ScienceWeek

ScienceWeek - June 28, 2002
Vol. 6 Number 26

An Online Research Digest Published Weekly Since 1997

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The world little knows how many of the thoughts and theories
which have passed through the mind of a scientific investigator
have been crushed in silence and secrecy; that in the most
successful instances not a tenth of the suggestions, the hopes,
the wishes, the preliminary conclusions have been realized.
-- Michael Faraday (1791-1867)

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Section 1

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

1. On Free-Floating Planets 

2. Chemistry: On George de Hevesy (1885-1966) 

3. On Global Sea-Level Rise 

4. On X-Ray Emission from Comets 

5. On Electron Transfer Reactions Under Restricted Geometry 

6. On the Hydrophobic Interaction 

7. On Altruistic Punishment in Humans

8. On Synthetic Gene Networks

9. On Centromeric DNA 

10. Development and Evolution: Theoretical Aspects 

11. Epithelia and Innate Immunity 

12. On Global Dispersal of Free-Living Microbial Eukaryote
Species 

13. On Automatic Analysis of Character Strings 

14. Building Nanostructures from the Bottom Up 

15. On the Physics of Oil Exploration 

16. On Double Heterostructure Lasers 

17. On Mixed Polymer Brushes 

18. On Synthetic Molecular Motors 

19. On Cardiac Physiology and Arrhythmias 

20. Visual Feedback and Vehicle Steering Control 

21. On the East African Highlands Resurgence of Malaria  

22. On Amyotrophic Lateral Sclerosis and Physician-Assisted
Suicide 

23. On World Poverty and Hunger 

24. On the Use of Antibiotics in Agriculture 

25. In Focus: On Morphogens

26. ScienceWeek Notices and Subscription Information

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Section 2

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1. ON FREE-FLOATING PLANETS

In 1995, astronomers reported the first tentative evidence of
planets orbiting stars outside our Solar System, and since then
astronomers have detected perturbations in the motions of dozens
of nearby stars, these perturbations presumably due to the
gravity of planets. Currently, the identification and study of
extrasolar planets depends for the most part on indirect methods
such as those involving the measurement of perturbations of the
observed brightness or motions of their parent stars.

One emerging problem is the classification of a number of giant
extrasolar planets: Are they planets or 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.
Such a star has a relatively short-lived luminosity
(approximately 100 million 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; at present, a number
of stars have been recognized as brown dwarfs. In addition to
the problem of classifying apparently supermassive extrasolar
giant planets, there is the even more important problem of
explaining their origin.

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.

J.R. Hurley and M.M. Shara (American Museum of Natural History,
US) discuss free-floating planets, the authors making the
following points:

1) The existence of planets outside our solar system has been a
delicate matter in astronomy ever since the 16th-century
philosopher Giordano Bruno (1548-1600) was burned at the stake
for (among other things) proposing that the Universe holds an
infinite number of other worlds. People are no longer set aflame
in the public square for proposing the existence of extrasolar
planets, but the field remains contentious. To date more than 70
planets have been found in orbit around other stars, generating
a considerable amount of excitement in the astronomical
community. Perhaps even more intriguing is the discovery of a
few dozen extrasolar planets that are not affiliated with any
star at all. These so-called "free-floating planets" are among
the most controversial objects yet found in the search for other
worlds.

2) The problem is that astronomers don't all agree on what it
means to be a planet. Some of the objects found orbiting other
stars are in fact much larger than any of the giant planets in
our own Solar System, weighing in at more than 10 times the mass
of Jupiter (although most are less than 3 or 4 Jupiter masses).
This approaches the size threshold of another type of substellar
object known as a "brown dwarf", often described as a "failed
star" because its too small to ignite the fusion of hydrogen in
its core. Brown dwarfs are intermediate in size between planets
and true stars, and the boundary lines at the upper and lower
limits of brown dwarfdom are still a little fuzzy. (To further
confuse the issue, it was recently reported that brown dwarfs
may themselves harbor planets.

3) On the other hand, some of the free-floating planets appear
to be no larger than Jupiter, but their very existence
challenges the traditional notions of what a planet is -- a
substellar object that orbits the star around which it formed.
Many people are reluctant to call the free-floating objects
"planets," and for now many scientists just call them
"free-floaters".

4) Free-floaters are interesting and important objects beyond
the fact that they are currently an astronomical novelty item.
The number and variety of bodies in our galaxy that are smaller
than a star_less than about 0.08 solar masses (or 80 Jupiter
masses) -- is simply not known. They are expected to come in a
range of sizes -- from the relatively large objects such as
brown dwarfs and giant gaseous planets to rocky planets like the
Earth and smaller bodies like the moons and the asteroids in our
Solar System. A quantitative measure of their existence is
important not only in the search for habitable worlds and
extraterrestrial life, but also to address fundamental questions
in astrophysics and cosmology, such as the relative numbers and
sizes of newborn stars in a cluster (the initial-mass function)
and the identity of normal (baryonic) dark matter in the
universe.(1-5)

References (abridged):

1. Hurley, J. R., and M. M. Shara. 2002. Free-floating planets:
Not so surprising. Astrophys. J. (in press)
http://www.arXiv.org/abs/astro-ph/0108350

2. Lucas, P. W., P. F. Roche, F. Allard and P. H. Hauschildt.
2001. A population of very young brown dwarfs and free-floating
planets in Orion. Monthly Notices of the Roy. Astron. Soc. (in
press) http://www.arXiv.org/abs/astro-ph/0105154

3. Smith, K. W., and I. A. Bonnell. 2001. Free-floating planets
in stellar clusters? Monthly Notices of the Royal Astronomical
Society 322:L1-L4.

4. Tamura, M., Y. Itoh, Y. Oasa and T. Nankajima. 1998. Isolated
and companion young brown dwarfs in the Taurus and Chamaeleon
molecular clouds. Science 282:1095-1097.

5. Zapatero Osorio, M. R., V. J. S. Bejar, E. L. Martin, R.
Rebolo, D. Barrado y Navacues, C. A. L. Bailer-Jones and R.
Mundt. 2000. Discovery of young, isolated planetary mass objects
in the o Orionis star cluster. Science 290:103-107.

American Scientist 2002 90:140

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2. CHEMISTRY: ON GEORGE DE HEVESY (1885-1966)

George de Hevesy (also known as George von Hevesy) received the
Nobel Prize in Chemistry in 1943 for his his work on the use of
isotopes as tracers in the study of chemical and biological
processes. It is interesting that Hevesy's first use of
radioactive tracers in 1923 was hardly noticed by chemists and
biologists at the time, but before long his methods became the
foundation for enormous progress in chemical dynamics,
biochemistry, and physiology. In 1923, Hevesy, prodded by Niels
Bohr and working with Dirk Coster, also discovered the element
hafnium.

J. Van Houten (St. Michael's College, US) discusses George de
Hevesy, the author making the following points:

1) George de Hevesy developed his interest in isotopes while
working in Ernest Rutherford's lab in Manchester, England
between 1910 and 1913, and with Frederic Paneth at the Vienna
Institute of Radium Research from 1913 to 1915, where de Hevesy
and Paneth carried out the first radioactive tracer research
(3). Rutherford had already received the Nobel Prize in 1908 for
his "investigations into the disintegration of the elements and
the chemistry of radioactive substances" (4). Prior to going to
work with Rutherford in 1910, de Hevesy studied at Budapest
University in his native Hungary and at Berlin Technical
University. After receiving his doctorate from the University of
Freiburg im Breisgau in 1908, de Hevesy worked for two years as
an assistant at the Institute of Physical Chemistry, Technical
University of Switzerland, and briefly with Fritz Haber, who was
then working on the catalytic synthesis of ammonia by what later
came to be known as the Haber process, and for which Haber
received the Nobel Prize in 1918 (5). After serving in the
Australia Hungarian army during World War I, de Hevesy went to
Copenhagen in 1919 to join the Institute for Theoretical Physics
headed by Niels Bohr. Bohr received the Nobel Prize in physics
in 1922 for his well-known theory of atomic structure (6). Bohr
and de Hevesy had worked simultaneously in Rutherford's lab in
Manchester a decade earlier. It was, of course, Rutherford's
famous alpha-particle scattering experiments, performed in 1909,
that led to the original nuclear model of the atom and
ultimately to the Bohr model.

2) de Hevesy pioneered the use of radioisotopes as tracers, a
technique that continues today in investigations of chemical
reactions as well as in physiological studies. In fact, de
Hevesy himself appears to have been more interested in the uses
of tracers in physiological studies than in mechanistic chemical
investigations. For example, he was among the first to employ
P32--labelled sodium phosphate injected into animals and humans
to study the rate of incorporation of phosphorus from the blood
stream into various tissues, organs, bones, and tooth enamel. He
performed similar experiments with radio-labeled sodium,
potassium, lead, bismuth, and thallium in plants and animals. He
also employed stable nuclides -- for example, using
deuterium-enriched water provided by Harold Urey, de Hevesy
found that fish and amphibians swimming in that water take up
deuterium and come to equilibrium with their environment with
respect to deuterium in about four hours, and that humans who
drink D(sub2)O excrete deuterium in their urine in approximately
26 minutes (2).

References (abridged):

2. Nobel e-Museum_Chemistry 1943 (with links to Prize
Presentation and Biography pages),
http://www.nobel.se/chemistry/laureates/1943/index.html

3. Van Houten,}.]. Chem. Educ. 2001, 78, 1570-1573; supplemental
material
http://jchemed.chem.wisc.edu/Journal/Issues/2001/Dec/abs1570.html

4. Nobel e-Museum_Chemistry 1908 (with links to Prize
Presentation and Biography pages),
http://www.nobel.se/chemistry/laureates/1908/index.html

5. Nobel e-Museum_Chemistry 1918 (with links to Prize
Presentation and Biography pages),
http://www.nobel.se/chemistry/laureates/1918/index.html

6. Nobel e-Museum_Physics 1922 (with links to Prize Presentation
and Biography pages),
http://www.nobel.se/physics/laureates/1922/index.html

J. Chem. Ed 2002 79:301

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3. ON GLOBAL SEA-LEVEL RISE

B.C. Douglas and W.R. Peltier (Florida International University)
discuss global sea-level rise, the authors making the following
points:

1) Global sea level embodies many aspects of the global
hydrological cycle and reflects the heat content of the oceans
because the density of sea water depends on temperature. Global
sea level is therefore a potent indicator of climate change and
a key observational constraint on climate models. Global sea
level is also of immense practical importance. More than 100
million people live within 1 mile of the mean sea level. Rising
global sea level threatens the existence of some island states
and deltaic coasts. Coastal wetlands are also endangered because
the plants there may be unable to respond to a rate of sea-level
rise much beyond what is occurring now, and they will drown if
the rate increases substantially. Another threat from rising sea
level is the increased erosion of sandy beaches. As a beach is
lost, storm waves can more easily reach fixed structures nearby.
Those waves will ultimately damage or destroy property unless
expensive protective measures are taken. Unfortunately,
effective coastal protection is beyond the resources of many
developing countries.

2) Compared with those of previous millennia, the changes in
global sea level occurring today are tiny. Ancient corals found
on Barbados reveal that global sea level increased by about 120
meters as a result of the deglaciation that followed the last
glacial maximum of 21 000 years ago. By about 5000-6000 years
ago, the melting of the great high-latitude ice masses was
essentially completed. Thereafter, global sea level rise was
small, and appears to have ceased by 3000-4000 years ago.

3) Although the long-term average global sea level rise for the
past few millennia has been stable at a level near zero, there
is reliable evidence from coastal land records,(1) lake and
river ice cover,(2) and water level measurements(3) that global
sea level abruptly began to rise near the mid-19th century. No
studies, however, have detected any significant acceleration of
global sea level rise during the 20th century.(4) In the last
dozen years, published values of 20th-century global sea level
rise have ranged from 1.0 to 2.4 mm/y, even though all
investigators used essentially the same database of tide-gauge
measurements.

The authors suggest that values of global sea level rise much
below 2 mm/y are inconsistent with regional observations of
sea-level rise and with the continuing physical response of
Earth to the most recent episode of deglaciation. The authors
suggest this point is not trivial. If the correct value of
global sea level rise is near 1 mm/y, then global warming
provides an appealingly simple explanation: 1 mm/y of global sea
level rise corresponds to that expected from the thermal
expansion of the oceans and the melting of small ice sheets and
mountain glaciers caused by the 0.6 degree C increase in global
surface temperature during the last 100 years. This explanation
would further imply that melting of the great Greenland and
Antarctic ice sheets is not contributing to global sea level
rise. But if the true rate of contemporary global sea level rise
is closer to 2 mm/y, current climate models will need to be
refined.

References (abridged):

1. M. S. Keamey, J. C. Stevenson, J. Coastal Res. 7 (2), 403
(1991).

2. J. J. Magnuson et al., Science 289, 1743 (2001).

3. P. L. Woodworth, Geophys. Res. Lett. 26, 1589 (1999).

4. B. C. Douglas, J. Geophys. Res. 7 (c8), 12699 (1992).

Physics Today 2002 March

Related Background:

GLOBAL WARMING, SEA-LEVEL RISE, AND LOSS OF COASTAL WETLANDS

J.P. Donnelly and M.D. Bertness (Brown University, US) discuss
sea-level rise and coastal wetlands, the authors making the
following points:

1) Recent studies indicate that both climate warming and
increases in the rate of sea-level rise in New England over the
last 150 years are unprecedented in at least the last 1000
years. The possibility that emission of greenhouse gases is
influencing and will continue to influence global climate and
potentially sea-level rise has prompted considerable research
into the possible implications for plant and animal communities.

2) The distribution of New England salt marsh communities is
intrinsically linked to the magnitude, frequency, and duration
of tidal inundation. Cordgrass (Spartina alterniflora)
exclusively inhabits the frequently flooded lower elevations,
whereas a mosaic of marsh hay (Spartina patens), spike grass
(Distichlis spicata), and black rush (Juncus gerardi) typically
dominate higher elevations.

3) The authors report that monitoring plant zonal boundaries in
two New England salt marshes revealed that low-marsh cordgrass
rapidly moved landward at the expense of higher-marsh species
between 1995 and 1998. Plant macrofossils from sediment cores
across modern plant community boundaries provided a 2500-year
record of marsh community composition and documented the
migration of cordgrass into the high marsh. Isotope dating
revealed that the initiation of cordgrass migration occurred in
the late 19th century and continued through the 20th century.
The timing of the initiation of cordgrass migration is
coincident with an acceleration in the rate of sea-level rise
recorded by the New York tide gauge.

4) The authors suggest these results indicate that increased
flooding associated with accelerating rates of sea-level rise
has stressed high-marsh communities and promoted landward
migration of cordgrass. If current rates of sea-level rise
continue or increase slightly over the next century, New England
salt marshes will be dominated by cordgrass. If climate warming
causes sea- level rise rates to increase significantly over the
next century, these cordgrass dominated marshes will likely
drown, resulting in extensive losses of coastal wetlands.

Proc. Nat. Acad. Sci. 2001 98:14218

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4. ON X-RAY EMISSION FROM COMETS

Composed of ice and dust, comets are relatively small objects in
orbit around the Sun. They are believed to exist in large
numbers in regions beyond the planets (the Oort Cloud and the
Kuiper Belt), where they are perturbed by the gravitational
influence of passing stars into new orbits that bring them into
the inner Solar System. When a comet is far from the Sun, its
nucleus is frozen solid and shines only by reflected light; as
the nucleus nears the Sun, its temperature increases and it
releases gas and dust. Like certain meteorites, comets are
apparently vestiges of the origin of the Solar System, with
comets believed to be icy *planetesimal remainders from the
formation of the outer planets. The total population of the Oort
Cloud and Kuiper belt may be 10^(12) objects, with a combined
mass greater than the Earth. The main component of cometary ice
is apparently frozen water, plus some methane, carbon monoxide,
and carbon dioxide. Also detected in comets are formaldehyde,
hydrogen cyanide, and methyl cyanide. All of these molecules,
detected by spectroscopy, are also found in interstellar nebulae
similar to the original "solar nebula" from which the Sun was
formed.

T.E. Cravens (University of Kansas, US) discusses x-ray emission
from comets, the author making the following points:

1) Extreme ultraviolet radiation, with wavelength ranging from
10 to 120 nm, and x-ray radiation with wavelength between
approximately 0.01 and 10 nm, are important for Solar System and
astrophysical applications because the photons are sufficiently
energetic to ionize neutral atoms and molecules (1). X-ray
emission in space is generally thought to originate from hot
collisional plasmas, such as the 10^(6) K gas found in the solar
corona (2) or the 10^(8) K gas observed in supernova remnants
(3). The Sun is not the only source of x-rays in the Solar
System (4). X-rays are observed in the aurora at Earth and at
Jupiter, and solar x-rays scattered off the surface of the Moon
have been observed. Nonetheless, the 1996 discovery, using ROSAT
(5), of strong x-ray emission from the Hyakutake comet was
surprising because cometary atmospheres are cold. The total
x-ray power, or luminosity, of Hyakutake was measured to be
approximately 10^(9) W. Extreme ultraviolet emission from
Hyakutake was also seen by ROSAT (5) and by the Extreme
Ultraviolet Explorer (EUVE) satellite (5). Hard x-rays with
energies in excess of about 2 keV were not observed.

2) Shortly after the Hyakutake observations, soft x-ray emission
from five other comets was also found, in the archived ROSAT
observational database. Extreme ultraviolet and soft x-ray
emissions were then reported from several other comets, for a
total of 14 comets. We now recognize that x-ray emission is a
characteristic of all active comets.

3) A comet is a mixture of frozen H(sub2)O, CO, CH(sub4),
H(sub2)CO, NH(sub3), and dust, with an ice-to-dust ratio of
approximately unity, although it differs from comet to comet.
When a comet (i.e., the nucleus, which is only a few km across)
is far from the Sun, the mixture remains frozen, but the surface
heats up, and volatiles are released as the comet enters the
inner solar system. The vapor produced by the now-active nucleus
escapes into space, where it becomes the cometary coma, or
atmosphere. The neutral gas coma extends far out into space
(10^(6) km), and the gas density varies inversely as the square
of the cometocentric distance. The gas atoms and molecules can
be photodissociated or photo ionized by solar radiation,
creating additional neutral and ion species. The outflowing gas
carries large quantities of dust along with it. What we see as a
"visible" comet is mainly sunlight reflected from the extensive
(approximately 10^(5) km) dust coma and tail, created when solar
radiation pressure pushes dust grains antisunward.

4) In summary: The discovery of x-ray emission from comet
Hyakutake was surprising given that comets are known to be cold.
Observations by x-ray satellites such as the R”ntgen Satellite
(ROSAT) indicate that x-rays are produced by almost all comets.
Theoretical and observational work has demonstrated that
charge-exchange collisions of highly charged solar wind ions
with cometary neutral species can explain this emission. X-ray
observations of comets and other solar system objects may be
used to determine the structure and dynamics of the solar wind.

References (abridged):

1. A photon is a unit, or quantum, of electromagnetic radiation
and has energy (E) = hc/L, where h is Planck's constant, c is
the speed of light, L is radiation wavelength. For example, an
x-ray photon with L = 1 nm has an E = 1240 eV, where 1 eV =
1.602 x 1019 J is an energy unit. X-ray photons have energies
greater than approximately 100 eV.

2. P. Foukal, Solar Astrophysics (Wiley, New York, 1990).

3. D. F. Cioffi, in Physical Processes in Hot Cosmic Plasma, W.
Brinkmann, A. C. Fabian, F. Giovannelli, Eds. (Kluwer,
Dordrecht, Netherlands, 1990), pp. 1-16. 

4. T. E. Cravens, Adv. Space Res. 26, 1443 (2000) .

5. One earlier x-ray observation of comet C/1979 Y1 (Bradfield)
by the orbiting Einstein observatory yielded negative results.
Lisse et al. reported on measurements made with two ROSAT
instruments and one Rossi X-ray Timing Explorer (XTE)
instrument. These instruments were the high-resolution imager
(HRI), with a spectral range (or band pass) of 0.10 to 2.0 keV
(i.e., soft x-rays); the wide-field camera, with a spectral
range in the S1A filter used of 0.09 to 0.206 keV (i.e., EUV
emission); and the XTE proportional counter array (PCA), with a
spectral range of 2 to 60 keV. The XTE PCA observations were
negative. EUV emission was also observed by the EUVE satellite.

Science 2002 296:1042

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5. ON ELECTRON TRANSFER REACTIONS UNDER RESTRICTED GEOMETRY

In this context, in general, an "electron transfer reaction" is
any reaction in which an electron transfers from one chemical
entity to another.

Progress toward a fundamental understanding of electron transfer
reactions has come from an intricate tapestry of theoretical
tools and techniques, new methods in synthetic chemistry, and
the development of spectroscopic apparatus capable of spanning
the time range from femtoseconds to hours. Early theoretical
treatments of electron transfer come from the work of Marcus
(1956) and Hush (1958), this work an extension of transition
state theory. Later theories, such as those developed by Jortner
(1976) and others, incorporate the quantum-mechanical nature of
high-frequency solvent and intramolecular vibrational modes that
are coupled to the electron transfer reaction coordinate. (W.B.
Davis: J. Am. Chem. Soc. 2001 123:7877)

P. Lopez-Cornejo et al (University of Seville, ES) discuss
electron transfer reactions, the authors making the following
points:

1) There is growing interest in the study of electron-transfer
reactions under conditions generally referred to as "restricted
geometry conditions",(1) that is, under conditions in which one
or both reactants are forced to remain at the surface of
micelles, or in the cavity of cyclodextrins and related
compounds, or at the surface of DNA, etc. These studies are of
interest for several reasons: (i) According to the charges of
the reactants, their local concentrations can increase or
decrease in relation to their bulk concentrations, thus allowing
the tuning of reaction rates. (ii) Generally speaking, the
properties of local reaction media are quite different from the
properties of the bulk of the solutions as a consequence of the
intense local electric fields.

2) These local fields affect all the relevant parameters that
modulate the rate of electron-transfer processes. Thus the
solvent reorganization energy depends on the dielectric
characteristics of the surrounding medium,(2) and these
characteristics are modified by the field through solvent
saturation effects.(3) Similarly, the free energy of the
reaction is also dependent on the field, because the free
energies of the reactant and product states also depend on the
dielectric constant of the medium. Moreover, the field may
change the adiabaticity of the reaction through the polarization
of the orbitals of the reactants involved in the electron
transfer.(4)

3) The dynamics of the solvent, and thus the preexponential term
in the rate constant, are also changed by the field.(5) Indeed,
the diffusion coefficients of the intervening species,
corresponding to the nonhomogeneous state (in the presence of
the field), are quite different from those of the homogeneous
state (without the field). Therefore, the equilibrium
correlations, such as the direct correlation functions, in the
presence of a field may also be rather different from those in
the absence of the field. Finally, it has been suggested that
the fluctuation dissipation theorem and other important theorems
of statistical mechanics may no longer be valid in the presence
of a strong field.

References (abridged):

1. (a) Turro, N. J.; Yekta, A. J. Am. Chem. Soc. 1978, 100,
5951. (b) Bernar, A.; Grand, D.; Hautecloque, S.; Gianotti, C.
J. Phys. Chem. 1986, 90, 6189, and references therein. (c)
Grand, D.; Hautecloque, S. J. Phys. Chem. 1990, 94, 837. (d)
Barber, D. J. W.; Morris, D. A. N.; Thomas, J. K. Chem. Phys.
Lett. 1976, 37, 481. (e) Almagren, M.; Grieser, F.; Thomas, J.
K. J. Phys. Chem. 1979, 83, 3232.

2. Marcus, R. A. Annu. Rev. Phys. Chem. 1964, 15, 155.

3. Boettcher, C. J. F. Theory of Dielectric Polarization, 2nd
ed.; Elsevier: Amsterdam, 1973; Vol. 1, Chapter 7.

4. Lao, K.; Frazen, S.; Stanley, R. J.; Lambright, D. G.; Boxer,
S. G. J. Phys. Chem. 1993, 97, 13165.

5. Weaver, M. J. Chem. Rev. 1992, 92, 463.

J. Am. Chem. Soc. 2002 124:5154

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6. ON THE HYDROPHOBIC INTERACTION

In this context, the term "hydrophobic interaction" (apolar
interaction) refers in general to any of the "entropy-driven"
interactions between nonpolar parts of molecules when in polar
solvents. Such interactions are believed to be important in
maintaining the structure of protein molecules in polar
solvents, in antigen-antibody interactions, in virus-protein and
enzyme-subunit aggregation and disaggregation, and in
determining enzyme specificity. As thus defined, hydrophobic
interactions are distinguished from van der Waals interactions
between nonpolar entities, which are specifically electric-field
driven (e.g., by permanent and/or instantaneous dipole moments),
and which occur with or without the presence of a solvent.

David Chandler (University of California Berkeley, US) discusses
the hydrophobic interaction, the author making the following
points:

1) Water and oil famously don't mix: the term "hydrophobic"
(water-fearing) is commonly used to describe substances that,
like oil, do not mix with water. Although it may look as if
water repels oil, in reality the separation of oil and water in
ambient conditions is not due to repulsion between water and oil
molecules, but to particularly favorable hydrogen bonding
between water molecules. Each water molecule can participate in
four such bonds, sharing its two hydrogen atoms with two
neighboring water molecules and sharing two further hydrogen
atoms associated with two other neighbors. Ice is a
tetrahedrally ordered array, and liquid water a disordered
network, of such hydrogen-bonded molecules.

2) Oil and water molecules actually attract each other, but not
nearly as strongly as water attracts itself. Mixing enough oil
with water therefore leads to a reduction in favorable bonding.
Strong mutual attractions between water molecules induce
segregation of oil from water and result in an effective oil-oil
attraction, in the same way that groups of people segregate when
one subgroup prefers to associate with its own kind. This
water-induced attraction between oil molecules is called the
"hydrophobic interaction". Without the aqueous environment,
hydrophobic interactions in aqueous solutions cannot occur.

3) In the 1950s, Walter Kauzmann identified hydrophobic
interactions as a primary source of protein stability. Proteins
are chains of amino acids that fold into specific, functional,
three-dimensional structures that are determined by the order of
the amino-acid sequence. Kauzmann reasoned that as amino acids
are either water-like or oil-like, a given linear sequence would
fold into the structure that best segregates oil-like amino
acids from water. Later, when protein structures were deduced
with the help of x-ray crystallography, Kauzmann's general
predictions were found to be correct. Yet subsequent attempts to
quantify his ideas by identifying a single parameter or function
that characterizes the strength of hydrophobic interactions have
been unsuccessful.(1-5)

References (abridged):

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

2. Stillinger, F. H. J. Solut. Chem. 2, 141-158 (1973).

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

4. Ball, P. H2O: A Biography of Water (Phoenix, London, 1999).

5. Tanford, C. & Reynolds, J. Nature's Robots: A History of
Proteins (Oxford Univ. Press, 2001).

Nature 2002 417:491

Related Background:

ON THE HYDROPHOBIC EFFECT

R. Breslow et al (Columbia University, US) discuss the
hydrophobic effect, the authors making the following points:

1) When organic reactions are performed in water they can be
influenced by the hydrophobic effect (1), which reflects the
high energy of a water interface with a nonpolar molecule or
region. Diels-Alder reactions (2-5) and the benzoin condensation
show such effects. The hydrophobic effect itself can lead to
higher rates for these reactions in water than in other
solvents, and higher endo selectivity for Diels-Alder reactions.
It can be diagnosed by seeing the effect of added substances
that increase or decrease the hydrophobic effect; prohydrophobic
additives are generally simple salts such as sodium or lithium
chloride, while antihydrophobic additives include salts of large
ions such as guanidinium perchlorate. It has been demonstrated
that such antihydrophobic ions, which are often used as protein
denaturants, function by bridging between the nonpolar surface
and the water solvent.

2) Cosolvents such as ethanol also serve as bridging species in
water, diminishing the hydrophobic effect. This is most easily
diagnosed from the increased solubility of nonpolar substances
in such mixed solvents. Because solubility is an equilibrium
constant, its log reflects a free energy of solution, and the
increased solubility produced from an antihydrophobic additive
to water can be described in terms of a change of the free
energy of solution. This free energy change is directly
proportional to the log of the ratio of the solubilities with
and without the cosolvent.

3) Antihydrophobic agents such as organic cosolvents have been
very useful as a method of experimentally measuring the
solvation properties of transition states for reactions in
water, particularly the amount of exposed hydrophobic surface
area relative to that of the starting materials (4,5). The use
of small amounts of cosolvents allows the observation of a
change in solvation of hydrophobic surfaces while preserving the
essentially aqueous environment.

4) Grunwald (1984) has proposed two additive terms to describe
the partial molar thermodynamic properties of water-rich aqueous
alcohol solutions. The first term, called the "isodelphic" term,
describes effects on a solute where the bulk aqueous solvent
network theoretically remains unchanged upon addition of small
amounts of an alcohol cosolvent. The second term, called the
"lyodelphic" term, describes effects due to changes in the
solvent network resulting from the cosolvent.

References (abridged):

1. Tanford, C. The Hydrophobic Effect: Formation of Micelles and
Biological Membranes, 2nd ed.; John Wiley & Sons: New York, 1980.

2. Breslow, R.; Rideout, D. C. J. Am. Chem. Soc. 1980, 102, 7817.

3. Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239-1240.

4. Breslow, R. Acc. Chem. Res. 1991, 24, 159-164.

5. Breslow, R. Hydrophobic and Antihydrophobic Effects on
Organic Reactions in Aqueous Solution; Cramer, C. J., Truhlar,
D. G., Eds.; American Chemical Society: Washington, DC, 1994; pp
291-302.

J. Am. Chem. Soc. 2002 124:3622

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7. ON ALTRUISTIC PUNISHMENT IN HUMANS

The past several decades have witnessed a renewed interest in
formulating the principles (if they can be identified) operating
in the evolutionary genetics of human social behavior. Although
this area of research has produced much controversy, it has also
attracted growing numbers of researchers and has produced an
expanding experimental and theoretical literature devoted the
interfaces between biology, anthropology, and sociology.

In this context, the term "altruistic punishment" refers to
punishment of non-contributing members of a group
("free-riders") by certain other members of the group
("punishers")  when the punishers are motivated to punish free
riders even though it is costly and yields no material benefits
for the punishers.

E. Fehr and S. Gaechter (University of Zurich, CH) discuss
altruistic punishment, the authors making the following points:

1) Throughout evolution, crucial human activities like hunting
big game, sharing meat, conserving common property resources,
and warfare constituted a public good. In situations like these,
every member of the group benefits from the "good", including
those who did not pay any costs of providing the good. This
raises the question of why people regularly participate in
costly cooperative activities like warfare and big-game
hunting(1-4). Several theories have been proposed to explain the
evolution of human cooperation. The theory of kin selection(5)
focuses on cooperation among individuals that are genetically
closely related, whereas theories of direct reciprocity focus on
the selfish incentives for cooperation in bilateral long-term
interactions. The theories of indirect reciprocity and costly
signalling show how cooperation in larger groups can emerge when
the cooperators can build a reputation. Yet these theories do
not readily explain why cooperation is frequent among
genetically unrelated people, in non-repeated interactions, when
gains from reputation are small or absent.

2) Punishment provides a solution to this problem. If those who
free ride on the cooperation of others are punished, cooperation
may pay(3). Yet this "solution" begs the question of who will
bear the cost of punishing the free riders. Everybody in the
group will be better off if free riding is deterred, but nobody
has an incentive to punish the free riders. Thus, the punishment
of free riders constitutes a second-order public good. The
problem of second-order public goods can be solved if enough
humans have a tendency for "altruistic punishment", that is, if
they are motivated to punish free riders even though it is
costly and yields no material benefits for the punishers.

3) The authors experimentally examined the question of whether
humans engage in altruistic punishment and how this inclination
affects the ability of achieving and sustaining cooperation. A
total of 240 students participated in a "public goods"
experiment with real monetary stakes and two treatment
conditions: punishment and no punishment. The authors report
they have demonstrated that cooperation flourishes if altruistic
punishment is possible, and breaks down if it is ruled out. The
authors suggest the evidence indicates that negative emotions
towards defectors are the proximate mechanism behind altruistic
punishment. The authors suggest their results indicate that
future study of the evolution of human cooperation should
include a strong focus on explaining altruistic punishment.

References (abridged):

1. Smuts, B. B., Cheney, D. L., Seyfarth, R. M., Wrangham, R.
W., & Struhsaker, T. T. (eds) Primate Societies (Univ. Chicago
Press, Chicago, 1987).

2. Richerson, P. & Boyd, R. in Ideology, Warfare and
Indoctrinability (eds Eibl-Eibesfeldt, I. & Salter, F.) 71-95
(Berghan Books, New York, 1998).

3. Sober, E. & Wilson, D. S. Unto Others: The Evolution and
Psychology of Unselfish Behaviour (Harvard Univ. Press,
Cambridge, Massachusetts, 1998).

4. Boyd, R. & Richerson, P. in Evolution and Culture (ed.
Levinson, S.) (MIT Press, Cambridge, Massachusetts, in the
press).

5. Hamilton, W. D. Genetical evolution of social behavior I and
II. J. Theor. Biol. 7, 1-52 (1964).

Nature 2002 415:137

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8. ON SYNTHETIC GENE NETWORKS

J. Hasty et al (Boston University, US) discuss synthetic gene
networks, the authors making the following points:

1) The flurry of genomic research has led to detailed lists of
the genes that are at the heart of cellular function. These
genes and their protein products form a complex web of
interactions, wherein the proteins serve to activate or repress
the transcription of the genes. The dissection and analysis of
the complex dynamical interactions involved in gene regulation
is thus a natural next step in genomic research, and tools from
nonlinear dynamics and statistical physics will no doubt play an
important role.

2) Although a theoretical framework for analyzing gene networks
has origins that date back nearly 30 years [1,2], it is
relatively recent that experimental progress has made genetic
networks amenable to quantitative analysis [3,4]. This progress
has rendered feasible the notion of an engineering-based
approach to the study of gene networks [5], whereby dynamical
modeling tools are used in the design of novel networks that
can, in turn, be constructed and studied in the laboratory.
Recent examples of this approach have yielded observed network
behavior which is consistent with predictions that arise from
continuum dynamical modeling. Such an inherently reductionist
decoupling of a simple network from its native and often complex
biological setting can lead to valuable information regarding
evolutionary design principles, and set the stage for a modular
description of the regulatory processes underlying basic
cellular function. additionally, this approach could have a
significant impact on postgenomic biotechnology. From the
construction of simple switches or oscillators, one can envision
the design of integrated biological circuits capable of
performing increasingly elaborate functions.

3) The authors present a model for a synthetic gene oscillator
and consider the coupling of the oscillator to a periodic
process that is intrinsic to the cell. The authors report they
have investigated the synchronization properties of the coupled
system, and show how the oscillator can be constructed to yield
a significant amplification of cellular oscillations. The
authors reduce the driven oscillator equations to a normal form,
and analytically determine the amplification as a function of
the strength of the cellular oscillations. The authors suggest
the ability to couple naturally occurring genetic oscillations
to a synthetically designed network could lead to possible
strategies for entraining and/or amplifying oscillations in
cellular protein levels.

References (abridged):

I. L. Glass and S.A. Kauffman, J. Theor. Biol. 39, 103 (1973).

2. M.A. Savageau, Nature (London) 252, 546 (1974).

3. P. Smolen, D. A. Baxter, and J. H. Byrne, Neuron 26, 567
(2000).

4. J. Hasty, D. McMillen, F. Isaacs, and J. J. Collins, Nat.
Rev. Genetics 2, 268 (2001).

5. J. Monod, J. Wyman, and J. P. Changeux, J. Mol. Biol. 12, 88
(1965).

Phys. Rev. Lett. 2002 88:148101

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9. ON CENTROMERIC DNA

S. Henikoff and H.S. Malik (Fred Hutchinson Cancer Research
Center, US) discuss centromeric DNA, the authors making the
following points:

1) We are entering the post-genomic era, in which complete
catalogues of genetic sequences will, it is widely believed,
greatly advance our understanding of biological function. Yet
there are large regions of genomes (the complete genetic
catalogues of organisms) for which sequencing has hardly begun.
Ironically, these are the same regions that were the first to be
functionally characterized. As long ago as 1880, cytologists
recognized that each chromosome in a cell nucleus has a single
region, the centromere, that is acted upon by the mitotic
spindle, a fibrous network that pulls sister chromosomes to
opposite poles at the beginning of cell division. Thus, even
before it was realized that the chromosomes' arms contain the
stuff of inheritance, the role of centromeres in chromosome
segregation was understood.

2) Molecular characterization of centromeres has been slow
because of technical difficulties, not because of any lack of
appreciation of the importance of these structures in cell
division. Centromeric DNA in complex genomes consists of tandem
repeats, which are difficult to clone, amplify or sequence.
Centromeric cores are the most uniformly repetitive regions,
consisting of megabase-sized, homogeneous arrays of short
tandem-repeat units. These are flanked by more heterogeneous
repeats, including the descendants of transposable elements --
sequences that can insert themselves randomly throughout
genomes. The flanking repeats mediate cohesion between sister
chromosomes, and simultaneous dissolution of cohesion on all
chromosomes defines the beginning of the anaphase of mitosis,
when sister chromosomes begin moving to opposite spindle poles.

3) This functional distinction between the centromere's core,
which is where the spindle microtubules attach, and its flanks,
which maintain cohesion, mirrors a biochemical distinction. Half
of our genetic material by weight is in the form of octamers
composed of four histone proteins (H2A, H2B, H3 and H4), around
which DNA is wrapped to form nucleosomes, the basic units of
chromatin. Centromeric cores consist of nucleosomes with a
variant H3 histone (CenH3) that replaces the usual version.
Flanking sequences are packaged into 'heterochromatin', which is
distinguished from gene-rich 'euchromatin' by the presence of
methyl groups attached to lysine at position 9 of H3. Just how
differences in H3 specify chromatin function is of substantial
current interest.(1-4)

References:

1. Henikoff, S., Ahmad, K. & Malik, H. S. Science 293, 1098-1102
(2001).

2. Pardo-Manuel de Villena, F. & Sapienza, C. Genetics 159,
1179-1189 (2001).

3. Schueler, M. G., Higgins, A. W., Rudd, M. K., Gustashaw, K. &
Willard, H. F. Science 294, 109-115 (2001).

4. Zwick, M. E., Salstrom, J. L. & Langley, C. H. Genetics 152,
1605-1614 (1999).

Nature 2002 417:227

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10. DEVELOPMENT AND EVOLUTION: THEORETICAL ASPECTS

Greg Gibson (North Carolina State University, US) discusses
development and evolution, the author making the following
points:

1) In the context of development, a process is "robust" if it
can proceed normally despite the enormous capacity for
perturbation inherent in all biological systems.

2) Theoretical quantitative genetics, one of the most successful
of all fields of biological enquiry, seems to have run into
somewhat of a dead end when it comes to the integration of
development and evolution. Robustness and the dynamics of
development are two particularly fundamental problems that have
proven difficult to approach with classical methods [1] . There
are signs though that fresh ideas [2,3] and fresh empirical
approaches [4] are opening up a productive new research program
that may see tighter interaction between mathematical and
experimental biology.

3) The developmental problem essentially boils down to the fact
that static statistical models cannot capture the full
complexity of dynamic interactions between genes and the
environment. Quantitative geneticists like to study the
relationship between genetic polymorphism and phenotypic
variation. Genotypes are constants, and phenotypes are captured
at a single point in time, usually well after all of the
interesting developmental processes have concluded. The null
hypothesis is no association, and departures are fit initially
as additive contributions and then, if necessary, dominance and
interaction terms are introduced. For those not accustomed to
quantitative genetic reasoning -- namely, most molecular and
cellular biologists -- the arcane algebra can seem distant and
irrelevant. Development, after all, is assumed to be complex and
dominated by interactions due to phenomena such as redundancy,
feedback and synergism. How do we reconcile these world views?

4) One place where it may be productive to integrate them is in
terms of our understanding of "robustness", or developmental and
physiological stability. Robustness is gaining increasing
attention as the flip side of diversification, and as a process
at the heart of disease processes from psychological disturbance
to diabetes to aging in general. The incredible observation is
that, despite the fact that it takes 20,000 genes to make a
complex multicellular organism, and that these have to work
together in environments as diverse as the jungles of Mauritius
or suburban Detroit, development works. Arms and legs are the
same length in each individual, livers and hearts are the
appropriate size, and the brain wires itself correctly, all in
the face of considerable potential for perturbation.

References (abridged):

1. Zhivotovsky L.A. and Feldman M.W. (1992) On models of
quantitative genetic variability: a stabilizing
selection-balance model. Genetics, 130:947-955.

2. von Dassow G., Meir E., Munro E. and Odell G.M. (2000) The
segment polarity network is a robust developmental module.
Nature, 406:188-192.

3. Meir, E., von Dassow, G., Munro, E. and Odell, G.M. (2002).
Robustness, flexibility, and the role of lateral inhibition in
the neurogenic network. Curr. Biol. 2002 12:778

4. Houchmanzadeh B., Wieschaus E. and Leibler S. (2002)
Establishment of developmental precision and proportions in the
early Drosophila embryo. Nature, 415:798-802.

Current Biology 2002 12:R347

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11. ON EPITHELIA AND INNATE IMMUNITY

Tomas Ganz (University of California Los Angeles, US) discuss
epithelia, the author making the following points:

1) Epithelia are tissues consisting of sheets of similar cells
bound closely together, which include the epidermis, the
surfaces of the eyes, the surfaces of the hollow tubes and sacs
that make up the digestive, respiratory, reproductive, and
urinary tracts, and the secretory cells and ducts of various
glands. Depending on their predominant function, epithelia can
be described further as barrier, secretory, or absorptive, but
often all three functions coexist. These are the tissues most
exposed to environmental bacteria. The importance of epithelia
in host defense is best illustrated by the common experience
that disruption of the epithelial layers, such as occurs in a
minor skin scrape or a burn, greatly increases the likelihood of
penetrating infection. Mechanical barrier properties of
epithelia, the physical cleansing effects of their secretions,
and the shedding of colonized cells normally contribute to
protection from microbes (1). Moreover, injured or infected
epithelial cells help initiate the inflammatory response by
emitting chemotactic signals that attract blood-borne host
defense cells.

2) Although the ability of various glands to produce
antimicrobial substances has been appreciated since Alexander
Fleming's (2) pioneering studies of lysozyme in tears,
respiratory secretions, and saliva, more recently it has become
clear that barrier and absorptive epithelia also produce
numerous antimicrobial substances (3-5). There are impressive
similarities between the polypeptide arsenal of various
epithelial cells and the prototypical professional host defense
cells, the polymorphonuclear leukocytes. In some cases (e.g.,
lysozyme and lactoferrin), the same genes are highly expressed
in both cell types; in other cases (e.g., defensins,
peroxidase), the two cell types express different members of the
same gene family. These similarities reinforce the notion that
epithelial cells, like polymorphonuclear leukocytes, are
important effectors of innate immunity.

3) Canny et al (Proc. Nat. Acad. Sci. 2002 99:3902) have now
demonstrated that appropriately stimulated human epithelial cell
lines, as well as several specimens of human epithelial tissues,
express on their cell membranes bactericidal
permeability-increasing protein (BPI), heretofore known as an
abundant antimicrobial constituent of polymorphonuclear
leukocytes. BPI is bactericidal to many Gram-negative bacteria,
a specificity that is determined by its avid binding to
lipopolysaccharide, the major component of the external layer of
the outer membrane of these bacteria.

References (abridged):

1. Metchnikoff, E. (1905) Immunity in Infective Diseases
(Cambridge Univ. Press, Cambridge, U.K.), pp. 403-432.

2. Fleming, A. (1922) Proc. R. Soc. London B Biol. Sci. 93,
306-317.

3. Diamond, G. , Zasloff, M. , Eck, H. , Brasseur, M. , Maloy,
W. L. & Bevins, C. L. (1991) Proc. Natl. Acad. Sci. USA 88,
3952-3956.

4. Valore, E. V. , Park, C. H. , Quayle, A. J. , Wiles, K. R. ,
McCray, P. B. & Ganz, T. (1998) J. Clin. Invest. 101, 1633-1642.

5. Harder, J. , Bartels, J. , Christophers, E. & Schroeder,
J.-M. (1997) Nature (London) 387, 861-862.

Proc. Nat. Acad. Sci. 2002 99:3357

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12. ON GLOBAL DISPERSAL OF FREE-LIVING MICROBIAL EUKARYOTE
SPECIES

Bland J. Finlay (Center for Ecology and Hydrology Windermere,
UK) discuss dispersal of microbial species, the author making
the following points:

1) During the great age of natural history exploration in the
19th century, it became abundantly clear that many animal
species -- especially the larger ones-- had restricted
geographical distributions. In many cases, isolation had
apparently led to speciation, resulting for example in
distinctive island faunas (1). A rather different picture was
provided by the small band of traveling naturalists who were
equipped with microscopes. Most hoped to discover new and exotic
species of microbial eukaryotes (e.g., protozoa, diatoms, and
other microalgae), but their hopes were dashed by the lack of
novelty they found. As early as 1887, the microscopist W. H.
Maskell conceded that the ciliated protozoa living in the fresh
waters of New Zealand were basically identical to those known
from Europe (2). At around this time, similar ideas also began
to appear with respect to the prokaryotes (bacteria).
Beijerinck's pioneering use of enrichment culture techniques
showed that diverse types of bacteria could be cultured from
almost any type of natural material (3), and species recorded
from a particular habitat type located in geographically distant
places were usually similar if not identical to each other.

2) Recent evidence indicates that these ideas can be extended to
the microbial eukaryotes. There is, for example, no evidence
that flagellated protozoan morphospecies have biogeographies (4)
-- communities from adjacent sites are not more similar to each
other than they are to those from more distant sites. The same
flagellate genotype has been isolated from a shallow inland
fjord in Denmark and from hydrothermal vents in the Pacific (5).
The same planktonic foraminiferan morphospecies are common to
both Arctic and Antarctic waters, and some of these are also
genetically identical. All 86 freshwater ciliated protozoan
morphospecies identified from a volcanic crater lake in
Australia in the late 1990s were already known from Northern
Europe by the mid-1930s.

3) There are strong indications that protozoa and other
microbial eukaryotes in general do not have biogeographies, and
one obvious explanation is that they are simply so abundant that
continuous large-scale dispersal sustains their global
distribution. The local abundance of microbial eukaryote species
is, indeed, impressively large. An average-sized protozoon with
a mass of about 1 ng typically has an areal abundance roughly 12
orders of magnitude greater than that of an average-sized
mammal, so sheer weight of numbers might be expected to drive
large-scale dispersal for purely statistical reasons. When we
consider the many forces in the natural environment that must
drive the dispersal of small organisms (e.g., hurricanes, global
oceanic circulation, labyrinthine groundwater networks, damp fur
and feathers), it is not surprising that some spectacular
examples have been recorded by explorer-naturalists. While the
Beagle was sailing in oceanic waters of the tropical Atlantic,
Darwin scraped from the mast and sails a fine layer of dust that
was rich in freshwater diatoms. These had been deposited by the
combined agency of a tornado and the Harmattan blowing from West
Africa.

In summary: The abundance of individuals in microbial species is
so large that dispersal is rarely (if ever) restricted by
geographical barriers. This "ubiquitous" dispersal requires an
alternative view of the scale and dynamics of biodiversity at
the microbial level, wherein global species number is relatively
low and local species richness is always sufficient to drive
ecosystem functions.

References (abridged):

1. S. Anderson, Q. Rev. Biol. 69, 451 (1994)

2. W. M. Maskell, Trans. N.Z. Inst. 20, 3 (1887)

3. C. B. van Niel, in Martinus Willem Beijerinck, His Life and
Work, G. van Iterson, L. E. Dooren de Jong, A. J. Kluyver, Eds.
(Science Tech., Madison, WI, 1983, Forward)

4. D. J. Patterson, W. J. Lee, in The Flagellates, B. S. C.
Leadbeater, J. C. Green, Eds. (Taylor & Francis, London, 2000),
pp. 269-287

5. M. S. Atkins, A. P. Teske, O. R. Anderson, J. Euk. Microbiol.
47, 400 (2000)

Science 2002 296:1061

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13. ON AUTOMATIC ANALYSIS OF CHARACTER STRINGS

D. Benedetto et al (La Sapienza University, IT) discuss analysis
of character strings, the authors making the following points:

1) Many systems and phenomena in nature are often represented in
terms of sequences or strings of characters. In experimental
investigations of physical processes, for instance, one
typically has access to the system only through a measuring
device which produces a time record of a certain observable,
i.e., a sequence of data. On the other hand, other systems are
intrinsically described by a string of characters, e.g., DNA and
protein sequences, and language.

2) When analyzing a string of characters, the main question is
to extract the information it brings. For a DNA sequence this
would correspond to the identification of the sub-sequences
codifying the genes and their specific functions. On the other
hand, for a written text one is interested in understanding it,
i.e., recognizing the language in which the text is written, its
author, the subject treated, and eventually the historical
background.

3) The problem being cast in such a way, one would be tempted to
approach it from a particular point of view: that of information
theory [1,2]. In this context, the word "information" acquires a
very precise meaning, namely that of the entropy of the string,
a measure of the "surprise" the source emitting the sequences
can provide to us. As is evident, the word information is used
with different meanings in different contexts. Suppose we have
the ability to measure the entropy of a given sequence (e.g., a
text). Is it possible to obtain from this measure the
information (in the semantic sense) we were trying to extract
from the sequence? This is the question addressed by the authors.

4) The authors present a general method for the automatic
recognition and classification of sequences of characters. The
authors discuss in particular the application to textual corpora
in several languages. The authors demonstrate how a suitable
definition of remoteness between texts, based on the concept of
relative entropy, allows the extraction from a text of much
important information: the language in which it is written, the
subject treated, and its author. In addition, the method allows
the classification of sets of sequences (a corpus) on the basis
of the relative distances among the elements of the corpus
itself and organizes them in a hierarchical structure (graph,
tree, etc.). The method is highly versatile and general. It
applies to any kind of corpora of character strings
independently of the type of coding behind them: time sequences,
language, genetic sequences (DNA, proteins, etc.). It does not
require any a priori knowledge of the corpus under investigation
(alphabet, grammar, syntax) nor about its statistics. The
authors suggest these features are potentially very important
for fields where human intuition can fail: DNA and protein
sequences, geological time series, stock market data, medical
monitoring, etc.

References (abridged):

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

2. Complexity, Entropy and Physics of Information, edited by
W.H. Zurek (Addison-Wesley, Redwood City, CA, 1990).

Phys. Rev. Lett. 2002 88:048702

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14. ON BUILDING NANOSTRUCTURES FROM THE BOTTOM UP

N.C. Seeman and A.M. Belcher (University of Texas Austin, US)
discuss building nanostructures, the authors making the
following points:

1) We hear continually that nanoscience and nanotechnology are
frontier areas. Everyone is aware that nanotechnology and
nanoscience involve the construction and analysis of objects and
devices that are very small on the macroscopic scale.
Nevertheless, if the ultimate feature sizes of nanoscale objects
are approximately a nanometer or so, we are talking about
dimensions an order of magnitude larger than the scale exploited
by chemists for over a century. Synthetic chemists have
manipulated the constituents, bonding, and stereochemistry of
vast numbers of molecules on the angstrom scale, and physical
and analytical chemists have examined the properties of these
molecules. So what is so special about the nanoscale?

2) There are many answers to this question, possibly as many as
there are people who call themselves nanoscientists or
nanotechnologists. A particularly intriguing feature of the
nanoscale is that this is the scale on which biological systems
build their structural components, such as microtubules,
microfilaments, and chromatin. The associations maintaining
these and the associations of other cellular components seem
relatively simple when examined by high-resolution structural
methods, such as crystallography or NMR -- shape
complementarity, charge neutralization, hydrogen bonding, and
hydrophobic interactions.

3) A key property of biological nanostructures is molecular
recognition, leading to self-assembly and the templating of
atomic and molecular structures. For example, it is well known
that two complementary strands of DNA will pair to form a double
helix. DNA illustrates two features of self-assembly. The
molecules have a strong affinity for each other and they form a
predictable structure when they associate. Those who wish to
create defined nanostructures would like to develop systems that
emulate this behavior. Thus, rather than milling down from the
macroscopic level, using tools of greater and greater precision
(and probably cost), they would like to build nanoconstructs
from the bottom up, starting with chemical systems.(1-5)

References (abridged):

1. Seeman, N. C. (1999) Trends Biotechnol. 17, 437-443

2. Seeman, N. C. (1982) J. Theor. Biol. 99, 237-247

3. Qiu, H. , Dewan, J. C. & Seeman, N. C. (1997) J. Mol. Biol.
267, 881-898

4. Robinson, B. H. & Seeman, N. C. (1987) Protein Eng. 1, 295-300

5. Petrillo, M. L. , Newton, C. J. , Cunningham, R. P. , Ma,
R.-I. , Kallenbach,
N. R. & Seeman, N. C. (1988) Biopolymers 27, 1337-1352

Proc. Nat. Acad. Sci. 2002 99:6451

Related Background:

SELF-ASSEMBLY OF METAL NANOSTRUCTURES ON POLYMER SCAFFOLDS

W.A. Lopes and H.M. Jaeger (University of Chicago, US) discuss
self-assembly of metal nanostructures, the authors making the
following points:

1) Self-assembly is emerging as an elegant "bottom-up" method
for fabricating nanostructured materials. This approach becomes
particularly powerful when the ease and control offered by the
self-assembly of organic components is combined with the
electronic, magnetic, or photonic properties of inorganic
components.

2) The authors report a demonstration of a versatile
hierarchical approach for the assembly of organic-inorganic
copolymer-metal nanostructures in which one level of self-
assembly guides the next. In a first step, ultrathin diblock
copolymer films form a regular scaffold of highly anisotropic
stripe-like domains. During a second assembly step, differential
wetting guides diffusing metal ions to aggregate selectively
along the scaffold, producing highly organized metal
nanostructures.

3) The authors report that in contrast to the usual requirement
of near-equilibrium conditions for ordering, the metal arranged
on the copolymer scaffold produces the most highly ordered
configurations when the system is far from equilibrium. The
authors delineate two distinct assembly modes of the metal
component -- each mode characterized by different ordering
kinetics and strikingly different current-voltage
characteristics. The authors suggest these results therefore
demonstrate the possibility of guided large-scale assembly of
laterally nanostructured systems.

Nature 2001 414:735

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15. ON THE PHYSICS OF OIL EXPLORATION

B. Clark and R. Kleinberg (Schlumberger-Doll Research, US)
discuss oil exploration, the authors making the following points:

1) In 1927, a small geophysical research company founded by two
French brothers developed a new approach to oil exploration.
Conrad and Marcel Schlumberger, physicist and engineer
respectively, demonstrated that electrical resistivity
measurements could be made in a well and that the readings were
different for different geological layers. Further investigation
showed that formations saturated with oil had higher
resistivities than ones saturated with saline water, so a high
resistivity reading could indicate an oil-bearing formation.
This discovery was so useful that, by 1935, 70 teams of
engineers with resistivity-measuring equipment were deployed to
oil-producing regions worldwide. Such was the birth of the
"well-logging" industry, named for the strip of paper -- the log
-- on which are recorded measurements as a function of depth
beneath the surface.(1)

2) Nowadays, oil and natural gas are located with the help of
sophisticated physical measurements of subsurface formations.
These measurements use electromagnetic fields and waves,
acoustic waves, neutron scattering, gamma-ray radiation, nuclear
magnetic resonance (NMR), infrared spectroscopy, and pressure
and temperature sensors -- all in a narrow (15- to 50-centimeter
diameter) hole, thousands of meters deep, where the pressure and
temperature are high and caustic fluids are present. No one
measurement is adequate to define the structure and properties
of an oil reservoir, and typically many measurements are made
simultaneously by combinations of instruments. Significant
advances have been made in instrumentation, modeling, and
inversion techniques. Using physics, the modern petroleum
engineer can find smaller petroleum reservoirs in more remote,
complex, and difficult geological settings than ever before.

3) A common misconception is that alternate energy sources will
soon replace hydrocarbons. But according to the US Department of
Energy, 20 years from now hydrocarbons will satisfy a greater
percentage of the world's energy demand than they do today.(2)
As a consequence, there is a need to develop new technologies
for finding and producing oil and natural gas. The DOE estimates
that the world will need 59% more energy in 2020 than in 1999.
This projected increase is due almost entirely to population
growth and industrialization in developing nations. Between 1999
and 2020, oil production will have to increase by 60%, and
natural gas production by 92%, to satisfy the world's growing
energy demands. Together, oil and natural gas supplied 63% of
the world's energy in 1999; they are projected to supply 68% by
2020.

4) Of perhaps equal significance is the uneven geographic
distribution of oil and gas reserves. For example, in 2000,
two-thirds of oil reserves were in the Middle East, compared to
2% in the US.(3) In the future, the Middle Eastern nations'
share of the oil market will be even larger than it is today.
Increased energy demands and the asymmetric distribution of
reserves present daunting challenges, especially given the
world's aging reservoirs and price fluctuations that tend to
inhibit long-term investment. There is some debate as to when
the production of conventional, relatively cheap oil will peak
and begin to decrease: Some predict it will happen within a
decade.(4) As oil becomes more expensive and difficult to find,
new technologies become ever more essential.

References (abridged):

1. J. Hearst, P. Nelson, F. Paillet, Well Logging for Physical
Properties: A Handbook for Geophysicists, Geologists and
Engineers, 2nd ed., Wiley, New York (2000). S. M. Luthi,
Geological Well Logs: Their Use in Reservoir Modeling,
Springer-Verlag, New York (2001).

2. Energy Information Administration, Office of Integrated
Analysis and Forecasting, International Energy Outlook2001, rep.
no. DOE/EIA-0484(2001), US Department of Energy, Washington, DC
(March 2001), available online at
http://www.eia.doe.gov/oiaf/ieo/index.html

3. Energy Information Administration, Office of Energy Markets
and End Use, International Energy Annual 1999, rep. no.
DOE/EIA-0219(99), US Department of Energy, Washington, DC
(February 2001). Data on reserves by region are available online
at http://www.eia.doe.gov/emeu/intemational/petroleu.html

4. C. J. Campbell, J. H. Haherrere, Sci. Am. March 1998, p. 78.

Physics Today 2002 April

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16. ON DOUBLE HETEROSTRUCTURE LASERS

In this context, the term "cladding" refers to a thin coating of
one material (e.g., doped semiconductor) bonded onto another
material.

F. Capasso et al (Bell Laboratories, US) discuss semiconductor
lasers, the authors making the following points:

1) Semiconductor lasers are an important light source for
fiber-optic communications and are key components of such common
appliances as compact disc players, supermarket scanners, laser
printers, fax machines, and laser pointers. The lasers in these
applications are so-called "double heterostructure lasers",
essentially diodes consisting of an active semi-conductor region
sandwiched between doped semiconductor cladding layers, one
n-type, the other p-type. The cladding regions supply electrons
and holes to the active region when an appropriate bias voltage
is applied. They also have a higher bandgap and a lower
refractive index than the active layer, so that the injected
electrons and holes as well as the photons generated by their
annihilation are confined to the active region. The share of the
2000 Nobel Prize in Physics awarded to Zhores Alferov and
Herbert Kroemer for their role in developing the double
heterostructure laser recognized the major impact of this device.

2) Double heterostructure lasers have demonstrated high
performance and have been successfully commercialized for
wavelengths ranging from blue to the near infrared (IR), up to
about 1.6 microns. Unfortunately, few semi-conductor materials
emitting in the mid-IR (2-20 microns) are reliable, easily
processed, and insensitive to temperature cycling -- the
repeated heating and cooling associated with laser operation.

3) The scientifically and technologically interesting mid-IR,
often called the molecular-fingerprint region, is the part of
the spectrum where gases and vapors have telltale absorption
features associated with vibrorotational transitions -- that is,
those in which the vibrational and, generally, rotational
quantum numbers change. These features can be mapped by a number
of spectroscopic techniques in a wide range of industrial,
military, and scientific applications.

4) Semiconductor diode lasers made of lead salts and emitting in
the mid-IR have been commercially available for twenty years or
more. Lead-salt lasers, however, have limited power (at most a
few milliwatts of peak and continuous wave power), have a small
continuous single-mode range, and have yet to operate at room
temperature.(1)

References (abridged):

1. M. Tacke, Infrared Phys. Technol. 36,447 (1995). M. Hodges,
U.W. Schiessl, Proc. SPIE 3628, 113 (1999)

Physics Today 2002 May

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17. ON MIXED POLYMER BRUSHES

In this context, the term "polymer brush" refers to an array of
densely packed polymers in which one or both ends of polymer
chains are grafted to a solid surface. Polymer brushes play an
important role in a number of technologies involving surface
modification, including the stabilization of colloidal
particles, production of biocompatible interfaces and
lubrication.

A simple linear polymer is a chain molecule composed of monomers
with two reactive sites (bifunctional monomers), with
monofunctional terminal units. If more than one bifunctional
monomer is present, the chain is known as a "copolymer". A
copolymer in which a number of units of the same monomer are
located adjacent to one another (in "blocks" of monomers) is
called a "block copolymer". A "diblock copolymer" is composed of
two types of monomers (e.g., A and B), and may be depicted thus:
AAAAAABBBBBAAAAAABBBBBAAAAAAA.

S. Minko et al (Institute for Polymer Research Dresden, DE)
discuss mixed polymer brushes, the authors making the following
points:

1) Tailoring materials with smart response to external fields is
of abiding interest to material science. Modern devices like
sensors, switches, or microactuators crucially rely on a
response in one or more physical properties (e.g., surface
composition and energy, or optical and electrical properties) on
external control. These properties may be employed to tune
stability [I], wettability [2], adhesion [3], or to regulate
interaction with cells and proteins in biomaterials [4], or
membranes' permeability [5].

2) Many polymeric and biopolymeric systems respond to external
control by cooperative changes of their conformation (e.g.,
collapse of the chain structure in a bad solvent or denaturation
of proteins). Combination of conformational changes with phase
separation can amplify the response, a mechanism which has been
recently exploited in the form of two component (mixed) polymer
brushes and block-copolymer brushes.

3) If such a mixed brush of hydrophilic and hydrophobic
homopolymers is exposed to a hydrophilic solvent, the
hydrophilic component preferentially segregates to the top of
the film and the surface becomes hydrophilic. Exposing the same
brush to a hydrophobic solvent reversibly switches the surface
from hydrophilic to hydrophobic. Such an adoptive behavior is
very promising for engineering of smart surfaces for biomedical
applications and micro- and/or nanodevices. Although these
experiments have demonstrated the usefulness of mixed brushes
for constructing surfaces with reversibly tunable wetting
properties, the contact angle is sensitive only to the
composition on the top of the brush and averages over the
lateral structure. The local structure has yet remained unknown.

4) Grafting two incompatible polymers randomly onto a surface
prevents macrophase separation. Two limiting types of
morphologies can be distinguished: (1) The two species segregate
perpendicular to the substrate (layered phase), one species
being enriched at the substrate while the other segregates to
the top of the brush. The mixed brush remains laterally
homogeneous. This homogeneity is advantageous for designing
surfaces with reversibly tunable wettability.(2) The two species
self-assemble laterally into two-dimensional structures (e.g.,
the "ripple" phase) with a well-defined lateral length scale,
which is of the order of the extension of the molecules. Similar
to thin films of diblock copolymers these systems might serve as
templates for nanostructures.

References (abridged):

1. R. Yerushalmi-Rozen et al., Science 263, 793 (1994).

2. P. Mansky et al., Science 275, 1458 (1997).

3. E. Raphael and P. G. de Gennes, J. Phys. Chem. 96, 4002
(1992).

4. C. S. Chen et al., Science 276, 1425 (1997).

5. Y. Ito et al., J. Am. Chem. Soc. 119, 1619 (1997).

Phys. Rev. Lett. 2002 88:035502

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18. ON SYNTHETIC MOLECULAR MOTORS

N. Koumura et al (University of Groningen, NL) discuss synthetic
molecular motors, the authors making the following points:

1) Molecular motors such as the ATP-synthase rotary motor(1) and
the muscle linear motor(2) are among the most fascinating
systems found in nature. The dynamic biological processes
involved are reminiscent of the movement in artificial motors,
ubiquitous in macroscopic machinery common to daily life, in
which energy consumption is utilized to accomplish controlled
motion.(3) In the recent endeavor toward nanotechnology and
molecular machinery, the biological motors are a main source of
inspiration.(4) Attempts to mimic the dynamic behavior via
synthetic design have resulted in several elegant molecular
systems in which translational or rotary motion is controlled by
means of chemical, electrochemical, photochemical, or thermal
input. Prominent examples are molecular ratchets,(5) turnstiles,
rotors, and a variety of molecular switches.

2) Catenanes and rotaxanes comprise a family of compounds which
have shown to be particularly useful to demonstrate several
features essential to molecular machines, like translational
motion of a ring on a string in a rotaxane or circumrotation of
two rings in a catenane. Sauvage and co-workers (2000) reported
the contraction and stretching of a linear rotaxane dimer
resembling a natural muscle at work. Recently, Stoddart and Zink
(2001) demonstrated the threading and dethreading of rotaxanes
assembled on a surface. Rotation in metal bisporphyrinate double
decker complexes in response to external electrochemical stimuli
was accomplished by Aida and co-workers (2000).

3) The following basic requirements must be satisfied in any
successful design of a rotary molecular motor: (i) rotary
motion, (ii) energy consumption, and (iii) unidirectional
rotation. The first synthetic molecular motors, performing
unidirectional rotary motion upon energy uptake, were reported
simultaneously by Kelly and Harada and Feringa in 1999. In both
systems, molecular chirality turned out to be an essential
feature to induce unidirectional rotation. Kelly's motor
comprises a helicene connected to a triptycene unit which
undergo a 120 degree rotation with respect to each other
exclusively in one direction induced by a number of chemical
steps. The architecture of the Harada-Feringa light-driven
molecular motor is based on helical-shaped sterically
overcrowded alkenes (symmetric biphenanthrylidenes). Repetitive
unidirectional rotation around the central double bond is
achieved by two photochemical trans-cis isomerizations, each
followed by a thermal conversion which adds up to a four-step
cycle completing a full 360 degree rotation process. It was
established that the direction of rotation -- clockwise or
counterclockwise -- is governed by the two stereogenic centers
present in the molecule. Further important structural features
in this first generation light-driven molecular motor are the
identical nature of the upper and lower parts of the
tetrahydrobiphenanthrylidene and the all-carbon framework of the
molecule. In second generation molecular motors, distinct upper
and lower halves as well as heteroatoms allow tuning of the
rotary motion.

References (abridged):

1. (a) Boyer, P. D. Biochim. Biophys. Acta 1993, 1140, 215-250.
(b) Abrahams, J. P.; Leslie, A. G. W.; Lutter, R.; Walker, J. E.
Nature 1994, 370, 621-628. (c) Noji, H.; Yasuda, R.; Yoshida,
M.; Kinosita, K., Jr. Nature 1997, 386, 299-302. (d) Mehta, A.
D.; Rief, M.; Spudich, J. A.; Smith, D. A.; Simmons, R. M.
Science 1999, 283, 1689-1695. (e) Sambongi, Y.; Iko, Y.; Tanabe,
M.; Omote, H.; Iwamoto-Kihara, A.; Ueda, I.; Yanagida, T.; Wada,
Y.; Futai, M. Science 1999, 286, 1722-1724

2. (a) Finer, J. T.; Simmons, R. M.; Spudich, J. A. Nature 1994,
368, 113-119. (b) Kitamura, K.; Tokunaga, M.; Iwane, A. H.;
Yanagida, T. Nature 1999, 397, 129-134. (c) Veigel, C.;
Coluccio, L. M.; Jontes, J. D.; Sparrow, J. C.; Milligan, R. A.;
Molloy, J. E. Nature 1999, 398, 530-533. (d) Wells, A. L.; Lin,
A. W.; Chen, L.-Q.; Safer, D.; Cain, S. M.; Hasson, T.;
Carragher, B. O.; Milligan, R. A.; Sweeney, H. L. Nature 1999,
401, 505-508. (e) Walker, M. L.; Burgess, S. A.; Sellars, J. R.;
Waang, F.; Hammler, J. A., III; Trinick, J.; Knight, P. J.
Nature 2000, 405, 804-807. (f) Endow, S. A.; Higuchi, H. Nature
2000, 406, 913-916

3. Special issue of Science 2000, 288, 79-106; Movement:
molecular to robotic.

4. Feringa, B. L. Acc. Chem. Res. 2001, 34, 504-513.

5. Kelly, T. R.; Tellitu, I.; Sestelo, J. P. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1866-1868

J. Am. Chem. Soc. 2002 124:5037

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19. ON CARDIAC PHYSIOLOGY AND ARRHYTHMIAS

Eduardo Marban (Johns Hopkins University, US) discuss cardiac
physiology and arrhythmias, the author making the following
points:

1) The heart pumps blood throughout the body and never rests,
undergoing roughly three billion cycles in a typical lifetime.
To achieve this, the heart must first relax so that its chambers
(the atria and ventricles) can fill with blood, and then
contract to propel the blood throughout the body. This cycle of
relaxation and contraction occurs in a single heartbeat.

2) Each heartbeat is initiated by a pulse of electrical
excitation that begins in a group of specialized pacemaker cells
and subsequently spreads throughout the heart. This electrical
impulse is made possible by the electrochemical gradient that
exists across the surface membrane of each heart cell, or
"myocyte". At rest, the membrane is selectively permeable to K+
ions, and the electrochemical potential inside the myocyte is
negative with respect to the outside. During electrical
excitation, the membrane becomes permeable to Na+ ions and the
electrochemical potential reverses or "depolarizes". Ca2+ ions
move into the cell and activate the contractile machinery -- a
process that, when it happens en masse, causes the atria and
ventricles to contract and expel blood. The wave of
depolarization is self-limiting; as a negative membrane
potential is restored, the heart relaxes and fills with blood
for the next cycle.

3) Because the heartbeat is so dependent on the proper movement
of ions across the surface membrane, disorders of ion channels
-- or "channelopathies" -- make up a key group of heart
diseases. Channelopathies predispose individuals to disturbances
of normal cardiac rhythm. If the heart beats too slowly
(bradyarrhythmias) or so rapidly that it cannot fill adequately
(tachyarrhythmias), then this leads to circulatory collapse and,
in the extreme case, death. The incidence of arrhythmias is
poorly defined, but conservative estimates are in the range of
several million per year in the United States. Arrhythmias lead
to more than 250,000 sudden deaths per year, countless lost work
days, and financial costs related to treatment, including the
implantation of more than 250,000 electronic pacemakers and more
than 60,000 defibrillators per year. The numbers worldwide are
certainly much greater. Several different genetic and acquired
channelopathies can cause such arrhythmias.(1-5)

4) In summary: Genetic alterations of various ion channels
produce heritable cardiac arrhythmias that predispose affected
individuals to sudden death. The investigation of such
"channelopathies" continues to yield remarkable insights into
the molecular basis of cardiac excitability. The concept of
channelopathies is not restricted to genetic disorders; notably,
changes in the expression or post-translational modification of
ion channels underlie the fatal arrhythmias associated with
heart failure. Recognizing the fundamental defects in
channelopathies provides the basis for new strategies of
treatment, including tailored pharmacotherapy and gene therapy.

References (abridged):

1. Catterall, W. A. Molecular properties of sodium and calcium
channels. J. Bioenerg. Biomembr. 28, 219-230 (1996).

2. Jan, L. Y. & Jan, Y. N. Voltage-gated and inwardly rectifying
potassium channels. J. Physiol. 505, 267-282 (1997).

3. Philipson, K. D. & Nicoll, D. A. Sodium-calcium exchange: a
molecular perspective. Annu. Rev. Physiol. 62, 111-133 (2000).

4. Marban, E., Yamagishi, T. & Tomaselli, G. F. Structure and
function of voltage-gated sodium channels. J. Physiol. 508,
647-657 (1998).

5. Zeng, J. & Rudy, Y. Early afterdepolarizations in cardiac
myocytes: mechanism and rate dependence. Biophys. J. 68, 949-964
(1995).

Nature 2002 415:213

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20. VISUAL FEEDBACK AND VEHICLE STEERING CONTROL

G. Wallis et al (Max Planck Institute for Biological Cybernetics
Tubingen, DE) discuss vehicle steering control, the authors
making the following points:

1) Some motor tasks can be completed, quite literally, with our
eyes shut. Most people can touch their nose without looking or
reach for an object after only a brief glance at its location.
This distinction leads to one of the defining questions of
movement control: is information gleaned prior to starting the
movement sufficient to complete the task (open loop), or is
feedback about the progress of the movement required (closed
loop)? One task that has commanded considerable interest in the
literature over the years is that of steering a vehicle, in
particular lane-correction and lane-changing tasks. Recent work
has suggested that this type of task can proceed in a
fundamentally open loop manner [1, 2] , with feedback mainly
serving to correct minor, accumulating errors.

2) Imagine changing lanes on a motorway/freeway. In particular,
try to recall the series of angles through which the steering
wheel passes in completing the maneuver. The vast majority of us
describe turning the wheel out to 20 degrees or 30 degrees and
then returning the wheel to the middle position. Our intuition
in this case is, however, wrong. It is wrong because we have
failed to describe the appropriate symmetrical movement of the
steering wheel in the opposite direction required to straighten
the car.(3-5)

3) The authors report they reevaluated the conclusions of
previous studies by conducting a new set of experiments in a
driving simulator. The authors report a demonstration that, in
fact, drivers rely on regular visual feedback, even during the
well-practiced steering task of lane changing. Without feedback,
drivers fail to initiate the return phase of the maneuver,
resulting in systematic errors in final heading. The results
provide new insight into the control of vehicle heading,
suggesting that drivers employ a simple policy of ''turn and
see,'' with only limited understanding of the relationship
between steering angle and vehicle heading.

References (abridged):

1. Godthelp J. (1985) Precognitive control: open and closed loop
steering in a lane change manoeuvre. Ergonomics, 28:1419-1438.

2. Hildreth E., Beusmans J., Boer E. and Royden C. (2000) From
vision to action: experiments and models of steering control
during driving. J. Exp. Psychol. Hum. Percept. Perform.,
26:1106-1132.

3. Donges E. (1978) A two-level model of driver steering
behaviour. Hum. Factors, 20:691-707.

4. Hess R. and Modjtahedzadeh A. (1990) A control theoretic
model of driver steering behavior. IEEE Contr. Syst. Mag.,
10:3-8.

5. McRuer D., Allen R., Weir D. and Klein R. (1977) New results
in driver steering control models. Hum. Factors, 19:381-397.

Current Biology 2002 12:295

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21. ON THE EAST AFRICAN HIGHLANDS RESURGENCE OF MALARIA

The disease malaria is caused by a protozoan parasite of the
genus Plasmodium, and it is one of the most dangerous diseases
infecting human populations. Approximately 300 million to 500
million people are infected annually, and 1.5 million to 2.7
million lives are lost to malaria each year, with most deaths
occurring among children in sub-Saharan Africa. Of the 4 species
that cause malaria in humans, P. falciparum is the greatest
cause of infection and mortality. The growing resistance of the
malaria parasite to drugs and the resistance of mosquitoes to
insecticides have resulted in a current resurgence of malaria in
many parts of the world and a pressing need for vaccines and new
drugs.

S.I. Hay et al (University of Oxford, UK) discuss malaria in
East Africa, the authors making the following points:

1) The public health and economic consequences of Plasmodium
falciparum malaria are once again regarded as priorities for
global development. There has been much speculation on whether
anthropogenic climate change is exacerbating the malaria
problem, especially in areas of high altitude where P.
falciparum transmission is limited by low temperature(1-4). The
International Panel on Climate Change has concluded that there
is likely to be a net extension in the distribution of malaria
and an increase in incidence within this range(5).

2) The authors report they investigated long-term meteorological
trends in four high-altitude sites in East Africa, where
increases in malaria have been reported in the past two decades.
The authors demonstrate that temperature, rainfall, vapour
pressure and the number of months suitable for P. falciparum
transmission have not changed significantly during the past
century or during the period of reported malaria resurgence. A
high degree of temporal and spatial variation in the climate of
East Africa suggests further that claimed associations between
local malaria resurgences and regional changes in climate are
overly simplistic.

3) If climate has not changed at the four study sites, other
changes must have been responsible for the observed increases in
malaria. At Kericho, the evidence suggests that the control of
malaria implemented since the large epidemics of the 1940s has
failed recently because of a rise in antimalarial drug
resistance. Likewise, the resurgence of malaria in the Usambara
mountains of Tanzania has been linked to a rise in drug
resistance, casting doubt on the previous interpretation of
local changes in climate caused by deforestation. In southern
Uganda, epidemiological changes have been attributed to the
shorter-term climate phenomenon of El Nino, which is suggested
to cause changes in vector abundance. At Muhanga, both land use
changes and elevated temperatures have been proposed to have
caused the malaria increases. In other highland locations in
Africa, increases in malaria have been attributed to population
migration and the breakdown in both health service provision and
vector control operations. Economic, social and political
factors can therefore explain recent resurgences in malaria and
other mosquito-borne diseases with no need to invoke climate
change.

4) In summary: The most parsimonious explanation for recent
changes in malaria epidemiology involves factors other than
climate change. The authors suggest that the more certain
climatologists become that humans are affecting global climates,
the more critical epidemiologists should be of the evidence
indicating that these changes affect malaria.

References (abridged):

1. Loevinsohn, M. E. Climatic warming and increased malaria
incidence in Rwanda. Lancet 343, 714-718 (1994).

2. McMichael, A. J., Haines, A., Sloof, R. & Kovats, S. Climate
Change and Human Health (World Health Organization, Geneva,
1996).

3. Epstein, P. R. et al. Biological and physical signs of
climate change: focus on mosquito-borne diseases. Bull. Am.
Meteorol. Soc. 79, 409-417 (1998).

4. Martens, P. How will climate change affect human health? Am.
Sci. 87, 534-541 (1999).

5. McCarthy, J. J., Canziani, O. F., Leary, N. A., Dokken, D. J.
& White, K. S. Climate change 2001: Impacts, Adaptation, and
Vulnerability -- Contribution of Working Group II to the Third
Assessment Report of the Intergovernmental Panel on Climate
Change (Cambridge Univ. Press, Cambridge, 2001).

Nature 2002 415:905

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22. ON AMYOTROPHIC LATERAL SCLEROSIS AND PHYSICIAN-ASSISTED
SUICIDE

J.H. Veldink et al (University of Utrecht, NL) discuss
amyotrophic lateral sclerosis, the authors making the following
points:

1) Amyotrophic lateral sclerosis (ALS) is a devastating disease
characterized by the progressive degeneration of motor neurons.
ALS can begin at any time during adulthood, with a median age at
onset in the mid-50s.(1) Initial manifestations include weakness
of limbs or weakness in the bulbar region leading to
abnormalities of speech and difficulties in swallowing. The
patient eventually becomes paralyzed, and approximately 50
percent of patients die within three years after the onset of
symptoms, usually as the result of respiratory failure.

2) Supportive care is still the best treatment available for
patients with ALS. Treatment with riluzole, an inhibitor of
glutamate release, prolongs survival by only three to six months
without affecting the quality of life.(2) Patients often have
depression, feelings of loss of control, and a sense of
isolation.(3) In the terminal phase of ALS, dyspnea and anxiety
develop and require adequate treatment.(4,5)

3) Death is usually caused by respiratory failure unless
ventilatory support is provided. Approximately 4 percent of
patients agree to undergo a tracheostomy for long-term
mechanical ventilation. Patients with ALS and their physicians
may be confronted by end-of-life medical decisions, such as
whether or not to withhold or withdraw life-sustaining therapy
and whether or not to treat dyspnea or pain with opioids in high
doses. Specialists in ALS do receive requests for
physician-assisted death. It is not known how many patients with
ALS, given the option, would end their lives by
physician-assisted suicide or euthanasia, nor at what stage of
the disease they would choose to do so.

4) In 1994, the death by euthanasia of a patient with ALS in the
Netherlands was broadcast widely on television. Concern was
raised that euthanasia would be considered an alternative to
palliative care. In the Netherlands, euthanasia and assisted
suicide are still illegal, but there is no punishment if they
are performed by a physician and under strict conditions,
including the presence of a voluntary and well-considered
request, unbearable and hopeless suffering, and consultation
with a second physician. Although the possibility of depression
is a major consideration, referral to a psychiatrist is not
mandatory. Furthermore, physicians are supposed to follow
technical guidelines: for euthanasia, barbiturates are used to
induce coma, followed by a neuromuscular blocking agent to cause
death; for physician-assisted suicide, high doses of
barbiturates are administered orally.

5) The authors report that in the Netherlands between 1994 and
1999 one in five patients with ALS died as a result of
euthanasia or physician-assisted suicide.

References (abridged):

1. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O.
Incidence and prevalence of ALS in Ireland, 1995-1997: a
population-based study. Neurology 1999;52:504-509.

2. Lacomblez L, Bensimon G, Leigh PN, et al. A confirmatory
dose-ranging study of riluzole in ALS. Neurology 1996;47:Suppl
4:S242-S250.

3. Ganzini L, Johnston WS, McFarland HB, Tolle SW, Lee MA.
Attitudes of patients with amyotrophic lateral sclerosis and
their care givers toward assisted suicide. N Engl J Med
1998;339:967-973.

4. Miller RG, Rosenberg JA, Gelinas DF, et al. The care of the
patient with amyotrophic lateral sclerosis (an evidence-based
review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 1999;52:1311-1323.

5. Voltz R, Borasio GD. Palliative therapy in the terminal stage
of neurological disease. J Neurol 1997;244:Suppl 4:S2-S10.

New Engl. J. Med. 2002 346:1638

ScienceWeek http://www.scienceweek.com

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23. ON WORLD POVERTY AND HUNGER

Ismail Serageldin (Library of Alexandria, EG) discusses world
poverty, the author making the following points:

1) Much has been done to make the world a better place. The 20th
century was one of struggle for emancipation. The colonies were
liberated; many women received the franchise; and racial,
ethnic, and religious minorities and nonconformists were
acknowledged to have political and civil rights arising from
their common humanity. There have been many socioeconomic
improvements over the last 40 years: developing countries have
doubled school enrollments, halved infant mortality and adult
illiteracy, and extended life expectancy at birth by 20 years.
Despite these advances, much remains to be done. A global
developmental agenda demands our efforts and our solidarity.

2) At the present time, 1.2 billion people live on less than a
dollar per day.
1 billion people do not have access to clean water. More than 2
billion people have no access to adequate sanitation. 1.3
billion people, mostly in cities in the developing world, are
breathing air below the standards considered acceptable by the
World Health Organization. 700 million people, mostly women and
children, suffer from indoor air pollution due to
biomass-burning stoves, equivalent to smoking three packs of
cigarettes per day. Hundreds of millions of poor farmers have
difficulty maintaining the fertility of soils from which they
eke out a meager living.

3) To this stock of problems, we can now add a slew of new
challenges. The human population is increasing by 80 million
persons a year, mostly in the poorest countries. Dramatic
overconsumption and waste in wealthy nations and population
pressure in poor countries are putting enormous pressures on the
ecosystems on which we all depend.

4) The world's marine fisheries are grossly overexploited. Soils
are eroding. Water is becoming scarcer. Deforestation is
continuing. We must redouble our efforts to address the global
challenges of desertification, climate change, and biodiversity.
Agriculture must be transformed to promote sustainable food
security for the billions of hungry people in the world. The
challenges of urban poverty and environmental destruction are
unprecedented, and will only increase with the urban populations
of developing nations expected to treble over the next two
generations. In the 47 "least developed" countries of the world,
10% of the world's population subsists on less than 0.5% of the
world's income. Some 40,000 people die from hunger-related
causes every day. One sixth or more of the human family lives a
marginalized existence. Therein lies the challenge before us.
Will we accept such human degradation as inevitable? Or will we
strive to help the less fortunate? Will we regard ourselves as
no longer responsible for future generations, or will we try to
act as true stewards of Earth? It is not resources that are
lacking; it is the will to harness them. Indeed, the world has
never been richer, and the future promises even more.(1,2)

References:

1. J. Bronowski, Science and Human Values (Harper and Row, New
York, 1956).

2. R. D. Putnam, Making Democracy Work: Civic Traditions in
Modern Italy (Princeton Univ. Press, Princeton, NJ, 1993)
[publisher's information].

Science 2002 296:54

ScienceWeek http://www.scienceweek.com

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24. ON THE USE OF ANTIBIOTICS IN AGRICULTURE

M. Lipsitch et al (Harvard University, US) discuss the use of
antibiotics in agriculture, the authors making the following
points:

1) Everyone knows that bacterial resistance to antibiotics is a
bad thing, at least for humans and animals, if not for bacteria.
Drugs that were effective for treating community- and
hospital-acquired infections are no longer effective because the
target bacteria are resistant to their action. To be sure, it
may be some time before we really enter the predicted
"postantibiotic era" in which common infections are frequently
untreatable. Even now, however, the consequences of resistance
in some bacteria can be measured as increases in the term and
magnitude of morbidity, higher rates of mortality, and greater
costs of hospitalization for patients infected with resistant
bacteria relative to those infected with sensitive strains (1).

2) Dozens of new antimicrobial compounds have been licensed in
the U.S. during the last half century, but almost all "new
antibiotics" introduced in the last 40 years have been
relatively minor chemical variants of compounds to which
bacteria have already developed resistance. As a result,
bacteria have rapidly adapted existing resistance mechanisms to
evade the new compounds. Indeed, only a single chemically novel
class of antibacterial agents, the oxazolidinones, has been
introduced into clinical use since the 1970s.

3) There is no question that the resistance problem is of our
own making, a direct consequence of the appropriate as well as
the inappropriate use of these "wonder drugs" by humans. The
abundant calls for the more prudent use of antibiotics are well
justified, if seemingly unnecessary. Who would admit to being
against the prudent use of anything? Although it is not clear
that by reducing our use of these drugs alone we will be able to
reverse the growing tide of resistance (2-5), we can certainly
slow and maybe even stop that tide. But how do we reduce
antibiotic use? Although many antibiotic-prescribing decisions
in human medicine may be black or white (clearly medically
necessary or clearly not indicated), there is a large gray area
in which they provide a small but significant clinical benefit
to the individual (for example, more rapid cure of acute otitis
media) or psychological benefit to the patient (for example, a
placebo effect) and/or the physician (for example, to facilitate
the closure of a consultation). These gray-area applications of
antibiotics must be weighed against the incremental harm to the
population as a whole caused by the additional selective
pressure for antimicrobial resistance. In such contexts,
determining what is an appropriate use of an antibiotic is a
judgment call in which cultural, social, psychological, and
economic factors play at least as great a role as clinical and
epidemiological considerations.

4) Over half of the antibiotics that are produced in the U.S.
are used for agricultural purposes, according to a recent
estimate, and there is no question that this application of
these drugs has contributed to the generally high frequency of
resistant bacteria in the gut flora of chickens, swine, and
other food animals. However, regulation of agricultural uses of
antibiotics has been controversial, largely because policymakers
have been urged to weigh the clear benefits to animal health as
well as the economic benefits of antibiotic use to food
producers, pharmaceutical companies, and possibly also to
consumers against a threat to human health that is often
difficult to quantify precisely.

References (abridged):

1. Rubin, R. J. , Harrington, C. A. , Poon, A. , Dietrich, K. ,
Greene, J. A. & Moiduddin, A. (1999) Emerg. Infect. Dis. 5, 9-17

2. Levin, B. R. , Lipsitch, M. , Perrot, V. , Schrag, S. ,
Antia, R. , Simonsen, L. , Walker, N. M. & Stewart, F. M. (1997)
Clin. Infect. Dis. 24, S9-S16

3. Stewart, F. M. , Antia, R. , Levin, B. R. , Lipsitch, M. &
Mittler, J. E. (1998) Theor. Popul. Biol. 53, 152-165

4. Lipsitch, M. (2001) Trends Microbiol. 9, 438-444

5. Levin, B. R. (2001) Clin. Infect. Dis. 33, Suppl. 3, S161-S169

Proc. Nat. Acad. Sci. 2002 99:5752

ScienceWeek http://www.scienceweek.com

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25. IN FOCUS: ON MORPHOGENS

J.B. Gurdon and P-Y. Bourillot (University of Cambridge, UK)
discuss morphogens and make the following points:

1) Morphogens are secreted signalling molecules that organize a
field of surrounding cells into patterns. They form a gradient
of concentration emanating from a localized source, and
determine the arrangement and fate of responding cells according
to the different concentrations of the morphogen perceived by
the cells. The idea of a morphogen gradient is intimately
associated with the concept of positional information.(1) A cell
is believed to read its position in a concentration gradient of
an extracellular signal factor, and to determine its
developmental fate accordingly.(2,3)

2) Morphogen action is of special importance in understanding
development. This is because a single event, the emission of
morphogen from a source, can lead to the formation of several
different cell types in a correct spatial relationship to each
other. This is a highly efficient way of creating complex
patterns of gene expression and spatial position from a
population of uncommitted cells in an embryo.

3) An understanding of morphogen gradients requires answers to
two different questions. The first asks how a desired
concentration gradient is formed. We need to know the identity
of the morphogen, the shape and absolute concentration of the
gradient, and the factors that create and maintain the gradient
in its various positions. Much current work is providing some
answers to these questions, especially by identifying
extracellular molecules that bind morphogens, and that thereby
influence the concentration of morphogen free to reach cells
whose responses they determine.(4,5)

4) The second question asks how cells interpret a morphogen
concentration. To understand this, we need to know how cells
recognize different threshold concentrations of morphogen
through receptors on their surface and how they transduce this
information to the nucleus to create the appropriate gene or
cell fate response. This second question has so far been little
explored.

5) In summary: A morphogen gradient is an important concept in
developmental biology, because it describes a mechanism by which
the emission of a signal from one part of an embryo can
determine the location, differentiation and fate of many
surrounding cells. The value of this idea has been clear for
over half a century, but only recently have experimental systems
and methods of analysis progressed to the point where we begin
to understand how a cell can sense and respond to tiny changes
in minute concentrations of extracellular signalling factors.

References (abridged):

1. Wolpert, L. Positional information revisited. Development
(Suppl.) 3-12 (1989).

2. Cooke, J. Morphogens in vertebrate development: how do they
work? BioEssays 17, 93-96 (1995).

3. Lawrence, P. A. & Struhl, G. Morphogens, compartments, and
pattern: lessons from Drosophila? Cell 85, 951-961 (1996).

4. Neumann, C. & Cohen, S. Morphogens and pattern formation.
BioEssays 19, 721-729 (1997).

5. Teleman, A. A., Strigini, M. & Cohen, S. M. Shaping morphogen
gradients. Cell 105, 559-562 (2001).

Nature 2001 413:797

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