ScienceWeek

SCIENCEWEEK

ScienceWeek - August 30, 2002 Vol. 6 Number 35

An Online Research Digest Published Weekly Since 1997

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At the present time it is of course quite customary for
physicists to trespass on chemical ground, for mathematicians to
do excellent work in physics, and for physicists to develop new
mathematical procedures. Trespassing is one of the most
successful techniques in science.
-- Wolfgang Koehler (1887-1967)

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Section 1

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1. Spotlight: On the Development of the Brain

2. On Regulation of the Size of the Cerebral Cortex

3. On the Aging Baboon

4. Spotlight: On Equilibrium vs. Nonequilibrium Statistical
Mechanics of Real Systems

5. On the Flow Behavior of Complex Fluids

6. On Protein Sequence-Structure Relationships

7. On the Market for Transplantable Tissues and Organs

8. On the Identification of In Vivo Expressed Antigens

9. On Metastasis in Cancer

10. On Miniaturized Chemical Analysis Systems

11. On Hydrophobic Polymer Collapse

12. On the Limits of Quantum Optical Communication Channels

13. ScienceWeek Notices and Subscription Information

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Section 2

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1. SPOTLIGHT: ON THE DEVELOPMENT OF THE BRAIN

Melvin Konner (Emory University, US) discusses the development
of the brain, the author making the following points:

1) The author poses "Changeux's paradox": how do 30,000 human
genes determine 10^(11) cells with 10^(15) connections?
Obviously they can't do it in the same way that the roundworm's
18,000 genes govern its 959 cells. There are several solutions:

2) First, pioneer cells and axons pave the way for thousands or
tens of thousands of others to track their guidance, offering
lots of hook-ups for the price of one. Second, the mammalian
brain forms many more cells and connections than it needs,
subsequently pruning back around half of them. Some of this
occurs through programmed cell death, but much depends on
activity -- meaning that spontaneous and reactive fetal
movements shape the brain. Third, small groups of neurons may
form under strict genetic control -- creating small,
deterministically wired systems similar to the roundworm's brain
-- and then compete for incoming stimulation and outgoing
actions.

3) These processes have been called "darwinian", but this is
only a partial analogy. The cells of the embryo are genetically
identical, and they produce no offspring, thus undermining two
pillars of Darwin's theory -- variation and inheritance. Still,
the processes involve competition, which is resolved by
environmental, adaptive selection. And the cells are not quite
genetically identical -- the same set of genes is always there,
but only some are switched on. Which switch on and which off in
any given cell -- and when, and how, and why -- determine the
cell's character and function. A main key to development is this
on–off pattern, a pulsing, embryo-wide light show that turns
genetic instructions into animals.

4) Elucidating the control of these switches -- by signals
inside the cell, beyond it, or even outside the body --is the
main task of biology in the 21st century. And the switches are
not flipped just in early life -- genes that confer Huntington's
and Alzheimer's diseases are switched on decades after the die
is cast. But of course, in a complex animal, much is left to
chance. Chaos in the formal sense -- exquisite sensitivity to
variations in starting conditions -- cumulatively amplifies
small differences. This embryonic butterfly effect gives
identical twins different brains within weeks of conception.
Such unpredictable paths help to explain why twins differ before
we even consider their environmental influences.

References (abridged):

1. Anastasi, A. Psychol. Rev. 65, 197–208 (1958).

2. Changeux, J.-P. Neuronal Man: The Biology of Mind (trans.
Garey, L.; Princeton Univ. Press, 1997).

3. Edelman, G. M. Neural Darwinism: The Theory of Neuronal Group
Selection (Basic, New York, 1987).

4. Wolpert, L. The Triumph of the Embryo (Oxford Univ. Press,
1991).

Nature 2002 418:279

Web Links: brain development

Related Background:

ON THE BRAINS OF MICE AND HUMANS

"No category of cell, no particular type of circuit is specific
to the human cerebral cortex. The components of our cerebral
machinery derive from a stock very similar, if not identical, to
that of the mouse. The major event in the evolution of the
mammalian brain is the expansion of the neocortex. This growth
is accompanied by an increase in the total number of neurons,
and thus in the number and complexity of the operations which
the cortex can perform. The number of cellular elements per unit
of surface area has not changed. The cortical thickness varies,
but much less than its surface area. On average, the cortex of
man is only three times thicker than that of the mouse, although
the increase is not uniform in all layers... The more the
surface area of the cortex expands, the more the number of
neurons capable of establishing association connections
increases... This translates, finally, into an increase in the
mean number of connections per neuron, with a consequent
burgeoning of the dendritic and axonal trees, reaching a maximum
in man. Nevertheless, the increase in the mean number of
synapses per neuron is not directly proportional to the increase
in cortical area. Far from it. The density of synapses per cubic
millimeter of cortex is of the same order in the rat as in
man... At the levels of both the macroscopic anatomy of the
cortex and its microscopic architecture, no sudden qualitative
reorganization marks the passage from the "animal" brain to the
human brain. There is, on the contrary, a continuous
_quantitative_ evolution in the total number of neurons, the
diversity of areas, the number of possible connections between
neurons, and, therefore, the complexity of the neuronal networks
that make up the cerebral machine."

Jean-Pierre Changeux: Neuronal Man: The Biology of Mind; Oxford
University Press, Oxford 1985, p.66

Related Background:

MAPPING IN THE BRAIN

Pasko Rakic (Yale University, US) discusses mapping in the
brain, the author making the following points:

1) The brain can be thought of as a map in which the position of
its constituent neurons indicates what they do. Nowhere is this
more evident than in the cerebral cortex, which consists of
structurally distinct cellular (cytoarchitectonic) areas
responsible for functions as diverse as sensory perception,
motor control, and cognition.

2) Apparently, as the cerebral cortex evolved, the number of
cytoarchitectonic areas increased and the number of sensory
representations also increased. Interest in how the map of the
cerebral cortex develops in the embryo has been sustained by the
belief that the mechanisms of development can help explain the
emergence of human mental capacity during evolution.

3) Traditionally, it has been presumed that the embryonic
telencephalon first forms an equipotential sheet of cells that
then becomes specified by input from subcortical centers
("tabula rasa model"). An alternative view -- derived from
experimental manipulations of cortical input to primate embryos
-- is that cells of the embryonic cerebral vesicle themselves
carry intrinsic programs for species-specific cortical
regionalization ("protomap model"). According to this
hypothesis, some region-specific cytoarchitectonic features can
develop independently of input. Indeed, the prefix "proto-"
emphasizes the malleable nature of this primordial map. Within
this primordial map, it is thought that cues generated within
cortical neurons attract appropriate input and cooperatively
create a final area-specific 3-dimensional organization.

Science 2001 294:1011

Related Background:

PLASTICITY AND HORMONE RESPONSE OF THE ADULT BRAIN

In this context, the term "plasticity" is the name given to the
capacity of neural tissue to adjust to change. One variant of
this concerns the dependence of the "wiring" of the nervous
system on its input. Another variant concerns the dependence of
the wiring of the nervous system on endogenous chemical
alterations (e.g., hormone secretions). Still another variant
concerns the degree to which one region can under certain
conditions assume the function of another region. Plasticity
does not occur everywhere in the nervous system, but it is often
evident in the cerebral cortex of the brain, the cortex being
the thin layer of cells apparently responsible for higher
analysis of sensory input, language, ideation, and other
so-called higher functions lumped together in the category
"cognitive processes".

Hormones are signaling molecules secreted into the blood stream
by endocrine cells and acting on target cells that possess
receptors for the hormone. Estrogen is a collective term for the
female hormones, the most powerful of which is *estradiol. They
control female secondary sexual characteristics, and prepare and
maintain the uterine lining. Estrogen affects the growth,
differentiation, and function of peripheral tissues of the
reproductive system, including the mammary gland, uterus,
vagina, and ovary. Estrogens also play an important role in bone
maintenance and may exert cardioprotective effects. In the
brain, estrogens modulate physiological parameters important for
regulating procreation, including reproductive behavior,
*gonadotropin production and release from the pituitary, and
mood. In recent years it has become apparent that although
estrogen is best known for its critical role in influencing
female secondary sexual characteristics, reproductive cycle,
fertility, and maintenance of pregnancy, there are important
actions of estrogen in male tissues such as the prostate,
testis, and *epididymis. Estrogens are essential for the normal
development of bone tissue in the male, in addition to their
well-known role in female bone.

In general, nerve cells have a single long extension (the
"axon") that propagates the electrical output (the action
potential) of the cell. The term "synapse" refers to the
junction between the terminal of a neuron's axon and another
neuron. When studying the synapse, the first neuron is called
the "presynaptic" neuron, and the second neuron is called the
"postsynaptic" neuron.

In this context, the term "dendrites" refers in general to input
extensions of nerve cells. Dendrites may be extensively
branched. In general, dendrites are considered to receive input
and axons to propagate output, but the electrical architecture
of most neurons is complicated, and in many types of nerve cells
activation of the axon produces electrical activity that not
only propagates down the axon but also propagates backward
through the cell body and dendrites.

During the past several decades, the detailed anatomy of
dendrites has been a focus of much research, in particular the
often-present parts of dendrites called "dendritic spines".
These spines are small (1 to 2 microns) thorn-like protuberances
along the length of a dendrite, and there is evidence that such
spines may be important components in many kinds of neural
microcircuits.

In addition to its ability to mediate specific functions, an
important property of the synapse is its small size. The area of
contact has a diameter of 0.5 to 2.0 microns, and the
presynaptic terminal ("bouton") has a diameter that
characteristically is only slightly larger. In the brain,
neuroanatomists distinguish "single-synapse boutons" and
"multiple-synapse boutons", depending on whether a terminal
bouton makes contact with only one spine or with several spines.

Concerning input to a nerve cell at the cellular level, in most
cases this input is the result of a neurotransmitter substance
released by the presynaptic terminal(s), with various
transmitters producing various effects on the postsynaptic
neuron, the effects categorized as "excitatory" or "inhibitory",
depending on whether they tend to increase or decrease the
firing rate of the postsynaptic neuron.

The "hippocampus" is a brain cortex structure in the medial part
of the temporal lobe. In humans, among other functions, the
hippocampus is apparently involved in short-term memory, and
analysis of the neurological correlates of learning behavior in
the rat indicates that the hippocampus is also involved in
memory in that species.

Hypersynchronous discharge of groups of neurons in the brain can
produce the motor symptoms of seizure activity if these neurons
are directly or indirectly connected to the part of the brain
controlling peripheral muscle tissue. When seizures are a
chronic syndrome, a diagnosis of "epilepsy" is usually made, but
it is important to understand that the term "epilepsy" refers to
chronic seizures produced by any cause, e.g., trauma, infection,
genetic dysfunction, neuroactive drugs, etc. Thus epilepsy is
not a unitary disease; it rather a label for a collection of
symptoms. The term "catamenial epilepsy" refers to a disorder
that occurs only in women, and the frequency of seizures in this
disorder is apparently linked to certain phases of the menstrual
cycle, with some suggestion that the condition may be explained
by heightened neuronal excitability due to an increased number
of dendritic spines on certain neurons in the hippocampus
(hippocampal pyramidal neurons).

M. Yankova et al (3 authors at Northwestern University, US)
present an experimental study of the effects of estrogen on
synaptic connections in the hippocampus of the rat, the authors
making the following points:

1) The authors report that the overwhelming majority of
multiple-synapse boutons in estrogen-treated animals form
synapses with more than one postsynaptic cell. Thus, in addition
to increasing the density of excitatory synaptic input to
certain hippocampal neurons (pyramidal cells in the CA1 layer of
the hippocampus), estrogen also increases the divergence of
input from individual presynaptic boutons to multiple
postsynaptic neurons. The authors suggest these findings
indicate the formation of new synaptic connections between
previously unconnected hippocampal neurons.

2) The authors conclude: "The estrogen-induced increase in
different-cell multiple-synapse bouton contacts has important
implications for hippocampal physiology, particularly if those
multiple-synapse boutons reflect the establishment of new
synaptic connections between previously unconnected cells. One
of the most robust effects of estrogen on the hippocampus is a
decrease in the threshold for seizure activity. The enhanced
divergence of presynaptic input reported here is predicted to
increase synchronization of synaptically driven activity in
[layer CA1 of the hippocampus]. As such, these structural
changes may contribute significantly to increasing
susceptibility to synchronous discharge associated with seizures.

In a commentary on this work, S.M. Breedlove and C.L. Jordan
(University of California Berkeley, US) state: "Mark your
scorecard to indicate another example of steroid hormones
altering adult neuroanatomy, and another example of how patterns
of neural connections can be reorganized in the adult brain.
Instead of asking whether new synapses can come or go, perhaps
now we should ask whether any particular synapse in the brain
remains unchanged for more than a short while."

Proc. Nat. Acad. Sci. 2001 98:2956,3525

Text Notes:

... ... *estradiol: 1,3,5(10)-estratriene-3,17beta-diol.
C(sub18)H(sub24)O(sub2). This is the natural hormone -- present
in pure form in the urine of pregnant mares and in the ovaries
of pigs.

... ... *gonadotropin: (gonadotrophin, gonadotrophic hormone)
Refers to a group of hormones capable of promoting growth and
function of the gonads.

... ... *epididymis: An elongated structure connected to the
surface of the testis, it stores and matures sperm cells.

ScienceWeek http://www.scienceweek.com

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2. ON REGULATION OF THE SIZE OF THE CEREBRAL CORTEX

A. Chenn and C.A. Walsh (Harvard University, US) discuss the
cerebral cortex, the authors making the following points:

1) A massive increase in the size of the cerebral cortex is
thought to underlie the growth of intellectual capacity during
mammalian evolution. The increased size of larger brains results
primarily from a disproportionate expansion of the surface area
of the layered sheet of neurons comprising the cerebral cortex
(1-5), with the appearance of convolutions of the cortical
surface (with crests known as "gyri" and intervening grooves
called "sulci") providing a means of increasing the total
cortical area in a given skull volume. This horizontal expansion
of the cerebral cortex is not accompanied by a comparable
increase in cortical thickness; in fact, the 1000-fold increase
in cortical surface area between human and mouse is only
accompanied by an approximately 2-fold increase in cortical
thickness.

2) The cerebral cortex is organized into columnar functional
units, and the expansion of the cerebral cortex appears to
result from increases in the number of radial columns rather
than from increases in individual column size (5). These
observations have led to the proposal that increases in the
number of columns result from a corresponding increased number
of progenitor cells (5). It has been suggested that minor
changes in the relative production of progenitors and neurons
could produce dramatic increases in cortical surface area (5).

3) One protein that might regulate the production of neural
precursors is beta-catenin, an integral component of adherens
junctions that interacts with proteins of the T cell
factor/lymphoid enhancer binding factor (TCF/LEF) family to
transduce Wnt signals. Wnts (a family of secreted signaling
molecules that regulate cell growth and cell fate) and TCF/LEF
family members are expressed in overlapping patterns in the
developing mammalian brain, and numerous studies support the
role of Wnt signaling in cell fate regulation during
development. Inactivation of specific Wnts TCF/LEF members, or
beta-catenin results in specific developmental brain defects,
and persistent activation of beta-catenin has been implicated in
a variety of human cancers, including some resembling neural
precursors such as medulloblastoma. These findings raise the
possibility that beta-catenin influences cell number or cell
fate decisions in the developing nervous system.

4) In summary: The authors report that transgenic mice
expressing a stabilized beta-catenin in neural precursors
develop enlarged brains with increased cerebral cortical surface
area and folds resembling sulci and gyri of higher mammals.
Brains from transgenic animals have enlarged lateral ventricles
lined with neuroepithelial precursor cells, reflecting an
expansion of the precursor population. Compared with wild-type
precursors, a greater proportion of transgenic precursors
reenter the cell cycle after mitosis. The authors suggest these
results demonstrate that beta-catenin can function in the
decision of precursors to proliferate or differentiate during
mammalian neuronal development and suggest that beta-catenin can
regulate cerebral cortical size by controlling the generation of
neural precursor cells.

References (abridged):

1. B.L. Finlay and R.B. Darlington, Science 268, 1578 (1995)

2. R.A. Barton and P.H. Harvey, Nature 405, 1055 (2000)

3. D.A. Clark, P.P. Mitra, S.S. Wang, Nature 411, 189 (2001)

4. V.S. Caviness Jr., T. Takahashi, R.S. Nowakowski, Trends
Neurosci. 18, 379 (1995)

5. P. Rakic, Trends Neurosci. 18, 383 (1995)

Science 2002 297:365

Web Links: catenins brain cortex

ScienceWeek http://www.scienceweek.com

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3. ON THE AGING BABOON

A.M. Bronikowski et al (Iowa State University, US) discuss the
aging baboon, the authors making the following points:

1) Modern human life expectancy now extends into the 7th decade
or beyond, and this longevity arises from reduced mortality
throughout life, including among the oldest old (1). These well
documented changes raise questions central to the evolutionary
theory of senescence and to public policy. First, how does human
life expectancy relate to the lifespan of other primate genera,
and in general how has human longevity evolved? Second, how long
will humans live in future decades and how healthy will they be?
At the same time, the genetic analysis of human longevity is
rapidly advancing. Human adult longevity is a heritable trait
where genetic factors can be mapped to defined chromosomal
regions (2-4). What will we learn about aging when the genes
underlying variation in lifespan are identified?

2) Although modern records of adult human lifespan and mortality
are clear, the notion of what constitutes our natural or
ancestral longevity is ambiguous. Evidence from osteological
analysis of mortuary samples suggests that ancestral human
adults lived until age 36 years on average and rarely beyond age
50 (5). Studies of precontact hunter-gatherers suggest that
humans naturally possess greater longevity. On average,
15-year-olds of the Dobe !Kung survive to 69 years of age.
Forest dwelling Ache at 15 live to 52 (males) and 58 (females)
years. As recently as 1900 in the U.S., a 15-year-old could
expect to live to 62 years; this value has gradually extended to
its current state of 77 years (combined for males and females
and all races). The variability among these observations
illustrates a fundamental challenge if we are to understand the
evolution of human senescence; we must fix a reference point to
describe how humans and other primates age in the absence of
modern environment and cultural practice.

3) The authors pose the question: Why do closely related primate
genera vary in longevity, and what does this teach us about
human aging? Life tables of female baboons (Papio hamadryas) in
two wild populations of East Africa and in a large captive
population in San Antonio, Texas, provide striking similarities
and contrasts to human mortality patterns. For captive baboons
at the Southwest Foundation for Biomedical Research, the authors
estimate the doubling time of adult mortality rate as 4.8 years.
Wild females in free-living populations in Tanzania and in Kenya
showed doubling times of 3.5 and 3.8 years, respectively.
Although these values are considerably faster than the estimates
of 7-8 years for humans, these primates share a demographic
feature of human aging: within each taxon, populations primarily
vary in the level of Gompertz mortality intercept (frailty) and
vary little in the demographic rate of aging. Environmental and
genetic factors within taxa appear to affect the level of
frailty underlying senescence. In contrast, primate taxa are
differentiated by rates of demographic aging, even if they
cannot be characterized by species-specific lifespan.

4) The authors conclude: "The replicate life tables of baboon
provide a robust basis for comparative analysis of primate
aging... We find that humans age at a slow demographic rate
relative to at least one non-human primate, Papio. The intrinsic
or typical life expectancy of any primate, however, remains an
elusive characteristic because baseline mortality varies widely
among populations within genera. To fully address questions on
the nature of past human life expectancy, current
post-reproductive lifespan, and the prospects for future human
longevity, we must discover why cohorts differ primarily in
frailty and how the environment and genes shape this plastic
demographic parameter of aging."

References (abridged):

1.  Vaupel, J. W. (1997) Philos. Trans. Biol. Sci. 352, 1799-1804

2.  Cournil, A. & Kirkwood, T. B. L. (2001) Trends Genet. 17,
233-235

3.  Herskind, A. M. , McGue, M. , Hom, N. V. , Sorensen, T. I.
A. , Harvald, B. & Vaupel, J. W. (1996) Hum. Genet. 97, 319-323

4.  Puca, A. A. , Daly, M. J. , Brewster, S. J. , Matise, T. C.
, Barrett, J. , Shea-Drinkwater, M. , Kang, S. , Joyce, E. ,
Nicoli, J. , Benson, E. , et al. (2001) Proc. Natl. Acad. Sci.
USA 98, 505-508.

5.  Paine, R. R. (1989) Am. J. Phys. Anthropol. 79, 51-61

Proc. Nat. Acad. Sci. 2002 99:9591

Web Links: aging in primates     baboons

ScienceWeek http://www.scienceweek.com

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4. SPOTLIGHT: ON EQUILIBRIUM VS. NONEQUILIBRIUM STATISTICAL
MECHANICS OF REAL SYSTEMS

J. Liphardt et al discuss statistical mechanics, the authors
making the following points:

1) Irreversible processes as diverse as mechanically induced
protein unfolding, the fracture of stressed materials, and the
sudden formation of crystallization nuclei all involve the time
evolution of states far removed from equilibrium. To
characterize these nonequilibrium states, it is generally
necessary to specify numerous details of the system and its
surroundings. By contrast, reversible processes are
idealizations in which a system passes only through a succession
of equilibrium states, which can be described completely with
only a few variables such as pressure and temperature.
Reversible processes are powerful tools in thermodynamics
because they make it possible to relate the measured heat and
work to the thermodynamic state variables. Yet many processes in
nature relax to equilibrium only very slowly, precluding
quasi-reversible experiments and thus preventing measurement of
the thermodynamic state variables. Solving the problem of
recovering thermodynamic variables from irreversible experiments
remains one of the unfinished tasks in thermodynamics.

2) It follows from the laws of thermodynamics, first formulated
in the early 19th century, that the increase in Gibbs free
energy delta-G and the mean work (w) needed to bring about that
increase are related by G =< w. The equality holds when a
process is carried out reversibly, and the inequality holds
otherwise. In 1951, Callen and Welton realized that for any
system that remains near equilibrium, the energy dissipated is
proportional to the system's fluctuations (1). With this
fluctuation-dissipation relation, researchers acquired a better
estimate of delta-G for irreversible processes.(2-4)
Unfortunately, this delta-G estimate is valid only in the
near-equilibrium regime, and so it was thought that free
energies could only be obtained for processes remaining close to
equilibrium. This state of affairs changed in 1997, when C.
Jarzynski derived an equality (5) that relates the free energy
difference separating states of a system at positions 0 and z
along a reaction coordinate, G(z), to the work done to
irreversibly switch the system between two states.

3) In summary: Recent advances in statistical mechanical theory
can be used to solve a fundamental problem in experimental
thermodynamics. In 1997, Jarzynski proved an equality relating
the irreversible work to the equilibrium free energy difference,
G. This remarkable theoretical result states that it is possible
to obtain equilibrium thermodynamic parameters from processes
carried out arbitrarily far from equilibrium. The authors test
Jarzynski's equality by mechanically stretching a single
molecule of RNA reversibly and irreversibly between two
conformations. Application of this equality to the irreversible
work trajectories recovers the delta-G profile of the stretching
process to within k(subB)T/2 (half the thermal energy) of its
best independent estimate, the mean work of reversible
stretching. The authors suggest this implementation and test of
Jarzynski's equality provides the first example of its use as a
bridge between the statistical mechanics of equilibrium and
nonequilibrium systems. The authors suggest this work also
extends the thermodynamic analysis of single molecule
manipulation data beyond the context of equilibrium experiments.

References (abridged):

1. H. B. Callen and T. A. Welton, Phys. Rev. 83, 34 (1951)

2. J. Hermans, J. Phys. Chem. 95, 9029 (1991)

3. D. A. Hendrix and C. Jarzynski, J. Chem. Phys. 114, 5974
(2001)

4. R. H. Wood, W. C. Muhlbauer, P. T. Thompson, J. Phys. Chem.
95, 6670 (1991)

5. C. Jarzynski, Phys. Rev. Lett. 78, 2690 (1997)

Science 2002 296:1832

Web Links: nonequilibrium statistical mechanics

Related Background:

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."

Proc. Nat. Acad. Sci. 2001 98:3636,3658

Text 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.

Related Background:

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.

Proc. Nat. Acad. Sci. 2001 98:11081

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) 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

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.

Related Background:

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

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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5. ON THE FLOW BEHAVIOR OF COMPLEX FLUIDS

D. Bonn et al (Ecole Normal Superieure Paris, FR) discuss
complex fluids, the authors making the following points:

1) The flow behavior of "complex fluids" such as, for instance,
colloidal suspensions is of both practical and fundamental
interest [1]. The large length scales present in these systems,
when compared to molecular dimensions, can lead to interactions
between the flow field and the organization of the complex
fluids. A structural change can affect the viscosity of the
fluid and thus, in turn, modify the flow field. This leads to a
non-Newtonian viscosity: in general, the resistance to flow
decreases with increasing flow velocity [1,2]. Unfortunately,
because of the existence of long-range hydrodynamic interactions
in these systems, it has turned out to be nearly impossible to
predict the non-Newtonian viscosity on the basis of the
structure and/or interactions in these systems [2].

2) It is for this reason that a completely different approach
has recently been tried to predict non-Newtonian behavior.
Instead of taking all the hydrodynamic interactions into
account, one starts [3-5] from a model of a glassy system that
has slow degrees of freedom: certain states are said to be
jammed. This jamming is a common property of a large number of
complex fluids such as foams, gels, and granular systems, which
in general hardly flow if a small stress is exerted on them. For
a glassy system, the slow modes are affected by an external
forcing, which is associated with a flow [3-5]. These models
have the advantage that both the linear (viscoelastic) response
and the nonlinear behavior under flow, i.e., the non-Newtonian
viscosity, can be calculated explicitly. The second advantage is
that this opens, for the first time, the possibility to relate
the macroscopic rheological behavior to the microscopic dynamics
[3-5].

3) The authors report a study of both the nonlinear rheological
behavior and the microscopic dynamics for a typical "soft glassy
material" (the colloidal glass of Laponite), to see whether
these ideas are applicable to a real system. The detailed
predictions that result from the different models and
simulations are the following [3-5]: (i) Without an external
forcing, the systems evolve spontaneously: they are said to age,
meaning that the relaxation time of the slow mode increases in
time. (ii) Under an external drive, the system can reach a
steady state: the aging stops, and the relaxation time is
constant. (iii) Upon increasing the forcing, the relaxation time
in steady state decreases, (iv) Both in the presence of an
external drive and during the aging, the viscosity is given by
the (distribution of) relaxation time(s) of the "slow mode" of
the glassy system, (v) The viscosity decreases strongly with the
shear rate (the velocity gradient) applied to the system.

4) In summary: The authors report a study the nonlinear
rheological behavior and the microscopic particle dynamics for a
colloidal glass, to see whether recently developed models for
driven glassy systems can be applied to predict the rheology.
Qualitatively, all the findings predicted by the models can be
retrieved in the present system system. Notably, the viscosity
decreases strongly with the shear rate. Since it is difficult to
predict non-Newtonian viscosities of colloidal systems due to
long-ranged hydrodynamic interactions, the authors suggests this
demonstrates the promise of this approach for predicting flow
behavior. In addition, the measurements allow one to relate the
microscopic diffusion dynamics to the macroscopic viscosity of
the system.

References (abridged):

1. R.G. Larson, The Structure and Rheology of Complex Fluids
(Oxford University Press, New York, 1999)

2. H.A. Barnes, J. F. Hutton, and K. Walters, An Introduction to
Rheology (Elsevier, Amsterdam, 1989).

3. R. Yamamoto and A. Onuki, Europhys. Lett. 40, 61 (1997);
Phys. Rev. ESS, 3515 (1998).

4. L.F. Cugliandolo, J. Kurchan, P. Le Doussal, and L. Peliti,
Phys. Rev. Lett. 78, 350-353 (1997).

5. P. Sollich, F. Lequeux, P. Hebraud, and M. Gates, Phys. Rev.
Lett. 78, 2020 (1997); P. Sollich, Phys. Rev. E 58, 738 (1998);
S.M. Fielding, P. Sollich, and M.E. Cates, J. Rheol 44, 323
(2000)

Phys. Rev. Lett. 2002 89:015701

Web Links: complex fluids     rheology

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6. ON PROTEIN SEQUENCE-STRUCTURE RELATIONSHIPS

A. Giuliani et al (Istituto Superiore di Sanita Rome, IT)
discuss proteins, the authors making the following points:

1`) The relationship between sequence-embedded information and
folding behavior of proteins is currently a dominant concern of
both theoretical and applied biochemical research. More
specifically, this concern redounds to areas such as (a)
sequence-based functional predictions, (b) 3D structure-based
functional predictions, and (c) folding mechanism elucidation.
These issues are regarded as key points in basic research, and
all of them have immediate applicable spin-offs in
biotechnology, where the elucidation of new protein structures
is of main interest for areas ranging from pharmaceutical
industry to electronics.(1) Moreover, the completion of the
sequencing phase of the human genome project shifted the
attention of the scientific community to so-called "structural
genomics" where the structural consequences of genome data in
terms of protein structure and activity are exploited.(2,3) This
new phase, called "post-genomic", in contrast with the previous
one is of direct interest to chemists.

2) In a fundamental paper published in 1994 entitled "Proteins:
where physics of simplicity and complexity meet", Hans
Frauenfelder and Peter Wolynes(4) focused on the peculiarity of
the sequence-structure relation and on the need to have a
microscopic (and in principle very accurate) physics of
cooperatively interacting "simple" systems (e.g., atoms) in
order to derive macroscopic principles that qualitatively
describe the complex systems of protein architecture. While we
do have an accurate knowledge of potentials (hydrophobic
interactions, hydrogen bonding, size constraints, etc.) acting
at microscopic levels,(5) the "mesoscopic" principles needed to
predict the 3D structure of proteins remain essentially unknown.
This blend of microscopic principles and macroscopic
consequences has been a typical feature of chemical sciences in
the last 150 years.

3) Proteins occupy a unique position in the hierarchy of natural
systems, since they lie in a gray region between chemistry and
biology. Proteins are large, complicated molecules that any
polymer chemist would have difficulty in modeling. From the
biological side, although any single protein would not be
considered as alive, it does not take many of them (plus a bit
of nucleic acid) before life-like behavior begins to emerge. For
example, some of the smallest viruses, such as HIV, which might
be considered on the borderline of life, are endowed with only
10 different types of proteins.

4) From a chemical viewpoint, proteins are linear heteropolymers
that, unlike most synthetic polymers, are formed of basically
nonperiodic sequences of 20 different monomers. While artificial
polymers are generally very large extended molecules forming a
matrix, the majority of proteins fold as self-contained
structures determined by the sequence of monomers. Thus, we can
consider the particular linear arrangement of amino acids as a
sort of "recipe" for making a water-soluble polymer with a
well-defined three-dimensional architecture. The task of being
water soluble while maintaining the structural specificity
necessary for a physiologically motivated activity is not easy,
and only a relative minority of linear amino acid arrangements
can actually accomplish this. Thus, the most basic problem in
the sequence-structure puzzle is "What particular linear
arrangement of amino acids makes a real protein?" This can be
rephrased as "Is it possible to discriminate between amino acid
sequences that in water, acquire a well-defined
three-dimensional structure, and sequences that never will?"

References (abridged):

1. Lutz, S.; Benkovic, S. J. Curr. Opin. Biotechnol. 2000, 11,
319

2. Skolnick, J.; Fetrow, J. S.; Kolinski, A. Nat. Biotechnol.
2000, 18, 283

3. Teichmann, S. A.; Murzin, A. G.; Chothia, G. Curr. Opin.
Struct. Biol. 2001, 11, 354

4. Frauenfelder, H.; Wolynes, P. Phys. Today 1994, 47, 58

5. Li, H., Tang, C.; Wingreen, N. S. Phys. Rev. Lett. 1997, 79,
765

Chem. Rev. 2002 102:1471

Web Links: protein structure

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7. ON THE MARKET FOR TRANSPLANTABLE TISSUES AND ORGANS

F.L. Delmonico et al (Massachusetts General Hospital, US)
discuss transplantable tissues and organs, the authors making
the following points:

1) Market forces influence the development of new drugs and
procedures, access to health care, and the specific treatment
options offered to individual patients. Nevertheless, an
important purpose of the National Organ Transplant Act was to
prohibit the assignment of a monetary value to an organ for
transplantation, thus preventing commercialization and ensuring
some level of equity in access to organs. This objective has
been undermined by the development of a market for
transplantable tissues.(14) Unlike solid organs, which are
transplanted immediately, tissues such as bone and skin are now
routinely stored for months after they have been altruistically
donated by grieving families. The ways in which these tissues
are handled make it possible to turn them into commodities, and
for-profit companies have become important processors and
distributors of such tissues. This aspect of American
transplantation practice has circumvented the intention of the
National Organ Transplant Act and makes the future of altruistic
organ donation uncertain.

2) The standard of uncompensated donation of organs from living
donors is also being eroded by the opportunity to obtain organs
outside the United States. Since a close genetic match is no
longer needed to ensure success, Americans (and others) are
purchasing kidneys from strangers in China, Peru, and the
Philippines.(15,16) The current federal law presents no obstacle
to these patients in returning to the United States for
post-transplantation care, further undercutting the objective of
the National Organ Transplant Act.(17)

3) Finally, the principles underlying the act are also
challenged by the increased frequency in the United States of
kidney donation by persons unrelated to the recipients (20
percent of living kidney donors), increasing the possibility of
the illegal purchase of kidneys by recipients and illegal profit
by donors and making it more difficult for transplantation
centers to prevent such transactions. Affluent patients from
other countries have allegedly paid at least $200,000 to undergo
transplantation at U.S. centers as part of a package prearranged
outside the United States that included compensation of
unrelated donors, who were coached by international brokers not
to disclose the monetary agreements.(18)

References (abridged):

14. Mahoney JD. The market for human tissue. Va Law Rev 2000
86:103-223.

15. Smith CS. On death row, China's source of transplants. New
York Times. October 18, 2001:A1.

16. Baard E, Cooney R. China's kidney transplant trade. Village
Voice. May 8, 2001.

17. Smith C. Doctors worry as Americans get organs from Chinese
inmates. New York Times. November 8, 2001.

18.Friedlaender MM. The right to sell or buy a kidney: are we
failing our patients? Lancet 2002;359:971-973.

New Engl. J. Med. 2002 346:2002

Web Links: transplantable organs

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8. ON THE IDENTIFICATION OF IN VIVO EXPRESSED ANTIGENS

H. Etz et al (InterCell Biomedical Corp. Vienna, AT) discuss
identification of expressed antigens, the authors making the
following points:

1) Infectious diseases are the second leading cause of death
worldwide, and the acquisition of antibiotic resistance by many
pathogenic bacteria has recently spurred interest in generating
vaccines to cure or prevent disease. Although vaccines composed
of polysaccharides have proven valuable for the prevention of
bacterial infections, in general they induce serotype-specific
immune responses and contribute to serotype redistribution (1).
Therefore, antigenic proteins that show little sequence
variation in diverse clinical isolates will likely be superior
antigens for the development of a broadly effective vaccine
against a particular pathogen.

2) To design potent and universally applicable subunit vaccines,
it is necessary to identify those antigens that are recognized
as nonself by the immune systems of many individuals of a wide
patient population during infection. The availability of
complete genomic sequences of bacterial pathogens has greatly
facilitated the search for these antigens among all
genome-encoded proteins. By applying bioinformatics to predict
surface-exposed or exported proteins from Neisseria meningitides
and Streptococcus pneumoniae, it was possible to express and
purify a limited number of antigens to identify potential
vaccine candidates (2,3). However, the identification of
relevant proteins by predictive algorithms and the subsequent
need for expression and purification of full-length proteins in
a heterologous host restrict the final selection of candidates
for vaccine development. A number of novel vaccine candidates
were also identified from Helicobacter pylori and Mycobacterium
tuberculosis by combining genomics and proteomics (4,5). Yet the
proteomic approach is severely limited by the number of proteins
expressed by the pathogen under in vitro growth conditions. The
described approaches determined the immunogenicity of
recombinant proteins in animal models (2, 3) or have used animal
models to produce mAbs for selection (4).

3) To overcome these constraints and to identify vaccine
candidates that are truly recognized by the human immune system,
the authors developed an approach based on genomic peptide
libraries in combination with well characterized human sera. S.
aureus peptides were displayed on the surface of Escherichia
coli via fusion to one of two outer membrane proteins (LamB and
FhuA) and probed with sera selected for high Ab titer and
opsonic activity. A total of 60 antigenic proteins were
identified, most of which are located or predicted to be located
on the surface of the bacterium or secreted. The identification
of these antigens and their reactivity with individual sera from
patients and healthy individuals greatly facilitate the
selection of promising vaccine candidates for further
evaluation. The authors suggest that this approach, which makes
use of whole genome sequence information, has the potential to
greatly accelerate and facilitate the formulation of novel
vaccines and is applicable to any pathogen that induces Abs in
humans and/or experimental animals.

References (abridged):

1. Pelton, S. I. (2000) Vaccine 19, S96-S99

2.  Pizza, M. , Scarlato, V. , Masignani, V. , Giuliani, M. M. ,
Arico, B. , Comanducci, M. , Jennings, G. T. , Baldi, L. ,
Bartolini, E. , Capecchi, B. , et al. (2000) Science 287,
1816-1820

3.  Wizemann, T. M. , Heinrichs, J. H. , Adamou, J. E. , Erwin,
A. L. , Kunsch, C. , Choi, G. H. , Barash, S. C. , Rosen, C. A.
, Masure, H. R. , Tuomanen, E. , et al. (2001) Infect. Immun.
69, 1593-1598

4.  Chakravarti, D. N. , Fiske, M. J. , Fletcher, L. D. &
Zagursky, R. J. (2000) Vaccine 19, 601-612

5.  Jungblut, P. R. , Schaible, U. E. , Mollenkopf, H. J. ,
Zimny-Arndt, U. , Raupach, B. , Mattow, J. , Halada, P. , Lamer,
S. , Hagens, K. , Kaufmann, S. H., et al. (1999) Mol. Microbiol.
33, 1103-1117

Proc. Nat. Acad. Sci. 2002 99:6573

Web Links: new vaccines     Staphylococcus aureus

Related Background Brief:

A WHOLE GENOME APPROACH TO IDENTIFY VACCINE MOLECULES. Microbial
targets for protective humoral immunity are typically
surface-localized proteins and contain common sequence motifs
related to their secretion or surface binding. Exploiting the
whole genome sequence of the human bacterial pathogen
Streptococcus pneumoniae, the authors identified 130 open
reading frames encoding proteins with secretion motifs or
similarity to predicted virulence factors. Mice were immunized
with 108 of these proteins, and 6 conferred protection against
disseminated S. pneumoniae infection. Flow cytometry confirmed
the surface localization of several of these targets. Each of
the six protective antigens showed broad strain distribution and
immunogenicity during human infection. The authors suggest their
results validate the use of a genomic approach for the
identification of novel microbial targets that elicit a
protective immune response. These new antigens may play a role
in the development of improved vaccines against S. pneumoniae.
T.M. Wizemann et al: Infect. & Immun. 2001 69:1593

ScienceWeek http://www.scienceweek.com

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9. ON METASTASIS IN CANCER

J.E. Gershenwald and I.J. Fidler (University of Texas, US)
discuss metastasis in cancer, the authors making the following
points:

1) The major cause of death from cancer is dissemination of the
primary tumor, leading to formation of metastases that are
resistant to conventional chemotherapy. Several factors account
for the failure to treat metastases. First, neoplasms are
biologically heterogeneous and contain subpopulations of cells
with different angiogenic, invasive, and metastatic properties.
Second, the process of metastasis selects for a small
subpopulation of cells that preexist within a parental neoplasm.
Third, and perhaps the greatest obstacle for therapy, is that
the outcome of metastasis depends on multiple interactions
between metastatic cells and homeostatic mechanisms that the
tumor cells usurp (1). A better understanding of the molecular
events that lead to metastasis and of the complex interactions
between metastatic cells and host factors is essential for the
design of more effective cancer therapies.(2)

2) To produce a metastasis, tumor cells must complete a series
of sequential, interrelated steps. These include growth;
neovascularization and lymphangiogenesis (development of new
lymphatic vessels); invasion of the host stroma, blood vessels,
and lymphatic system; survival in the circulation; arrest in
small blood vessels; extravasation (migration out of blood
vessels) into the parenchyma of organs; and continuous
proliferation, which depends on establishing an adequate blood
supply (angiogenesis) (1). Early clinical observations suggested
that solid tumors (carcinomas) spread primarily via the
lymphatic vessels and that mesenchymal (connective tissue)
tumors spread mainly through the bloodstream. In truth, the
lymphatic and vascular systems have numerous connections that
allow disseminating tumor cells to pass rapidly from one system
to the other (3).

3) Although the importance of the lymphatic system has been
recognized for centuries (4), its involvement in the metastatic
cascade has taken a back seat to the recent explosive interest
surrounding the formation of tumor-associated blood vessels.
Fortunately, recent work is beginning to elucidate the molecular
mechanisms of lymphangiogenesis and lymphatic metastases. Among
the unresolved controversies is the question of whether cancer
cells in a primary tumor are transported to regional lymph nodes
through intratumor lymphatic vessels. New techniques, such as
intradermal administration of vital blue dye and radiolabeled
colloid at the periphery of primary tumors, can identify the
specific lymph nodes that receive afferent lymphatic drainage
from the primary tumor site. These sentinel lymph nodes are the
most likely to contain tumor metastases, which are often
harbingers of future tumor development at sites distant from the
lymph node (5).

References (abridged):

1. J. Fidler, in Clinical Oncology, M. D. Abeloff, J. O.
Armitage, A. S. Lichter, J. E. Niederhuber, Eds. (Churchill
Livingstone, New York, ed 2, 2000), pp. 29-53

2. T. P. Padera et al., Science 296, 1883 (2002).

3. Carr, Cancer Metastasis Rev. 2, 307 (1983)

4. R. S. Foster Jr., Surg. Oncol. Clin. N. Am. 5, 1 (1996)

5. J. E. Gershenwald et al., J. Clin. Oncol. 17, 976 (1999)

Science 2002 296:1811

Web Links: cancer metastasis     lymphatic metastasis

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10. ON MINIATURIZED CHEMICAL ANALYSIS SYSTEMS

Mark A. Burns (University of Michigan, US) discusses miniature
chemical analysis systems, the author making the following
points:

1) Miniaturized chemical analysis systems ("labs-on-chips")
(1-4) have the potential to revolutionize analytical chemistry.
A roomful of equipment and several trained technicians may be
replaced with a few small, battery-powered devices. These
portable systems could make complex chemical analysis available
to the untrained, providing individuals with better tools for
investigating the world around them.

2) What stands in the way of further advancing this technology?
An analogy with the computer industry may help to understand the
challenges ahead. The computer industry was born not when the
transistor was invented but when versatile and efficient
integrating systems on and off the chip were invented (5). For
microfabricated integrated chemical systems, one of the biggest
challenges has been how to control fluid flow on a micrometer
scale. Many individual components now exist, from pipes and
fluid channels to the pumps and valves needed for full fluidic
control. The difficulty lies in integrating them into the same
device with other analysis components.

3) Over the past 15 years, the length scale of fabrication has
continued to decrease from the micrometer-scale that is widely
used in the production of computer chips to the submicrometer
scale. Recent advances in molecular-level engineering and
assembly ("nanofabrication") and soft lithography are expanding
the pool of microfabrication tools and materials. By combining
these and other fabrication or manipulation techniques, simple
but powerful components can be constructed. An example of
combining different techniques for component development is
given by Terray et al (Science 2002 296:1841). The authors use
latex spheres manipulated by optical traps to pump fluids. To
fabricate their devices, they use standard channel-etching
procedures combined with latex spheres that serve as pump vanes,
and optical traps to control the spheres' motion. The beauty of
their approach is that they have accounted for future
integration into larger, more complex devices: Multiple pumps
are controlled on the same device with the aid of a
piezoelectric mirror. A range of other microfabricated pumps,
valves, and fluid-handling systems have been reported. Some
pumping systems rely on surface tension, exploiting the surface
forces that dominate fluid motion at micrometer-length scales.

References (abridged):

1. D. Figeys, D. Pinto, Anal. Chem. 79, 330A (2000)

2. J. Khandurina, A. Guttman, J. Chromatography A 943, 159 (2002)

3. P. Mitchell, Nature Biotechnol. 19, 717 (2001)

4. J. M. Ramsey, A. van den Berg, Eds., Proceedings of the Micro
Total Analysis Systems 2001 (Kluwer Academic Publishers, London,
2001)

5. G. E. Moore, Electronics 38, 114 (1965)

Science 2002 296:1818

Web Links: miniaturized chemical analysis         nanofabrication

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11. ON HYDROPHOBIC POLYMER COLLAPSE

P. ten Wolde and D. Chandler (University of California Berkeley,
US) discuss hydrophobic polymer collapse, the authors making the
following points:

1) For nearly a half-century, hydrophobic interactions have been
considered the primary cause for self assembly in soft matter,
and a major source of stability in biophysical assembly (1,2).
Studying these interactions in perhaps their most basic form,
the authors report they use computer simulations to demonstrate
the mechanism for the collapse of a hydrophobic polymer in
water. The authors demonstrate that solvent fluctuations induce
the transition from the extended coil to the collapsed globule
state, where a vapor bubble of sufficient size is formed to
envelop and thereby stabilize a critical nucleus of hydrophobic
units. This mechanism is different from that usually considered,
where coil to globule transitions are attributed to effective
interactions between pairs of chain segments and a change in
sign of second virial coefficient (3). Rather, the mechanism
found by the authors is evocative of the n-cluster model, where
hydrophobic collapse is produced by solvent-induced interactions
between a relatively large cluster of segments (4).

2) As expected from earlier work on the equilibrium theory of
hydrophobicity (5), the authors find that the solvent length
scales pertinent to hydrophobic collapse extend over nanometers.
They also find that pertinent time scales extend beyond
nanoseconds. Given these molecularly large lengths and times, it
is understandable that no work before this has provided
statistically meaningful computer simulations of the process.
The present use of a statistical field model of water allows the
authors to simulate solvent dynamics over large length and time
scales that would be impractical to study with purely atomistic
simulation. Spatially complex small length-scale fluctuations
are analytically integrated out, thus removing the most
computationally costly features from the simulation. Their
integration can be performed at the outset because their
relaxation is relatively fast and their statistics is
essentially Gaussian. Only the polymer degrees of freedom and a
coarse-grained density field remain.

3) By "small length" the authors refer to distances smaller than
approximately 0.3 nm. In the absence of any strong perturbation,
such as those that can occur close to a solute, these small
length-scale fluctuations are the only fluctuations of
significance. Larger length-scale fluctuations are generally
insignificant in water at ambient conditions. The liquid is
relatively cold and incompressible, and spatial correlations
extend over only one or two water molecules. But the presence of
a hydrophobic polymer can change this situation, making large
length-scale fluctuations important. The liquid lies close to
macroscopic vapor-liquid equilibrium, and vapor-like behavior is
stabilized in the vicinity of a sufficiently extended
hydrophobic surface, a surface formed, for example, by the
clustering of hydrophobic groups in a polymer chain. This effect
can be captured by the behavior of a coarse-grained density
field (5), and such a field is conveniently simulated with a
field of binary numbers.

References (abridged):

1. Kauzmann, W. (1959) Adv. Protein Chem. 14, 1-63

2. Tanford, C. (1973) The Hydrophobic EffectFormation of
Micelles and Biological Membranes (Wiley Interscience, New York)

3. Yu Grosberg, A. & Khokhlov, A. R. (1994) Statistical Physics
of Macromolecules (AIP, New York)

4.  DeGennes, P.-G. (1991) C. R. Acad. Sci. Ser. II 313,
1117-1122

5.  Lum, K. , Chandler, D. & Weeks, J. D. (1999) J. Phys. Chem.
B 103, 4570-4577

Proc. Nat. Acad. Sci. 2002 99:6539

Web Links:  hydrophobicity hydrophobic polymer collapse

ScienceWeek http://www.scienceweek.com

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12. ON THE LIMITS OF QUANTUM OPTICAL COMMUNICATION CHANNELS

J. Tworzydlo and C.W. Beenakker (University of Leiden, NL)
discuss quantum communication channels, the authors making the
following points:

1) To faithfully transmit information through a communication
channel, the rate of transmission should be less than the
capacity of the channel [1,2]. Although current technology is
still far from the quantum limit, there is an active scientific
interest in the fundamental limitations to the capacity imposed
by quantum mechanics [3,4]. Ultimately, these limitations
originate from the uncertainty principle, which is the source of
noise that remains when all external sources have been
eliminated.

2) An important line of investigation deals with strategies to
increase the capacity. One remarkable finding of recent years
has been the beneficial role of multiple scattering by disorder,
which under some circumstances can increase the capacity by
increasing the number of modes that effectively carry the
information [5]. Quite generally, the capacity increases with
increasing signal-to-noise ratio, so that amplification of the
signal is a practical way to increase the capacity. When
considering the quantum limits, however, one should include not
only the amplification of the signal (e.g., by stimulated
emission), but also the excess noise (e.g., due to spontaneous
emission). The two are linked at a fundamental level by the
fluctuation-dissipation theorem, which constrains the beneficial
effect of amplification on the capacity.

3) While the effects of disorder and amplification on
communication rates have been considered separately in the past,
their combined effects are still an open problem. Even the basic
question, "Does the capacity go up or down with increasing
gain?", has not been answered. The authors were motivated to
look into this problem by the recent interest in so-called
"random lasers". These are optical media with gain, in which the
feedback is provided by disorder instead of by mirrors. Below
the laser threshold, these materials behave similar to linear
amplifiers with strong intermode scattering, and this results in
some unusual noise properties. As the authors demonstrate, the
techniques developed in connection with random lasers can be
used to predict under what circumstances the capacity is
increased by amplification.

4) In summary: The authors report a study of the competing
effects of stimulated and spontaneous emission on the
information capacity of an amplifying disordered waveguide. At
the laser threshold the capacity reaches a "universal" limit,
independent of the degree of disorder. Whether or not this limit
is larger or smaller than the capacity without amplification
depends on the disorder, as well as on the input power. Explicit
expressions are obtained for heterodyne detection of coherent
states, and generalized for an arbitrary detection scheme.

References (abridged):

1. C.E. Shannon, Bell Syst. Tech. J. 27, 379 (1948); 27, 623
(1948)

2. T. M. Cover and J. A. Thomas, Elements of Information Theory
(Wiley, New York, 1991)

3. C. M. Caves and P. D. Drummond, Rev. Mod. Phys. 66, 481 (1994)

4. M.A. Nielsen and I.L. Chuang, Quantum Computation and Quantum
Information (Cambridge University, Cambridge, England, 2000)

5. G.J. Foschini, Bell Labs Tech. J. 1, 41 (1996)

Phys. Rev. Lett. 2002 89:043902

Web Links: quantum optical communication        random lasers

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