving as a temperature bath." The author concludes:
"The system studied here possesses some important differences
from true equilibrium systems. Perhaps the most intriguing is
that the effective noise strength (or temperature) is internally
generated and dependent on the state of the system, rather than
imposed by an external temperature bath. This difference poses a
challenge for explorations of the *second law of thermodynamics
in these systems."
-----------
Science 2000 287:101
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Notes:
... ... *white dwarf stars: White dwarf stars are extremely dense
and compact stars that have undergone gravitational collapse.
Such stars, the final stage in the evolution of low-mass stars
after they have lost their outer layers, are approximately the
size of Earth, but with a mass approximately that of the Sun.
... ... *chaos: In this context, the term "chaos" refers to
unpredictable behavior arising in a system that obeys
deterministic laws but exhibits unpredictability. The essential
idea is that in certain systems small perturbations may produce a
cascade of larger perturbations, so that eventually the behavior
of such systems cannot be predicted from prior states no matter
if the systems appear simple and obey deterministic laws.
... ... *fibrillating heart tissue: Heart muscle fibrillation,
which is a dysfunction, is an extremely rapid desynchronized
contraction or twitching of individual muscle fibers in a muscle.
... ... *ergodicity: In general, ergodicity is a property of
dynamic systems containing a random variable (stochastic
systems): a system is said to be ergodic if it tends in
probability to a limiting form which is independent of the
initial conditions.
... ... *detailed balance: The principle of detailed balancing
(also called the principle of microscopic reversibility) states
that in equilibrium the probability (frequency) of the transition
of any microscopic part of a system from state A to state B
equals the probability (frequency) of the transition from state B
to state A.
... ... *dissipative: In general, a dissipative system
is a system that loses energy by conversion of energy into heat.
... ... *second law of thermodynamics: This law concerns the
direction that a natural process can take, and the law can be
stated in various ways, for example: a) heat cannot be
transferred from one body to a second body at a higher
temperature without producing some other effect; b) the entropy
of a closed system increases with time.
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SCIENCE-WEEK 2000 7 Apr
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Related Background:
PHYSICS: ON STATISTICAL PHYSICS AND ITS APPLICATIONS
Statistical physics (statistical mechanics) is the branch of
physics that attempts to explain the macroscopic properties of a
system on the basis of the properties of its microscopic
constituents. Usually the number of constituents is extremely
large, and all the characteristics of the constituents and their
interactions are presumed to be known. Although as a distinct
research area, statistical physics dates back to James Clerk
Maxwell (1831-1879) and Ludwig Boltzmann (1844-1906) and their
work on probability distributions in the kinetic theory of gases,
the field was substantially transformed in the 20th century, and
it has now been fruitfully applied to nearly all states of matter
including biological systems.
... ... Philip Ball (_Nature_, UK) presents a commentary on the
history and applications of statistical physics, the author
making the following points:
1) Statistical physics, and more specifically the theory of
transitions between states of matter, more or less defines what
we know about everyday matter and its transformations. In
addition, statistical physics provides a conceptual apparatus for
dealing with complex collective quantum phenomena of current
intense interest, particularly: a) Bose-Einstein condensation (in
which a collection of particles all occupy the same quantum
ground state); and b) high-temperature superconductivity (i.e.,
superconductivity above 35 degrees kelvin). Many of the states of
condensed matter that promise new technological applications,
ranging from *block copolymers to magnetic multilayers, can be
understood as the consequence of the kind of collective behavior
that statistical physics describes.
2) From the 1960s to the 1980s, statistical physicists were
primarily concerned with "critical points", the points in
thermodynamic phase diagrams at which two or more phases become
identical. The reasons for this interest are twofold: a) the
behavior of a system at its critical point also determines its
behavior in the broad vicinity of the critical point (within a
so-called "critical region"; b) the behavior of a system at a
critical point reveals kinships between different systems. For
example, liquid-gas criticality and the behavior of some magnets
at their Curie point (the temperature above which they lose their
*ferromagnetism) have numerically equal *critical exponents, and
both can be modeled by the so-called "*Ising model", a model
based on a lattice of two-state *spins. Commonality of critical
exponents gives rise to the idea of universality, the idea that
there are generic models in statistical physics that describe a
variety of apparently different many-body systems. This means
that solving one problem in statistical physics generally
delivers solutions for several other problems at the same time.
In addition, there is an implication that many-body behavior is
fundamentally determined only by global aspects such as the range
of interparticle forces, the dimensionality of the system, and
the nature of the "*order parameter" (whose abrupt change from a
zero to a non-zero value defines the transition from one state to
another).
3) A fruitful present area of research is the intersection
of statistical physics with quantum mechanics, in particular, the
many-body behavior of electrons in condensed matter. Correlated
behavior of electrons, in which electrons display a degree of
collective or coherent dynamics, produces superconductivity, the
*integer and fractional quantum Hall effect, so-called "*heavy-
fermion" behavior, *spin density waves, and *colossal
magnetoresistance. All of these collective phenomena have in
recent years been shown to underlie unexpected and potentially
useful properties of novel materials. Colossal magnetoresistance,
for example, may lead to the development of highly-sensitive
read-out heads for magnetic memories.
4) The author suggests that despite the proven value to cell
biology of some concepts from the study of phase transitions (for
example, the entropic effect of fluctuations on interactions of
lipid membranes), there remains much skepticism as to whether
biological phenomena can be approached as arising from collective
emergent behavior of statistical interacting ensembles rather
than from the closely controlled protein relays to which cell
biologists are accustomed. Yet statistical physics must
inevitably provide the baseline even in the cell: proteins may
phase-separate and membranes may adopt equilibrium conformations
unless actively opposed by cell processes.
-----------
Nature 1999 402supp:C73
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Notes:
... ... *block copolymers: A copolymer in which a number of units
of the same monomer are located adjacent to one another (in
"blocks" of monomers).
... ... *ferromagnetism: A "ferromagnet" is a material (such as
iron) in which there may be a permanent *magnetic moment, and in
which the *spins of the atoms are aligned parallel to each other.
... ... *magnetic moments: (magnetic dipole moment) The intrinsic
spins of the electrons in an atom, together with the motion of
the electrons around the nucleus, give rise to a magnetic field
around the atom, and the magnitude of this field is related to
the magnetic dipole moment of the atom or ion.
... ... *critical exponents: In this context, a "critical
exponent" is a parameter that characterizes the temperature
dependence of a thermodynamic property of a substance near its
critical point. The temperature dependence has the form
|T-T(subc)|^(n), where T is the temperature, T(subc) is the
critical temperature, and (n) is the critical exponent.
... ... *Ising model: In general, a simplified model in which the
atomic *spins are assumed to be aligned parallel or antiparallel
in a given direction.
... ... *spins: In quantum mechanics, electrons, protons, and
neutrons have an intrinsic angular momentum known as "spin", and
a magnetic moment parallel or antiparallel to that angular
momentum. When electrons are combined together to form an atom or
ion, there is a resultant angular momentum which is a combination
of the intrinsic spin of the electrons and the angular momentum
due to their motion about the nucleus, and this is the "spin" of
the atom or ion. Atoms or ions with non-zero spin are magnetic
atoms or ions. The idea of electron spin was first proposed by
Goudsmit and Uhlenbeck in 1925 to explain the splitting of atomic
spectroscopic emission lines in the presence of a magnetic field.
Elementary particle spin involves a virtual rotation about the
axis of the particle, which means only two spin states are
possible, one clockwise and one counterclockwise.
... ... *order parameter: In general, a quantity that
characterizes the phase of a system below its transition
temperature, the parameter having a nonzero value below the
transition temperature and a zero value above the transition
temperature. If the phase transition is continuous, the order
parameter falls to zero continuously as the transition
temperature is approached.
... ... *integer and fractional quantum Hall effect: In classical
physics, the Hall effect is the development of a transverse
voltage across a current-carrying conductor in a magnetic field,
the voltage being perpendicular to both the direction of the
current and the direction of the magnetic field. In quantum
physics, there are two other Hall effects, an integer charge
quantum Hall effect, and a fractional charge quantum Hall effect,
these quantum Hall effects being observed at extremely low
temperatures (a few degrees Kelvin) and extremely intense
magnetic fields (at least several tesla). Both quantum Hall
effects were first noted in the 1980s, and the fractional quantum
Hall effect, although experimentally observed, has not been
theoretically resolved.
... ... *heavy-fermion: "Heavy-fermion systems" are solids in
which electrons behave as if they have masses several hundred
times their normal masses. Substances containing such electrons
have unusual thermodynamic, magnetic, and superconducting
properties that are not completely understood.
... ... *spin density waves: In general, propagating collective
spin-variation excitations associated with certain magnetic
systems.
... ... *colossal magnetoresistance: (giant magnetoresistance)
The term "magnetoresistance" refers to a change in the electrical
resistance of a conductor or semiconductor upon the application
of a magnetic field, a property of certain systems. Giant
magnetoresistance is a quantum mechanical effect observed in
magnetic thin-film structures composed of alternating
ferromagnetic and nonmagnetic layers.
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SCIENCE-WEEK 2000 3 Mar
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7. IMMUNOLOGY: ON ANTIBODY ALTERATIONS
A. Martin and M.D. Scharff (Albert Einstein College of Medicine,
US) discuss antibody alterations. One of the ways in which the
immune system fights off intruders is to produce antibodies,
which bind to and neutralize foreign molecules (antigens). The
immune system -- specifically B cells -- must be able to generate
enough different antibodies to recognize every possible antigen,
so extraordinary antibody diversity is generated before exposure
to foreign antigens. But these primary antibodies almost always
have low affinity for their targets and they cannot neutralize
pathogens or toxins. Thus, after exposure to an antigen, the
variable regions ("V regions") of the antibody genes, which
encode the antigen-binding site, acquire many changes, some of
which result in higher-affinity binding sites. In some cases,
this occurs by a process called "gene conversion"; in other
cases, by "somatic hypermutation". In some species, such as
chickens, rabbits, pigs, and cows, the diversification of the V
region occurs mainly by gene conversion. This process basically
involves the acquisition of new DNA sequences copied from parts
of nearby pseudo-genes (regions of DNA that are similar to genes
but cannot encode a protein) on the same chromosome. In other
species, such as sharks, frogs, mice, and humans, the V regions
of the antibody genes acquire large numbers of single nucleotide
base changes by somatic hypermutation. It is not clear why these
two different processes evolved, and why their species
distribution is so sporadic.
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Nature 2001 412:870
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8. ON DNA METHYLATION AND EPIGENETICS
W. Reik et al (Babraham Institute Cambridge, UK) discuss DNA
methylation and epigenetics. DNA methylation is one of the best-
studied epigenetic modifications of DNA in all unicellular and
multicellular organisms. In mammals and other vertebrates,
methylation occurs predominantly at the symmetrical cytosine-
guanine dinucleotide (CpG). Symmetrical methylation and the
recent discovery of a DNA methyltransferase that prefers a hemi-
methylated substrate, have suggested a mechanism by which
specific patterns of methylation in the genome could be
maintained. Thus, patterns imposed on the genome at defined
developmental time points in precursor cells could be maintained
by the enzyme and would lead to predetermined programs of gene
expression during development in descendants of the precursor
cells. This provided a means to explain how patterns of
differentiation could be maintained by populations of cells. In
addition, specific demethylation events in differentiated tissues
could then lead to further changes in gene expression as needed.
Neat and convincing as this model is, it is still largely
unsubstantiated. While effects of methylation on expression of
specific genes, particularly imprinted genes and some
retrotransposons, have been demonstrated in vivo, it is still
unclear whether or not methylation is involved in the control of
gene expression during normal development. Although enzymes have
been identified that can methylate DNA de novo, it is unknown how
specific patterns of methylation are established in the genome.
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Science 2001 293:1089
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9. ON THE FIXATION OF NITROGEN IN THE OCEAN
J.P. Zehr et al (University of California Santa Cruz, US) discuss
nitrogen fixation in the ocean. Fixed nitrogen often limits the
growth of organisms in terrestrial and aquatic biomes, and
nitrogen availability has been important in controlling the
carbon dioxide balance of modern and ancient oceans. The fixation
of atmospheric dinitrogen gas [N(sub2)] to ammonia is catalyzed
by nitrogenase and provides a fixed nitrogen for nitrogen-limited
environments. The filamentous cyanobacterium Trichodesmium has
been assumed to be the predominant oceanic dinitrogen-fixing
microorganism since the discovery of dinitrogen fixation in this
organism in 1961. Attention has recently focused on oceanic
dinitrogen fixation because nitrogen availability is generally
limiting in many oceans, and attempts to constrain the global
atmosphere-ocean fluxes of carbon dioxide are based on basin-
scale nitrogen balances. Biogeochemical studies and models have
suggested that total dinitrogen-fixation rates may be
substantially greater than previously believed but cannot be
reconciled with observed Trichodesmium abundances. It is curious
that there are so few known dinitrogen-fixing microorganisms in
oligotrophic oceans when it is clearly ecologically advantageous.
The authors demonstrate that there are unicellular cyanobacteria
in the open ocean that are expressing the enzyme nitrogenase, and
these organisms are abundant enough to potentially have a
significant role in nitrogen dynamics. The authors suggest that
the discovery that these microorganisms are present and actively
expressing nitrogenase in the open ocean implies that conceptual
models of the magnitude, timing, and control of dinitrogen
fixation in the ocean need to be re-evaluated.
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Nature 2001 412:635
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10. ON TROPICAL SPECIES DIVERSITY
E. Bermingham and C. Dick (Smithsonian Institute, US) discuss
species diversity. Writing in 1878, the evolutionary biologist
Alfred Russel Wallace (1823-1913) suggested that the high species
diversity of the tropics could be accounted for by the greater
age of tropical environments -- providing more time for species
to accumulate -- compared with environments of temperate regions.
After all, parts of lowland South America have been draped in
tropical vegetation for over 100 million years, whereas the
distribution of temperate forests has tracked the push and pull
of glaciers. A century after Wallace, G.Ledyard Stebbins
introduced the "museum hypothesis", providing a name for the more
refined idea that "plant communities that have suffered the least
disturbance during the last 50 to 100 million years... have
preserved the highest proportion of archaic forms." This view of
Stebbins challenged the "cradle of diversity hypothesis" that had
largely supplanted Wallace's early notion of the importance of
time for explaining tropical species diversity. The cradle of
diversity hypothesis held that the tropics are a crucible of
evolution in which adaptive complexes arise owing to the biotic
complexity of tropical forests. The explosive radiation of New
World orchids, for example, is partly due to the group's
intricate coevolutionary interaction with pollinators. The idea
that high rates of tropical speciation, rather than age or
reduced rates of extinction, contribute to tropical forest
diversity gained added prominence with the publication of the
"refugia model" in the 1960s. This model posited that allopatric
divergence (i.e., divergence of very similar organisms that
cannot interbreed due to geographical isolation) in fragmented
ice-age forests acted as a species pump, supporting the
prediction that tropical species diversity is a recent event.
Thus, the question still remains: is most tropical diversity
ancient or new?
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Science 2001 293:2214
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11. ON THE MEASUREMENT OF PAST BIODIVERSITY
J.B. Jackson and K.G. Johnson (University of California San
Diego, US) discuss past biodiversity. The diversity of animal
life on Earth increased from near zero at the beginning of the
Cambrian period (approximately 570 million years ago) to the 4
million to 6 million species alive today. Two important questions
are: a) What was the trajectory of this increase? and b) Can we
measure the trajectory empirically with the fossil record? Most
attempts to answer these questions have been based on shell-
formed marine macroinvertebrates, the animals with the most
extensive and well-preserved fossil record. Approximately 300,000
living species of marine macroinvertebrates have been described,
but estimates that account for inadequate sampling range from
500,000 to 5 million. Only one-third of these species contain
hard parts likely to be preserved as fossils. Furthermore, fossil
species are often unnamed, and most compilations are therefore
based on genera or families to increase taxonomic consistency.
Assuming 1 million living species and less than 5 species per
genus on average, approximately 67,000 genera of living marine
macroinvertebrates would be preserved as fossils. How many such
genera have ever lived? Fossil marine invertebrate genera survive
on average approximately 28 million years. If the increase in
diversity during the Phanerozoic (from approximately 570 million
years ago to today) was logistic, with a maximum of approximately
67,000 genera as today, then the total number of fossilizable
marine macroinvertebrates that ever lived would be approximately
1 million. If Phanerozoic diversity increased exponentially, with
most of the increase in the Cenozoic (65 million years ago to
today), then the total might be only 200,000 genera.
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Science 2001 293:2401
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12. ON TELOMERASE AND DYSKERATOSIS CONGENITA
R. Marciniak and L. Guarente (University of Texas San Antonio,
US) discuss dyskeratosis congenita and telomerase. Dyskeratosis
congenita is an inherited human disease from which sufferers die
between the ages of 16 and 50. Problems tend to occur in tissues
in which cells multiply rapidly -- skin, nails, hair, gut, and
bone marrow -- with death usually occurring as a result of bone-
marrow failure. The disease is inherited in one of two ways: a)
some people carry mutations in a gene, identified in 1998, on the
X chromosome; b) in other people, mutations occur in unknown
genes on non-sex chromosomes (autosomes). The gene that is
mutated in the X-linked disorder encodes the protein dyskerin,
which is found in a subsection of the nucleus of the cell called
the "nucleolus". Although at first it was proposed that nucleolar
dysfunction underlies the disease, it was later discovered that
mutations in dyskerin actually affect the RNA part of telomerase,
and enzyme with both RNA and protein portions that helps to
maintain the ends of chromosomes (telomeres). This suggested that
dyskeratosis congenita might instead result from a defect in
telomerase activity. Now T. Vuillamy et al (2001) have confirmed
this idea with the discovery that an autosomal dominant form of
the disease is caused by mutations in the gene that encodes the
RNA part of telomerase itself. The symptoms of dyskeratosis
congenita apparently provide a glimpse of the effects of
telomerase defects on the maintenance of human tissues: cells in
rapidly dividing tissues, with progenitors that usually express
telomerase, are more strongly affected.
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Nature 2001 413:371,432
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SCIENCE-WEEK 18 Jan 2002 http://scienceweek.com
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Related Background:
MEDICAL BIOLOGY: TELOMERES, TELOMERASE, AND CANCER
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are essential for normal chromosome
replication, and since their length shortens a bit with each
replication, they are believed to be involved in the aging of the
cell. Telomerase is an enzyme that repairs damage to telomeres,
and it is thought by some researchers that cancerous cells may
have mutant telomerase, the mutant enzyme conferring immortality
on the cancer cell.
... ... Charles H. Buys (University of Groningen, NL) presents a
short review of current research on telomere targeting in the
treatment of cancer, the author making the following points:
1) Before any biological cell can divide, it must first
replicate the double-stranded DNA in its chromosomes. Each cell,
however, has a problem replicating the DNA at the telomeres,
where there are over 1000 short base sequences, thymine-thymine-
adenine-guanine-guanine (TTAGGG), repeated again and again, and a
variety of attached DNA-binding proteins. In a normal cell, the
replication machinery is unable to copy the last few bases of the
telomeres on one of the strands of DNA in the chromosome. As a
consequence, the telomeres shorten with each round of DNA
replication.
2) Telomeres are essentially molecular caps, protecting
the ends of chromosomes against degradation and preventing
ligation of the ends of DNA by DNA repair enzymes. These
functions are crucial to the cell, but the wearing away of
telomeres with each cell division, when repeated during many cell
cycles, eventually eliminates the protective functions, and
chromosomes become unstable, fused, or lost. Cells with such
chromosome defects are not able to divide and may not survive.
Attrition of telomeres thereby limits the lifespan of many types
of biological cells.
3) Two distinctive types of cells -- *germ cells and early
embryonic cells -- solve the problem of truncated telomeres by
means of a complex of proteins and RNA called "telomerase". The
RNA component of this complex contains a template sequence on
which the TTAGGG repeated groups ("repeats") at the ends of DNA
can by synthesized.
4) Unlike germ cells and early embryonic cells, most other
cells (somatic cells) switch off the activity of telomerase after
birth. In contrast, many types of cancer cells, perhaps as much
as 90 percent of various types of cancer cells, reactivate
telomerase. This essentially "rewinds the clock" on run-down
telomeres and contributes to the growth of the malignant clone
population of cancer cells.
5) With these considerations in mind, several recent studies
have explored the possibility of inhibiting telomerase as a way
of arresting the growth of tumor cells. Although the results have
been interesting and have suggested new possibilities for the
treatment of cancer, there are several cautionary points that
must be noted:
... ... a) Experiments have been conducted in vitro in cultured
cell lines, with efficient uptake of inhibitors ensured by means
unavailable in in vivo treatment.
... ... b) The inhibitors apparently work best in cultured tumor
cells when telomeres are shortest, but little is known about the
length of telomeres in *primary human tumors, and there is some
evidence that certain types of tumor cells may actually have
shorter telomeres than benign cells of the same type of tissue.
... ... c) Up to 20 percent of human tumors do not have
telomerase activity and may use other mechanisms to preserve
their telomeres.
6) Concerning the above cautionary points, the author
concludes: "Even though the therapeutic potential of telomerase
inhibitors may be limited by these considerations, further
investigation of this approach is certainly worthwhile."
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New Engl. J. Med. 2000 342:1283
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Notes:
... ... *germ cells: A germ cell is any cell from which gametes
(sperm cells and egg cells) are derived. All other cells are
called "somatic" cells.
... ... *primary human tumors: The term "primary tumor" refers to
the original tissue malignancy. Malignant cells from a primary
lung cancer, for example, may relocate ("metastasize") to the
brain, where they replicate as malignant lung-tissue cells,
causing a "secondary tumor".
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SCIENCE-WEEK 2000 7 Jul
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Related Background:
ROLE OF MOUSE TELOMERASE IN HIGHLY PROLIFERATIVE ORGANS
Telomeres are guanine-rich repeat sequences that form the
physical ends of the chromosomes of cells containing membrane-
bound organelles, and there is evidence these terminal structures
may be important in chromosome function. Synthesis and
maintenance of telomeric repeats are mediated by the specialized
ribonucleoprotein complex "telomerase". ... ... Lee et al (6
authors at 4 installations, US ES) report a study of the role of
the enzyme telomerase in highly proliferative organs in
successive generations of mice lacking telomerase RNA. Late
generation animals exhibited defective spermatogenesis, with
increased programmed cell death (apoptosis) and decreased
proliferation in the testis. The proliferative capacity of
hematopoietic cells in bone marrow and spleen was also
compromised. These progressively adverse effects coincided with
substantial erosion of telomeres and fusion and loss of
chromosomes. The authors suggest their findings indicate an
essential role for telomerase, and hence telomeres, in the
maintenance of genomic integrity and in the long-term viability
of high-renewal organ systems. They also suggest that the high
proliferation index of most cancer cells compared with the more
sporadic cycling of normal stem-cell populations indicates that
telomerase inhibition should be well tolerated in clinical
settings. QY: Ronald A. DePinho, Albert Einstein College of
Medicine 718-430-2106.
-----------
Nature 1998 392:569
Science-Week 1998 1 May
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Related Background:
EXTENSION OF MITOTIC LIMITS BY TELOMERASE EXPRESSION
Somatic cells are all cells other than germline cells such as egg
cells and sperm cells, and the term "cellular replicative
senescence" refers to the observation that somatic cells, in
contrast to germline cells, can proliferate (divide) only a fixed
number of times, the actual number dependent on the organism from
which the somatic cells derive. Since there is a general
correlation between cellular replicative senescence in vitro and
the average life-spans of various animals (including humans),
cellular replicative senescence has been implicated in aging and
age-related pathologies. Telomeres are regions at the ends of
chromosomes consisting of repeats of particular nucleotide
sequences, and with each somatic cell division a small part of
the telomere is ordinarily lost. What has been observed is that
in germline cells the lengths of telomeres are maintained
constant by repair, while in somatic cells this repair does not
occur, and this difference has led to the idea that the finite
proliferative capacity of somatic cells is related to the
ultimate depletion of telomere lengths. The enzyme telomerase is
the enzyme that causes repair of telomeres, and this enzyme is
active in germline cells, but it is not expressed in most somatic
cells. In animals, epithelial cells compose the cell layers that
form the interface between a tissue and the external environment,
for example, the cells of the skin, the lining of the intestinal
tract, and the lung airway passages, and fibroblasts are a type
of connective tissue cell that secret structured proteins such as
collagen. Transfection is the uptake of exogenous (foreign) DNA
fragments in solution directly into animals cells in laboratory
culture, and is one method of introducing foreign genes into
cells. The term "vector", in the context of DNA cloning, is any
DNA fragment used in a transfection process. ... ... Bodnar et al
(10 authors at 2 installations, US) now report that two normal
human cell types (retinal pigment epithelial cells and foreskin
fibroblasts) that do not ordinarily express telomerase, can be
transfected with vectors encoding the human telomerase catalytic
subunit, the transfected cells (as opposed to controls) then
exhibiting elongated telomeres, dividing vigorously and exceeding
their normal life-span by at least 20 doublings. The authors
suggest their results establish a causal relationship between
telomere shortening and in vitro cellular replicative senescence,
and that the ability to maintain normal human cells in a youthful
state can have important applications in research and medicine.
-----------
Science 1998 16 Jan
ScienceWeek 1998 30 Jan
-----------
Related Background:
NEW DATA AGAINST IMPORTANT TELOMERASE ROLE IN CANCER
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are essential for normal chromosome
replication, and since their length shortens a bit with each
replication, they are believed to be involved in the aging of the
cell. Telomerase is an enzyme that repairs damage to telomeres,
and it is thought by some that cancerous cells may have mutant
telomerase, the mutant enzyme conferring immortality on the
cancer cell. Now M. A. Blasco et al (Cell 91:25 1997) have
genetically engineered telomerase-deficient mice and have shown
that after 6 generations these mice are both viable and fertile.
Commenting on this research, David Wynford-Thomas and David
Kipling (University of Wales College of Medicine, Cardiff UK)
suggest that telomerase inhibitors that have been envisaged for
cancer therapy will therefore not have any acute toxicity against
cancer cells or other cells. Blasco et al have suggested that
current dogma that telomerase facilitates tumor growth may be
wrong, with telomerase nothing more than a "passive bystander" in
oncogenesis.
-----------
Nature 1997 9 Oct
ScienceWeek 1997 24 Oct
-----------
SCIENCE-WEEK 18 Jan 2002 http://scienceweek.com
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13. POSTDOCTORAL FELLOWSHIP PROFILE:
Laboratory of Jingwu Xie at University of Texas Medical Branch
--------------------------------------------------------------
INSTALLATION: University of Texas Medical Branch
DEPARTMENT: Department of Pharmacology and Sealy Center for
Cancer Cell Biology
GENERAL RESEARCH AREA: Cancer biology
HEAD OF THIS SPECIFIC LABORATORY: Jingwu Xie
POSTDOCTORAL FELLOWSHIPS ARE AVAILABLE IN THE FOLLOWING
RESEARCH PROBLEMS: Cancer molecular genetics and cancer cell
signaling
PREVIOUS RESEARCH EXPERIENCE AND DEGREES REQUIRED: Ph.D. in
biological sciences. Experience with transgenic mice preferred.
USUAL STARTING STIPEND: $28,000
SPECIAL REQUIREMENTS: Requires working permit in the US.
APPROXIMATELY NUMBER OF PEOPLE CURRENTLY WORKING IN THIS
SPECIFIC LABORATORY (FACULTY, STAFF, STUDENTS, POSTDOCS): 5: One
visiting scientist; two postdoctoral fellows; one research
associate and one Ph.D. student.
CONTACT FOR MORE INFORMATION: jinxie@utmb.edu
FURTHER RELEVANT INFORMATION: See URL: www2.utmb.edu/scccb
--------------------------------------------------------------
Please note: Postdoctoral Fellowship Profiles are provided to
ScienceWeek by the heads of laboratories, and ScienceWeek does
not charge for their publication. For information about
publishing a Postdoctoral Fellowship Profile, contact Claire
Haller at haller@scienceweek.com
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14. IN FOCUS: ON EMPTY SPACE
"Let us assume we can remove all matter from some region of
space. What will we be left with? A region of empty space? Not
necessarily. In the universe, between galaxies, each atom is at a
distance of about 1 meter from its next neighbor. Still, the
space between these atoms is not empty; it is bright with light
and other radiation from very different sources. It is only in
the absolutely empty space of our imagination that no light, no
radiation penetrates -- that space is as dark as the legendary
rooms of Schilda, in the German fairy tale. A region of space is
not really empty simply by virtue of not containing matter. If we
wanted to produce a region of really empty space, we would have
to remove from it not only all matter but also all radiation. To
keep it from exchanging matter and radiation with the space
around it, we would have to shield it effectively -- say, by
surrounding it with walls. We might then take an ideal pump to
evacuate this enclosed space, hoping that the radiation it
contained would gradually be absorbed by the walls and that the
final result would in fact be a truly empty space. Unfortunately,
that is not how it works. First of all, walls not only absorb
radiation but also emit it. Every enclosed space is filled with
the radiation absorbed and emitted by its walls. That is why a
space free of matter is not necessarily empty space. The
radiation we are discussing here might be thermal radiation; at
higher temperatures, it might be red light, like that emitted by
an overheated electric stove; and at still much higher
temperatures, it might be the light of the Sun. This radiation
weakens as the temperature of the emitting body decreases, but we
would have to go to what the physicists call _absolute zero_ --
that is, -273 degrees Celsius (C) -- to have it die off
altogether. It follows that above the unreachable temperature of
absolute zero, the radiation emitted by the walls will never
permit an enclosed space that is truly empty."
-----------
Henning Genz: _Nothingness: The Science of Empty Space_
(Perseus Publishing, Cambridge MA 1999, p.1)
[The author is Professor of Theoretical Physics at the University
of Karlsruhe, DE].
http://www.amazon.com/exec/obidos/ASIN/0738206105/scienceweek
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15. FROM PRAXIS:
ON THE GLOBALIZATION OF SEISMOLOGY
B. Romanowicz and D. Giardini (Berkeley Seismological Laboratory,
US) discuss seismic networks. Seismologists record and analyze
elastic waves produced by an earthquake to determine its location
and size and the orientation of the rupture plane, and to unravel
the physical processes at its source. Seismologists also apply
imaging techniques to infer the 3-dimensional structure of the
interior of the Earth from propagating elastic waves. These
observations are made at a variety of spatial scales, from local
to global, depending on the magnitude of the earthquake or the
purpose of the study. Seismic data collection is also important
for monitoring nuclear explosions in the framework of the
Comprehensive Test-Ban Treaty. Observational seismology is a
young science. The first seismographs that accurately recorded
ground motion and time were developed 100 years ago. The first
standardized global network (World Wide Standard Seismic Network)
was deployed in the early 1960s and used analog recording on
photographic paper; this recording method was replaced, beginning
in the mid 1970s, by digital recording. Seismic practice
gradually evolved from local data storage and analysis at the
seismographic station to a modern database system where full
waveforms are exchanged by modern media (satellite, digital phone
links, or the Internet). It is only since the 1970s that the
largest globally recorded earthquakes (magnitude greater than
5.5) have been reliably quantified, and only since the early
1980s were there sufficient recordings to systematically analyze
strain release or to initiate global tomographic investigations
of Earth's interior structure.
-----------
Science 2001 293:2000
-----------
PRAXIS 14 Jan 2002 http://scienceweek.com/praxis
-----------
SCIENCE-WEEK 18 Jan 2002 http://scienceweek.com
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16. THIS WEEK IN PRAXIS (14 Jan 02):
-------------------------------
1. Rapid Killing of Streptococcus Bacteria
2. On Pluripotent Stem Cells
3. On Breast Cancer
4. Cellular Senescence, Cancer, and Aging
5. On Beta-Lactam Antibiotics
6. Limitations of Gene Expression Analysis
7. Globalization of Seismology
8. Design of Nanoscale Materials
9. Protein Engineering: Enzyme Redesign
10. Fabrication of Silver Nanowires
11. Bose-Einstein Condensation on a Microelectronic Chip
12. Monolayer Organic Field-Effect Transistors
For information about PRAXIS, see:
http://www.scienceweek.com/praxis
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In the text, the affiliation following the names of authors is
the affiliation of the lead author.
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