ScienceWeek

SCIENCE-WEEK - Part 1/3

A Free Weekly Digest of the News of Science

April 3, 1998

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All these fifty years of conscious brooding have brought me no
nearer to the answer to the question, What are light quanta?
Nowadays every Tom, Dick, and Harry thinks he knows it, but he is
mistaken.
-- Albert Einstein
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Contents of This Issue:

Part 1:
1. PRESTIGIOUS MEDICAL JOURNAL OPPOSES BAN ON HUMAN CLONING
2. ETHICS OF PLACEBO-CONTROLLED 3RD WORLD STUDIES REVISITED
3. NO LARGE US COMMERCIAL MARKET FOR CANCER GENE TESTING
4. SIMULATION OF CLUMPY STAR-FORMING REGIONS IN HIGH Z GALAXIES
5. ON THE LIFE HISTORY OF BARE VISCOUS BUBBLES
6. ON LATTICE EFFECTS IN MAGNETORESISTIVE MANGANESE PEROVSKITES
7. ON QUANTUM THEORY OF CHEMICAL REACTION DYNAMICS
8. ON LASER CONTROL OF CHEMICAL REACTIONS

Part 2:
9. SOLUBILIZATION OF FULLERENES BY GIANT BLOCK-COPOLYMER MICELLES
10. REDESIGN OF ENZYME TOPOLOGY BY DIRECTED EVOLUTION
11. TOTAL SYNTHESIS OF A POTENT MARINE ORGANISM NEUROTOXIN
12. A DROSOPHILA HOMOLOG OF RX VERTEBRATE HOMEOBOX GENE
13. DENDRITIC CELLS AND THE CONTROL OF IMMUNITY
14. A NEUROPEPTIDE THAT BLOCKS NOCICEPTIN ACTION

Part 3:
15. IDENTIFICATION OF THE INDUCER OF MOSQUITO MALARIA DEVELOPMENT
16. ON POST-POLIO SYNDROME
17. EVIDENCE THAT BREAST CANCER GENE IS APOPTOSIS COACTIVATOR
18. APPARENT DECLINING MORTALITY IN ADVANCED HUMAN HIV INFECTION

---------------------------------------------

1. PRESTIGIOUS MEDICAL JOURNAL OPPOSES BAN ON HUMAN CLONING
In an editorial in the New England Journal of Medicine, the
Editor-in-Chief Jerome P. Kassirer, and the journal's molecular
medicine consultant Nadia A. Rosenthal, discuss the problem of
whether human cloning should be prohibited, and they state: "Like
many others, we believe that any plan to ban research on cloning
human cells is seriously misguided." The authors conclude: "The
difficult ethical judgments about how to apply this new
technology can be made only with the full knowledge of the
scientific facts. The burden of educating the public about these
facts falls squarely on the shoulders of the scientists
themselves, whose commitment to full disclosure may never be more
stringently tested." (New England J. Med. 26 Mar 98)


2. ETHICS OF PLACEBO-CONTROLLED 3RD WORLD STUDIES REVISITED
The New England Journal of Medicine has now published a
collection of 19 letters from 41 researchers and clinicians in 7
countries concerning the journal's condemnation last year of
placebo-controlled trials in underdeveloped countries of a drug
(zidovudine) to prevent transmission of HIV from pregnant women
to their fetuses, and of another study involving placebo-
controlled trials of preventive therapy for tuberculosis in HIV-
infected people in Uganda. The US National Institutes of Health
and the US Centers for Disease Control were and/or are intimately
involved in these studies, but the heads of these two federal
agencies (H. Varmus and D. Satcher) apparently declined to
respond to any of the letters directly addressing their public
statements. This is a complex subject that cannot be done justice
in a few lines, but the problems addressed by people on all sides
of these issues are of extreme importance to the current and
future development of international medical research ethics, and
this collections of letters in the NEJM will be a classic
collection for a long time to come.
(New England J. Med. 19 Mar 98)


3. NO LARGE US COMMERCIAL MARKET FOR CANCER GENE TESTING
Contrary to the expectations of financial analysts, commercial
genetic tests for breast cancer and colon cancer in the US are
not only not making money for the companies that offer them, but
they are proving to be overwhelmingly rejected by the public. The
tests are based on identification of inherited mutations in
specific genes, and have high predictive value for certain types
of family-related breast and colon cancers. Oncormed Inc.
(Gaithersburg, Md US), which offers breast and colon cancer
tests, is reports to be doing approximately 100 tests a month,
one-tenth of what was expected. Myriad Genetics Inc. (Salt Lake
City, Ut US), which offers the breast cancer gene test, has
reported only 262 tests in the entire last quarter of 1997. A
third company, Genetics IVF Institute (Fairfax, Va US) declines
to give numbers, but admits a similar low total of tests
administered. One problem is apparently that genetic testing may
result in individuals being refused health insurance coverage by
US insurers. At the present time, cancer gene tests cost
approximately $2000 each, and are often paid for by insurance
companies. Wall Street analysts had predicted a US$100 million a
year market in the US, but the market has not materialized.
Timothy Triche, CEO at Oncormed, says, "Everyone misunderstood
this field." (New York Times 27 Mar 98)


4. SIMULATION OF CLUMPY STAR-FORMING REGIONS IN HIGH Z GALAXIES
According to the current view, a galaxy forms from the
gravitational condensation of massive amounts of hydrogen and
helium in the cool, high-density interstellar clouds. First, a
galactic sphere of gas is formed. This gravitational condensation
sphere flattens and becomes a rotating disk of gas. In the disk,
perturbations produce internal clusterings of gas molecules.
These clusterings lead to protostars in clusters. The protostars,
when they reach a certain density and total mass, ignite into
ordinary stars. Each cluster of true stars slowly dissipates,
with the individual stars remaining associated by gravitational
forces with the galaxy as a whole. Redshift (symbol: z) is a
lengthening of the wavelengths of electromagnetic radiation from
a source caused either by the movement of the source (Doppler
effect) or by the expansion of the universe (cosmological
redshift). Redshift is defined as the change in wavelength of a
particular spectral line divided by the unshifted wavelength of
that line. Large redshifts imply large radial velocities (which
imply large distances, according to current cosmological theory),
but at redshifts greater than about 0.2 there is a relativistic
divergence from a linear relation. A redshift of 4.0 corresponds
to an object receding with a radial velocity 92% that of the
velocity of light. The term "Hubble type galaxies" refers to the
classical elliptical, spiral, and barred spiral types first
categorized by the astronomer Edwin Hubble in 1925.
... ... M. Noguchi (Tohoku University, JP) reports the results of
numerical simulation of protogalaxy evolution, the calculations
indicating the gas-rich disk of a young galaxy becomes
gravitationally unstable and fragments into massive clumps of
sub-galactic size. Most of the stars are formed in these discrete
clumps, thus providing a natural explanation for the peculiar
morphology of high-redshift galaxies. The dynamical evolution of
these young systems is dominated by the clumps and ultimately
leads to structures representing present-day galaxies, with a
spheroidal bulge and an exponential disk. The author suggests the
differences between Hubble type galaxies result from different
time-scales of disk formation, and that the clumpy galaxy model
provides a causal link between the emergence of quasar activity
and the dynamical evolution of the host galaxy.
QY: Masafumi Noguchi (noguchi@astroa.astr.tohoku.ac.jp)
EMAIL
(Nature 19 Mar 98)


5. ON THE LIFE HISTORY OF BARE VISCOUS BUBBLES
The relaxation time of a physical system is a measure of the time
required by the system to reestablish a new equilibrium after one
or more state variables have been displaced from first equilibr-
ium values. The term "viscoelasticity" refers to a viscous
material that exhibits certain elastic properties such as the
storage of deformation energy and a slow strain response to the
application of stress. Spectrin is a filamentous contractile
protein that together with actin and other cytoskeleton proteins
forms a network that gives the red blood cell surface its shape
and flexibility. ... ... Debregeas et al (3 authors at 3 install-
ations, US FR) report a study of two different model systems of
air bubbles at the surface of viscous liquids: a polymer melt
(silicone oil) and a molten borosilicate glass of comparable
viscosity. Although the two systems differ greatly in their
relaxation times, they are described by the same set of laws
understandable from a relatively simple hydrodynamic model. The
authors suggest their findings may be transposed to other
viscoelastic systems, for example, to physical gels with no
permanent cross-links, and possibly to cytoskeletons such as the
spectrin network of red blood cells and other biological gels.
QY: G. Debregeas (debregea@rheo.uchicago.edu)
EMAIL
(Science 13 Mar 98)


6. ON LATTICE EFFECTS IN MAGNETORESISTIVE MANGANESE PEROVSKITES
Magnetoresistance is a change in the electrical resistance of a
conductor or semiconductor upon the application of a magnetic
field. A perovskite is a naturally occurring mineral type with an
ideally cubic crystal structure modified by octahedral and
dodecahedral forms. Electron-lattice interactions are interact-
ions between electrons and the lattice of a crystal or quasi-
crystal, and the term "local electron correlations" refers to
effective localized interactions between electrons, as opposed to
interactions between electrons and, for example, a crystal
lattice. ... ... A.J. Millis (Johns Hopkins University, US)
reviews the recent evidence of extremely large magnetoresistive
responses of manganese perovskites. Regardless of the any
practical uses for these materials, they provide an ideal system
to elucidate the properties of metals in which electron-lattice
interactions play a key role. The authors suggest that as
sophisticated techniques for examining local electron correl-
ations become available, the manganites seem an ideal system for
developing and validating them, and that this, plus the intrinsic
interest of the materials, should stimulate research for a long
time to come.
QY: A.J. Millis (millis@pha.jhu.edu)
EMAIL
(Nature 12 Mar 98)


7. ON QUANTUM THEORY OF CHEMICAL REACTION DYNAMICS
Scattering theory is a quantitative approach to describing
collision based interactions between particles, and quantum
scattering theory is such an approach applied to particles in a
quantum mechanical domain. ... ... D.C. Clary (University College
London, UK) reviews the current quantum theory of chemical
reaction dynamics. It is now possible to use rigorous quantum
scattering theory to perform accurate calculations of the
detailed state-to-state dynamics of chemical reactions in the gas
phase, and calculations of the simplest reactions compete with
experiments in their accuracy. Recent advances promise to extend
such accurate predictions to more complicated reactions involving
polyatomic molecules, and even to reactions of molecules on solid
surfaces. New experimental techniques for probing reaction
transition states, such as femtosecond spectroscopy, are
stimulating the development of new theories. QY: David C. Clary,
Dept. of Chemistry, University College London, London WC1H OAJ UK
(Science 20 Mar 98)


8. ON LASER CONTROL OF CHEMICAL REACTIONS
In general, the term "vibrational energy" in physical chemistry
refers to an internal energy inherent in polyatomic molecules
that arises from the oscillations of atomic components about
their equilibrium positions, and the term "vibrational modes"
refers to the possible resonant frequencies of a polyatomic
system considered as a set of quantum mechanical harmonic
oscillators. The term "orbital alignments" refers to relations
between the space-dependent parts of the Schroedinger wave
functions of electrons, and in the context of this report the
term "quantum interference between different reaction pathways"
refers to a method of reaction control involving the excitation
of an atom or molecule by two different optical pathways,
controlling relative wave function phases and thus controlling
transition probabilities. "Chirped pulses" are produced by a
"chirped-pulse" laser, a device whose essential basis is the use
of ultra-short pulses [10^(-15) seconds] whose parameters are
manipulated before amplification. ... ... R.N. Zare (Stanford
University, US) reviews experimental procedures involving laser
control of chemical reactions. Product pathways can be controlled
by irradiation with one or more laser beams during individual
bimolecular collisions or during unimolecular decompositions. For
bimolecular collisions, control has been achieved by selective
excitation of reagent vibrational modes, by control of reagent
approach geometry, and by control of orbital alignment. For
unimolecular reactions, control has been achieved by quantum
interference between different reaction pathways connecting the
same initial and final states, and by adjusting the temporal
shape and spectral content of ultrashort chirped pulses of
radiation. The author suggests that the pursuit of laser-based
collision control of chemical reactions is likely to produce
increased understanding of how chemical reactions occur, and in
time will no doubt lead to important applications.
QY: Richard N. Zare (zare@stanford.edu)
EMAIL
(Science 20 Mar 98)

(continued in Part 2)

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

SCIENCE-WEEK - Part 2/3

A Free Weekly Digest of the News of Science

April 3, 1998

Contents of Part 2:

9. SOLUBILIZATION OF FULLERENES BY GIANT BLOCK-COPOLYMER MICELLES
10. REDESIGN OF ENZYME TOPOLOGY BY DIRECTED EVOLUTION
11. TOTAL SYNTHESIS OF A POTENT MARINE ORGANISM NEUROTOXIN
12. A DROSOPHILA HOMOLOG OF RX VERTEBRATE HOMEOBOX GENE
13. DENDRITIC CELLS AND THE CONTROL OF IMMUNITY
14. A NEUROPEPTIDE THAT BLOCKS NOCICEPTIN ACTION

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9. SOLUBILIZATION OF FULLERENES BY GIANT BLOCK-COPOLYMER MICELLES
An amphiphile is a molecule that has a polar head attached to a
long hydrocarbon tail. The result is that one part of the
molecule (the polar head) interacts strongly with water, while
the other part of the molecule (the long hydrocarbon tail)
interacts strongly with nonaqueous phases or with the hydrocarbon
tails of neighboring same-species molecules via dispersion forces
(van der Waals forces). Amphiphile molecular systems are usually
self-organizing, the spontaneous organization maximizing all
possible interaction energies, and a "micelle" is a spontaneously
forming colloidal aggregate of amphiphiles. In chemistry, a
"copolymer" is a mixed polymer, a compound formed by the
combination of two or more substances, or monomers, and a "block
copolymer" is a copolymer in which the monomer units occur in
relatively long sequences in a chain. Fullerenes are large
molecules composed entirely of carbon, with the chemical formula
C(sub n), where n is any even number from 32 to over 100. They
apparently have the structure of a hollow spheroidal cage with a
surface network of carbon atoms connected in hexagonal and
pentagonal rings. ... ... Jenekhe and Chen (University of
Rochester, US) report the formation of giant micelles by
amphiphilic poly(phenylquinoline)-{block}-polystyrene rod-coil
diblock copolymers. Robust, micrometer-scale, spherical,
vesicular, cylindrical, and lamellar aggregates form from
solution. Compared to coil-coil block copolymer micelles, the
present aggregates are larger by about 2 orders of magnitude and
have aggregation numbers of over 10^(8). The spherical and
cylindrical aggregates have large hollow cavities. In the
presence of fullerenes, only spherical aggregates with
aggregation numbers in excess of 10^(9) were formed in solution,
resulting in the solubilization and encapsulation of over 10^(10)
fullerene molecules per aggregate. The authors suggest these
results demonstrate the macromolecular self-assembly of stable
well-defined aggregates with size scales in the tens of
micrometers and molecular weights of up to 10^(13), which makes
these aggregates among the largest known self-assembled
nonbiological structures. Possible applications include
microencapsulation; catalyst support; low dielectric constant
materials for electronic packaging; extraction, purification, and
processing of fullerenes; electrophotographic imaging and other
opto-electronic applications.
QY: Samson A. Jenekhe (jenekhe@che.rochester.edu)
EMAIL
(Science 20 Mar 98)


10. REDESIGN OF ENZYME TOPOLOGY BY DIRECTED EVOLUTION
In the context of this report, the term "directed evolution"
refers to the controlled in vitro evolution of enzymes via a
selection process that selects moieties with greater and greater
catalytic efficiency. A "dimeric enzyme" is an enzyme composed of
two identical subunit proteins, and "native activity" refers here
to activity under natural (i.e., biological) conditions. "Turn
sequences" are amino acid sequences in a protein involved in
conformational turns, and they are thus important in the higher
order architecture of an enzyme. ... ... MacBeath et al (Scripps
Research Institute, US) report the use of genetic selection in
combination with structure-based design and directed evolution to
transform an intimately entwined dimeric enzyme (chorismate
mutase) into a monomeric four-helix-bundle protein with near
native activity. Contrary to expectations based on studies of
other four-helix-bundle proteins, only a small fraction of
possible turn sequences (less than 0.5%) yielded well-behaved
monomeric and highly active enzymes. The authors suggest that
selection for catalytic function provides an efficient yet
stringent method for rapidly assessing correctly folded
polypeptides, and that proteins with redesigned topology may
serve as model systems for studying how structure, stability, and
function interrelate.
QY: Donald Hilvert (hilvert@org.chem.ethz.ch)
EMAIL
(Science 20 Mar 98)

-------------------

Related Background:

ADDING METAL-BINDING SITES TO PROTEINS CREATES NEW ENZYMES
The 21st century will no doubt see the rational design and
synthesis of biologically active enzymes, but the first steps
toward this objective are already being taken. This week John P.
Carodonna et al (Yale University, Duke University; US) reported
the implantation of metal-binding sites into a host protein,
thioredoxin, which ordinarily does not have a metal-center and is
not catalytic. They showed that excising the active site from
another protein (the enzyme superoxide dismutase) and grafting it
into thioredoxin, turns thioredoxin into a catalytic enzyme while
retaining its own surface chemical properties. What is most
interesting is that the molecular engineering was completely
rational, being based on a computer program called "Dezymer"
developed by one of the authors (H. W. Hellinga, Duke Univers-
ity). They state the algorithm used can be applied to any
metallo-enzyme system to produce rationally designed new enzymes,
or even proteins with bifunctional enzymatic activity.
(Proc. Natl. Acad. Sci. US 94:5562,6635 1997)

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POLYKETIDE SYNTHASES AS MODULAR ENZYMES
Enzymes are proteins that serve as highly specific catalysts of
various biological reactions, and there is much research underway
attempting to understand the mechanisms of enzyme catalysis and
to construct new enzymes for the specific catalysis of nonbiolog-
ical reactions. ... ... R. Rawls (Chem. & Eng. News, US) reviews
the use of polyketide synthases as modular enzymes. The polyket-
ides are a large and structurally diverse family of natural
compounds produced primarily by bacteria and fungi, with
approximately 10,000 of them identified in nature. They are all
synthesized by repetitive additions of two- or three-carbon acyl
building blocks to form a linear chain frequently cyclized after
its formation. Some commercially important polyketides are the
antibiotics erythromycin and spiramycin, the veterinary drug
avermectin, and the immunosuppressant rapamycin. These substances
are synthesized by giant multifunctional enzymes that are modular
in their structure, each module constructing a section of the
final molecule and then passing the intermediate to the next
synthesis station for the attachment of an additional section.
During the past 5 years, chemists have learned how to shuffle the
pieces of the polyketide synthases to make new molecules,
changing the enzymes functional domains to produce non-natural
products.
QY: Rebecca L. Rawls
edit.cen@acs.org
(Chem. & Eng. News 9 Mar 98)


11. TOTAL SYNTHESIS OF A POTENT MARINE ORGANISM NEUROTOXIN
Brevotoxin A is a molecule of complex molecular structure
involving 10 oxygen atoms and a chain of 44 carbon atoms woven
into a polycyclic macromolecule that includes 10 rings
(containing between 5 and 9 atoms) and 22 stereogenic centers.
The compound is a potent neurotoxin secreted by the marine
organism Gymnodinium breve Davis, which is often associated with
harmful algal blooms known as "red tides". The mechanism of
action of the compound involves binding to and opening of sodium
channels in nerve cell membranes, which destroys the ability of
nerve cells to produce and conduct electrical signals, and the
toxin is potent enough to kill fish at concentrations of
nanograms per milliliter, and to poison humans who consume
filter-feeding shellfish. The precise pathway for the biological
production of the toxin is unknown. ... ... Nicolaou et al (6
authors at 2 installations, US) now report an overall strategy
for the total synthesis of brevetoxin A in its naturally
occurring form. The authors suggest their reported synthesis will
make this scarce neurotoxin available as a synthetic product, and
will allow the design and synthesis of analogs for further
biochemical studies.
QY: K.C. Nicolaou (kcn@scripps.edu)
EMAIL
(Nature 19 Mar 98)


12. A DROSOPHILA HOMOLOG OF RX VERTEBRATE HOMEOBOX GENE
Homeobox genes are a family of similar nucleotide sequences that
encode sequence-specific DNA binding proteins that are essential
for embryological development and cell differentiation. They were
first discovered in the fruit fly Drosophila, but they have
homologs in the genomes of many organisms, including humans and
plants. A homeodomain is a protein motif encoded by a homeobox
DNA sequence, and an {Rx} gene is a vertebrate homeobox gene that
has been linked to the embryological development of the
vertebrate eye. Xenopus is a vertebrate, a species of African
toad. ... ... Eggert et al (5 authors at 2 installations, DE CH)
report the isolation of an Rx gene from Drosophila (called DRx).
The homeodomains of the Drosophila and the Xenopus Rx genes are
identical, suggesting that the Drosophila DRx gene is a homolog
of the vertebrate Rx gene. The Drosophila gene is expressed
during early embryonic development, and later in the brain and
central nervous system, and the sequence conservation and
expression pattern suggest an important role of the gene during
brain development in Drosophila. But no expression of this gene
has been detected in embryological precursor tissue of the eye.
The authors suggest that vertebrate Rx genes might be involved in
brain patterning processes and specification of eye fields in
different phyla.
QY: Uwe Walldorf (walldorf@uni-hohenheim.de)
EMAIL
(Proc. Natl. Acad. Sci. US 3 Mar 98)


13. DENDRITIC CELLS AND THE CONTROL OF IMMUNITY
Dendritic cells are cells of the immune system with many thin
extensions (dendrites) and highly changeable shapes. Lymphocytes
are a type of immune system white blood cell, and B- and T-
lymphocytes (also called B- and T-cells) are subtypes of
lymphocytes, with B-cells producing antibodies and T-cells
involved in a variety of other immune system responses. In
general, an "antigen" is any substance that produces a response
from the immune system when it contacts that system. "Lymphoid
organs" are any organs containing lymphatic tissue and therefore
involved in the circulation of lymph fluid, and "cytokines" are
substances that promotes cell growth and cell division. An
autoimmune reaction is a response of the immune system against a
"self-antigen", a response against the body's own cells or
tissues. ... ... Banchereau and Steinman (2 installations, US)
review recent research concerning dendritic cells and the control
of vertebrate immunity. B- and T-lymphocytes are the mediators of
immunity, but their function is under the control of dendritic
cells. Dendritic cells in the periphery capture and process
antigens, express lymphocyte co-stimulatory molecules, migrate to
lymphoid organs, and secrete cytokines to initiate immune
responses. Dendritic cells not only activate lymphocytes, they
also tolerize T-cells to antigens that are innate to the body
(self-antigens), thereby minimizing autoimmune reactions. Once a
neglected cell-type, dendritic cells can now be readily obtained
in sufficient quantities to allow molecular and cell biological
analysis, and these cells are a powerful tool for manipulating
the immune system. The authors suggest that although studies of
pathogenesis have long focused on the core of immunology by
identifying antigens and lymphocytes, recent evidence has
provoked a new emphasis on the role of dendritic cells in the
control of immunity. QY: Jacques Banchereau, Immunology Inst.,
Baylor Research Institute, 3409 Worth St., Dallas TX 75246 US
(Nature 19 Mar 98)


14. A NEUROPEPTIDE THAT BLOCKS NOCICEPTIN ACTION
A "peptide" is any chain of two or more amino acids linked by
peptide bonds (thus forming substituted amides). Nociceptin is a
recently identified peptide involved in the neural response to
painful or injurious stimuli. "Allodynia" is a condition in which
ordinarily non-painful stimuli evoke pain, and "hyperalgesia" is
a condition of extreme sensitivity to painful stimuli. The
prostaglandins are a class of physiologically active substances
that produce a variety of effects: vasodilation, vasoconstrict-
ion, stimulation of intestinal and bronchial smooth muscle,
uterine stimulation, etc. They are prostanoic acids with varying
side chains, and prostaglandin E(sub2) is dinoprostone, a sub-
type. An "analgesic" is any substance that relieves pain without
producing anesthesia or loss of consciousness (e.g., aspirin or
morphine). ... ... Okuda-Ashitaka et al (7 authors at 4
installations, JP SG) report the identification of the
biologically active peptide nocistatin, which is evidently also
produced by the nociceptin precursor, and which blocks
nociceptin-induced allodynia and hyperalgesia, and attenuates
pain evoked by prostaglandin E(sub2). Endogenous nocistatin was
isolated from bovine brain. Although nocistatin apparently does
not bind to the nociceptin receptor, it binds to membranes of
mouse brain and spinal cord with high affinity. The authors
suggest that nocistatin is a new biologically active peptide
produced from the same precursor as nociceptin, and that these
two peptides may play opposite roles in pain transmission. They
further suggest that the discovery of nocistatin may lead to the
design of a novel analgesic devoid of the addiction and
dependence associated with morphine.
QY: Seiji Ito (ito@takii.kmu.ac.jp)
EMAIL
(Nature 19 Mar 98)

-------------------

Related Background:

ON THE MECHANISM OF PAIN MODULATION BY CANNABINOIDS
In general, the clinical entity "hyperalgesia" (sometimes known
as "hyperalgia") is a heightened sensitivity to painful stimuli.
Cannabinoids are derivatives or preparations from the plant
Cannabis sativa (the marijuana plant), a group of a dozen
compounds chemically related to cannabinol, including delta-9-
tetrahydrocannabinol (THC), and the cannabinoid receptor is the
binding site for the psychoactive component of marijuana, as well
as for anandamide, the endogenous physiological ligand. Anand-
amide is known to modulate the pain pathway, but the mechanisms
are not clear. ... ... Richardson et al (3 authors at Univ. of
Minnesota Minneapolis, US) now report studies in animal models
that indicate that hyperalgesia may be linked to a faulty
cannabinoid system in the spinal cord. The authors suggest that
endogenous cannabinoids attenuate pain by preventing the release
of glutamate from presynaptic terminals of neurons that transmit
pain messages to the spinal cord. QY: Jenelle D. Richardson,
Harvard Univ. Medical School, Dept. Neurobiology 617-432-1550
(Chem. & Eng. News 19 Jan 98)

(continued in Part 3)

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

SCIENCE-WEEK - Part 3/3

A Free Weekly Digest of the News of Science

April 3, 1998

Contents of Part 3:

15. IDENTIFICATION OF THE INDUCER OF MOSQUITO MALARIA DEVELOPMENT
16. ON POST-POLIO SYNDROME
17. EVIDENCE THAT BREAST CANCER GENE IS APOPTOSIS COACTIVATOR
18. APPARENT DECLINING MORTALITY IN ADVANCED HUMAN HIV INFECTION

----------------------------------------------------------------

15. IDENTIFICATION OF THE INDUCER OF MOSQUITO MALARIA DEVELOPMENT
The disease malaria is caused by a type of protozoan with the
general name Plasmodium, an organism characterized by a sequence
of life cycles involving different organismic forms. The asexual
cycle occurs in the liver and red blood cells of vertebrates
(including humans), and the sexual cycle occurs in mosquitoes.
Essentially, the asexual form is ingested by blood-sucking
mosquitoes, and in the mosquito the asexual form is induced to
produce the sexual form necessary to complete the total life
cycle. The details of the process are as follows: Plasmodium
cells called "gametocytes" (precursors of gametes) in human blood
are ingested by the mosquito, and in the mosquito, apparently
within seconds, gametocytes are induced into "gametogenesis",
producing gametes. These gametes produce a cell-type called
"sporozoites", which accumulate in the salivary gland of the
mosquito, from where they are injected into the vertebrate blood
stream when the mosquito feeds on vertebrate blood. The sporo-
zoites accumulate in the vertebrate liver, where they multiply
and produce a form (merozoites) that invades red blood cells,
replicates, destroys red blood cells, and so on, with an eventual
decline in this asexual replication. However, after invasion of
red blood cells, some merozoites produce gametocytes, which have
the genomic potential for restarting the total life cycle. These
gametocytes cannot self-replicate, and they die unless ingested
by a mosquito, but once in the mosquito, the total life cycle
begins again. There are apparently 2 inducers of gametogenesis in
vivo (i.e., in the mosquito): one inducer is a pH of 7.5 to 7.6,
and the other inducer has been thought to be an unknown mosquito-
derived gametocyte-activating factor. ... ... Now Billker et al
(9 authors at 2 installations, UK US) report that the second
inducer in vivo of gametocyte induction in the mosquito is
apparently xanthurenic acid, and that low concentrations of
xanthurenic acid can act together with pH to induce gametogenesis
in vitro. The authors suggest these data could form the basis of
the rational development of new drugs to interrupt the
transmission of malaria, or for the development of methods
producing the selection of new mosquito genotypes (species
variants) resistant to infection. QY: R.E. Sinden, Dept. of
Biology, Imperial College London, SW7 2BB UK. (Nature 19 Mar 98)


16. ON POST-POLIO SYNDROME
The term "paralytic polio" refers to one of the forms of the
viral disease poliomyelitis, namely, the form that produces
flaccid paralysis or weakness of various muscle groups. Motor
neurons are nerve cells in the central nervous system whose
function is to excite muscle cells, the excitation effected by
the release at the nerve endings of excitatory neurotransmitter
substances, one of which is the chemical acetylcholine.
... ... Lauro S. Halstead, (Georgetown University, US) a
physician who contracted paralytic polio at the age of 18,
reviews the post-polio syndrome. Decades after recovering much of
their muscular strength, survivors of paralytic polio are
reporting unexpected fatigue, pain, and weakness. The cause
appears to be degeneration of regenerated motor neuron
terminations with muscle cells, and/or a faulty synthesis or
release of the neurotransmitter acetylcholine. The author
suggests the new federal polio vaccination recommendation of two
initial immunizations with the injected killed-virus vaccine
followed some time later by two doses of oral live-virus vaccine
may finally control the disease.
QY: L.S. Halstead, Georgetown University 202-687-3600.
(Scientific American April 1998)


17. EVIDENCE THAT BREAST CANCER GENE IS APOPTOSIS COACTIVATOR
In molecular biology, the term "transcription" refers to the
sequence of biochemical events producing the conversion of DNA
code to RNA code. Apoptosis is programmed cell death produced by
control mechanisms designed to destroy defective cells or cells
that must be discarded in the process of tissue differentiation.
Mutations of the gene {BRCA1} have been linked to 45% of the
cases of familial breast cancer, and to 80% to 90% of families
with both breast and ovarian cancer. ... ... Now Ouchi et al (5
authors at 4 installations, US) report that {BRCA1} stimulates
artificial and genomic entities that contain elements responsive
to the tumor suppressor protein p53, which is known to be
involved in apoptosis. The authors suggest their findings
indicate the gene {BRCA1} is involved in transcriptional
regulation and has a function as a p53 coactivator.
QY: Hidesaburo Hanafusa (saburo@rockvax.rockefeller.edu)
EMAIL
(Proc. Natl. Acad. Sci. US 3 Mar 98)

-------------------

Related Background:

NEW TECHNIQUE USES COMMON COLD VIRUS TO KILL TUMOR CELLS
Human cells have a suicide program that is triggered by a
protein (p53) when the cell's genetic machinery is damaged. Some
viruses possess a gene that inactivates the protein p53, which
enables them to use the cell's genetic apparatus to reproduce,
with the eventual death of the host cell. The common cold virus
(adenovirus) is one of these viruses. That is fact #1. Fact #2
is that in many kinds of tumor cells, their protein p53 has
become intrinsically inactivated. Fact #3 is that a strain of
adenovirus exists that has lost the p53 jamming gene. This
mutant adenovirus will therefore be lethal to tumor cells with
already inactivated p53, but not to ordinary cells. So Frank
McCormack and his colleagues (Onyx Pharmaceuticals, Richmond CA
US) injected the mutant strain of adenovirus into head and neck
tumors in patients who had failed to respond to surgery,
radiation, or chemotherapy, and they found significant
destruction of tumors in 25% of the patients. The mutant
adenovirus killed the tumor cells in these large, refractory
cancers. These are preliminary trials, but the beginning of
what may be an extremely important approach to cancer therapy --
the use of pathogens with a specificity for tumor cells. The
results were reported at the recent meeting of the American
Society of Clinical Oncology. (New York Times 20 May 97)

-------------------

EVIDENCE FOR RECEPTOR DECOYS IN APOPTOSIS
In the previous report, we mentioned tumor suppressor genes,
sequences of DNA that code for proteins that prevent or inhibit
the growth of tumors. One of these genes codes for a protein
called p53, and evidently the function of this protein, closely
studied in many laboratories, is to trigger an internal suicide
program after the DNA of a cell has been damaged by drugs or
radiation. The process is called apoptosis -- programmed cell
death -- and what is characteristic of many types of cancer cells
is that the gene that codes for p53 has been damaged, the damaged
gene replicated from one generation of cancer cell to another,
and in the resulting absence of the protein p53 no apoptosis
occurs. In other words, the program whose function is to elim-
inate cells with corrupted DNA has itself been corrupted, and an
important fail-safe mechanism has been destroyed. There are other
endogenous cytotoxic proteins beside p53. One of them is called
TRAIL (also called Apo2L), and it is quite remarkable in that it
apparently induces apoptosis of many transformed cancer cell
lines but not of normal cells, even though its receptor is
evidently present in both cell types. Reports this week by Guohua
Pan et al (University of Michigan, US; Human Genome Sciences,
Rockville MD US) and James P. Sheridan et al (Genentech, San
Francisco CA US) indicate that normal cells contain a decoy
receptor for TRAIL, the decoy receptor not activating apoptosis,
while cancer cells susceptible to TRAIL do not contain the decoy
receptor, only the receptor that does activate apoptosis. Why
this difference in receptors should exist, given the evolution
pressures on cancer cells, is a mystery. But there is some hope
now that if the complexities of these "death-domain" receptors
can be unraveled, means may be found to use the TRAIL receptors
in cancer cells to kill them. QY: V. M. Dixit; A. Ashkenazi
(Science 8 Aug 97)

-------------------

MECHANISM OF ACTION OF TUMOR SUPPRESSOR PROTEIN P53
Tumor suppressor genes apparently code for proteins that either
prevent cell division or provoke cell death, and since the
molecular mechanisms involved in these events are of great
importance in current efforts in cancer research, all the
elements in the sequences are of significance. Apoptosis is the
name given to the programmed cell death provoked by the proteins
expressed by tumor suppressor genes. Kornelia Polyak et al (Johns
Hopkins University, US) have investigated the genes whose
transcription is activated by protein p53, perhaps the most
important tumor suppressor protein, and they present a model for
the mechanism of apoptosis produced by this protein. The model
involves the transcriptional induction of redox related genes,
the formation of reactive oxygen species, and finally the
oxidative degradation of mitochondrial components, this sequence
then culminating in the death of the cell. QY: Kenneth W.
Kinzler, Johns Hopkins Oncology Center, 424 N. Bond St.,
Baltimore MD 21241 US (Nature 18 Sep)


18. APPARENT DECLINING MORTALITY IN ADVANCED HUMAN HIV INFECTION
Retroviruses are single-stranded RNA viruses that have an enzyme
called reverse transcriptase, and with this enzyme the viral RNA
is used as a template to produce viral DNA from cellular
material. This DNA is then incorporated into the host cell's
genome, where it codes for the synthesis of viral components. The
human immune deficiency virus (HIV) is a retrovirus. Proteases
are enzymes that cleave proteins by the hydrolysis of peptide
bonds, and many pathogens, including viruses, use proteases in
their replication process. HIV, for example, encodes only 4
enzymes in its genome, one of which is a reverse transcriptase,
and another of which is a specific protease essential for viral
replication. ... ... Palella et al (8 authors at 5 installations,
US) report that national surveillance data indicate recent marked
reductions in morbidity and mortality associated with AIDS. The
authors attribute the declines to the use of antiretroviral
therapies, and suggest that an intensive combination drug therapy
regimen that includes a protease inhibitor should be considered
the standard of care for patients with HIV infection.
QY: Frank J. Palella, Northwestern University 847-491-3741.
(New England J. Med. 26 Mar 98)

-------------------

Related Background:

ESTIMATED 20 MILLION INFECTED WITH AIDS IN SUB-SAHARAN AFRICA
There is perhaps too much of a tendency in many quarters to think
of a plague only as a state of affairs in which people drop dead
in expensive restaurants and get hauled away in trucks
containing piles of bodies. Our current plague, although not as
dramatic as some plagues of the past, is no less an international
calamity. The United Nations AIDS Program recently released a
report containing the following: 
-- In 1997, 5.8 million people worldwide were newly infected with
HIV.
-- The number of new HIV infections this year rose 9% over 1996.
-- The total number of infected adults is now a little under 30
million, about 1% of the world's adult population.
-- This year, the total number of people infected with HIV
increased by 13%
-- More than 20 million people in sub-Saharan Africa are infected
with HIV, which is 7% of that adult population.
-- This year, 2.3 million people worldwide will have died of
AIDS, the consequent stage of HIV infection.
-- In South and Southeast Asia, 6 million people are infected
with HIV.
-- In Latin America, 1.3 million people are infected with HIV.
-- In North America, 860,000 people are infected with HIV.
-- In Western Europe, 150,000 people are infected with HIV.
(Nature 27 Nov 97)

---------------------------------------------

BOOK NOTES:

Eric G. Bolen: ECOLOGY OF NORTH AMERICA
Wiley, 1998, 464p, US79.95
An introduction to the interactions of the various plant and
animal communities of North America. 150 photographs and
diagrams.

Gina Kolata: CLONE
The Road to Dolly and the Path Ahead
William Morrow, 1998, 276p, US23
A journalistic account of cloning and the work of Ian Wilmut. The
author is a New York Times science writer.

Philip Lieberman: EVE SPOKE
Human Language and Human Evolution
W.W. Norton, 1998, 178p, US25
A mix of anthropology, neuroscience, psychology, and linguistics
by a specialist in the field of cognitive linguistic science.

Gary G. Matthews: NEUROBIOLOGY
Molecules, Cells, and Systems
Blackwell Science, 1998, 603p, US49.95
An undergraduate text. Cellular aspects of neurobiology, motor
control systems, sensory systems, neuronal plasticity.

Lyman Spitzer Jr.:
INTERSTELLAR PHYSICAL PROCESSES IN THE INTERSTELLAR MEDIUM
Wiley, 1998, 336p, US39.95
An updated classic, including recent research on interstellar
matter. Local phenomena in interstellar gas, properties of dust
grains, equilibrium and dynamics of interstellar gas, explosions
of H II regions, supernova shells, processes of star formation.

Robert M. Wald (ed.): BLACK HOLES AND RELATIVISTIC STARS
University of Chicago, 1998, 296p, US50.00
A collection of papers given at a symposium in honor of
Subrahmanyan Chandrasekhar, the renowned astrophysicist who
proposed, among other things, the theory of stellar gravitational
collapse. Included are papers by Valeria Ferrari, John Friedman,
Kip Thorne, Martin Rees, Roger Penrose, Saul Teukolsky, Werner
Israel, Robert M. Wald, Rafael Sorkin, Stephen Hawking, Gary
Horowitz. Part I deals with black holes and relativistic stars
from the standpoint of classical general relativity; Part 2
focuses on black holes as fundamental objects in quantum
gravitational physics.

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