ScienceWeek

SCIENCEWEEK

ScienceWeek - July 19, 2002 Vol. 6 Number 29

An Online Research Digest Published Weekly Since 1997

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Experimenters are the shocktroops of science. -- Max Planck
(1858-1947)

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Section 1

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1. Life and the Evolution of Earth's Atmosphere

2. On the Coupled Network of Gene Expression Machines

3. On the Motility of Bacteria on Solid Surfaces

4. History of Chemistry: On Wilhelm Ostwald (1852-1932)

5. Self-Organization and Complex Matter

6. On C-H Bond Activation

7. On Myocardial Gene Therapy

8. The Glycemic Index and Obesity, Diabetes, and Cardiovascular
Disease

9. On the Hormone Ghrelin

10. On Noncovalent Synthesis

11. Microelectronics: On Metal Interconnects for Integrated
Circuits

12. On Corrosion of Stainless Steel

13. In Focus: On Frustration in Condensed Matter Systems

14. ScienceWeek Notices and Subscription Information

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Section 2

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1. LIFE AND THE EVOLUTION OF EARTH'S ATMOSPHERE

J.F. Kasting and J.L. Siefert (Pennsylvania State University,
US) discuss life on Earth, the authors making the following
points:

1) Microorganisms are important for many reasons, not the least
of which is their responsibility, direct or indirect, for the
production of nearly all of the oxygen we breathe. Oxygen is
produced during photosynthesis by a reaction that can be written
as CO(sub2) + H(sub2)O --> CH(sub2)O + O(sub2). Here,
"CH(sub2)O" is a geochemist's shorthand for more complex forms
of organic matter. Most photosynthesis on land is carried out by
higher plants, not microorganisms; but terrestrial
photosynthesis has little effect on atmospheric oxygen because
it is nearly balanced by the reverse processes of respiration
and decay. By contrast, marine photosynthesis is a net source of
oxygen because a small fraction (approximately 0.1%) of the
organic matter synthesized in the oceans is buried in sediments.
This small leak in the marine organic carbon cycle is
responsible for most of our atmospheric oxygen.

2) Although higher plants (e.g., kelp) are found in the oceans,
most marine photosynthesis is performed by single-celled
organisms. The most abundant of these are eukaryotic algae, such
as diatoms and coccolithophorids. Roughly 99% of primary
production can be attributed to such organisms(1). Prokaryotic
bacteria are also important for another reason. Though they make
up only approximately 1% of marine biomass, cyanobacteria (or
blue-green algae) are the main organisms responsible for fixing
nitrogen(1). This capability is quite remarkable because the
enzyme responsible for reducing N(sub2), nitrogenase, is
poisoned by oxygen. Thus, cyanobacteria have had to evolve
complex mechanisms for protecting their nitrogenase. Some, such
as the filamentous Anabaena spp., do so by fixing nitrogen only
in specialized cells called heterocysts. Other cyanobacteria fix
nitrogen at night and photosynthesize by day. Still others, such
as Trichodesmium spp. (very abundant in tropical waters), fix
nitrogen in the morning and photosynthesize in the afternoon
(2). Such specificity shows that these are highly evolved pieces
of biological machinery.

3) In summary: Harvesting light to produce energy and oxygen
(photosynthesis) is the signature of all land plants. This
ability was co-opted from a precocious and ancient form of life
known as cyanobacteria. Today these bacteria, as well as
microscopic algae, supply oxygen to the atmosphere and churn out
fixed nitrogen in Earth's vast oceans. Microorganisms may also
have played a major role in atmosphere evolution before the rise
of oxygen. Under the more dim light of a young sun cooler than
today's, certain groups of anaerobic bacteria may have been
pumping out large amounts of methane, thereby keeping the early
climate warm and inviting. The evolution of Earth's atmosphere
is linked tightly to the evolution of its biota.(3-5)

References (abridged):

1. T. Tyrell, Nature 400, 525 (1999)

2. I. Berman-Frank et al., Science 294, 1534 (2001)

3. H. D. Holland, in Early Life on Earth, S. Bengtson, Ed.
(Columbia Univ. Press, New York, 1994), pp. 237-244

4. J. Farquhar, H. Bao, M. Thiemans, Science 289, 756 (2000)

5. L. Margulis, Symbiosis in Cell Evolution: Microbial
Communities in the Archean and Proterozoic Eons (Freeman, San
Francisco, ed. 2, 1993), chap. 7, pp. 327-343

Science 2002 296:1066

Web Links: evolution of Earth's atmosphere

Related Background:

ON THE FIXATION OF NITROGEN IN THE OCEAN

J.P. Zehr et al (University of California Santa Cruz, US)
discuss nitrogen fixation in the ocean. Fixed nitrogen often
limits the growth of organisms in terrestrial and aquatic
biomes, and nitrogen availability has been important in
controlling the carbon dioxide balance of modern and ancient
oceans. The fixation of atmospheric dinitrogen gas [N(sub2)] to
ammonia is catalyzed by nitrogenase and provides a fixed
nitrogen for nitrogen-limited environments. The filamentous
cyanobacterium Trichodesmium has been assumed to be the
predominant oceanic dinitrogen-fixing microorganism since the
discovery of dinitrogen fixation in this organism in 1961.
Attention has recently focused on oceanic dinitrogen fixation
because nitrogen availability is generally limiting in many
oceans, and attempts to constrain the global atmosphere-ocean
fluxes of carbon dioxide are based on basin- scale nitrogen
balances. Biogeochemical studies and models have suggested that
total dinitrogen-fixation rates may be substantially greater
than previously believed but cannot be reconciled with observed
Trichodesmium abundances. It is curious that there are so few
known dinitrogen-fixing microorganisms in oligotrophic oceans
when it is clearly ecologically advantageous. The authors
demonstrate that there are unicellular cyanobacteria in the open
ocean that are expressing the enzyme nitrogenase, and these
organisms are abundant enough to potentially have a significant
role in nitrogen dynamics. The authors suggest that the
discovery that these microorganisms are present and actively
expressing nitrogenase in the open ocean implies that conceptual
models of the magnitude, timing, and control of dinitrogen
fixation in the ocean need to be re-evaluated.

Nature 2001 412:635

Related Background:

PLANT BIOLOGY/EVOLUTIONARY BIOLOGY: ON THE ORIGIN OF
PHOTOSYNTHETIC MEMBRANE ASSEMBLY

In general, photosynthesis is the utilization of light energy to
power biosynthesis, and chloroplasts are the plant cell
organelles in which photosynthesis occurs, the chloroplasts
containing several photosynthetic pigments (chlorophylls).
Chloroplasts are found in all photosynthetic plant cells, but
not in photosynthetic prokaryotes (i.e., not in cells without
membrane-bound organelles). The typical higher plant chloroplast
is lens-shaped, approximately 5 microns across the larger
dimension, and the number of chloroplasts per cell can vary from
1 to 100 depending on the type of cell. A mature chloroplast is
typically bounded by two membranes, an inner membrane and an
outer membrane, the membranes possessing significantly different
chemical constituents. In addition to a number of enzymes
involved in photosynthesis, chloroplasts also contain in their
interior a circular DNA molecule and protein synthetic machinery
typical of prokaryotes. The current consensus is that
chloroplasts may have originated from *cyanobacteria that became
*endosymbionts, an origin similar to that of *mitochondria,
which are believed to have originated from so-called "*purple
bacteria".

The term "oxygenic photosynthesis" refers to photosynthesis that
produces oxygen. Cyanobacteria exhibit oxygenic photosynthesis,
but a number of photosynthetic bacteria (e.g., sulfur bacteria)
are not oxygenic (nonoxygenic). In addition to the absence of
oxygen production, nonoxygenic photosynthesis differs from
oxygenic photosynthesis in two other ways: a) nonoxygenic
photosynthesis involves absorption of light of longer
wavelengths by pigments called bacteriochlorophylls; b) in
nonoxygenic photosynthesis, reduced compounds other than water
(e.g., hydrogen sulfide or organic molecules) provide the
electrons needed for the reduction of carbon dioxide.

In this context, the term "plastid" refers in general to any of
various types of intracellular organelles found in plant cells.
Chloroplasts are a type of plastid. In general, each plastid is
surrounded by an envelope of two membranes. Plastids arise
either from division of existing plastids or from protoplastids
(proplastids), and plastids are believed to have originated as
endosymbionts in plant cells. Proplastids are double
membrane-bound organelles with little internal structure that
act as precursors for the development of plastids.     The term
"granum" refers to the part of the internal structure of a
chloroplast that consists of 5 to 30 membranaceous disks
(thylakoids) 0.25 to 0.8 microns in diameter, with 40 to 80
grana in a typical chloroplast. In this context, the term
"stroma" refers to the interior matrix of the chloroplast, the
matrix within which the grana are embedded. Cyanobacteria have
no chloroplasts, but they do have thylakoids: it is the
thylakoid system that is the basis for oxygenic photosynthesis.

S. Westphal et al (Christian-Albrecht University Kiel, DE)
present a report on the biogenesis of thylakoid protein, the
authors making the following points:

1) The authors point out that oxygenic photosynthesis is a
feature specific to cyanobacteria and chloroplasts that
apparently developed several billion years ago in an ancestor of
present cyanobacteria. The current consensus view is that an
endosymbiotic event, in which a cyanobacterium was engulfed by
an early *eukaryote and subsequently transformed into a cell
organelle, transferred this capacity to plants. During this
process many of the genes encoded by the cyanobacterial genome
were transferred to the nucleus of the host cell or were lost
completely. Many of the features of the cyanobacterium vanished;
other features (e.g., the photosynthetic machinery) remained,
which explains why homologues to many proteins involved in
chloroplast biogenesis and function are found in cyanobacteria.
The photosynthetic machinery is located in a special internal
membrane system, the thylakoids, and the ability to build up and
alter this membrane system appears to be an important feature of
oxygenic photosynthesis.

2) The authors point out that chloroplasts can develop from
proplastids, and it assumed that the thylakoid membranes that
are formed during the chloroplast maturation process are derived
from the inner envelope of the proplastid and chloroplast. No
anatomical connection between thylakoids and inner membranes can
be found in later states of maturation; thylakoids seem to be
maintained by a flux of chloroplast inner membrane vesicles.
Thylakoids consist of a complicated network of protein
complexes, pigments, and other accessory components built into a
membrane support structure. In mature chloroplasts, thylakoids
are continuously altered for adaptation to different
environmental conditions, e.g., variations in light or
temperature. Thylakoid proteins encoded by the chloroplast
genome are synthesized on chloroplast stromal *ribosomes and are
*co- or post-translationally inserted into the chloroplast
membrane. Despite the importance of the thylakoid membrane
system for oxygenic photosynthesis, many questions concerning
the processes of thylakoid formation and maintenance remain
unanswered. Even less is known about how this membrane system
originated in the first place. The photosynthetic machinery of
purple bacteria that carry out nonoxygenic photosynthesis is
often located in intracytoplasmic membranes, but it remains
unclear whether these are a separate entity similar to
thylakoids or are a continuum of the plasma membrane. The
authors suggest it is therefore tempting to speculate that the
genesis of the thylakoid membrane system is directly connected
to the development of oxygenic photosynthesis.

3) The authors point out that Vipp1, a vesicle-inducing protein
in plastids, in the garden pea (Pisum sativum) and *Arabidopsis
thaliana, is located in both the inner chloroplast envelope and
the chloroplast thylakoids. In Arabidopsis, disruption of the
VIPP1 gene severely affects the ability of the plant to form
properly structured thylakoids, and as a consequence severely
limits the ability to carry out photosynthesis. In contrast, the
protein Vipp1 in the cyanobacterium Synechocystis appears to be
located exclusively in the plasma membrane, but as in higher
plants, disruption of the VIPP1 gene locus leads to the complete
loss of thylakoid formation. So far, VIPP1 genes are found only
in organisms carrying out oxygenic photosynthesis. These genes
share sequence homology with a subunit encoded by the bacterial
gene PspA (*phage shock operon), but they differ from PspA by a
C-terminal extension of approximately 30 amino acids.     4) The
authors report that in two cyanobacteria (Synechocystis and
Anabaena) both a VIPP1 and a PSPA gene are present, and
phylogenetic analysis indicates that VIPP1 originated from a
gene duplication of the latter and thereafter acquired its new
function. It also appears that the C-terminal extension that
distinguishes Vipp1 proteins from Pspa proteins is important for
its function in thylakoid formation.

Proc. Nat. Acad. Sci. 2001 98:4243

Text Notes:

... ... *cyanobacteria: A phylum of bacteria characterized by
blue-green (cyan) photosynthetic pigments, abundant in a variety
of habitats, particularly in fresh water and soil. Cyanobacteria
are responsible for generating a large portion of the free
oxygen in the Earth's atmosphere. They apparently produced
stromatolite limestone deposits, as well as the bulk of modern
petroleum deposits. (Stromatolites are laminated calcareous
microbial fossil deposits formed principally by cyanobacteria
and algae.)

... ... *endosymbionts: Endosymbiosis is an arrangement in which
one organism lives inside another organism, but the term is
usually restricted to arrangements of mutual benefit, thus not
including parasite-host relationships. A number of eukaryotic
cell organelles (including mitochondria) are believed to have
originated from endosymbiotic relationships between eukaryotic
cells and simpler cells.

... ... *mitochondria: Mitochondria are double-membrane enclosed
organelles of cells that are involved with several important
biochemical pathways, including electron transport and oxidative
metabolism. Various types of *eukaryotic cells may contain from
a few to several thousand mitochondria in each cell type. The
mitochondria are relatively large cylindrical structures up to
10 microns long and up to 2 microns in diameter, and most
biologists believe mitochondria are cell organelles that may
have originated as separate organisms that became resident in
eukaryotic cells. Mitochondrial DNA is independent of nuclear
DNA. It consists of a circular molecule, 16,569 base pairs long
in humans, with a known nucleotide sequence.

... ... *purple bacteria: Specifically, any of the various
photosynthetic bacteria that contain bacteriochlorophyll, and
are thus distinguished by purplish or reddish-brown pigments.
But the term "purple bacteria" is sometimes used as a synonym
for the phylum Proteobacteria, a general category comprising a
large number of diverse forms.

... ... *eukaryote: In general, cells (or organisms composed of
such cells) that contain internal membrane-bound organelles.

... ... *ribosomes: A ribosome (not to be confused with
riboZYME) is a small particle, a complex of various ribonucleic
acid component subunits and proteins that functions as the site
of protein synthesis.

... ... *co- or post-translationally: In this context,
translation is protein synthesis, the process during which
polypeptides are synthesized in accordance with RNA code.

... ... *Arabidopsis thaliana: (thale cress) A weed of the
mustard family with a small genome of 120 million base pairs.
Arabidopsis is now an important laboratory species, and it is
presently the model for physiological, biochemical, cell
biological, and developmental studies of over 250,000 plant
species.

... ... *phage shock operon: The term "phage" (bacteriophage)
refers to a type of virus that infects bacteria. In bacteria, an
"operon" is a cluster of functionally interacting genes whose
expression is tightly coordinated. The phage shock operon
protein PspA was originally characterized in the bacterium E.
coli, where it is a peripherally bound inner membrane protein,
its expression strongly induced upon infection of E. coli cells
with a filamentous phage (f1) or upon severe stresses such as
heat, ethanol, or altered osmolarity. Under certain conditions,
this protein also appears to be involved in protein
translocation processes.

ScienceWeek http://www.scienceweek.com

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2. ON THE COUPLED NETWORK OF GENE EXPRESSION MACHINES

T. Maniatis and R. Reed (Harvard University, US) discuss gene
networks, the authors making the following points:

1) Eukaryotic gene expression is a complex stepwise process that
begins with transcription initiation, elongation and
termination. During transcription, the nascent pre-mRNA is
capped at the 5' end, introns are removed by splicing, and the
3' end is cleaved and polyadenylated. The mature mRNA is then
released from the site of transcription and exported to the
cytoplasm for translation. Superimposed on this pathway is an
RNA surveillance system that eliminates aberrantly processed or
mutant pre-mRNAs and mRNAs. Distinct machines carry out each of
the steps in the gene expression pathway. Despite the unique
reactions they catalyse, each machine also interfaces both
physically and functionally with other machines in the pathway
as detailed in several recent reviews(1-5).

2) The authors discuss evidence that coupling is even more
extensive than previously imagined. Indeed coupling occurs not
only between sequential steps in the gene expression pathway but
also between the earliest and latest steps. Coupling may solve
many of the logistical problems inherent in the gene expression
pathway. For example, the production of mature mRNA requires
that the nascent pre-mRNA is sufficiently stable to complete its
synthesis, processing and export. One of the many functions of
the 5' cap is to protect the pre-mRNA from degradation. By tight
coupling between the capping and transcription machineries,
rapid capping of the nascent pre-mRNA is ensured, thereby
protecting it from degradation.

3) Coupling also plays a critical role in gene expression by
tethering machines to each other and to their substrates, a
mechanism that dramatically increases the rate and specificity
of enzymatic reactions. The possible consequences of tethering
are illustrated by metazoan pre-mRNA splicing where small exons
must be recognized in a vast sea of introns. This recognition
problem may be solved at least in part by coupling transcription
to splicing, which results in tethering splicing factors
directly adjacent to the nascent pre-mRNA as it emerges from the
polymerase. Tethering in general is widely used for regulating
the activities within individual cellular machines. As with the
example of splicing above, tethering is also used to coordinate
activities between machines.

4) In summary: Gene expression in eukaryotes requires several
multi-component cellular machines. Each machine carries out a
separate step in the gene expression pathway, which includes
transcription, several pre-messenger RNA processing steps, and
the export of mature mRNA to the cytoplasm. Recent studies lead
to the view that, in contrast to a simple linear assembly line,
a complex and extensively coupled network has evolved to
coordinate the activities of the gene expression machines. The
extensive coupling is consistent with a model in which the
machines are tethered to each other to form "gene expression
factories" that maximize the efficiency and specificity of each
step in gene expression.

References (abridged):

1. Bentley, D. Coupling RNA polymerase II transcription with
pre-mRNA processing. Curr. Opin. Cell Biol. 11, 347-351 (1999)

2. Hirose, Y. & Manley, J. L. RNA polymerase II and the
integration of nuclear events. Genes Dev. 14, 1415-1429 (2000)

3. Proudfoot, N. Connecting transcription to messenger RNA
processing. Trends Biochem. Sci. 25, 290-293 (2000)

4. Shatkin, A. J. & Manley, J. L. The ends of the affair:
capping and polyadenylation. Nature Struct. Biol. 7, 838-842
(2000)

5. Cramer, P. et al. Coordination between transcription and
pre-mRNA processing. FEBS Lett. 498, 179-182 (2001)

Nature 2002 416:499

Web Links: gene expression network

Related Background:

CELL BIOLOGY: FUNCTIONAL MODULES IN BIOLOGICAL ORGANIZATION

The term "phenomenology" has a variety of meanings, but in this
report we are concerned with only one meaning of the term: we
take the term "phenomenology" to refer to a scientific approach
that focuses on explanations based on formal relationships among
observed entities or processes, as opposed to an approach
("reductionist") that focuses on explanations based on analysis
of the fundamental constituents of such entities or processes.
Using the terms in this way, we have the following examples: a)
Thermodynamics is a phenomenological approach to the behavior of
a gas; statistical mechanics is a reductionist approach to the
behavior of a gas. b) Mendelian genetics is a phenomenological
approach to the inheritance of traits; molecular genetics is a
reductionist approach to the inheritance of traits. One can
think of similar dichotomies in almost every field in science.

The term "reductionist" has had an unfortunate history in
biology, where it has been used to characterize the idea that
any biological entity or process can be "explained" in terms of
the laws of physics and chemistry. Certainly, the behavior of
every entity or process in the natural world is ultimately
totally dependent on the laws of physics and chemistry (which
leads to the idea that the behavior can "in principle" be
derived ["explained"] from such laws), but the actual practical
possibility of any explanations of the behavior of observable
entities or processes in terms of the laws of physics and
chemistry depends on the current state of our knowledge
concerning both the observables and the fundamental laws. In the
practice of science, it can be argued that it does not matter
much which approach is used, phenomenological or reductionist,
provided the approach produces results that are useful, or which
help in understanding the behavior of the entity or process, or
which suggest new and intriguing questions. Beyond this, the
discussion properly belongs in the domain of philosophy and not
science.

The above preamble is necessary in the context of the present
report, since the report concerns a recent article in which a
group of authors (2 molecular biologists, a biophysicist, and a
physiologist) call for a more "phenomenological" approach to
cell biology, an interesting idea, since cell biology is not one
of those areas of biology where such appeals are common. During
the last 50 years, in fact, cell biology has experienced a
remarkable flowering based on the application of fundamental
biochemistry, biophysics, and molecular biology to entities and
processes recognizable at the cellular level (i.e., micron-scale
objects).

L.H. Hartwell et al (4 authors at 3 installations, US) present
an essay calling for a transition from molecular to "modular"
cell biology, the authors making the following points:

1) The authors begin their essay with the following statement:
"Although living systems obey the laws of physics and chemistry,
the notion of function or purpose differentiates biology from
other natural sciences. Organisms exist to reproduce, whereas,
outside religious belief, rocks and stars have no purpose.
Selection for function has produced the living cell, with a
unique set of properties that distinguish it from inanimate
systems of interacting molecules." [Editor's note: Contrast with
this the remarks in the relevant background material below.]

2) The authors propose that a major challenge for science in the
21st century is to develop an integrated understanding of how
biological cells and organisms survive and reproduce. The
authors suggest that cell biology is in transition from a
science that was preoccupied with assigning functions to
individual proteins or genes, to a science that is now
attempting to cope with the complex sets of molecules that
interact to form "functional modules".

3) The authors define a "functional module" as a discrete entity
whose function is separable from those of other modules. This
separation depends on chemical isolation, which can originate
from spatial localization or from chemical specificity. For
example, a ribosome, the module that synthesizes proteins,
concentrates the reactions involved in making a polypeptide into
a single particle, thus spatially isolating its function.
Modules can be insulated from or connected to each other. The
authors suggest that in the future, the higher-level properties
of cells, such as their ability to integrate information from
multiple sources, will be described by the pattern of
connections among their functional modules.

4) The authors point out that the number of cellular functional
modules that have been analyzed in detail is very small, and
each of these efforts has required intensive study. The authors
suggest that biologists need to study more functions at the
modular level and develop methods that make it easier to
determine the relationship of inputs to outputs of modules,
their biochemical connectivity, and the states of key
intermediates within them.

5) The authors suggest that the best test of our understanding
of cells will be to make quantitative predictions about their
behavior and test them. This will require detailed simulations
of the biochemical processes occurring within the modules. "But
making predictions is not synonymous with understanding. We need
to develop simplifying, higher-level models and find general
principles that will allow us to grasp and manipulate the
functions of biological modules."

6) The authors summarize their essay: "Cellular functions, such
as signal transmission, are carried out by 'modules' made up of
many species of interacting molecules. Understanding how modules
work has depended on combining phenomenological analysis with
molecular studies. General principles that govern the structure
and behavior of modules may be discovered with help from
synthetic sciences such as engineering and computer science,
from stronger interactions between experiment and theory in cell
biology, and from an appreciation of evolutionary constraints."

Editor's note: The essential idea here can be presented as
follows: Consider a computer, a machine with a "purpose" -- to
compute. A computer operates on its inputs in specific ways to
produce specific outputs. A "flow diagram" of computer dynamics
is a phenomenological description of the behavior of the
machine. A complete "wiring diagram" of electrical entities and
events in the machine is a reductionist description of the
behavior of the machine. (Of course, from the perspective of
quantum mechanics, the wiring diagram is itself
phenomenological.) Suppose we are given a machine and know
nothing about it except that it operates on inputs to produce
outputs. If our problem is to predict the behavior of the
machine in response to particular inputs, there will come a time
when a flow diagram, albeit "phenomenological", will be of
immense value in understanding how the machine works. What the
authors propose is that much of the future of cell biology will
lie in the construction of the equivalent of detailed and
predictive flow diagrams for the internal operations of
biological cells.

Nature 1999 402supp:C47

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3. ON THE MOTILITY OF BACTERIA ON SOLID SURFACES

A.J. Merz and K.T. Forest (Dartmouth Medical School, US) discuss
bacterial motility, the authors making the following points:

1) Considerations of bacterial motility usually refer to cells
swimming and tumbling through fluid media, propelled by rotary
flagella. Over the last thirty years, studies of flagellar
motility have yielded insights into molecular motor function,
signal transduction and type III bacterial protein secretion.
But bacterial life is not limited to the aqueous phase, and
bacterial motility is not limited to swimming: many bacteria
crawl, glide or twitch their way over solid substrates [1–5] .
Bacterial surface locomotion is involved in many aspects of
microbiology including morphogenesis, biofilm formation and
microbe--host interactions. Studies of surface motility engines
can also improve our understanding of protein export and of
proteinaceous channels that conduct macromolecules.

2) We can recognize two modes by which Gram-negative bacteria
move over surfaces. Adventurous gliding results from compressive
forces generated by the hydration, expansion and rearward
extrusion of polyelectrolyte slime. Twitching or "social
gliding" motility is due to tensile forces generated through the
attachment and retraction of type IV pilus fibers. Many
questions remain about the molecular machines that power
twitching and adventurous gliding, but they share at least one
common feature: both rely on the flux of large volumes of
macromolecules through proteinaceous pores in the bacterial
outer membrane.

3) Several mechanisms have been proposed to account for gliding
motility including treadmill-like motors on the cell surface
[1,3,6]  and secretion of surfactants that draw the cell forward
[3,4] . Recent experiments support another idea: that the
gliding of filamentous bacteria -- linked chains of dozens to
hundreds of cells -- is powered by compressive forces arising
from the rearward secretion of slime, a polyelectrolyte gel
composed of complex carbohydrates [3].

4) In summary: It has been known for decades that bacteria
locomote over surfaces, but the mechanisms that power motility
have been unclear. Recent experiments have begun to explain two
modes of surface motility. Twitching or social gliding motility
is powered by the retraction of type IV pili. Adventurous
gliding motility is powered by the rearward secretion of
carbohydrate slime. In both cases, cell movement depends on the
translocation of enormous volumes of macromolecules through
outer membrane pore complexes. The authors describe molecular
models for surface motility and discuss how these models can
inform studies of macromolecule secretion across bacterial
membranes.

References (abridged):

1. Hoiczyk E. (2000) Gliding motility in cyanobacteria:
observations and possible explanations. Arch. Microbiol.,
174:11-17

2. Kaiser D. (2000) Bacterial motility: how do pili pull? Curr.
Biol., 10:R777-780

3. McBride M.J. (2001) Bacterial gliding motility: multiple
mechanisms for cell movement over surfaces. Annu. Rev.
Microbiol., 55:49-75

4. Spormann A.M. (1999) Gliding motility in bacteria: insights
from studies of Myxococcus xanthus Microbiol. Mol. Biol. Rev.,
63:621-641

5. Wall D. and Kaiser D. (1999) Type IV pili and cell motility.
Mol. Microbiol., 32:1-10.

Current Biology 2002 12:R297

Web Links: bacterial motility

Related Background:

ON PATTERN FORMATION IN CELL POPULATIONS

L. Jelsbak and L. Segaard-Andersen (University of Southern
Denmark, DK) discuss cell pattern formation, the authors making
the following points:

1) Formation of spatial patterns of cells from a mass of
initially identical cells is a recurring theme in developmental
biology. The dynamics that direct pattern formation in
biological systems often involve morphogenetic cell movements
(1-3). An example is fruiting body formation in the gliding
bacterium Myxococcus xanthus in which an unstructured population
of identical cells rearranges into an asymmetric, stable pattern
of multicellular fruiting bodies in response to starvation (4).

2) M. xanthus cells are rod shaped and move by gliding, a
process whereby a bacterial cell moves in the direction of its
long axis on a solid surface (5). Fruiting body morphogenesis
absolutely depends on starvation of cells at a high cell density
on a solid surface (4). It represents a true de novo pattern
formation process as it starts from a homogeneous and symmetric
population of starving cells, and occurs without the
contribution of external cues. In the presence of nutrients, M.
xanthus cells form cooperatively spreading swarms. In response
to starvation, swarming behavior is constrained, and, after 6
hours of starvation, small aggregates are evident. Some of these
aggregates enlarge into hemispheres as a consequence of
continued accumulation of cells, and, after 24 hours,
haystack-shaped fruiting bodies have formed, each containing
approximately 100.000 densely packed cells. Within the nascent
fruiting bodies, the motile, rod-shaped cells differentiate into
non-motile spores. Aggregates that do not mature into fruiting
bodies dissipate as their cells migrate to other aggregation
centers. Before the appearance of aggregation centers, cells
become organized in streams, in which the cells are arranged
end-to-end and with their long axes roughly in parallel with
each other, and cells move toward the aggregation centers
organized in these streams.

3) Aggregation is induced by the cell surface-associated
"C-signal", the latest acting of several extracellular signals
required for fruiting body morphogenesis. The C-signal is a cell
surface-associated protein encoded by the csgA gene. Cells that
carry mutations in the csgA gene are conditionally defective in
aggregation and sporulation.

4) The authors propose that C-signal transmission is a local
event involving direct contacts between cells that results in a
global organization of cells, and that the pattern formation
mechanism does not require a diffusible substance or other
actions at a distance. Rather it depends on contact-induced
changes in motility behavior to direct cells appropriately.

References (abridged):

1. Le Douarin, N. M. (1984) Cell 38, 353-360

2. De Felici, M. , Dolci, S. & Pesce, M. (1992) Int. J. Dev.
Biol. 36, 205-213

3. Melchers, F. , Rolink, A. G. & Schaniel, C. (1999) Cell 99,
351-354

4. Dworkin, M. (1996) Microbiol. Rev. 60, 70-102

5. Spormann, A. M. (1999) Microbiol. Mol. Biol. Rev. 63, 621-641

Proc. Nat. Acad. Sci. 2002 99:2032

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4. HISTORY OF CHEMISTRY: ON WILHELM OSTWALD (1852-1932)

J. Van Houten (Saint Michael's College, US) discusses Wilhelm
Ostwald, the author making the following points:

1) It seems fitting that Wilhelm Ostwald should receive the
Nobel Prize in 1909 for his work in chemical dynamics shortly
after the awards to J. van't Hoff (1852-1911) and S. Arrhenius
(1859-1927) because both of them had studied with Ostwald -- as
what we would now call post-doctoral fellows. Another Nobel
Laureate, Walther Nernst (1864-1941), winner of the 1920
chemistry Nobel Prize "for his work in thermochemistry", also
worked with Ostwald in Leipzig. Ostwald and van't Hoff are
regarded together as the founders of the discipline of modern
physical chemistry. Ostwald organized the Department of Physical
Chemistry at Leipzig University; he founded the Deutsche
Elektrochemische Gesellschaft (German Electrochemical Society)
in 1894, which expanded to become the Deutsche
Bunsen-Gesellschaft fuer Angewandte Physikalische Chemie (German
Bunsen-Society for Applied Physical Chemistry) in 1902. Ostwald
and van't Hoff together founded the first journal in physical
chemistry, Zeitschrift fuer Physikalische Chemie in 1887, and
Ostwald himself edited the first 100 volumes, until 1922 (4).

2) Ostwald's work served to validate the catalytic theories of
J. Berzelius (1779-1848) as well as Berzelius's theories of acid
and base dissociation. In particular, Ostwald observed that the
rates of reactions with acids and bases could be related to the
strengths of those acids and bases. Thus Ostwald laid the
groundwork for systematic study of reaction kinetics and of
catalysis. In addition, Ostwald utilized conductivity
measurements to confirm Arrhenius's theories regarding ionic
dissociation of acids and bases. In particular he showed that
weak acids and bases were incompletely ionized in solution --
the concept that we now associate with pK(suba). By correlating
his results from kinetic studies with his conductivity studies,
Ostwald concluded that the effect of acids and bases in
determining reaction rates was directly related to the hydrogen
ion or hydroxide ion concentration, hence the strength, of the
acid or base.

3) As a result of his study of various catalytic processes,
Ostwald developed the principle that a catalyst can modify the
rate of a reaction without any net change in the catalytic
material itself over the full course of the reaction. At the
time Ostwald received the Nobel Prize in 1909, the importance of
catalysts was just becoming widely recognized. Thus his Nobel
presentation includes the statement: "The significance of this
new idea is best revealed by the immensely important role --
first pointed out by Ostwald -- of catalytic processes in all
sectors of chemistry. Catalytic processes are a commonplace
occurrence, especially in organic synthesis. Key sections of
industry ... are based on the action of catalysts. A factor of
perhaps even greater weight, however, is the growing realization
that the enzymes, so-called, which are extremely important for
the chemical processes within living organisms, act as catalysts
and hence the theory of plant and animal metabolism falls
essentially in the field of catalyst chemistry" (4). Ostwald
first proved the catalytic action of enzymes in 1893.

References (abridged):

4. Nobel e-Museum -- Ostwald 1909 (with links to Prize
Presentation and Biography pages),
http://www.nobel.se/chemistry/laureates/1909/index.html
(accessed Nov 2001)

J. Chem Ed. 2002 79:146

Web Links: Wilhelm Ostwald

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5. SELF-ORGANIZATION AND COMPLEX MATTER

Jean-Marie Lehn (Louis Pasteur University, FR) discusses
supramolecular chemistry, the author making the following points:

1) Noncovalent interactions play critical roles in the
biological world. Thus, with just a few building blocks, strands
of nucleic acids allow huge amounts of information to be stored,
retrieved, and processed via weak hydrogen bonds. Similarly, a
large array of signaling molecules within cells recognize subtle
differences in protein surfaces. Supramolecular chemistry has
implemented these principles of molecular information in
chemistry. Through manipulation of intermolecular noncovalent
interactions, it explores the storage of information at the
molecular level and its retrieval, transfer, and processing at
the supramolecular level via interactional algorithms operating
through molecular recognition events based on well-defined
interaction patterns (such as hydrogen bonding arrays, sequences
of donor and acceptor groups, and ion coordination sites). Its
goal is to gain progressive control over the complex spatial
(structural) and temporal (dynamic) features of matter through
self-organization (1-5). This has first involved the design and
investigation of preorganized molecular receptors that are
capable of binding specific substrates with high efficiency and
selectivity.

2) Three main themes outline the development of supramolecular
chemistry. (a) Molecular recognition between artificial
receptors and their substrates relies on design and
preorganization and implements information storage and
processing. (b) The investigation of self-organization relies on
design for inducing the spontaneous but controlled assembly of
sophisticated supramolecular architectures. It implements
programming and programmed systems. (c) The third, emerging,
phase introduces adaptation and evolution. It relies on
self-organization through selection in addition to design, and
implements chemical diversity and "informed" dynamics.

3) Supramolecular chemistry first harnessed preorganization for
the design of tailor-made molecular receptors effecting
molecular recognition, catalysis, and transport on a variety of
substrates, from metal ions to anions and chiral molecular
substrates (1, 2). It also opened new vistas to chemical
synthesis, establishing procedures for the construction of
supramolecular entities and providing supramolecular assistance
to synthesis in which noncovalent positioning of the components
is followed by covalent bond formation (1). Both areas will
continue to provide access to highly sophisticated noncovalent
and covalent entities.

4) In summary: Beyond molecular chemistry based on the covalent
bond, supramolecular chemistry aims at developing highly complex
chemical systems from components interacting through noncovalent
intermolecular forces. Over the past quarter century,
supramolecular chemistry has grown into a major field and has
fueled numerous developments at the interfaces with biology and
physics.

References (abridged):

1. J.-M. Lehn, Supramolecular Chemistry: Concepts and
Perspectives (VCH, Weinheim, Germany, 1995).

2. J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle,
J.-M. Lehn, Eds., Comprehensive Supramolecular Chemistry
(Pergamon, Oxford, 1996).

3. J.-M. Lehn, in Supramolecular Science: Where It Is and Where
It Is Going, R. Ungaro, E. Dalcanale, Eds. (Kluwer, Dordrecht,
Netherlands, 1999), pp. 287-304.

4. M. Eigen, Naturwissenschaften 58, 465, 1971.

5. F. E. Yates, Ed., Self-Organizing Systems (Plenum, New York,
1987).

Science 2002 295:2400

Web Links: supramolecular self-organization

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6. ON C-H BOND ACTIVATION

J.A. Labinger and J.E. Bercaw (California Institute of
Technology, US) discuss C-H bond activation, the authors making
the following points:

1) Alkanes, or saturated hydrocarbons, are major constituents of
natural gas and petroleum, but there are very few practical
processes for converting them directly to more valuable
products. The reason for this difficulty is alluded to by their
other name, "paraffin" (meaning "not enough affinity"): alkanes
are relatively inert. This chemical inertness arises from the
constituent atoms of alkanes all being held together by strong
and localized C–C and C–H bonds, so that the molecules have no
empty orbitals of low energy or filled orbitals of high energy
that could readily participate in a chemical reaction, as is the
case with unsaturated hydrocarbons such as olefins and alkynes.

2) Alkanes do react at high temperatures, as encountered in
combustion, but such reactions are not readily controllable and
usually proceed to the thermodynamically stable and economically
unattractive products, carbon dioxide and water. The currently
prevalent use of alkanes in combustion applications exploits
their energy content, but not their considerable potential as
valuable precursors for more important and expensive chemicals.
Although cracking and thermal dehydrogenation convert alkanes to
valuable olefins, these processes require high temperatures and
are energy intensive. Similarly, although alkanes can be induced
to react by exposure to highly reactive species such as
superacids or free radicals, these reactive species are usually
demanding and expensive to make, and offer little control over
product selectivity.

3) A variety of enzymes efficiently and selectively catalyze
alkane oxidation at physiological temperatures and pressures,
and the direct use of biological organisms for industrial alkane
conversion under such benign conditions is possible in
principle. But in practice, these approaches may be primarily
applicable to the small-scale production of specialized
chemicals, given that large-scale bioprocesses for converting
alkane resources seem to be problematic(1). However, despite
their practical limitations, enzymatic alkane transformations
are much studied in order to understand the underlying reaction
mechanisms and guide the design of synthetic catalysts mimicking
the function, efficiency and selectivity of their biological
counterparts.

4) In summary: The selective transformation of ubiquitous but
inert C–H bonds to other functional groups has far-reaching
practical implications, ranging from more efficient strategies
for fine chemical synthesis to the replacement of current
petrochemical feedstocks by less expensive and more readily
available alkanes. The past twenty years have seen many examples
of C–H bond activation at transition-metal centres, often under
remarkably mild conditions and with high selectivity. Although
profitable practical applications have not yet been developed,
our understanding of how these organometallic reactions occur,
and what their inherent advantages and limitations for practical
alkane conversion are, has progressed considerably. In fact, the
recent development of promising catalytic systems highlights the
potential of organometallic chemistry for useful C–H bond
activation strategies that will ultimately allow us to exploit
Earth's alkane resources more efficiently and cleanly.(2-5)

References (abridged):

1. Duetz, W. A., van Beilen, J. B. & Witholt, B. Using proteins
in their natural environment: potential and limitations of
microbial whole-cell hydroxylations in applied biocatalysis.
Curr. Opin. Biotech. 12, 419-425 (2001)

2. Ortiz de Montellano, P. R. (ed.) Cytochrome P450: Structure,
Mechanism and Biochemistry 2nd edn (Plenum, New York, 1995)

3. Brazeau, B. J. & Lipscomb, J. D. in Enzyme-Catalyzed Electron
and Radical Transfer (ed. Holzenburg, A.Scrutton, N. S.) 233-277
(Kluwer, New York, 2000)

4. Gradassi, M. J. & Green, N. W. Economics of natural gas
conversion processes. Fuel Proc. Technol. 42, 65-83 (1995)

5. Collman, J. P., Hegedus, L. S., Norton, J. R. & Finke, R. G.
Principles and Applications of Organotransition Metal Chemistry
Ch. 7, 2nd edn (Univ. Science, Mill Valley, 1987)

Nature 2002 417:507

Web Links: carbon-hydrogen bond activation

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7. ON MYOCARDIAL GENE THERAPY

Jeffrey M. Isner (Tufts University, US) discusses myocardial
gene therapy, the author making the following points:

1) After a decade of pre-clinical and early phase 1 clinical
investigations, gene therapy has emerged as a genuine
therapeutic option with the potential to alter the manner in
which cardiologists manage the two most common cardiac disorders
afflicting adults -- coronary artery disease and congestive
heart failure. The idea that angiogenic growth factors might
promote revascularization of ischemic tissues -- a strategy
termed "therapeutic angiogenesis"(1) -- was first investigated
in individuals with peripheral artery disease, specifically
critical limb ischaemia(2). Gene transfer of plasmid DNA
encoding vascular endothelial growth factor (VEGF) brought about
clinical benefits, such as the abolition of rest pain, limb
salvage and the healing of ischaemic ulcers. These benefits were
associated with angiographic evidence of new collateral vessels
and also improved leg blood flow as monitored by magnetic
resonance angiography(3,4). The concept of therapeutic
angiogenesis in human subjects thus proved, phase 1 clinical
trials involving different gene transfer strategies were
undertaken to test this scheme in people affected with
myocardial ischemia(5).

2) In contrast to non-cardiovascular applications of gene
therapy, most of which use viral vectors including adenovirus,
adeno-associated virus, retrovirus and lentivirus,
cardiovascular trials are remarkable for their use of non-viral
vectors. Forty-seven per cent of these trials used either naked
plasmid DNA (39%) or liposome carriers (8%).The disproportionate
use of non-viral vectors runs counter to the notion that the use
of naked DNA is too inefficient to be an effective strategy for
gene transfer. This notion prevailed for most of the first
decade of gene therapy, and attention was instead focused on the
use of viral vectors, which were intended to increase the
magnitude and/or duration of gene expression.

3) Genes encoding proteins that must remain intracellular to
achieve a biological effect have to be delivered to a relatively
large target population of cells to correct the underlying
pathogenetic defect. In contrast, genes encoding proteins that
are naturally secreted can achieve favorable effects when
limited numbers of cells are transfected, provided that the
transfected cells secrete substantial amounts of the gene
product. The paracrine effect of the secreted gene product can
then modulate the bioactivity of several target cells.

References (abridged):

1. Takeshita, S. et at. Therapeutic angiogenesis: a single
intra-arterial bolus of vascular endothelial growth factor
augments revascularization in a rabbit ischemic hindlimb model.
/. Clin. Invest. 93, 662-670(1994).

2. Isner, J. M. et al. Arterial gene therapy for therapeutic
angiogenesis in patients with peripheral artery disease.
Circulation 91,2687-2692 (1995).

3. Isner, J. M. etal. Clinical evidence of angiogenesis
following arterial gene transfer of phVEGF(sub165), Lancet 348,
370-374 (1996).

4. Baumgartner, I. etal. Constitutive expression of
phVEGF(sub165) following intramuscular gene transfer promotes
collateral vessel development in patients with critical limb
ischaemia. Circulation 97,    1114-1123(1998).

5. Losordo, D. W. et al. Gene therapy for myocardial
angiogenesis: initial clinical results with direct myocardial
injection ofphVEGFiy as sole therapy for myocardial ischaemia.
Circulation 98, 2800-2804(1998).

Nature 2002 415:234

Web Links: myocardial gene therapy

Related Background:

GENE THERAPY FOR AGING-RELATED LOSS OF MUSCLE FUNCTION

One of the primary consequences of aging, a consequence which
leads to significantly impaired function in the elderly
population, is the loss of *skeletal muscle strength and mass.
Both of these decrease up to one-third in humans between the
ages of 30 and 80 years. In addition, loss of the fastest and
most powerful muscle fiber types has been documented. Similar
aging-related muscle alterations have been observed in rats and
mice, indicating that the trend is maintained in other mammalian
species. The mechanisms underlying this aging-related muscle
loss have remained unclear, but there is some evidence that
so-called "insulin-like growth factor-I" may be involved. The
term "insulin-like growth factor" refers to a group of
polypeptides structurally homologous to *insulin, and which
share many of the biological activities of insulin, but which
are apparently biochemically distinct from it. These substances
are "mitogens", i.e., they enhance or induce cell division
(mitosis). Insulin-like growth factor-I (insulin-like growth
factor type I) is a monomer of 70 amino acids.

E.R. Barton-Davis et al (5 authors at 2 installations, US) now
report an attempt to moderate the aging-related loss of muscle
in mice by increasing the regenerative capacity of muscle. The
study involved the injection of a genetically engineered virus
to direct overexpression (i.e., genome-based protein
overproduction) of insulin-like growth factor-I in adult muscle.
The authors report that insulin-like growth factor-I expression
promotes an average increase of 15 percent in muscle mass and a
14 percent increase in strength in young adult mice, and
prevents aging-related muscle changes in old adult mice. In old
adult mice, muscle mass and fiber type distributions were
maintained at levels similar to those in young adults. The
authors propose that these effects are primarily due to
stimulation of muscle regeneration via the activation of
*satellite cells by insulin-like growth factor-I. The authors
suggest this supports the hypothesis that the primary cause of
aging-related impairment of muscle function is a cumulative
failure to repair damage sustained during muscle utilization.
The authors further suggest that gene transfer of insulin-like
growth factor-I into muscle could form the basis of a human gene
therapy for preventing the loss of muscle function associated
with aging, and may be of benefit in diseases where the rate of
damage to skeletal muscle is pathologically accelerated.

Proc. Nat. Acad. Sci. 1998 95:15603

Text Notes:

... ...*skeletal muscle: (striated muscle, voluntary muscle)
Muscle in which cross striations occur in the fibers as a result
of regular overlapping of thick and thin filament structures.
Although cardiac muscle is not "voluntary" muscle, it is also
striated in appearance.

... ... *insulin: A protein hormone that promotes uptake by body
cells of free glucose and/or amino acids, depending on target
cell type.

... ... *satellite cells: The satellite cells of skeletal muscle
are cells associated with muscle fibers that are believed to
play a role in muscle repair and regeneration.

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8. THE GLYCEMIC INDEX AND OBESITY, DIABETES, AND CARDIOVASCULAR
DISEASE

David S. Ludwig (Children's Hospital Boston, US) discusses the
glycemic index, the author making the following points:

1) All dietary carbohydrates, from starch to table sugar, share
a basic biological property: they can be digested or converted
into glucose. Digestion rate, and therefore blood glucose
response, is commonly thought to be determined by saccharide
chain length, giving rise to the terms complex carbohydrate and
simple sugar. This view, which has its origins in the beginning
of the century,(1) receives at least tacit support from
nutritional recommendations that advocate increased consumption
of starchy foods and decreased consumption of sugar.(2)

2) Throughout the past 25 years, however, the relevance of chain
length in carbohydrate digestion rate has been questioned.
Wahlqvist et al(3) demonstrated similar changes in blood
glucose, insulin, and fatty acid concentrations after glucose as
a monosaccharide, disaccharide, oligosaccharide, or
polysaccharide (starch) had been consumed. Bantle et al(4) found
no differences in blood glucose responses to meals with 25%
sucrose compared with meals containing a similar amount of
energy from either potato or wheat starch. Nevertheless, the
physiological effects of carbohydrates may vary substantially,
as demonstrated by marked differences in glycemic and
insulinemic responses to ingestion of isoenergetic amounts of
white bread vs pasta.(5) For this reason, Jenkins et al (1981)
proposed the "glycemic index" as a system for classifying
carbohydrate-containing foods according to glycemic response.

3) "Glycemic index" is defined as the incremental area under the
glucose response curve after a standard amount of carbohydrate
from a test food relative to that of a control food (either
white bread or glucose) is consumed. The glycemic index of a
specific food or meal is determined primarily by the nature of
the carbohydrate consumed and by other dietary factors that
affect nutrient digestibility or insulin secretion.

4) Glycemic index of representative foods as a percentage of the
value for glucose: Instant rice: 91; Baked potato: 85; Corn
flakes: 84; Carrot: 71; White bread: 70; Rye bread: 65; Muesli:
56; Banana: 53; Spaghetti: 41; Apple: 36; Lentil beans: 29;
Milk: 27; Peanuts: 14; (The values for most non-starchy
vegetables are too low to measure.)

5) The rate of carbohydrate absorption after a meal, as
quantified by glycemic index, has significant effects on
postprandial hormonal and metabolic responses. High–glycemic
index meals produce an initial period of high blood glucose and
insulin levels, followed in many individuals by reactive
hypoglycemia, counterregulatory hormone secretion, and elevated
serum free fatty acid concentrations. These events may promote
excessive food intake, beta cell dysfunction, dyslipidemia, and
endothelial dysfunction. Thus, the habitual consumption of
high–glycemic index foods may increase risk for obesity, type 2
diabetes, and heart disease, a hypothesis that derives
considerable support from laboratory studies, clinical trials,
and epidemiological analyses. Despite areas of continuing
controversy, clinical use of glycemic index as a qualitative
guide to food selection would seem to be prudent in view of the
preponderance of evidence suggesting benefit and absence of
adverse effects.

References (abridged):

1. Allen FM.Experimental studies on diabetes: production and
control of diabetes in the dog: effects of carbohydrate diets. J
Exp Med.1920;31:381-402.

2. Public Health Service.The Surgeon General's Report on
Nutrition and Health.Washington, DC: Dept of Health and Human
Services; 1988.

3. Wahlqvist ML, Wilmshurst EG, Richardson EN. The effect of
chain length on glucose absorption and the related metabolic
response. Am J Clin Nutr. 1978;31:1998-2001.

4. Bantle JP, Laine DC, Castle GW, Thomas JW, Hoogwerf BJ, Goetz
FC. Postprandial glucose and insulin responses to meals
containing different carbohydrates in normal and diabetic
subjects. N Engl J Med. 1983;309:7-12.

5. Granfeldt Y, Bjorck I, Hagander B. On the importance of
processing conditions, product thickness and egg addition for
the glycaemic and hormonal responses to pasta: a comparison with
bread made from "pasta ingredients." Eur J Clin Nutr.
1991;45:489-499.

J. Am. Med. Assoc. 2002 287:2414

Web Links: glycemic index

Related Background:

OBESITY AND MORTALITY: SPINNING SCIENCE NEWS

Stevens et al (6 authors at 4 installations, US), in a study of
the mortality of 62,116 men and 262,019 women during a 12 year
period (1960-1972), report that excess body weight increases the
risk of death from any cause and from cardiovascular disease in
adults between 30 and 74 years of age, and that the relative
risk associated with greater body weight is higher among younger
subjects. The above words are essentially the exact conclusions
chosen to be published by the authors. Nevertheless, two
variants of contrary journalistic "spin" have appeared, an
interesting illustration of how public health news is
formulated. In the first variant, in an editorial in the same
journal in which the Stevens et al report appeared, two journal
editors emphasize that the mortality increase with body-mass is
modest and age-dependent, and they urge an end to people
"suffering immeasurable torment in fruitless weight-loss schemes
and scams." In the second variant, published by the New York
Times and echoed by many newspapers across the US, news items
took note of the journal editorial and went a step further in
headlines suggesting excess weight has now been shown to be
harmless. The spin-logic in the case of both the journal editors
and the news media is apparently that since the effect is small,
the public can well disregard it. The researchers and authors of
the article, however, apparently believe otherwise, and the last
sentence of their article is unequivocal: "In healthy white
adults below the age of 75 who have never smoked cigarettes, our
results are consistent with the healthy weight ranges proposed
in the 1995 Dietary Guidelines for Americans."

New Engl. J. Med. 1998 1 Jan 98

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9. ON THE HORMONE GHRELIN

D.E. Cummings et al (University of Washington, US) discuss the
hormone ghrelin, the authors making the following points:

1) Obesity represents a global epidemic(1) and is a leading
cause of illness and death worldwide.(2,3) Weight reduction
achieved by dieting, exercise, or medical therapy often elicits
compensatory changes in appetite and energy expenditure(4,5)
that make weight loss of more than 5 to 10 percent unlikely to
be sustained. In contrast, gastric bypass surgery, in which most
of the stomach and duodenum are bypassed with the use of a
gastrojejunal anastomosis, typically causes substantial,
long-term weight loss. The operation appears to undermine the
normal compensatory physiologic responses to energy deficit.
This effect is unlikely to result from gastric restriction
alone, and it has been proposed that a disruption of gut-derived
factors that regulate eating behavior is involved, although no
such factors have been identified.

2) Ghrelin is a recently discovered orexigenic hormone that is
secreted primarily by the stomach and duodenum and has been
implicated in both meal-time hunger and the long-term regulation
of body weight. In humans, plasma ghrelin levels rise shortly
before and fall shortly after every meal, a pattern that is
consistent with a role in the urge to begin eating. If
circulating ghrelin participates in long-term regulation of body
weight, its level should increase with weight loss as part of
the compensatory response to an energy deficit. In contrast,
gastric bypass may disrupt ghrelin secretion by isolating
ghrelin-producing cells from direct contact with ingested
nutrients, which normally regulate ghrelin levels, and this
effect may contribute to the efficacy of the procedure in
reducing weight.

3) To test these hypotheses, the authors determined the 24-hour
plasma ghrelin profiles in subjects before and after
diet-induced weight loss, and compared these values with those
in subjects who had lost weight after proximal gastric bypass
surgery. The authors report that the increase in  plasma ghrelin
level with diet-induced weight loss is consistent with the
hypothesis that ghrelin has a role in the long-term regulation
of body weight. Gastric bypass is associated with markedly
suppressed ghrelin levels, possibly contributing to the
weight-reducing effect of the procedure.

4) In summary: 24-hour plasma ghrelin levels increase in
response to diet-induced weight loss, suggesting that ghrelin
may play a part in the adaptive response that limits the amount
of weight that may be lost by dieting. We also found that
ghrelin levels are abnormally low after gastric bypass, raising
the possibility that this operation reduces weight in part by
suppressing ghrelin production. These data suggest that ghrelin
antagonists may someday be considered in the treatment of
obesity.

References (abridged):

1. Taubes G. As obesity rates rise, experts struggle to explain
why. Science 1998;280:1367-1368

2. Kopelman PG. Obesity as a medical problem. Nature
2000;404:635-643

3. Lew EA. Mortality and weight: insured lives and the American
Cancer Society Studies. Ann Intern Med 1985;103:1024-1029

4. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy
expenditure resulting from altered body weight. N Engl J Med
1995;332:621-628. [Erratum, N Engl J Med 1995;333:399.]

5. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG.
Central nervous system control of food intake. Nature
2000;404:661-671

New Engl. J. Med. 2002 346:1623

Web Links: ghrelin hormone

Related Background:

ON CHILDHOOD OBESITY

Albert P. Rocchini (University of Michigan, US) discusses
childhood obesity, the author making the following points:    
1) Childhood obesity has reached epidemic proportions.
Worldwide, approximately 22 million children under 5 years of
age are overweight, and during the past 3 decades, the number of
overweight children in the US has more than doubled. In 1983,
18.6 percent of preschool children in the US were defined as
overweight, and 8.5 percent were defined as obese. By the year
2000, 22 percent of preschool children were overweight and 10
percent were obese. Data indicate that the prevalence of
overweight has increased by 21.5 among non-Hispanic black
children, 21.8 percent among Hispanic children, and 12.3 percent
among non-Hispanic white children. Similar increases in the
prevalence of obesity have been observed worldwide, and
childhood obesity is the most serious and prevalent nutritional
disorder in the US.     2) Obesity has a substantial effect on
cardiovascular risk. Childhood obesity is directly linked to
abnormalities in blood pressure, lipid, lipoprotein, and insulin
levels in adults, as well as to the risk of both coronary artery
disease and diabetes. It has been documented that 80 percent of
obese adolescents have elevated systolic blood pressure,
diastolic blood pressure, or both. Furthermore, 97 percent of
such adolescents have 4 or more of the following cardiovascular
risk factors: elevated serum triglyceride levels (more than 100
milligrams per deciliter), low levels of high-density
lipoprotein cholesterol, increased total cholesterol levels
(more than 200 milligrams per deciliter), elevated systolic
blood pressure, diastolic blood pressure, or both, diminished
maximal oxygen consumption, and a strong history in the
immediate family of coronary heart disease, myocardial
infarction, angina pectoris, or high blood pressure.

New Engl. J. Med. 2002 346:854

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10. ON NONCOVALENT SYNTHESIS

D.N. Reinhoudt and M. Crego-Calama (University of Twente, NL)
discuss noncovalent synthesis, the authors making the following
points:

1) With increasing understanding of the individual interactions
that govern the molecular recognition process, the focus is now
shifting to supramolecular chemistry as a tool for noncovalent
synthesis. Cooperative, weak interactions are used for the
spontaneous formation of large aggregates that have well-defined
structures (helicates, grids, molecular containers, capsules,
cyclic arrays, and the like), in which the individual components
are not connected through covalent but through noncovalent bonds.

2) In this emerging field of noncovalent synthesis, one might
expand the definition of a molecule to "a collection of atoms
held together by covalent and noncovalent bonds." Contrary to
the classical definition of a molecule, these supramolecules may
be highly dynamic on the human time scale. On the other hand,
noncovalent and covalent synthesis are not fundamentally
different; both have as the objective to introduce specific
connectivities between atoms. The advantage of noncovalent
synthesis is that noncovalent bonds are formed spontaneously and
reversibly under conditions of thermodynamic equilibrium, with
the possibility of error correction and without undesired side
products. Furthermore, it does not require chemical reagents or
harsh conditions.

3) In biosynthesis, chemical transformations are highly
stereoselective with only one of the many possible stereoisomers
(compounds with the same molecular formula that differ in the
way their atoms are arranged in space) being formed. With the
current state of chemical synthesis, a comparable stereocontrol
over covalent bond formation is possible for many types of
reactions as well. In the synthesis of noncovalent systems, this
control over stereochemistry is much more difficult, because
bonds between individual components are kinetically labile and
are continuously broken and formed. However, in noncovalent
synthesis, the stereochemistry of reaction products
(regioselectivity, diastereoselectivity, and enantioselectivity)
must also be controlled.

4) One of the areas where noncovalent synthesis has a great
advantage over covalent synthesis is the bottom-up (chemical)
assembly of nanostructures. Large-scale nanometer fabrication
will be a requirement for future molecular electronic devices,
high-density data storage, or drug delivery. Covalent synthesis
has been proven to be extremely fruitful for the synthesis of
compounds with molecular weights in the range of 100 to 3000
daltons such as palytoxin, norbrevetoxin, and taxol.
Nevertheless, with the exception of the sequential methodologies
for the synthesis of biopolymers (or oligomers), there are no
simple covalent strategies for the synthesis of pure molecules
that have molecular weights between 10^(4) and 10^(6)
kilodaltons. Such molecules have dimensions between 3 and 20
nanometers and fill the gap between small molecules and larger
nano-objects that are now accessible by top-down (physical)
fabrication methods, mainly based on lithography. This is also
the size range where quantum confinement influences the
electronic and optical properties of matter.

5) In summary: In chemistry, noncovalent interactions are now
exploited for the synthesis in solution of large supramolecular
aggregates. The aim of these syntheses is not only the creation
of a particular structure, but also the introduction of specific
chemical functions in these supramolecules.

References (abridged):

1. C. J. Pedersen, Angew. Chem. Int. Ed. 27, 1021 (1988)

2. J.-M. Lehn, Angew. Chem. Int. Ed. 27, 89 (1988)

3. D. J. Cram, Angew. Chem. Int. Ed. 27, 1009 (1988)

4. R. Ungaro, A. Arduini, A. Casnati, A. Pochini, F. Ugozzoli,
Pure Appl. Chem. 68, 1213 (1996)

5. P. Wallimann, T. Marti, A. Fürer, F. Diederich, Chem. Rev.
97, 1567 (1997)

Science 2002 295:2403

Web Links: noncovalent synthesis

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11. MICROELECTRONICS: ON METAL INTERCONNECTS FOR INTEGRATED
CIRCUITS

J. Rickerby and J.H.G. Steinke (Imperial College of Science,
Technology, and Medicine, UK) discuss integrated circuits, the
authors making the following points:

1) The microelectronics industry is undergoing rapid expansion
and miniaturization, producing semiconductor devices which are
increasingly smaller, faster and of higher density.(1)
Increasing the degree of integration on semiconductor devices is
governed by the material and practical limits of the device
features. These limits include properties of the semiconducting
and insulating materials, the layout of the device, and the
circuit configuration.(2) In real manufacturing terms, the most
severe limitation for chip fabrication is not the transistor or
other complex features, but the metal interconnects performing
signal communication and power distribution.(1) These conducting
networks are currently impeding the development of chips with
shorter response delays. This issue is presently circumnavigated
by keeping the interconnects short.(2) To roll back the
frontiers of interconnect technology, considerable efforts are
directed toward more conductive interconnects which are easier
to manufacture.

2) Ultra large-scale integration has led to metal interconnects
on these devices being processed well below 0.25 cubic microns.
On, for example, a 1 Gb dynamic random access memory (DRAM)
wafer, the via holes (vertical interconnects) measure only 0.2
microns across.(4) The logic speed of a device is determined by
its RC time constant (a = rL^(2), where (a) is the time
constant, (r) is the resistivity, and (L) is the total length of
the interconnects). To produce faster and smaller devices it has
become necessary to use a metal with lower resistivity.(4-5)

3) Traditionally, aluminum has been widely used in the
fabrication of metal interconnects.(4) Metallization with
aluminum can be carried out by physical vapor deposition
techniques such as high-temperature sputtering for reflow,
sputtering with a collimator, long distance sputtering, and
chemical vapor deposition.(4) With all these techniques aluminum
films can be produced with excellent conformity, though only a
limited number of chemical vapor deposition precursors are
available. Metallization with aluminum becomes unreliable below
0.5 microns due to its high tendency for electromigration and
stress-induced migration, which can lead to voiding.(2)

4) The next generation of faster integrated circuits will have
higher device densities, faster operating frequencies, and
larger die sizes, but it may be limited by metal interconnects.
There is an obvious need for new interconnect materials with
lower resistivities, and that is true especially for longer
global interconnects that run from one end of a chip to the
other.(2) In recent years Cu has attracted increasing attention
as a candidate to replace aluminum due to its low bulk
resistivity.

References (abridged):

1. Andricacos, P. C. Interface 1999, 32

2. Kodas, T. T.; Hampden-Smith, M. J. The Chemistry of Metal
CVD; VCH: Weinheim, 1994.

3. Doppelt, P.; Combellas, C.; Kanoufi, F.; Chen, T. Y.;
Richardson, S.; Thiebault, A. Microelectron. Eng. 2000, 50, 383

4. Hwang, S. T.; Shim, I.; Lee, K. O.; Kim, K. S.; Kim, J. H.;
Choi, G. J.; Cho, Y. S.; Choi, H. J. Mater. Res. 1996, 11, 1051

5. Chichibu, S.; Yoshida, N.; Higuchi, H.; Matsumoto, S. Jpn. J.
Appl. Phys., Part 2 1992, 31, L1778

Chem. Rev. 2002 102:1525

Web Links: microelectronics in integrated circuits

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12. ON CORROSION OF STAINLESS STEEL

Roger C. Newman (University of Manchester, UK) discusses
stainless steel, the author making the following points:

1) Stainless steel is "stainless" because it is more resistant
to rusting than ordinary steel. Most modern stainless steel is a
ductile alloy containing iron, chromium and nickel, a technology
pioneered early in the twentieth century by the German company
Krupp. At the same time. Harry Brearley in Sheffield (UK)
introduced hard iron-chromium-carbon grades for cutlery. All
these materials have very good corrosion resistance. But, on
close inspection, stainless steel does suffer corrosion, and it
usually begins at sites in the metal where there are sulfide
impurities. Ryan et al (Nature 2002 415:770-774) have recently
reported a new explanation for how the presence of sulfides can
lead to corrosion.

2) Stainless steel resists corrosion because its chromium
content (typically 13-25%) is enough to transform the surface
oxidation process in wet environments. If we abrade a piece of
stainless steel and dip it into water, a protective,
chromium-rich oxide film forms over its surface within a
fraction of a second. Electrochemical experiments show that
after a few weeks the corrosion rate of the stainless steel is
about 10 nanometres per year -- 10,000 times slower than that of
ordinary carbon steel. At this rate, a plate of stainless steel
1 cm thick should last a million years (it would actually last
much longer than that -- research related to nuclear waste
containment has indicated that the corrosion rate falls off
indefinitely over time, following a 1/t law).

3) There was no stainless steel a million years ago, but the
material has been used in wet environments for more than 80
years -- and not just for cutlery and kitchen sinks. In 1929,
the seven-story pinnacle of the Chrysler Building in New York
was faced with stainless steel. The steel has been cleaned only
two or three times since, and shows few signs of corrosion,
despite the urban environment. But if we were to examine the
metal surface with a microscope, we would find small pits caused
by intense local corrosion. Closer study would reveal residues
of sulfur in many of these cavities. The pitting is the result
of the combined action of aqueous chloride ions from the
environment, and manganese sulfide particles -- known as
inclusions -- in the steel. Sulfides are an unavoidable
contaminant in the steel-making process.

Nature 2002 415:743

Web Links: stainless steel corrosion chemistry

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13. ON FRUSTRATION IN CONDENSED MATTER SYSTEMS

S.T. Bramwell and M.J. Gingras (University College London, UK)
discuss condensed matter systems, the authors making the
following points:

1) Competing or "frustrated" interactions are a common feature
of condensed matter systems. Broadly speaking, frustration
arises when a system cannot, because of local geometric
constraints, minimize all the pair-wise interactions
simultaneously (1). In some cases, the frustration can be so
intense that it induces novel and complex phenomena. Frustration
is at the origin of the intricate structure of molecular
crystals, various phase transitions in liquid crystals, and the
magnetic domain structures in ferromagnetic films. It has also
been argued to be involved in the formation of the stripe-like
structures observed in cuprate high-temperature superconductors.
The concept of frustration is a broad one that extends beyond
the field of condensed matter physics. For example, the ability
of naturally occurring systems to "resolve" frustrated
interactions has been argued to have bearings on life itself,
exemplified by the folding of a protein to form a single and
well-prescribed structure with biological functionality.

2) Historically, the first frustrated system identified was
crystalline ice, which has frozen-in disorder remaining down to
extremely low temperature, a property known as residual, or
zero-point entropy. In 1933, Giauque and co-workers accurately
measured this entropy (2, 3), enabling L. Pauling to offer his
now famous explanation in terms of the mismatch between the
crystal symmetry and the local bonding requirements of the water
molecule (4). He predicted a special type of proton disorder
that obeys the so-called "ice rules." These rules, previously
proposed by J.D. Bernal and R.H. Fowler (5), require that two
protons are near to and two are further away from each oxide
ion, such that the crystal structure consists of hydrogen-bonded
water molecules, H(sub2)O. Pauling showed that the ice rules do
not lead to order in the proton arrangement but rather, the ice
ground state is "macroscopically degenerate." That is to say,
the number of degenerate, or energetically equivalent proton
arrangements diverges exponentially with the size of the sample.
Pauling estimated the degeneracy to be approximately
(3/2)^(N/2), where (N) is the number of water molecules,
typically approximately 10^(24) in a macroscopic sample. This
leads to a disordered ground state with a measurable zero-point
entropy related to the degeneracy. Pauling's estimate of the
zero-point entropy is very close to the most accurate modern
estimate and consistent with experiment (2). The disordered
ice-rules proton arrangement in water ice was eventually
confirmed by neutron diffraction experiments.

References (abridged):

1. G. Toulouse, Commun. Phys. 2, 115 (1977)

2. W. F. Giauque and M. F. Ashley, Phys. Rev. 43, 81 (1933)

3. W. F. Giauque and J. W. Stout, J. Am. Chem. Soc. 58, 1144
(1936)

4. L. Pauling, J. Am. Chem. Soc. 57, 2680 (1935)

5. J.D. Bernal and R. H. Fowler, J. Chem. Phys. 1, 515 (1933)

Science 2001 294:1495

Web Links: condensed matter frustration

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