ScienceWeek

SCIENCE-WEEK - February 1, 2002 - Vol. 6 Number 5
An Email Research Digest Published Weekly Since 1997

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Nature is that lovely lady to whom we owe polio,
leprosy, smallpox, syphilis, tuberculosis, and cancer.
-- Stanley Cohen

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Section 1
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Contents of this Issue (Full reports in Section 2):

1. On Turbulence in the Early Universe
2. Optical Nonlinearity in Liquid Crystals
3. Brown Dwarf Stars and Dark Matter
4. Light Interference from Single Atoms
5. On Classical and Quantum Phase Transitions
6. Magnetic Carbon
7. Calcium Regulation of Neuronal Gene Expression
8. The Rhythm of Microbial Adaptation
9. Polyglutamine Sequences and Neurodegenerative Diseases
10. Protein Folding: Energy Landscape Theory
11. On Vascular Endothelial Growth Factor
12. On Plant Cell Walls
13. PostDoctoral Fellowship Profile:
Laboratory of Claire L. Moore, Tufts University (US)
14. In Focus: On Time and Positivism
15. New Books
16. From PRAXIS: Angiogenesis
17. This Week in PRAXIS

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Section 2
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1. ON TURBULENCE IN THE EARLY UNIVERSE
     The term "radiation era" refers to the period from
approximately 10^(-43) seconds to 30,000 years after the Big
Bang. During this era, according to current theory, the expansion
of the Universe was dominated by the effects of radiation or high
speed particles. The radiation era was followed by the "matter
era", during which slow-moving particles dominated the expansion
of the Universe.
     The usual change of state (solid to liquid, liquid to gas,
etc.) is called a "first-order transition". In such a transition,
at the transition temperature, at constant pressure, the free
energies of the two forms are equal, but there is a discontinuous
change in the slope of the free energy versus temperature curve
for the substance. The terminology "first-order, second-order"
(also "third-order", etc.), in this context, derives from a
theoretical analysis by Paul Ehrenfest (1880-1933) of various
categories of discontinuities in the differential behavior of
thermodynamic equations of state.
     The above thermodynamic concepts are usually applied to
ordinary phases, but they can be applied to cosmic phases as well
in a cosmic thermodynamic analysis.
... ... A.D. Dolgov and D. Grasso (INFN, IT) discuss turbulence
in the early Universe, the authors making the following points:
     1) The idea that the early Universe went through one or more
turbulent phases has been recurring in the scientific literature
since the beginning of modern cosmology. Among other reasons,
cosmic turbulence has often been invoked to explain the origin of
the magnetic fields observed in most spiral galaxies and galaxy
clusters.
     2) One of the first explanatory attempts was based on the
observation that in the radiation era a weak magnetic field
should be generated by turbulent eddies because the rotational
velocities of relativistic electrons and nonrelativistic ions
would change differently during Universe expansion. Subsequently,
turbulence may have induced a magneto-hydro-dynamical dynamo that
exponentially amplified the field until equipartition between the
plasma turbulent kinetic energy and the magnetic field energy was
eventually reached. However, this attractive scenario remains
unclarified in the absence of a plausible mechanism of turbulence
generation.
     3) Another scenario considers that since gravitational
forces conserve angular momentum, vorticity must have been
produced by nongravitational forces. Primordial phase transitions
might have produced magnetic fields if they were first order
phase transitions. The idea is that the expanding bubble walls
between two phases give rise to small electric currents that
power a seed magnetic field. Turbulence appears when bubbles
collide at the end of the phase transition, or hydrodynamic
instabilities develop in the bubble walls, producing magneto-
hydro-dynamic amplification of the seed magnetic field. The major
problem with this type of scenario is that it can hardly account
for large scale magnetic fields.
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Phys. Rev. Lett. 2002 88:011301
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2. ON OPTICAL NONLINEARITY IN LIQUID CRYSTALS
     Liquid crystals can be considered a 4th phase of matter, a
state qualitatively different from the ordinary 3 phases, gas,
liquid, and solid. Liquid crystals flow like a liquid, but there
is order in at least one dimension in the arrangement of the
molecules. "Nematic crystals" are liquid crystals with long
molecules all aligned in the same direction.
     The electro-optical Kerr effect is an effect in which
certain liquids and gases become double-refracting (birefringent)
when placed in an electric field at right angles to the direction
of the light. Calcite is the classical birefringent crystal,
forming two refracted rays from a single incident ray.
... ... M. Kreuzer et al (Darmstadt University of Technology, DE)
discuss optical nonlinearity in liquid crystals, the authors
making the following points:
     1) When a material undergoes irreversible dissipative
processes as a consequence of an external perturbation, its
behavior may often exhibit a striking sensitivity to small
details of its microscopic structure. In general, this is due to
the fact that kinetic molecular properties may acquire a dominant
role in irreversible phenomena, while not contributing at all to
the reversible part of the material response.
     2) A remarkable example of this behavior is found in the
optical nonlinearity associated with light-induced molecular
reorientation of liquids and liquid crystals. Although the
isotropic liquid phase and the liquid crystalline phase exhibit
very different overall nonlinear responses, owing to the
different range of the orientational correlations between
molecules, they share the basic mechanism driving the
reorientation. For the case of transparent materials, this
mechanism is well understood in terms of reversible dielectric
properties.
     3) In contrast to transparent materials, the orientational
nonlinearity of light-absorbing liquids and liquid crystals is
not fully understood yet. In the early 1990s, it was discovered
that nematic liquid crystals made light absorbing by the addition
of small amounts (less than 1 percent) of certain dichroic dyes,
such as substituted anthraquinones, could present an
orientational optical nonlinearity that is enhanced by more than
two orders of magnitude with respect to the pure transparent
material. In 1997, a similar enhancement of optical nonlinearity
was observed in the optical Kerr effect of ordinary isotropic
liquids.
     4) It is clear that the mechanism driving the molecular
reorientation in absorbing materials is completely different from
the mechanism in the transparent case, but there are as yet no
completely satisfactory models for the mechanism in the absorbing
materials case.
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Phys. Rev. Lett. 2002 88: 013902
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SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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3. BROWN DWARF STARS AND DARK MATTER
     Contemporary cosmology distinguishes two kinds of matter,
"ordinary matter" and "dark matter". In general, a baryon is a
nuclear particle (e.g., a proton) built from 3 quarks
(fundamental particles that combine to make up protons, neutrons,
and mesons), and so-called "ordinary matter" is baryonic. In this
context, the term "dark matter" refers to material whose presence
can be inferred from its effects on the motions of stars and
galaxies, but which cannot be seen directly because it emits
little or no radiation. It is believed that as much as 90 percent
of the mass in the Universe may exist as some form or dark
matter, although the proposed percentage of dark matter varies
widely with different cosmological models.
     In general, the term "interstellar cloud" refers to gas and
dust between stars. These clouds are mainly hydrogen gas, some
helium, and approximately 1 percent dust grains. The temperatures
of these clouds vary, with hot clouds having temperatures of
10^(6) kelvins.
     One of the important discoveries of the 1980s was the
existence of circumstellar disks of dust around some stars, the
disks apparently replenished by unseen parent bodies such as
comets and asteroids.
... ... John E. Gizis (University of Delaware, US) discusses
brown dwarf stars, the author making the following points:
     1) Below approximately 75 times the mass of Jupiter,
astronomical objects cannot achieve core temperatures hot enough
for sustained nuclear fusion of hydrogen, and these failed stars
are called "brown dwarfs". The hydrogen burning limit thus
defines the cutoff between stars and brown dwarfs, but the term
"brown dwarf" is usually also considered to refer to objects that
form via a collapse and fragmentation of an interstellar cloud
(e.g., stars) rather than originating in a circumstellar disk
(e.g., planets). 
     2) It has long been expected that star formation will
produce brown dwarfs, particularly because the time scales of
brown dwarf formation are too short for hydrogen burning to be
relevant. However, the detection of brown dwarfs has proved
difficult because they are very faint, and the first unambiguous
brown dwarfs were discovered only in 1995.
     3) Star and planet formation models need to account for the
properties of brown dwarfs at the extreme low-mass end of the
stellar mass distribution. Thanks to improved telescopes and
detectors, the observational characterization of brown dwarfs is
now well under way. But although models of the evolution of brown
dwarfs are well developed, models of their formation are still in
a preliminary stage.
     4) There is now wide agreement that brown dwarfs are
numerous but not a substantial source of dark matter. Counts of
brown dwarfs indicate that they represent a small (less than 15
percent) fraction of the total stellar mass, but a substantial
fraction by number.
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Science 2001 294:801
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SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com
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Related Background:
ASTROPHYSICS: A BROWN DWARF RADIO STAR
     Brown dwarf stars are formed by the contraction of a lump of
gas with a mass too small (less than approximately 0.08 the mass
of the Sun) for nuclear reactions to begin in the core. Such a
star has a relatively short-lived luminosity (approximately 100
million years to several billion years) as the result of
conversion of gravitational energy to radiation. The surface
temperature of a brown dwarf is below 2500 kelvins. As recently
as 1994, brown dwarfs were "theoretical" stars, with no brown
dwarfs considered to be unambiguously identified. In the past few
years, however, a number of stars have been recognized as brown
dwarfs, and they are under intensive study.
     In this context, the term "gas giant" (giant planet) refers
to a planet of much larger mass and diameter than the Earth, and
which consists mostly of gas. In our own Solar System, Jupiter,
Saturn, Uranus, and Neptune are gas-giant planets. 
     A synchrotron is a device for accelerating electrons or
protons in closed orbits in which the frequency of the
accelerating voltage and the strength of an applied magnetic
field are simultaneously varied to keep the orbit radius
constant, and laboratory synchrotron radiation is electromagnetic
radiation generated by the acceleration of charged relativistic
particles in a synchrotron (or in any magnetic field). In
astronomy, the term "synchrotron emission" refers to
electromagnetic radiation emitted by charged particles moving in
a magnetic field at a velocity close to that of light, and
emissions from various types of astronomical objects are
apparently synchrotron emissions. In general, relativistic
electrons gyrating in a magnetic field emit radio waves at high
harmonics of the electron gyrofrequency, so emission of radio
waves can be an indication of synchrotron emission by
astronomical objects.
     The term "radio waves" refers to electromagnetic radiation
of wavelength longer than approximately 1 millimeter (30
gigahertz). The longest radio waves observable in astronomy have
a wavelength of approximately 30 meters. The shortest radio
wavelengths, from approximately 1 millimeter to 30 centimeters,
are known as "microwaves". In this context, the term "radio
emission" refers to radio wave emission from an astronomical
source. Astronomical radio sources produce either continuum
radiation or line radiation. Line radio radiation is emitted at
only one specific wavelength and is equivalent to an optical
spectral line. The most important of such lines is the 21-
centimeter line emitted by neutral hydrogen atoms. Of continuum
radio radiation there are two kinds: a) thermal radio radiation
is electromagnetic energy emitted by hot ionized interstellar
gases; b) non-thermal radio radiation is a result of a process of
synchrotron emission, the release of radiation by electrons
spiraling in magnetic fields at speeds near the speed of light.
     In this context, the term "x-ray emission" refers to x-rays
emitted from various astronomical sources. Most stars emit only
an extremely small fraction of their energy as x-rays, with young
massive stars the most powerful x-ray emitters. In general, gases
heated to temperatures above 10 million kelvins will emit x-rays.
     An "M star" is a star of spectral type "M", i.e., with a
very cool surface (below 3900 kelvins), appearing reddish in
color and emitting most of its radiation in the infrared. M-type
dwarf stars ("red dwarfs") have masses below 0.5 solar-masses and
potential lifetimes longer than the present age of the Universe.
     In this context, the term "corona" refers to the hot 
outer atmosphere of certain stars, where the temperature can be 2
million kelvins or more. The term "flare" refers to a sudden
release of corona energy.
... ... E. Berger et al (14 authors at 14 installations, US)
report the discovery of radio emission from a brown dwarf star,
the authors making the following points:
     1) The authors point out that brown dwarf stars are not
massive enough to sustain thermonuclear fusion of hydrogen at
their centers, but they are distinguished from gas-giant planets
by their ability to burn deuterium. Brown dwarf stars older than
approximately 10 million years are expected to have short-lived
magnetic fields and to emit only weak radio waves and x-rays from
their coronas. An x-ray flare was recently detected on the brown
dwarf star LP944-20.
     2) The authors report the discovery of both quiescent and
flaring radio emission from LP944-20, with luminosities several
orders of magnitude larger than that predicted by the empirical
relation between the x-ray and radio luminosities that has been
found for many types of stars. An analysis of the radio data
within the context of synchrotron emission indicates that the
brown dwarf star LP944-20 has an unusually weak magnetic field in
comparison to M-dwarf stars.
... ... In a commentary on the above work, Arnold O. Benz (ETH-
Zentrum Zurich, CH) makes the following points:
     1) The author (Benz) points out that this is the first time
that radio emission has been recorded from a bona fide brown
dwarf star. Although brown dwarf stars are too small to burn
hydrogen, they can fuse deuterium in their cores, provided they
are at least 12 times the mass of Jupiter. But this fusion of
deuterium is possible only when the brown dwarf star is young, in
the first 10 million years or so. The brown dwarf star LP944-20,
however, is apparently 500 million years old and should have no
deuterium source left in its core. This suggests that the radio
emission of LP944-20 may be synchrotron emission associated with
a hot corona. However, the apparently weak magnetic field of this
star makes this explanation for the radio emission tenuous. The
author (Benz) concludes: "The whistling brown dwarf is a new
mystery for astronomers to puzzle over, and may indicate that
these dusky little objects have more surprises in store."
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Nature 2001 410:310,338
SCIENCE-WEEK 2001 1 Jun
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Related Background:
ON BROWN DWARF STARS
Brown dwarf stars are formed by the contraction of a lump of gas
with a mass too small for nuclear reactions to begin in the core
[*Note #1]... The surface temperature of a brown dwarf is
estimated to range from below 2500 kelvins to less than 1000
kelvins...
... ... C.G. Tinney (Anglo-Australian Observatory Epping, AU)
presents a review of recent observations of brown dwarf stars,
the author making the following points: 1) Most stars spend most
of their lives in a state of pressure balance maintained between
gravitational contraction and the energy generated by nuclear
reactions. In 1963, Kumar suggested there may exist a class of
star-like bodies with masses too low to create the central
temperature and densities required to ignite nuclear fusion
reactions. These "failed stars" became known to astronomers as
"brown dwarfs". 2) The lowest-mass ordinary stars can
theoretically maintain a quasi-equilibrium luminosity for almost
6000 billion years. Brown dwarf stars, in contrast, are expected
to fade throughout their lifetime, cooling to temperatures below
1000 kelvins and becoming undetectable by direct observation
after just a few billion years. This has engendered considerable
interest in brown dwarf stars as possible candidates for the
*dark matter which apparently composes more than 90 percent of
the mass our Galaxy. 3) The past 4 years have seen success
finally achieved in the hunt for brown dwarf stars. These
detections have confirmed predictions that both methane and dust
play an important role in determining the spectral behavior of
these objects. But the detection of brown dwarf stars in
significant numbers, when combined with results for the space
density of low-mass stars and *gravitational microlensing
results, allows us to conclude that brown dwarf stars do not make
a significant contribution to the dark matter of our Galaxy. The
author concludes: "No matter how nicely brown dwarfs would solve
the *baryonic dark matter problem, it appears we must look
elsewhere for a solution to this long-standing astronomical
quandary."
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Nature 1999 397:37
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Notes:
... ... *Note #1: Present theoretical models predict a lower
mass-limit for fusion burning stars with the same element mix as
the Sun of 0.07 solar-mass, equivalent to 74 times the mass of
Jupiter.
... ... *dark matter: In general, in this context, the term "dark
matter" refers to material whose presence can be inferred from
its effects on the motions of stars and galaxies, but which
cannot be seen directly because it emits little or no radiation.
It is believed that at least 90 percent of the mass in the
Universe exists as some form or dark matter.
... ... *gravitational microlensing: Gravitational lensing is the
bending of light and other radiation by a massive gravitational
entity such as a star, a black hole, a galaxy, or a cluster of
galaxies. The effect is predicted by Einstein's theory of
relativity and was first detected during a total solar eclipse by
Eddington in 1919. Large-scale gravitational lensing causes
multiple images of an object, the type and arrangement of the
images determined by the specifics of the lensing entity.
Gravitational "microlensing" is a small-scale lensing effect, the
gravitational field of the lensing object not strong enough to
form distinct images of the background source, but instead
causing an apparent brightening of the source. Stars are expected
to vary in brightness in a characteristic manner if low-mass
stars pass in front of them.
... ... *baryonic dark matter: Ordinary matter too dim to be
observed. A baryon is a nuclear particle, e.g., a proton, built
from 3 quarks (fundamental particles that combine to make up
protons, neutrons, and mesons).
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SCIENCE-WEEK 1999 19 Mar
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Related Background:
THE DUSTY ATMOSPHERE OF A BROWN DWARF STAR
... C.A. Griffith et al (3 authors at 3 installations, US) now
report observations of the brown dwarf star Gliese 229B, which
exhibits certain unique characteristics. At 900 kelvins, the
atmosphere of this object is too warm to contain ice clouds
like those on Jupiter and too cool to contain silicate clouds
like those on low-mass stars. These unique conditions (high
gravity and the lack of high clouds) permit spectroscopic
visibility of the atmosphere down to higher pressures (i.e.,
closer to the surface) than possible in cool stars or planets.
The authors investigated the structure of the atmosphere of
Gliese 229B by analyzing its optical spectrum in the interval
0.85 to 1.0 micron, the spectrum obtained at the *Keck 1
telescope. The authors report that the spectrum of Gliese 229B
indicates deep-atmosphere particulate matter with the optical
properties of neither ice nor silicates. The authors suggest the
reddish color of the particles indicates an organic composition
characteristic of aerosols in planetary stratospheres, and that
the *mass fraction of the particles agrees with a photochemical
origin involving incident radiation from its companion primary
star (Gliese 229A).
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Science 1998 282:2063
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Notes:
... ... *Keck 1 telescope: The Keck telescopes are a pair of twin
telescopes at the W. M. Keck Observatory on Mauna Kea, HI US,
each with a 10 meter mirror, the pair constructed 1992-1996. The
installation is managed by the University of California (US) and
the California Institute of Technology (US).
... ... *mass fraction: The mass fraction of aerosols is related
to the *eddy diffusion coefficient k, the mass density of the
atmosphere d, the net mass flux f, and the scale height of the
atmosphere h according to F = fh/kd.
... ... *eddy diffusion coefficient: (turbulent diffusion
coefficient) The exchange coefficient for the diffusion of a
conserved property by eddies in a turbulent flow. In general, an
"eddy" is a vortex-like motion of fluid running contrary to the
main current.
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SCIENCE-WEEK 1999 12 Feb
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4. LIGHT INTERFERENCE FROM SINGLE ATOMS
J. Eschner et al (University of Innsbruck, AT) discuss single-
atom light emission. A single atom emitting single photons is a
fundamental source of light, but the characteristics of this
light depend strongly on the environment of the atom. For
example, if an atom is placed between two mirrors, both the total
rate and the spectral composition of the spontaneous emission can
be modified. Such effects have been observed using various
systems: molecules deposited on mirrors, dye molecules in an
optical cavity, an atom-beam traversing a two-mirror optical
resonator, single atoms traversing a microwave cavity, and a
single trapped electron. A related and equally fundamental
phenomenon is the optical interaction between two atoms of the
same kind when their separation is comparable to their emission
wavelength. In this situation, light emitted by one atom may be
reabsorbed by the other, leading to cooperative processes in the
emission. The authors report they observe these phenomena with
high visibility by using one or two single atom(s), a collimating
lens and a mirror, and by recording the individual photons
scattered by the atom(s). In these experiments, single barium
ions are trapped in an ion trap, laser-cooled, and well localized
for hours. The authors suggest their experiments highlight the
intimate connection between one-atom and two-atom effects, and
allow their continuous observation using the same apparatus.
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Nature 2001 413:495
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5. ON CLASSICAL AND QUANTUM PHASE TRANSITIONS
G. Aeppli and Y-A. Soh (NEC Research Institute, US) discuss phase
transitions, the authors making the following points:
     1) In ordinary phase transitions, raising the temperature
induces a transformation between ordered and disordered states.
Examples are the freezing point of water, where the crystalline
solid transforms into a liquid, and the Curie point of iron,
where the metal loses its spontaneous magnetization. Such
transitions are driven by increasing thermal fluctuations that
destabilize the low-temperature ordered state
     2) Classical phase transitions in clean and defect-free
materials are now well understood. Experiment and theory have
converged on the concept of "universality": No matter how complex
the system, its behavior near the phase transition should be
largely (but not exclusively) governed by its spatial
dimensionality. Fluids confined to surfaces should thus have more
in common with the magnetic layers in some transition metal salts
than with ordinary 3-dimensional fluids.
     3) Does universality also exist for quantum phase
transitions, where quantum rather than thermal fluctuations are
responsible for a change of state? Because the probabilities of
quantum fluctuations depend on their profiles as a function of
both time and space, quantum transitions should be analogous to
classical transitions in a system of higher dimensionality given
by the sum of time and space dimensionalities. Thus, 25 years
ago, the problem of quantum transitions in clean materials was
reduced to the study of classical phase transitions in higher
dimensional systems and regarded as essentially solved.
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Science 2001 294:315
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6. MAGNETIC CARBON
T.L. Makarova et al (Ioffe Physico-Technical Institute, RU)
discuss magnetic carbon. The discovery of nanostructured forms of
molecular carbon has led to a renewed interest in the varied
properties of this element. Pristine C(sub60) fullerene is a van
der Waals crystal that can be converted to covalently bonded
crystalline phases by compression. Depending on the treatment,
the molecules interconnect to form 1-, 2-, or 3-dimensional
polymers. Ferromagnetism has previously been observed in two
C(sub60) compounds, in one case below 17 kelvins and in the other
case below 19 kelvins. Both graphite and C(sub60) can be
electron-doped by alkali metals to become superconducting, and
transition temperatures of up to 52 kelvins have been attained by
field-induced hole-doping. Recent experiments and theoretical
studies have suggested that electronic instabilities in pure
graphite may give rise to superconducting and ferromagnetic
properties even at room temperature. The authors report the
accidental discovery of strong magnetic signals in rhombohedral
C(sub60). The intention of the authors was to search for
superconductivity in polymerized C(sub60); however, it appears
that the high-pressure, high-temperature polymerization process
used by the authors results in a magnetically ordered state. The
material exhibits features typical of ferromagnets: saturation
magnetization, large hysteresis, and attachment to a magnet at
room temperature. The authors suggest the temperature dependence
of the saturation and remanent magnetization indicate a Curie
temperature near 500 kelvins.
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Nature 2001 413:716
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7. CALCIUM REGULATION OF NEURONAL GENE EXPRESSION
A.E. West et al (Children's Hospital Boston, US) discuss calcium
signaling in neurons, the authors making the following points:
     1) Electrical activity within the brain rapidly encodes
information about the world, but for these fleeting perceptions
to have a lasting impact, long-term changes in the structure and
function of neurons must follow. At the synapse, neurotransmitter
reception initiates a number of biochemical signaling cascades in
the postsynaptic cell, one of the most important of which is the
elevation of intracellular calcium. This calcium rise is a
critical component of signaling pathways whose functional
consequences include activity-dependent survival and the synaptic
plasticity of long-term potentiation.
     2) Early events induced by the rise of calcium in dendrites
are likely to be local, resulting from post-translational
modifications of the synaptic machinery. However, for long-term
structural and functional changes in the neuron, the calcium
signal must regulate the expression of new gene products. There
are several potential calcium-dependent steps in the process of
new gene expression: elements of messenger RNA (mRNA)
transcription, elongation, splicing, stability, and translation
have all been suggested to be regulated by calcium in neurons.
     3) New evidence is accumulating in favor of the idea that
some calcium-regulated mRNA translation occurs locally at
postsynaptic sites, providing a means for rapid and accurate
expression of activity-induced gene products at activated
synapses. The relative importance of dendritic mRNA translation
in calcium-dependent biological processes will become clearer
when the specific mRNAs that are regulated in this manner are
identified.
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Proc. Natl. Acad. Sci. 2001 98:11024
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SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com
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Related Background:
CELL BIOLOGY: ION CHANNEL PROTEINS AND CALCIUM CHANNELS
     The regulated permeabilities of the biological cell membrane
to various ions are important factors in a number of crucial
cellular mechanisms. In general, these permeabilities involve
specific ion-selective pores constructed of proteins, the pores
called "ion channels", with ion channels of different types
available for any one ion species. Evidence suggests that an ion
channel protein spans the membrane and has a central water-filled
pore open to both the intracellular and extracellular
compartments. On each side, the pore widens to form a vestibule,
with the restricted region within the plane of the membrane
containing an effective "gate" that can open or close to control
the passage of ions.
     Ion channels are highly regulated, linked to key cellular
processes, and during the past two decades, an intensive effort
in many laboratories has led to identification of the proteins of
some ion channels, studies of the configuration of these
proteins, and an improved understanding of the complex events
associated with the passage of simple ions such as sodium,
potassium, calcium, and chloride into and out of biological
cells. A very powerful technique used in much of this work
involves genetic engineering of ion channels. The essential idea
is to isolate a DNA sequence that encodes the protein for a
particular ion channel, then transfect this DNA sequence into the
genome of a host cell type amenable to detailed electrical and
transport measurements. When the ion channel protein is expressed
in this host cell and becomes part of the host cell plasma
membrane, the various properties of the ion channel become open
to investigation. Although the results of such experiments must
be carefully interpreted, the ability to make specific and
discrete alterations in channel protein membrane structure has
led to important insights into the relation between the
structures of ion channel proteins and their control of ion
permeabilities.
     Of the ions that diffuse back and forth across cell
membranes, calcium ions are of great importance in many
physiological processes. In biological cells, extracellular and
intracellular concentrations of calcium ion differ by several
orders of magnitude, and cells are therefore exposed to a steep
calcium ion gradient across their membranes. In general, the
control of cellular calcium ion is maintained by an elaborate
system of channels, exchangers, and pumps located both in the
plasma membrane and in intracellular membranes.
... ... James W. Putney Jr. (National Institutes of Health, US)
presents a commentary on recent studies of a calcium ion channel
(L. Yue et al: Nature 2001 410:705), with the author (Putney)
making the following points:
     1) The author points out that calcium ions are important
biological signals, controlling processes such as protein
secretion, muscle contraction, cell death, and tissue
development. In general, calcium signalling involves an increase
in the intracellular concentration of calcium ions, and one of
the mechanisms by which this occurs is so-called "capacitative
calcium entry" (also called "store-operated calcium entry"), a
process that requires the regulated opening of ion channels in
the plasma membrane. These ion channels, however, have not yet
been identified. (The process is called "store-operated calcium
entry because it is somehow activated by a fall in the
concentration of calcium ions stored in an internal membrane
system, the endoplasmic reticulum.)
     2) Yue et al now present evidence that implicates a newly
discovered protein (CaT1) as a constituent of a capacitative
calcium-entry channel, and the author (Putney) suggests this
discovery may lead to an improved understanding of the cellular
and molecular mechanism by which this channel is controlled.
     3) The author (Putney) points out that although the weight
of evidence supports the conclusion of Yue et al that the protein
CaT1 (or, in some instances, a closely related protein [ECaC])
constitutes the ion-conducting pore of the calcium channel they
investigated, there are also other calcium-specific channels,
known from electrophysiological studies, that have properties
distinct from the channel investigated by Yue et al. Putney
points out that it is possible and even likely that other channel
proteins form part of these channels. Putney concludes: "In the
near future, I anticipate continuing progress in the search for
the complete molecular definition of the capacitative calcium-
entry channels, as well as a solution to the mystery of how they
are regulated."
-----------
Nature 2001 410:648
-----------
SCIENCE-WEEK 2001 25 May
-----------
Related Background:
NEUROBIOLOGY: INTRACELLULAR CALCIUM IONS AND NERVE GROWTH CONES
After neurons have differentiated and migrated to their intended
specific destinations, they extend *axons that select connection
targets from an enormous number of possibilities, and eventually
these axons form *synapses with appropriate cells in the target
region. These events depend on a complex of cellular and
molecular signals that guide axons and facilitate correct
connections. The signals involve *cell adhesion molecules that
regulate the interactions between axons and the surfaces upon
which they grow, diffusible molecules that attract growing axons,
and a family of molecules called "*neurotrophins" that promotes
and maintains stable synapses between axons and their targets.
The circuitry of the developing nervous system is thus gradually
constructed by means of such intricate interactions. The local
dynamics of growing axons are now known to involve the properties
of the "growth cone", a specialized structure at the tip of the
extending axon. Growth cones are highly motile structures that
explore the extracellular environment and respond to local cues
by changing the speed or direction of growth. Experiments
indicate that in vitro the intracellular calcium ion
concentration of growth cones is correlated with their motility,
but the links between environmental cues and axon growth in vivo
are unknown.
... ... James Q. Zheng (Univ. of Medicine and Dentistry of New
Jersey, US) now reports new evidence concerning the role of
calcium ion in nerve growth cone directionality, the author
making the following points:
     1) Although guidance of developing axons involves turning of
the growth cone in response to a variety of extracellular cues,
little is known concerning the intracellular mechanism by which
the directional signal is transduced. Calcium ion is apparently a
key "*second messenger" in growth cone extension and has been
implicated in growth-cone turning.
     2) The author reports that with cultured amphibian neurons
(Xenopus laevis; African clawed toad) a direct spatially
restricted elevation of intracellular calcium ion concentration
on one side of the growth cone by focal laser-induced photolysis
(FLIP) of caged calcium ions consistently induced turning of the
growth cone to the side with elevated calcium ion concentration.
Furthermore, when the resting intracellular calcium ion
concentration at the growth cone was decreased by the removal of
extracellular calcium ion concentration, the same focal elevation
of intracellular calcium ion concentration by FLIP induced
repulsion.
     3) The authors suggests these results provide direct
evidence that a localized calcium ion signal in the growth cone
can constitute the intracellular directional cue for extension,
and this cue is sufficient to initiate either attraction or
repulsion, depending on ambient conditions. By integrating local
and global calcium ion signals, a growth cone could thus generate
different turning responses under different environmental
conditions during guidance. The author concludes: "Such diversity
of regulation along the signal transduction pathway... could
provide the potential for the specific and accurate wiring of
millions of axons through a limited number of cues available
during development."
-----------
Nature 2000 403:89
-----------
Notes:
... ... *axons: In those animals that have nervous systems, one
task of embryological development is to ensure the proper
functional connections between nerve cells and other nerve cells,
and between nerve cells and muscle cells. The innervation must be
exact, in the sense that the growing nerve cell extension (the
axon), which will ultimately serve to propagate information, must
reach a specific and often distant target. In humans, for
example, there are nerve cells whose growing axons reach specific
targets as much as a meter distant from the cell body.
... ... *synapses: The junction between the terminal of the axon
of one neuron and another neuron is called a "synapse".
 ... ... *cell adhesion molecules: In general, substances that
regulate the interactions between axons and the surfaces upon
which they grow.
... ... *neurotrophins: In general, neurons in the central
nervous system apparently depend for their survival on a number
of secreted substances called neurotrophins (neurotrophic
factors). These substances are polypeptides of 200 to 300 amino
acids, and at least 4 different neurotrophins have been
identified.
... ... *second messenger: In general, the "second messenger" is
an intermediary compound that couples extracellular signals to
intracellular processes with amplification of the transduced
signal.
-----------
SCIENCE-WEEK 2000 28 Apr
-----------
Related Background:
NEUROBIOLOGY: MODIFICATION OF DENDRITIC SPINES BY CALCIUM
     Nerve cells (neurons), the cellular units of all nervous
systems, have diverse morphologies within an individual, and a
variety of unique morphologies across species. In general,
however, all neurons have two fundamental anatomic components: a
cell body (soma) and a single long filamentary extension from the
cell body, the so-called "axon" (which may branch along its
length), that propagates electrical activity from the cell body
(or from the vicinity of the cell body) to other locations (e.g.,
to muscle cells or to other nerve cells).
     Most neurons also possess a third anatomic component:
extensions of the cell body (few or numerous) that provide
junction points for the axons of other neurons (i.e., provide
surface area for synapses), and thus serve as loci for receiving
inputs. In some neurons, dendrites are extensively branched
(arborized), the single neuron as a whole receiving inputs from
as many as 100,000 other neurons, while at the other extreme
there are neurons with only one dendrite receiving input from
only one or a few other neurons.
     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 the human nervous system, dendritic spines are
especially prominent in the *cerebellar cortex, *basal ganglia,
and *cerebral cortex, and in the cerebral cortex approximately 80
percent of all *excitatory synapses are evidently made onto
dendritic spines, whereas only approximately 30 percent of
*inhibitory synapses are made onto dendritic spines. Currently,
neurobiologists have ascribed literally dozens of different
functions to dendritic spines, and investigations of these
structures are underway in many laboratories.
... ... Kristen M. Harris (Boston University, US) presents a
commentary on current research concerning the involvement of
calcium ions in dendritic spine morphology, the author making the
following points:
     1) Since the discovery of dendritic spines at the turn of
the century by *Ramon y Cajal (1852-1934), these structures have
been of interest to neurobiologists because of their special
morphology and their possible involvement in cognitive functions
such as learning and memory.
     2) Dendritic spines have diverse shapes that range more than
100-fold in size. Larger spines have proportionately larger
synapses and more diversity in subcellular organelles and
molecular composition, and such differences may be involved in
functional differences of the synapses located upon spines.
     3) Existing data suggest that spines are maintained by
optimal activation: more spines form when neurons have less
excitatory activation, and spines are lost when activation is too
high or when presynaptic axons degenerate. This pattern suggests
that neurons may *homeostatically regulate input by means of the
number of axon-dendritic spine synapses.
     4) New evidence by Korkotian and Segal (1999) now points to
the release of calcium ions from intracellular stores as a
possible modulator of dendritic spine structure. When neurons in
culture are exposed to caffeine, calcium is released from the
intracellular stores into dendrites and dendritic spines, and
under these conditions most of the dendritic spines elongate
approximately 33 per cent during the following several hours.
     5) The finding that release of calcium from intracellular
stores might have a direct effect on dendritic spine structure is
especially interesting because changes in spine structure have
long been thought to be an important mechanism of memory. The
increase in intraspine calcium caused by release of calcium from
intracellular stores is much less than the increase in intraspine
calcium resulting from high synaptic activity (which decreases
the number of spines), and this suggests that a small increase in
intraspine calcium causes a spine to elongate, whereas high
intraspine calcium from excessive activity causes a spine to
collapse. Thus, spine morphology may be closely regulated by
local intracellular calcium ion concentration.
-----------
Proc. Natl. Acad. Sci. 1999 96: 12213
-----------
Notes:
... ... *cerebellar cortex: The cerebellum is a large neural
structure at the base of the brain involved in motor
coordination, posture, and balance. The cortex of the cerebellum
is a thin corrugated outer layer containing cell bodies of
cerebellar neurons.
... ... *basal ganglia: The term "basal ganglia" refers to a
group of nuclei lying deep in the subcortical white matter of the
frontal lobes, these nuclei involved in the organization of motor
behavior. In this context, a "nucleus" is a cluster of nerve
cells.
... ... *cerebral cortex: The cerebral cortex is a thin surface
layering of nerve cells of the brain, the region only  several
millimeters thick but covering all of the brain surface. This is
the part of the central nervous system most intimately involved
with the so-called "higher faculties", although the cortex
operates in concert with other parts of the brain. The structure
is primitive in lower mammals, and is found progressively more
pronounced and with greater surface area in primates and man.
... ... *excitatory synapses: A synapse which when activated
produces excitation of the postsynaptic nerve cell.
... ... *inhibitory synapses: A synapse which when activated
produces inhibition of the postsynaptic nerve cell.
... ... *Ramon y Cajal (1852-1934): Santiago Ramon y Cajal is one
of the more important historical figures in neurobiology. His
specialty was the histology of the nervous system as revealed by
cellular staining. By 1889 he worked out the connections of the
cells of the gray matter of the brain and spinal cord with a
demonstration of the extreme complexity of the system. He also
worked out the structure of the retina of the eye. He established
the "neuron theory", which postulated the nervous system to
consist entirely of individual nerve cells and their processes.
In 1906, Ramon y Cajal shared the Nobel Prize in Physiology and
Medicine with Camillo Golgi (1843-1926), whose stains for the
nervous system were used by Ramon y Cajal in his work.
... ... *homeostatically regulate: The term "homeostasis" refers
to a physiological equilibrium necessary in general for the
viability of an organism, and in particular for the operation of
many cellular functions. Homeostatic mechanisms in biological
systems usually involve an element of negative feedback
signaling. In vertebrates, for example, when blood temperature is
too high, temperature receptors provoke a sequence of events
involving many pathways that ultimately results in a lowering of
body temperature. Similar homeostatic mechanisms operate at
cellular levels. 
-----------
SCIENCE-WEEK 1999 24 Dec
-----------
Related Background:
MOLECULAR CHARACTERIZATION OF A NEURONAL CALCIUM CHANNEL
Ion channels are protein channels in cell membranes that allow
ions to pass from extracellular solution to intracellular
solution and vice versa. Most ion channels are selective,
allowing only certain ions to pass, and an individual cell has
ion channels with various ion selectivities. The selectivity of
an ion channel can be "gated", the channel effectively opened or
closed, and ion channels are said to voltage-gated or ligand-
gated, depending on how the change in selectivity is provoked.
The term "T-type channels" refers to channels whose ion currents
are both transient (due to rapid inactivation) and small (due to
small conductance), and such ion channels are believed to be
involved in pacemaker activity, low-threshold calcium ion spikes,
neuronal oscillations, etc. Frog oocytes are frog egg cells, and
they are a common laboratory vehicle for expressing the proteins
of genetically engineered material from other species and
coupling this expression with electrophysiological measurements
of frog oocyte membrane behavior. ... ... Perez-Reyes et al (9
authors at 4 installations, US UK) report the identification via
cloning methods of a neuronal T-type calcium ion channel, with
expression of the protein constituting the channel in frog
oocytes, and electrophysiological characterization of the channel
in these cells. The authors suggest they have cloned the first
member of the low-voltage-activated T-type Ca(sup2+) family, and
one with identified human and mouse genetic homologues.
-----------
Nature 1998 26 Feb
ScienceWeek 1998 13 Mar
-----------
SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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8. THE RHYTHM OF MICROBIAL ADAPTATION
Philip Gerrish (Los Alamos National Laboratory, US) discusses
microbial adaptation, the author making the following points:
     1) Populations of organisms adapt to their environment
through the production of beneficial mutations and the subsequent
spread of these mutations to predominance in the population via
natural selection, a process known as "fixation". The fixation of
a given beneficial mutation often takes a long time, and during
this time it is possible and likely, in large microbial
populations, that one or more alternative beneficial mutations
will appear in the still-prevalent parental lineage in which the
given beneficial mutation appeared. The result is the
simultaneous presence in the population of several new lineages
that each carry a selective advantage over their common
progenitor.
     2) Quoting Ernst Mayr, the evolutionary biologist "studies
the steps by which the miraculous adaptations so characteristic
of every aspect of the organic world have evolved." But the
general nature of such adaptive steps is still unclear. Evolution
is often thought to be random and dependent on unpredictable
events. In this light, one might expect the steps taken by
adaptation to be completely random, both biologically and
temporally.
     3) The author presents a mathematical derivation to
demonstrate that, on the contrary, adaptive steps can have fairly
strong rhythm. The author reports that the strength of the
adaptive rhythm, i.e., its relative temporal regularity, is equal
to a constant that is the same for all microbial populations. As
a consequence, numbers of accumulated adaptations are predicted
to have a universal variance/mean ratio. The author suggests the
derived theory is potentially applicable to the study of
molecular evolution.
-----------
Nature 2001 413:299
-----------
SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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9. POLYGLUTAMINE SEQUENCES AND NEURODEGENERATIVE DISEASES
Gillian P. Bates (King's College, UK) discusses repeat sequences
and neurodegenerative diseases, the author making the following
points:
     1) A potentially deadly repetitive sequence of nucleotides,
CAGCAGCAG... (cytosine-adenine-guanine...), lies at the start of
the huntingtin gene associated with Huntington's disease. The
triplet CAG codes for the amino acid glutamine, and the
repetitive sequence therefore codes for a stretch of
polyglutamine at one end of the huntingtin protein. People with
more than 40 glutamines in the sequence will develop Huntington's
disease, while those with fewer than 38 glutamines in the
sequence will be unaffected.
     2) The elongated polyglutamine tract is associated with the
progressive degeneration and death of neurons characteristic of
Huntington's disease, and new work by Steffan et al (2001)
demonstrates that the expanded tract interferes with the
apparatus for switching on and regulating genes.
     3) There are currently 9 neurodegenerative diseases
apparently caused by the expansion of a polyglutamine tract in
one protein or another, and all of these disorders are associated
with the formation in nerve cells of insoluble aggregates
containing the affected protein. However, stretches of
polyglutamine are not always harmful: such polyglutamine
sequences are also occur normally in many of the proteins that
constitute transcription factor complexes that regulate gene
expression. For example, an acetyltransferase enzyme known as CBP
contains a tract of 18 glutamines. Acetyltransferases activate
transcription by adding acetyl groups to histones, the proteins
that help to package DNA into a compact form.
-----------
Nature 2001 413:691,739
-----------
SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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10. PROTEIN FOLDING: ENERGY LANDSCAPE THEORY
Jeffery G. Saven (University of Pennsylvania, US) discusses
protein folding. A predictive understanding of protein folding is
obscured by the complexity of proteins. The hallmark of protein
folding is the ability of an amino acid sequence to reversibly
acquire a well-defined and unique structure in a moderate amount
of time even though an extremely large number of structures are
possible. In the energy landscape approach to understanding
protein folding, the process is viewed as a collective and
cooperative phenomenon, with the focus of theory on the global
nature of the protein's free energy surface. Such a picture
emphasizes those general characteristics shared by proteins in a
structural class as well as those properties specific to
particular proteins. In such an approach, information about the
energetics of the unfolded as well as folded states must be
accounted for. This is an obvious consideration, since the
protein must effectively recognize and acquire one conformation
when a huge number of conformations are possible. Although much
has been learned about the energetics and features of unfolded
states from detailed atom-based simulations, such calculations
are computationally time-consuming. Given the apparent complexity
of the conformational free energy surface of a protein, the
energy landscape approach focuses on developing concepts that
simplify the description of the process. A prime goal of energy
landscape theory is to identify a handful of thermodynamic and
other simplifying parameters and variables that characterize
protein folding in both the folded state and in the ensemble of
partially folded conformational states.
-----------
J. Am. Chem. Soc. 2001 123:3113
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SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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11. ON VASCULAR ENDOTHELIAL GROWTH FACTOR
R.A. Bruick and S.L. McKnight (University of Texas, US) discuss
vascular endothelial growth factor, the authors making the
following points:
     1) Throughout embryogenesis, establishment of the vascular
network is mediated by a complex and highly regulated interplay
between positive and negative growth factors. In adults, this
vascular network is relatively stable, and formation of new
microvasculature is generally associated with pathophysiological
conditions such as tumorigenesis, ischemic insult, and chronic
inflammatory diseases.
     2) Vascular endothelial growth factor (VEGF) is a critical
positive regulator of both physiological and pathophysiological
neovascularization. As such, VEGF has become an important
therapeutic target in the fight against cancer, against blindness
resulting from age-related macular degeneration or diabetic
retinopathy, and against pulmonary hypertension. Conversely,
induction of VEGF with the intent to promote angiogenesis may
benefit patients suffering from myocardial ischemia, limb
ischemia resulting from diabetes, and insufficient wound healing.
While overexpression of VEGF alone has been shown to promote
angiogenesis, the resulting capillaries are often leaky and
accompanied by edema, inflammation, and spontaneous hemorrhagic
ulcers.
     3) In general, new vasculature networks can arise via de
novo assembly (vasculogenesis) or by branching from preexisting
vessels (angiogenesis). VEGF is a potent inducer of both
processes, forming active disulfide-linked homodimers that are
recognized by VEGF receptors expressed in endothelial cells.
----------
Genes & Development 2001 15:2497
-----------
SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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12. ON PLANT CELL WALLS
Herman Hoefte (INRA Versailles, FR) discusses plant cell walls.
More than 300 years ago, Robert Hooke (1635-1703) pointed his
primitive microscope at a slice of cork and discovered the
cellular basis of organisms. Unfortunately, since then, plant
cell walls, which formed the compartments he actually observed,
have never been considered particularly entertaining structures.
Indeed, the word "wall" itself evokes something dull and rigid,
built only to enclose, support, divide, and protect. However, a
closer look reveals just how erroneous this view is. Walls of
growing plant cells are extremely sophisticated composite
materials made of dynamic networks of polysaccharides, protein,
and phenolic compounds. Cellulose microfibrils with a tensile
strength comparable to that of steel provide the plant with a
load-bearing framework. These microfibrils are rigid wires made
of crystalline arrays of beta-1,4-linked chains of glucose
residues, which are extruded from little hexameric spinnerets in
the plant cell plasma membrane and which surround the growing
cell like the hoops around a barrel. Because cellulose
microfibrils constrain turgor-driven cell expansion in one
preferential direction, they control the shape of plant cells and
ultimately the shapes of the plants themselves. Hemicelluloses,
such as xyloglucans, are tethered by hydrogen bonds to cellulose
and form cross-links that may control the separation of the
cellulose microfibril hoops. The cellulose-hemicellulose network
is embedded in a matrix of complex galacturonic acid-rich pectic
polysaccharides that form a hydrated gel inside the wall,
providing a dynamic operating environment for cell wall
processes. In all higher plants, one of the apparently essential
polysaccharides in this hydrated gel is a mysterious
polysaccharide known as rhamnogalacturonan II (RGII), which is
believed to be the most complex polysaccharide on Earth. It is
composed of 11 kinds of sugar monomers, and apparently at least
21 enzymes are dedicated to the construction of all the linkages
between the sugar residues.
-----------
Science 2001 294:795
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SCIENCE-WEEK 1 Feb 2002 http://scienceweek.com

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13. POSTDOCTORAL FELLOWSHIP PROFILE:
Laboratory of Claire L. Moore, Tufts University (US)
----------------------------------------------------
     INSTALLATION: Tufts University School of Medicine
     DEPARTMENT: Molecular Biology and Microbiology
     GENERAL RESEARCH AREA: Eukaryotic gene expression, mRNA
processing.
     HEAD OF THIS SPECIFIC LABORATORY: Claire L. Moore, PhD
     POSTDOCTORAL FELLOWSHIPS ARE AVAILABLE IN THE FOLLOWING
RESEARCH PROBLEMS: a) The molecular mechanism of mRNA cleavate
and polyadenylation using Saccharomyces cerevisiae as a model
organism. b) The regulation of mRNA 3' end formation during the
cell cycle and under different growth conditions. c) The
interaction of the cleavage/polyadenylation machinery with other
processes involved in mRNA synthesis and utilization, such as
transcription, mRNA export from the nucleus, and degradation of
improperly processed transcripts. d) Structural analysis of
factors involved in mRNA 3' end formation using X-ray
crystallography and NMR.
     PREVIOUS RESEARCH EXPERIENCE AND DEGREES REQUIRED:
Experience in yeast genetics, biochemistry, and/or the
molecular biology of nucleic acid/protein and protein/protein
interactions is preferred. A PhD degree is required.
     USUAL STARTING STIPEND: Approx. $32,000/year for someone
with no previous postdoctoral experience. Stipend increases with
additional experience.
     NUMBER OF PEOPLE CURRENTLY WORKING IN THIS
SPECIFIC LABORATORY: 1 faculty, 1 graduate student, 1
undergraduate student, 5 postdocs, 1 research scientist.
     CONTACT FOR MORE INFORMATION: claire.moore@tufts.edu
     FURTHER RELEVANT INFORMATION: The Tufts Health Sciences
campus is in the center of Boston near Chinatown, around the
corner from the theater district, a short walk to shopping
districts and the Public Gardens, and close to public
transportation with access to the numerous biomedical research
institutions in the Boston area.
--------------------------------
Claire L. Moore, Ph.D.
Department of Molecular Biology and Microbiology
Tufts University School of Medicine
136 Harrison Avenue
Boston, MA 02111
----------------
Phone:  617-636-6935
FAX:  617-636-0337

--------------------------------------------------------------
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 TIME AND POSITIVISM
"What is time? Is it an ever-rolling stream that bear all our
dreams away, as the old hymn says? Or is it a railroad track?
Maybe it has loops and branches, so you can keep going forward
and yet return to an earlier station on the line. The 19th
century author Charles Lamb wrote: 'Nothing puzzles me like time
and space. And yet nothing troubles me less than time and space,
because I never think of them.' Most of us don't worry about time
and space most of the time, whatever that may be, but we all do
wonder sometimes what time is, how it began, and where it is
leading to. Any sound scientific theory, whether of time or of
any other concept, should in my opinion be based on the most
workable philosophy of science: the positivist approach put
forward by Karl Popper and others. According to this way of
thinking, a scientific theory is a mathematical model that
describes and codifies the observations we make. A good theory
will describe a large range of phenomena on the basis of a few
simple postulates and will make definite predictions that can be
tested. If the predictions agree with the observations, the
theory survives that test, though it can never be proved to be
correct. On the other hand, if the observations disagree with the
predictions, one has to discard or modify the theory. (At least
that is what is supposed to happen. In practice, people often
question the accuracy of the observations and the reliability and
moral character of those making the observations.) If one takes
the positivist position, as I do, one cannot say what time
actually is. All one can do is describe what has been found to be
a very good mathematical model for time and say what predictions
it makes."
-----------
Stephen Hawking: _The Universe in a Nutshell_
(Bantam Books, New York 2001, p.31)
http://www.amazon.com/exec/obidos/ASIN/055380202X/scienceweek

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15. NEW BOOKS

Darrigol: Electrodynamics from Ampere to Einstein
http://www.amazon.com/exec/obidos/ASIN/0198505949/scienceweek

Smolin: Three Roads to Quantum Gravity
http://www.amazon.com/exec/obidos/ASIN/0465078354/scienceweek

Anishchenko et al: Nonlinear Dynamics of Chaotic and Stochastic
Systems
http://www.amazon.com/exec/obidos/ASIN/3540424199/scienceweek

Mikharov et al: From Swarms to Societies: Models of Complex
Coherent Action
http://www.amazon.com/exec/obidos/ASIN/3540421645/scienceweek

Restak: The Secret Life of the Brain
http://www.amazon.com/exec/obidos/ASIN/0309074355/scienceweek

Wilson: The Future of Life
http://www.amazon.com/exec/obidos/ASIN/0679450785/scienceweek

Gillham: A Life of Sir Francis Galton: From African Exploration
to the Birth of Eugenics
http://www.amazon.com/exec/obidos/ASIN/0195143655/scienceweek

Shipman: The Man Who Found the Missing Link: Eugene Dubois and
his Lifelong Quest to Prove Darwin Right
http://www.amazon.com/exec/obidos/ASIN/068485581X/scienceweek

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16. FROM PRAXIS: ANGIOGENESIS
R.K. Jain and P.F. Carmeliet (Harvard University, US) discuss
angiogenesis, the authors making the following points:
     1) Angiogenesis, the formation of new blood vessels, might
one day be manipulated to treat disorders such as cancer and
heart disease. First-generation drugs are now in the final phase
of human testing.
     2) The term "angiogenesis" technically refers to the
branching and extension of existing capillaries, whose walls
consist of only one layer of endothelial cells. Normally,
angiogenesis helps to repair injured tissues. In females,
angiogenesis also builds the lining of the uterus each month
before menstruation and forms the placenta after fertilization.
     3) More than 20 compounds that manipulate angiogenesis,
either by stimulating new blood vessel growth or by blocking it,
are now in human tests against a range of disorders from cancer
to heart disease.
     4) Angiogenesis inhibitors are generally safe and less toxic
than cancer chemotherapeutic drugs, but they are unlikely to
treat cancer effectively on their own. Instead, clinicians will
probably use angiogenesis inhibitors in conjunction with standard
treatments such as surgery, chemotherapy, and radiation.
     5) The blood vessels of tumors are abnormal, and
angiogenesis inhibitors appear to "normalize" tumor blood vessels
before they kill them. This normalization can help anticancer
agents reach tumors more effectively.
-----------
Scientific American 2001 December
-----------
PRAXIS 28 Jan 2002 http://scienceweek.com/praxis
----------
Related Background:
ON THE ANGIOSTATIN-ENDOSTATIN-ENTREMED BUBBLE
In May of 1998 [see background material below] a front-page
article in _The New York Times_ reported a "breakthrough" in
cancer research, the breakthrough involving two drugs called
"angiostatin" and "endostatin" developed by Judah Folkman
(Harvard University, US) and licensed to Entremed Inc., a startup
biotechnology company. _The New York Times_ article produced a
media and financial bubble that in turn provoked considerable
criticism of both _The New York Times_ and the author of the
article. A new chapter in the brouhaha has now evidently
appeared: The Bristol-Meyers Squibb Company, the world's largest
manufacturer of cancer drugs, has announced it has abandoned its
agreement with Entremed Inc. to develop the drug angiostatin
because Bristol-Meyers no longer considers the compound a good
candidate for human tests. The stock of Entremed immediately (10
Feb 99) fell 47 percent (current share price US$12.9). Two days
after this announcement (12 Feb), it was reported that the US
National Cancer Institute has announced that its researchers have
finally duplicated some of the results obtained by Folkman with
the drug endostatin. Three months ago, the same institute
publicly announced that they could not reproduce Folkman's work.
James M. Pluda, a senior clinical investigator at the cancer
institute, is quoted as follows: "Lots of drugs have had great
activity in mice and then have not worked in people... It's very
premature to extrapolate from mouse data that this drug
[endostatin] will have the same activity in people that the mouse
version had in mice in Folkman's lab. We need careful clinical
trials to evaluate whether this drug will have any activity at
all." As expected, following the new cancer institute
announcement, the stock of Entremed regained the loss of the
previous days. Meanwhile, Entremed has announced that it has
licensed a new company to produce large quantities of
angiostatin, the drug rejected by Bristol-Meyers. These new
events provide another chapter in this story, the details of
which are found in the background material below. As specialists,
most biologists are perhaps fully aware of the many hurdles
between laboratory research and clinical applications. For people
outside the biology community, this might be a cautionary tale.
In any case, the saga of angiostatin and endostatin is apparently
not yet finished.
-----------
New York Times 11 Feb 99
New York Times 12 Feb 99
SCIENCE-WEEK 1999 19 Feb
-------------------
Related Background:
SCIENCE NEWS, STOCK PRICES, AND BOOK DEALS
     A cogent example of the interaction of science, medicine,
the media, the stock market, and personal riches came into public
view recently. The sequence of events in this episode was
apparently as follows:
     1) On Sunday, May 3, 1998, _The New York Times_ ran a front
page story by Gina Kolata, one of the chief science writers of
_The New York Times_, and a reporter who has been writing about
science for at least 30 years. The story concerned the two
chemicals angiostatin and endostatin that have been known for
some time to block angiogenesis in tumors in mice. The chemicals
have never been tested in humans, they are not the only chemicals
that achieve this effect, and they are not available as "drugs"
that can be administered by a physician. But the thrust of the
story was that this was new information, the headline, "A
Cautious Awe Greets Drugs That Eradicate Tumors in Mice." The
story quoted Nobel Laureate James Watson as telling Kolata that
Judah Folkman, one of the primary researchers in the field of
anti-angiogenesis chemicals, "will cure cancer within 2 years"
and "will be remembered along with scientists like Darwin as
someone who permanently altered civilization." Kolata also
reported that Richard Klausner, director of the US National
Cancer Institute said the two chemicals were "the single most
exciting thing on the horizon" for the treatment of cancer, and
that they were the top priority of the National Cancer Institute.
     2) On the afternoon of the same day the story was published
in _The New York Times_, a New York book agent named John
Brockman telephoned reporter Gina Kolata about the story and
apparently told her he could get her a US$2 million advance for a
book on the subject. Kolata immediately began writing a book
proposal, and sent the proposal via Email to Brockman within
hours.
     3) That evening, all major television networks highlighted
the story that had appeared in _The New York Times_. Brockman
sent the proposal to New York publishers at midnight of that
first day, following the network news reports.
     4) At 9:30 the next morning (Monday), Brockman informed
Kolata that he already had the first offer from a major New York
publishing house.
     5) Also on Monday morning, the stock of EntreMed Inc. (US),
the company that holds the rights to turn the two chemicals
angiostatin and endostatin into drugs, rose immediately from a
previous Friday closing of US$12 a share to a Monday morning
opening at US$83 a share.
     6) Also beginning Monday morning, oncologists and other
physicians around the country found themselves deluged with
inquiries from cancer patients, many of whom were saying they
would be putting off chemotherapy to wait for the new drugs.
     7) By the end of the week, the bubble had completely burst:
Other reporters published stories revealing the chemicals named
in the May 3rd _New York Times_ story were already well-known,
tested only on mice, and not available at all as drugs. Both
Watson and Klausner backed off from their reported comments,
saying they had been misinterpreted. The price of EntreMed shares
fell back to $30. Kolata withdrew her revealed book proposal
after a discussion with her editors, and the agent Brockman
already had a substitute deal in the works for a book on the
subject by a reporter at another newspaper. Finally, around the
country, physicians had the task of explaining to their patients
that no, a miracle cancer cure was not yet available.
     As expected, much is being written about this episode, with
one question in the minds of many people: Why does this happen?
Well, one reason why it happens is that these days news editors
are prone to present features to their readers as "news". This
was a feature article, and it should have appeared as an article
in a magazine, and not on the front news page of _The New York
Times_.
     Secondly, the habit that reporters have of using direct
sound-bite quotes from scientists to bolster the apparent
importance of their stories too often produces misinformation,
inappropriate emphasis, and whatnot, and certainly there is a
tendency to avoid quotes that reduce the significance of the
"news". Science-news reporting propped and hyped to be "exciting"
does a disservice to the public and can be dangerous as well. The
James Watson comment, apparently, actually occurred during a
conversation Kolata had with Watson _two months before_ at a
dinner table.
     In summary, this so-called news story should never have
appeared in the first place as "news", should never have included
quotes from scientists with the quotes deliberately used to hype
the material beyond any significance attributed by specialists,
should never have been used as a prop for a quick lucrative book
deal, should never have been reported the way it was by
television broadcasters. The media, and in particular _The New
York Times_, have been deservedly embarrassed by this episode,
and the credibility of science-reporting by _The New York Times_
has been seriously and unfortunately compromised.
-----------
Science 1998 280:996
ScienceWeek 1998 5 Jun
-----------
Related Background:
CANCER TREATMENT BY TARGETING TUMOR BLOOD VESSELS
     Bacteriophage (phage) is a virus type that infects bacteria,
and it has been useful as a cloning vector in genetic
engineering. The phage injects its own DNA into the bacterium,
effectively assuming enough control of the bacterial genome to
replicate itself, with the ultimate disintegration of the
bacterium and liberation of the phage clones.
     A "phage library" is a collection of genomic DNA fragments,
each contained in a bacteriophage cloning vector and propagated
by infection of a host bacterium (usually E. coli). The essential
idea, in the context of this report (and in many other research
efforts), is to use the genetic machinery of the phage to control
the metabolic machinery of the bacterium to produce (synthesize)
particular complex biomolecules (such as polypeptides) needed for
testing.
     "Nude mice" are a genetic variant of laboratory mice lacking
a thymus gland, which means they are unable to produce the
T-cells (Thymus-cells) necessary for various aspects of the
mammalian immune response.
     The origin and development of tumor blood vessels
(angiogenesis), is an important consideration in the growth of
cancerous tumors, since the tumor provokes directed angiogenesis
into itself with the end result that the tumor is supplied with
oxygen and nutrients. Without angiogenesis, tumors can attain
only a small size before becoming self-inhibiting. A "xenograft"
is a graft of tissue from one species into the body of another
species.
... ... Arap et al (3 authors at Burnham Institute, US) report
the use of in vivo selection of phage libraries to isolate
peptides that home specifically to tumor blood vessels. When
coupled to the anticancer drug doxorubicin, two peptides were
found that enhance the efficacy of the drug against human breast
cancer xenografts in nude mice and also reduced the toxicity of
the drug. The authors suggest their results indicate it may be
possible to develop targeted chemotherapy strategies based on
selective expression of receptors in tumor blood vessels.
-----------
Science 1998 16 Jan
Science-Week 1998 30 Jan
-------------------
Related Background:
CANCER: NO ACQUIRED DRUG RESISTANCE TO ANTI-ANGIOGENIC AGENT
     Angiogenesis is the generation of new blood vessels, a
controlled sequence of cell differentiation and tissue formation
programmed by the genome. It is of obvious importance during
embryological development, since new tissues need a blood supply
in order to continue macroscopic growth, and the angiogenesis
process is also of great importance during tissue trauma repair.
     Like new embryological tissue, a neoplasm (a tumor) also
needs a blood supply, and one of the characteristics of tumor
growth is the provocation of angiogenesis by the cancer cells so
that the mass of such cells becomes supplied with adequate
vascularization. It is known, for example, that tumors will not
grow beyond a few millimeters in diameter in the absence of a
newly forming blood supply.
     Cancer cells apparently provoke angiogenesis by secreting
growth factor substances, and if this is prevented, tumor growth
will be severely limited.
     But attempts to chemically interfere with the secretion of
growth factors by cancer cells usually fail because the high
proliferation rate of cancer cells ultimately results in drug
resistance produced by a mutational selection process.
     However, the normal epithelial tissue involved in
angiogenesis is not rapidly mutating. Recently, a substance named
endostatin, a 20,000 molecular weight fragment of a type of
collagen, has been found to be a specific inhibitor of
endothelial cell proliferation (which means also of new blood
vessel growth), and it was found that endostatin effects only
proliferating endothelial cells, not resting cells, and not
normal, transformed, or neoplastic cells. It has been shown that
systemic administration of endostatin to tumor bearing mice
results in the regression of tumors to a microscopic size, and
one important question has been whether drug resistance to
endostatin would develop.
... ... Now Boehm et al (4 authors at Harvard Univ., US)
report that endostatin causes three tumor types in mice to
regress without the production of drug resistance, and that
repeated cycles of anti-angiogenic therapy are followed by
prolonged tumor dormancy without further therapy. The authors
suggest that angiogenesis inhibitors that do not induce drug
resistance may be valuable for long-term maintenance therapy.
This is important work, and one expects much will be heard about
endostatin in the future.
-----------
Nature 1997 27 Nov
Science-Week 1997 19 Dec
-------------------
Related Background:
MOLECULAR TARGET OF ANTI-ANGIOGENESIS COMPOUNDS DISCOVERED
... Any clinically useful anti-angiogenesis compound is of
great interest to cancer specialists (oncologists). There are 10
or so anti-angiogenesis agents presently undergoing clinical
trials. One of these (TNP-470) is a derivative of the natural
fungal product fumagillin, whose anti-angiogenesis activity was
first discovered in 1985. Now the cellular target of fumagillin
and TNP-470 has been discovered, a specific protein which appears
to play an important role in the proliferation of endothelial
cells, the cells that line blood vessels. The work was reported
by Craig M. Crews et al (Yale University, US), who suggests the
identification of this protein target will open new avenues of
research for the understanding of tumor-induced
neo-vascularization. The results have been independently
confirmed by Jun O. Liu et al (Massachusetts Institute of
Technology, US).
-----------
Proc. Natl. Acad. Sci. 1997 94:6099 1997
Chemistry & Biology 1997 June
Science-Week 1997 26 Jun
-----------
PRAXIS 28 Jan 2002 http://scienceweek.com/praxis

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

17. THIS WEEK IN PRAXIS (28 Jan 02):
-----------------------------------
1. Pathways in Stem Cell Research
2. Problems in DNA Microarray Analysis of Gene Expression
3. On Proteomics
4. Dementia: Evaluation by Positron Emission Tomography
5. On Angiogenesis
6. Health and Human Society
7. Photonic Crystals and Optoelectronics
8. On Spin Devices
9. Scanning Tunneling and Atomic Force Microscopy
10. Field-Effect Modulation of Single-Molecule Conductance
11. On Graft Copolymers
12. On Polymer Nanocomposites


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