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ScienceWeek
SCIENCE-WEEK
A Weekly Digest of the News of Science
August 21, 1998
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There is no doubt that great revolutions of human
scientific thought will occur in the next century,
and in the century after that, and in thousands of
centuries afterward. So which of our current pet
scientific dogmas will be among the first washed
away by new facts and sudden clarities?
-- Anonymous
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Contents of This Issue:
1. The Bleak Outlook for Russian Science
2. A Cluster of Massive Stars Near Our Galactic Center
3. On Pressure in Condensed Matter
4. Analysis of Hydration in a Series of Hydrocarbons
5. On Evolutionary Adaptability
6. On Gaia and Natural Selection
7. Neurobiology: Gating Modifier Toxins and Ion Channels
8. An Analysis of Hypermutation Antibody Gene Targets
9. New Evidence of Transmission of Multi-Drug Resistant HIV
10. DNA Evidence for Neolithic Ancestry of European Gene Pool
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1. THE BLEAK OUTLOOK FOR RUSSIAN SCIENCE
The disintegration of Russian science is continuing, and most
observers apparently have the sense they are witnessing a
catastrophe. As is indicated in the background material below,
nothing much has changed during the past year. On April 30th,
Vladimir Bulgak became the new science and technology minister.
Bulgak holds a PhD in economics and has studied electrical
engineering, but Russian scientists are pessimistic about the
prospect of Bulgak saving the country's science, since there is
an evident lack of respect for science in the top levels of
government. Valery Soyfer, a molecular biologist now working in
the US, says, "They say they have no money. But they have money
to build new churches, new dachas, and new government buildings."
The number of working scientists at the various research
institutes of the Russian Academy of Sciences is apparently now
10 to 20 percent of the number working in 1991. In an open letter
on June 19th to President Boris Yeltsin, 37 scientists and
cultural leaders warned of the impending "absolute degradation
and annihilation" of Russian science and education. A major
neutrino project, the Russian-American *Gallium Experiment (SAGE)
in southern Russia is threatened by government efforts to sell
off some of the 60 tons of gallium involved in the experiment. A
recent demand by the government that the project turn over 7 tons
of gallium to the government for sale was refused by the
Institute of Nuclear Research, which administers the
neutrino/gallium project. The price of gallium on the world
market is approximately US$400 per kilogram.
(Physics Today August 1998) (Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *Gallium Experiment (SAGE): In this experiment, the
incident neutrino flux is measured by extracting radioactive
germanium atoms, which are produced when neutrinos interact with
gallium.
-------------------
Related Background:
ON THE CONTINUING DISINTEGRATION OF RUSSIAN SCIENCE
The situation of science in Russia is simply stated: Science is
dying. No matter the impressive past or the optimistic statements
by Russian bureaucrats concerning the future of Russian science,
the evidence indicates a disintegration of all the scientific
disciplines. The funding of science is now 10% of what it was
before the breakup of the Soviet Union, scientists receive on the
average US$100 a month in salary, cannot afford to eat in a cheap
restaurant, must work at non-science jobs to survive. A recent
review of conditions states, "The scientific community in Russia
has been scrapping for morsels from a free-market economy riddled
with corruption." There is a constant struggle by scientists to
find adequate research funds, a scarcity of materials, decrepit
equipment, lack of foreign scientific journals, low esteem by the
public, and pitiful salary levels. A research scientist at the
Institute of Theoretical and Experimental Physics in Moscow
supplements his income by driving his car as a taxi. Approxi-
mately 80,000 scientists emigrate from Russia each year, typic-
ally 30 to 45 years of age, and there is no incentive for young
people to choose science as a career. Mikhail P. Egorov, a
research scientist at the Zelinsky Institute, says, "Without
science, Russia will become a Third World country."
(Chem. & Eng. News 22 Dec 97) (Science-Week 2 Jan 98)
-------------------
Related Background:
CONTINUING COLLAPSE OF SCIENCE IN RUSSIA
Following the departure of the Soviet regime in Russia, and the
transformation of Russia to a private-enterprise market economy,
Russian science effectively collapsed. The two chief character-
istics of Soviet science policy were the use of a command and
control structure, with various governmental departments tightly
controlling various areas of scientific research, and a severe
restriction of both publication of results and contacts with the
international scientific community. These aspects no longer exist
in what is called "Russian science". The new problem is the
national budget crisis, which has resulted in a severe shortage
of funds, coupled with a tangle of bureaucratic difficulties in
the government administration of large scientific projects. There
has also been a severe brain-drain, as the average income of
Russian scientists has dropped from 10% to 20% above the national
average under the Soviet regime to 20% below the national average
in 1996. Detailing the situation, physicist Boris G. Saltykov,
the Minister of Science and Technology Policy 1991 - 1996, is
nevertheless optimistic "that Russia's scientific community will
find both the strength and ability to overcome its present
crisis."
(Nature 3 Jul 97) (Science-Week 10 Jul 97)
2. A CLUSTER OF MASSIVE STARS NEAR OUR GALACTIC CENTER
The relative number of newborn stars of different masses in a
galaxy (the "*initial mass function") determines whether the
galaxy's interstellar gas condenses mainly into long-lived low-
mass stars, as in the disk of normal spiral galaxies, or into
short-lived massive stars, as has been proposed for "*starburst
galaxies". The center of our own Galaxy is not a full-fledged
starburst region, but its star-formation rate per unit volume of
space is nevertheless approximately 1000 times that of the disk.
It is usually extremely difficult to study the initial mass
function near the center of the Galaxy, because the dust in the
gas clouds obscures the starlight, and the relatively rare young
stars are mixed with much more numerous older stars. ... ...
Serabyn et al (3 authors at 2 installations, US) now report high-
resolution infrared observations of a compact cluster of stars in
the central region of our Galaxy, the observations revealing
approximately 100 young massive *main-sequence stars, several of
which seem to be among the most massive in the Galaxy. The
authors suggest this cluster may be a weak analogue of the large
star clusters in starburst galaxies, and that this opens the
possibility of studying the starburst phenomenon by means of a
local example.
QY: E. Serabyn
(Nature 30 Jul 98) (Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *initial mass function: In what is known as the "Salpeter
mass function", the number of stars of a given mass in a unit
volume of space is proportional to the mass to the (-2.35) power.
But after birth, the masses of stars change as a result of mass
loss and mass transfer, and the Salpeter mass function holds
strictly only for stars at the instant of birth. Under this
constraint, the Salpeter mass function is called the "initial
mass function".
... ... *starburst galaxies: A starburst galaxy is a galaxy in
which a massive burst of star formation is taking place, and such
galaxies are characterized by high infrared luminosities.
... ... *main-sequence stars: The Hertzsprung-Russell diagram is
a plot of stellar absolute magnitude against spectral type, and
is one of the most useful diagrammatic aids in astrophysics. The
Main Sequence is a region on the Hertzsprung-Russell diagram
where most stars, including our own Sun, are situated. The course
of a star's evolution can be traced as a particular path in the
H-R diagram, with the paths of various types of stars showing
significant differences.
3. ON PRESSURE IN CONDENSED MATTER
Hemley and Ashcroft (2 installations, US) review recent research
involving manipulation of pressure in condensed systems and make
the following points: 1) Of all physical variables, pressure
possesses one of the greatest ranges -- over 60 orders of
magnitude. At the high end, the pressures are those of the
interiors of *neutron stars; at the low end, the pressures gauge
the conditions of the remotest vacua of outer space. 2) Recent
experimental advances make it possible to change densities in the
condensed state by more than an order of magnitude. 3)
Compression offers a route to "breaking down" the electronic
structure of atoms and to the possibility of entirely different
bulk properties. Through the application of pressure, it is
possible to produce one of the most basic of all changes, the
transition from insulators to metals. 4) The stationary states of
the fundamental Schroedinger equation for a system are clearly
functions of volume and hence alterable by pressure... Pressure
induces myriad changes in materials, typically a tendency toward
closer packing of atoms, ions, or molecules. This is often
assumed to mean a corresponding tendency toward simpler
structures, but sometimes the opposite is true. 5) The diamond-
anvil cell has emerged as the dominant and most versatile tool
for achieving ultrahigh pressures. The cell uses two diamond
anvils, which exert pressure and serve as windows on the sample.
Since pressure is simply force divided by area, large pressures
can be produced by reducing the area over which a force of
relatively modest proportions is directed. Because diamond is the
strongest material known and is transparent over a wide range of
the electromagnetic spectrum, pressures above 3 megabars (300
*gigapascals) can be achieved and the effects on the sample
studied. 6) Exploration of the pressure variable is increasing
the number of known materials, and entirely new classes of
materials are appearing as a result of pressure-induced changes
in the chemistry of otherwise familiar elements. The authors
conclude: "The important feedback between static and dynamic
compression techniques is advancing high-pressure research as a
new dimension, not just in condensed matter physics, but in
physical science as a whole."
QY: Russell Hemley, Carnegie Institute., 5241 Broad Branch Rd.
NW, Wash., DC 20015 US.
(Physics Today August 1998) (Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *neutron stars: During the terminal stages of the
evolution of a star, part of the mass of the star is blown off
and lost. If the remnant mass is between 1.4 and 2 to 3 solar-
masses, the star will collapse into a neutron star, a body with a
radius of only 10 to 15 kilometers, but with a core so dense that
its component protons and electrons have merged into neutrons.
The average density of a neutron star is 10^(15) grams per cubic
centimeter.
... ... *gigapascals: 1 gigapascal = 10^(4) atmospheres.
4. ANALYSIS OF HYDRATION IN A SERIES OF HYDROCARBONS
The interaction energy of nonpolar species with water is usually
less than the interaction energy of the same species with
nonpolar solvents, and once situated in water, since water
interacts poorly with nonpolar species, attractive forces between
two nonpolar moieties can become significant. There are various
theoretical approaches to these nonpolar attractive forces, but
regardless of the origin of the effective attraction between
nonpolar solutes in water, it is clear that to dissolve nonpolar
solutes a cavity in the water (and in any water "structure") of
appropriate size must be created to accommodate the solute. One
question, then, is what is the significance of this cavity
requirement in the energetics of nonpolar aqueous solvation? The
term "hydrophobic interactions" essentially refers to nonpolar
interactions that become significant when nonpolar solutes are in
an aqueous environment with minimal direct interaction between
solute and solvent, and it is currently thought that such
hydrophobic interaction between nonpolar species is the major
driving force in the self-assembly of proteins. Considering all
of the above, computer simulations involving equations derived
from first principles are at the present time an important means
of approaching an understanding of what is happening in these
systems. ... ... Mountain and Thirumalai (2 installations, US)
report an analysis of the aqueous solvation of hydrocarbons
(hydrophobic hydration) in a series of hydrocarbons using
molecular dynamics simulations. The simulations involved a
population of 216 water molecules at ambient conditions; the
system initially equilibrated; equations of motion, degrees of
freedom, etc., computed; and then alkanes introduced sequentially
one molecule at a time. The series of alkanes examined consisted
of methane to octane. The authors report that examination of the
shapes of the *hydration shell indicates there is no single
stable structure surrounding these solutes, and that the
structure of water molecules around the solute is not
significantly perturbed, even for octane, and the hydrogen bond
network is essentially preserved. The solutes are apparently
accommodated in the voids of the *tetrahedral network of water in
such a way as to leave the local environment almost intact. The
hydrophobic hydration apparently arises primarily because of the
plasticity of the hydrogen bond network. Even for octane, the
authors report very little evidence for water-mediated
interactions between non-bonded carbon atoms, and thus the
authors suggest that the transition to globular conformations can
occur only for very long linear hydrocarbon chains.
QY: Raymond D. Mountain, National Institute of Standards and
Technology, Gaithersburg, MD 20899 US.
(Proc. Natl. Acad. Sci. US 21 Jul 98 95:8436)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *hydration shell: In general, "hydration" refers to the
association of water molecules with molecules of another species.
When a molecule of another species is introduced into a
population of water molecules, a subset of water molecules will
become associated with the foreign molecule through interactions,
the degree and quality of the interactions determining the
"solubility" of the foreign species. This subset of water
molecules is called the "hydration shell", but its geometry,
extent, physical properties, etc., can vary markedly from one
system to another, and the term is perhaps best operationally
defined in the context of experimental procedure. If one is
considering anything beyond nearest neighbor water molecules, the
term "hydration cloud" is probably more useful.
... ... *tetrahedral network: Because of the molecular geometry
of the individual water molecule, and the possibility for
hydrogen bonding between water molecules, bulk liquid water at
room temperature has a relatively sustained local tetrahedral
structure.
5. ON EVOLUTIONARY ADAPTABILITY
Although developmental and evolutionary biology classically have
been distinct research disciplines, one of the consequences of
the emergence of molecular biology during the latter half of the
20th century is the apparent active merging of evolutionary and
developmental biology at several levels. Kirschner and Gerhart (2
installations, US) present a detailed analysis of the interaction
of development and evolution, the analysis amplified in a
contiguous paper by West-Eberhard (Smithsonian Tropical Research
Institute, US). The essential idea of Kirschner and Gerhart is
that flexible development, rather than being an alternative to
selection in the evolution of form, mediates the production of
selectable variation. They propose that environmentally sensitive
developmental flexibility, far from merely interfering with the
effects of genes, can ameliorate the deleterious results of
mutation and of environmentally induced variation, increasing the
viability of novel forms. The authors make the following points:
1) Evolvability (evolutionary adaptability) is an organism's
capacity to generate heritable *phenotypic variation. 2)
*Metazoan evolution is marked by great morphological and
physiological diversification, although the core genetic, cell
biological, and developmental processes are largely conserved. 3)
Metazoan diversification has entailed the evolution of various
*molecular regulatory processes controlling the time, place, and
conditions of use of the conserved core processes. 4) These
molecular regulatory processes, and certain of the core
processes, have special properties relevant to evolutionary
change, and these special properties reduce the interdependence
of components and confer robustness and flexibility on processes
during embryonic development and in adult physiology. 5) These
processes also confer evolvability on the organism by reducing
constraints on change and allowing the accumulation of nonlethal
variation. 6) Evolvability may have been generally selected in
the course of selection for robust flexible processes suitable
for complex development and physiology, and specifically selected
in evolutionary lines undergoing repeated *radiations. The
authors present detailed specific examples of various special
processes that may be relevant for evolvability, and they
conclude: "Today. we see the survivors of lineages that underwent
multiple radiations. These lineages have diversified by
maintaining a core of highly conserved processes and modifying
others. The core processes have unusual capacities to deconstrain
change in other processes and components. This has proven to be a
powerful strategy for the variation side of Darwin's variation
and selection principle of evolution."
QY: Marc Kirschner
QY: Mary Jane West-Eberhard, Smithsonian Tropical Research
Institute, Unit 2511, APO AA 34020-9511
(Proc. Natl. Acad. Sci. US 21 Jul 98 95:8417,8420)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *phenotypic: The term "phenotype" refers to the total
appearance of an organism as determined by the interaction during
development between its genetic constitution (genotype) and the
environment. Thus, the concept of phenotype has always implied a
liaison between developmental and evolutionary biology. The idea
of Kirschner and Erhart is that the capacity for phenotypic
variation is itself an important evolving evolutionary element.
... ... *Metazoan: In general, the term "metazoa" refers to all
multicellular animals. Among important distinguishing
characteristics of metazoa are cell differentiation and
intercellular communication. For certain multicellular colonial
entities such as sponges, some biologists prefer the term
"parazoa".
... ... *molecular regulatory processes: An example of a
molecular regulatory process discussed by the authors is the
regulation of intracellular calcium ion concentration by the
calmodulin proteins, this regulation in turn activating or
deactivating physiological processes or other regulatory
processes.
... ... *radiations: In this context, the term "radiation" refers
to the spread of a group of biological entities into new
environments with consequent diversification.
6. ON GAIA AND NATURAL SELECTION
Considering a global system as complex as the planet Earth and
its resident biological entities, there are many possible
schemes, some more metaphorical than others, for organizing
observations and predicting future events. In recent years, The
*Gaia hypothesis first formulated by James E. Lovelock in 1979
has emerged as a possible conceptual framework for studying the
interaction of the environment of the surface of the Earth and
Earth's biota. The essential aspect of the Gaia hypothesis is the
consideration of feedback mechanisms whose consequence is self-
regulation of the environment-biota global system with an
emphasis on the importance of the biotic component in the
physical history of the planet. The Gaia hypothesis has its
severe critics, as evidenced in the following view of Tjeerd H.
Van Andel (*1994) (University of Cambridge, UK): "The conflict
between accepting what science teaches us and what the human
heart would like to believe is well illustrated by James
Lovelock's Gaia concept that places life in charge of the
functioning of our planet. It is a lovely thought, a tempting one
too, because it is a form of religion and the human soul requires
the comfort of a guided universe; it needs religion. Alas, it is
also unnecessary, because the world as it was, has evolved, and
now exists, is not explicable. It is merely very complex, and
life plays a role in it, but not the main one." This evaluation
notwithstanding, the effort to find a workable scheme to generate
understanding of environment-biota interactions continues.
... ... Timothy M. Lenton (University of East Anglia, UK)
presents an extensive review of the Gaia hypothesis and the place
of Darwinian natural selection in that scheme. The author makes
the following points: 1) Organisms alter their material
environment, and their environment constrains and naturally
selects organisms. This connection indicates feedback between
life and its environment. 2) The Gaia theory proposes that
organisms contribute to self-regulating feedback mechanisms that
have kept Earth's surface environment stable and habitable for
life, and the theory seeks to explain these mechanisms and how
they arise. 3) Natural selection, acting on faithful replication
of inherited variation, determines that the organisms that
dominate are the ones that leave the most descendants. Together,
natural selection and Gaia pose a puzzle: How can self-regulation
at the planetary level emerge from natural selection at the
individual level? 4) The author attempts to address this puzzle
by focusing on the feedbacks to biospheric growth and selective
pressures that can arise from environment-altering traits of the
biota. Land ecosystems and marine phytoplankton are discussed in
terms of several models. The author concludes: "The implications
may be far-reaching; simple principles suggest that environmental
regulation can emerge at levels from the individual to the
global. Natural selection is seen as an integral part of Gaia,
and Gaia theory also has something to offer evolutionary biology.
Gaian models suggest that we must consider the totality of
organisms and their material environment to fully understand
which traits come to persist and dominate."
QY: Timothy M. Lenton
(Nature 30 Jul 98 394:439) (Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *Gaia hypothesis: The theory was named for Gaia, the
Greek Earth-mother goddess.
... ... *1994: T. H. Van Andel, *New Views on an Old Planet: A
History of Global Change*, Cambridge University Press, 1994, p.
402.
7. NEUROBIOLOGY: GATING MODIFIER TOXINS AND ION CHANNELS
The venom produced by many animals has been a useful source of
ligands that interact with different types of *ion channels. In
some cases, these toxins bind to the outer vestibule of the pore
and physically block ion conduction, whereas in other cases, the
toxins modify channel gating. Toxins that act as modifiers of
channel gating have been described for *voltage-gated sodium ion
channels, voltage-gated potassium ion channels, and voltage-gated
calcium ion channels. The different effects of the pore-blocking
toxins and the gating modifier toxins arise because they interact
in specific ways with different regions of ion channels.
Hanatoxin and grammotoxin are two related protein toxins found in
the venom of the Chilean Rose Tarantula, Phrixotrichus spatulata.
Hanatoxin inhibits voltage-gated potassium ion channels and
grammotoxin inhibits voltage-gated calcium ion channels. Both
toxins inhibit their respective channels by interfering with the
normal operation of the voltage-dependent gating mechanism. The
sequence homology of hanatoxin and grammotoxin, as well as their
similar mechanisms of action, suggest the possibility that they
interact with the same region of voltage-gated calcium ion and
voltage-gated potassium ion channels. ... ... Li-Smerin and
Swartz (National Institutes of Health, US) present an
electrophysiological study of the action of hanatoxin and
grammotoxin on *genetically engineered ion channels in the
membranes of oocytes of Xenopus laevis (African clawed toad), and
the authors report that each toxin can interact with both
voltage-gated calcium ion and voltage-gated potassium ion
channels and modify channel gating. They further report that
*mutagenesis studies of voltage-gated potassium ion channels
suggests that hanatoxin and grammotoxin recognize the same
structural motif. The authors propose that these toxins recognize
a voltage-sensing domain or module present in voltage-gated ion
channels, and that this domain has a highly conserved 3-dimens-
ional structure. They conclude: "It is as if voltage-gated ion
channels follow a multi-domain architecture whereby the ion
selective pore domain has diverged to confer selectivity for
potassium ion, calcium ion, or sodium ion, and a separate
voltage-sensing domain, which is conserved in its structure, is
share by all of them."
QY: Kenton J. Swartz
(Proc. Natl. Acad. Sci. US 21 Jul 98 95:8585)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *ion channels: Ion channels are protein channels in cell
membranes that allow ions to pass from extracellular solution to
intracellular solution and vice versa. Most ion channels are
selective, allowing only certain ions to pass, and an individual
cell has ion channels with various ion selectivities. The
selectivity of an ion channel can be "gated", the channel
effectively opened or closed, and ion channels are said to
voltage-gated or ligand-gated, depending on how the change in
selectivity is provoked.
... ... *voltage-gated: The "voltage" in the voltage-gating
referred to here is the potential difference across the cell
membrane, a potential difference that can be quantitatively step-
changed with experimental procedures. One then studies the force-
response characteristic (voltage-current curve) to determine ion
specificities and ion permeabilities. Under natural conditions,
changes in potential difference (and consequent voltage-gating)
are a result of the electrical behavior of regions of the
membrane contiguous to the channel.
... ... *genetically engineered: In this report, the oocytes were
genetically engineered to express specific ion channels in their
membranes. The experimental advantage of the oocytes used is that
genetic engineering methods are easily applied, and the cells are
large enough to facilitate electrical measurements. The toad
oocytes, then, are merely a vehicle for the production of the ion
channels, which in this case were derived genetically from
mammalian (rat) brain and muscle cells.
... ... *mutagenesis: In general, mutagenesis is any alteration
of the genome. In this report, genetic engineering methods were
used to produce specific protein residue changes in ion channels,
so that the electrical behavior of such specifically mutated ion
channels could be studied.
8. AN ANALYSIS OF HYPERMUTATION ANTIBODY GENE TARGETS
In vertebrates, the immune system provides protection against
foreign agents, for the most part by recognizing molecular
entities (antigens) that are interpreted by the immune system as
of foreign origin. Many types of cells are involved in the immune
response, with 3 primary types the so-called B-cells, cytotoxic
T-cells, and helper T-cells. In general, cytotoxic T-cells
recognize and kill host cells that are infected, while B-cells
are cells that secrete antibodies, protein molecules that bind to
antigens. Helper T-cells (and other immune system cells) are
involved in both processes, provoking particular steps in the
immune response. The ability of the immune system to recognize
and respond to the enormous number of antigens encountered by an
individual in a lifetime is due in large part to the diversity of
antibodies (also called *immunoglobulins) produced by B-cells.
Each B-cell produces only a single species of antibody, and
during the systemic immune response, the presence of a specific
antigen results in the proliferation by *clonal selection of
B-cells producing antibody specific for that antigen. All
antibody molecules are proteins consisting of two light
polypeptide chains and two heavy polypeptide chains that are
joined together by disulfide bonds. Each polypeptide chain
contains regions of variable amino acid sequence and regions of
constant amino acid sequence, resulting in an antigen-binding
locus with a variable specific affinity for particular ligands.
Further antibody variability arises from a variability in the way
the particular segments of the antibody are joined. The ability
of antibodies to recognize a large variety of antigens is thus
controlled, in part, by the variability of the variable segments
of the amino acid sequences of the antibody polypeptide chains.
This amino acid variability in the light and heavy chains is the
result of a variability in B-cell DNA generated by somatic
recombination, an alteration and reassembly of genes. During the
past 15 years, it has become evident that in immune system B-
cells, the part of the genome coding for the variable parts of
antibodies is involved in a process of "hypermutation", a
substantial increase in mutation rate, the effect of which is to
provide the immune system with a rapidly changing enormous
library of possible antibodies. This hypermutation process is
highly specific to the immune system, and it occurs only within a
DNA segment of approximately 1000 to 2000 DNA bases, the segment
that encodes the bulk of the variable regions of the antibody
polypeptides. The mechanism of the hypermutation process remains
unknown. ... ... Milstein et al (3 authors at Medical Research
Council, UK) report an analysis of the average frequency of
mutations of each of the 3 bases of all *nucleotide triplets in
the relevant DNA segment. Their focus was the question of whether
the B-cell hypermutation process involves one strand or both
strands of the DNA double helix. Many hypermutation models
propose that only one of the strands of DNA is involved in
hypermutation. The Milstein et al analysis used large databases
of mutations involving both variable and non-variable mutation
targets. The essential idea is that by using large databases of
such mutations, one can contrast the mutation distributions
observed with what would be expected if either one or both DNA
strands are hypermutation targets. The authors report their
analysis indicates there are two aspects of the hypermutation
process, one aspect that is DNA strand-dependent and the other
aspect that is not. The strand-independent aspect is sensitive to
local DNA sequences (i.e., mutation hot spots correlate with
local sequence environments), but without strand preference. The
authors report a similar conclusion has been reached by a
separate research group (Dorner et al, Immunol Rev. 162:161
1998).
QY: Cesar Milstein, Medical Research Council Laboratory of
Molecular Biology, MRC Centre, Hills Road, Cambridge CB2 2QH, UK.
(Proc. Natl. Acad. Sci. US 21 Jul 98 95:8791)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *immunoglobulins: The immunoglobulins are a large
glycoprotein category that includes antibodies as a subset.
... ... *clonal selection: In this context, the process by which
an antigen selectively stimulates the proliferation of those
B-cells that possess antigen receptors targeted against the
stimulating antigen.
... ... *nucleotide triplets: Nucleotides are molecules
consisting a purine or pyrimidine base joined to a 5-carbon sugar
(ribose or deoxyribose) containing an attached phosphate group.
Nucleotides are the fundamental building blocks of nucleic acids,
and nucleotide triplets of 3 contiguous nucleotides are the
fundamental coding units of the genome.
9. NEW EVIDENCE OF TRANSMISSION OF MULTI-DRUG RESISTANT HIV
Combination treatments with agents that inhibit *protease and
*reverse transcriptase of human immunodeficiency virus type 1
(*HIV-1) decrease mortality and slow disease progression.
However, the development of resistance to these drugs limits the
benefit of such treatments. There have already been reports of
the transmission of HIV-1 variants that are resistant to
*nucleoside and non-nucleoside inhibitors of reverse
transcriptase. The transmission of HIV-1 variants that are
resistant to protease inhibitors could represent an important
emerging clinical and public health problem. ... ... Now Hecht et
al (11 authors at 4 installations, US) report a case of
transmission of an HIV-1 variant with multiple mutations that
conferred resistance to both protease inhibitors and reverse
transcriptase inhibitors, the spectrum of drugs resisted
comprising zidovudine, lamivudine, saquinavir, ritonavir,
indinavir, and nelfinavir. In a related editorial in the same
issue of the journal, Cohen and Fauci (National Institute of
Allergy and Infectious Diseases, US) make the following points:
1) The availability of potent antiretroviral drugs capable of
long-term suppression of HIV replication is a welcome advance
that has rapidly improved the prognosis for HIV-infected persons.
However, it must be anticipated that in all but exceptional
cases, the virus will have sufficient genetic plasticity to
develop drug resistance during periods of subtotal suppression of
replication. 2) Transmission of multi-drug resistant HIV will
most likely occur with increasing frequency, and the wake-up call
provided by the report of Hecht et al should reinforce the
lessons taught by the already encountered multi-drug resistance
of the tubercle bacillus, the pathogen Staphylococcus aureus, and
the pathogen Streptococcus pneumononiae [Editor's note: see
background material below]. Cohen and Fauci conclude:
"Appropriate prescription of potent antiretroviral regimens,
maximal adherence to the regimens, the development of new drugs
directed against different stages of the viral-replication cycle,
and the creation of accurate and reliable assays to assess drug
resistance are all essential for the successful long-term control
of HIV replication."
QY: Frederick M. Hecht, Univ. of Calif. San Francisco 415-476-
4044.
QY: Oren J. Cohen, US Nat. Inst. of Health, Bethesda, MD 20892-
0148.
(New England J. Med. 30 Jul 98 339:307,343)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *protease: A protease is an enzyme that splits proteins
and thereby degrades them. Many pathogens use proteases as part
of the pathogenic disease process.
... ... *reverse transcriptase: Retroviruses such as HIV 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 host-cell material. This DNA
is then incorporated into the host cell's genome, where it codes
for the synthesis of viral components.
... ... *HIV-1: HIV-1 is the subtype of HIV that causes most
cases of AIDS in the Western Hemisphere, Europe, and Central,
South, and East Africa.
... ... *nucleoside: Nucleosides are the base-sugar moieties of
nucleotides.
-------------------
Related Background:
ANTI-TUBERCULOSIS DRUG RESISTANCE 1994-1997
In the past 50 years, the proliferation of anti-microbial agents
for use in humans and animals has placed enormous selective
pressure on microorganisms. Drug resistance in patients with
Mycobacterium tuberculosis infection became apparent soon after
the introduction of effective antituberculosis agents in the
1940s, but it was not until the early 1990s, when outbreaks of
multi-drug-resistant tuberculosis were reported in patients with
human immunodeficiency virus (HIV) infection in the US and
Europe, that the problem received international attention.
... ... Pablos-Mendez et al (12 authors at 7 installations, US FR
CA NL KR and the World Health Organization) report a study of
the
prevalence of resistance to 4 first-line drugs (isoniazid,
rifampin, ethambutol, streptomycin) in 35 countries participating
in an international collaborative study of the problem between
1994 and 1997. Among patients with no prior treatment, a median
of 9.9 percent of M. tuberculosis strains were resistant to at
least one drug. The prevalence of primary multi-drug resistance
(resistance to at least isoniazid and rifampin) in this group was
1.4 percent. Among patients with histories of treatment for one
month or less, the prevalence of resistance to any of the four
drugs was 36 percent, and the prevalence of multi-drug resistance
was 13 percent. Particularly high prevalences of multi-drug
resistance were found in the former Soviet Union, Asia, the
Dominican Republic, and Argentina. The authors conclude that
resistance to antituberculosis drugs exists in all 35 countries
and regions surveyed, and they suggest that it is a global
problem. In an editorial in the same issue of the journal, D.E.
Snider and K.G. Castro (Centers for Disease Control, US) warn
that a greater commitment by the developed countries is needed
"if we are to ward off what could become a global health
disaster."
QY: Ariel Pablos-Mendez, Columbia University (US) 212-854-1754.
QY: Dixie E. Snyder, Centers for Disease Control and Prevention,
Atlanta, GA 30333 US.
(New England J. Med. 4 Jun 98 338:1641,1689)
(Science-Week 26 Jun 98)
-------------------
Related Background:
ON THE PROBLEM OF MULTI-DRUG MICROBIAL RESISTANCE
S. Levy (Tufts University, US) reviews the problem of multi-drug
resistant microbes. Antibiotic resistance, initially a problem in
hospitals and developing countries, today affects the world at
large. Some strains of disease-causing bacteria in the US may now
be untreatable: the vancomycin-resistant enterococcus,
Mycobacterium tuberculosis, Pseudomonas aeruginosa, and
Acinetobacter baumanii. The author proposes 5 principles
underlying the problem: 1) Given sufficient time and drug use,
antibiotic resistance will emerge. 2) Resistance is progressive,
evolving from low levels through intermediate to high levels. 3)
Organisms that are resistant to one drug are likely to become
resistant to others. 4) Once resistance appears, it is likely to
decline slowly, if at all. 5) The use of antibiotics by one
person affects others in the extended as well as immediate
environment.
QY: Stuart B. Levy, Tufts Univ. School of Medicine 617-636-6639
(New England J. Med. 7 May 98 338:1377) (Science-Week 15 May 98)
-------------------
Related Background:
VIRULENCE OF ANTIBIOTIC RESISTANT SALMONELLA
Bjorkman et al (3 authors at 2 installations, SE) report a study
of the virulence of antibiotic resistant Salmonella typhimurium.
During the last decade there has been an alarming increase in the
appearance of antibiotic-resistant bacteria as a result of an
increased use of antibiotics combined with the exceptional
ability of bacteria to develop resistance. One strategy to
reverse this development is to decrease the use of antibiotics to
promote the disappearance of the resistant bacteria present in
human and environmental reservoirs. Implicit in this reasoning is
that mutated resistant bacteria will be less viable in an
antibiotic-free environment. An associated question is whether
resistant bacteria with reduced or no virulence might accumulate
compensating mutations that restore fitness and virulence without
loss of resistance. In this study, the authors examined the
fitness of S. typhimurium in mice, and their results indicate
that most resistant mutants are less virulent than the wild type,
but that the avirulent mutants rapidly accumulate various types
of compensating mutations that restore virulence to wild-type
levels without loss of high-level resistance. The authors suggest
that if their results are general and apply to other medically
relevant pathogens, then the strategy of getting rid of
antibiotic resistant bacteria by a decreased use of antibiotics
may not be successful.
QY: Dan I. Andersson (dan.andersson@smi.ki.se)
(Proc. Natl. Acad. Sci. US 31 Mar 98 95:3949)
(Science-Week 8 May 98)
-------------------
Related Background:
EMERGENCE OF MULTI-DRUG-RESISTANT SALMONELLA IN THE US
Strains of salmonella that are resistant to antimicrobial agents
have become a worldwide health problem, with a distinct strain of
Salmonella enterica serotype typhimurium becoming a major cause
of illness in humans and animals in Europe, especially in the UK.
Glynn et al (6 authors at 2 installations, US) report an analysis
of data collected in the US by local and state health departments
and public health laboratories between 1979 and 1996 in national
surveys of the antimicrobial-drug resistance of salmonella. The 5
drugs involved were ampicillin, chloramphenicol, streptomycin,
sulfonamides, and tetracycline. The authors report that the
prevalence of S. typhimurium resistance to the 5 antibiotics
increased from 0.6% in 1979-1980 to 34% in 1996, and they
conclude that multi-drug resistant S. typhimurium has become a
widespread pathogen in the US. The authors suggest that more
prudent use of antimicrobial agents in farm animals and more
effective disease prevention on farms are necessary to reduce the
dissemination of this bacterial mutant and to slow the emergence
of resistance to additional antimicrobial agents in this and
other strains of salmonella.
QY: M. Kathleen Glynn, Centers for Disease Control and
Prevention, Atlanta, GA 30333 US.
(New England J. Med. 7 May 98 338:1333) (Science-Week 8 May 98)
-------------------
Related Background:
ON THE RESISTANCE OF BACTERIA TO ANTIBIOTICS
S. Levy (Tufts University, US), in a review of recent
developments in antibiotic resistance, notes that strains of at
least 3 pathogenic bacterial species -- Enterococcus faecalis,
Mycobacterium tuberculosis, Pseudomonas aeruginosa -- have
already developed resistance to every one of the 100 antibiotic
drugs in use by clinicians. Levy says a change in attitudes of
the public and clinicians concerning the overuse of antibiotics
is badly needed, and that a reversal of increasing bacterial
resistance to antibiotics, as well as increasing resistance of
parasites, fungi, and viruses to antimicrobials and antivirals,
will require a new global awareness of the broad consequences of
anti-pathogen drug usage.
QY: Stuart B. Levy, Tufts Univ. School of Medicine 617-636-6571
(Scientific American March 1998) (Science-Week 20 Feb 98)
-------------------
Related Background:
STUDIES SHOW MARKED INCREASE IN DRUG RESISTANCE OF MICROBES
Widespread use of antibiotics continues to force the evolution of
strains of pathogens resistant to the drugs. For example, the
incidence in the U.S. of microbes resistant to penicillin has
increased fourfold since 1994. At the May 19th International
Conference of the American Lung Association and American Thoracic
Society in San Francisco, researchers from the State University
of New York (Buffalo NY US) and the University of Iowa College of
Medicine (Iowa City IA US) found the increase in resistance of
Streptococcus pneumoniae, a common cause of respiratory
infections, to be dramatic. 10.5% of the samples were highly
resistant to antibiotics and 24.9% moderately resistant. In 1994,
those figures stood at only 3.2% and 14.1%, respectively. In the
Southeastern part of the U.S., 41% of the samples were found to
be resistant. The researchers suggest that the medical community
must be on the watch for rapidly developing epidemics caused by
antibiotic resistant strains of pathogens, and that antibiotics
themselves should be administered only when necessary if we are
to slow down the evolution of these resistant microbes.
(UPI 19 May 97)
-------------------
Related Background:
APPEARANCE OF A STAPHYLOCOCCUS STRAIN RESISTANT TO VANCOMYCIN
Staphylococcus aureus is a common pathogenic bacterium in
hospitals, and causes thousands of often fatal infections each
year. Vancomycin is an antibiotic of last resort, which is used
when all other antibiotics fail. Now the first case has appeared
in Japan of a 4 year old boy infected with a strain of
Staphylococcus aureus resistant to vancomycin. Health experts
say it is only a matter of time before the pathogen reaches U.S.
hospitals. Fred Tenover, laboratory chief of the U.S. Center for
Disease Control Hospital Infections Branch says, "The strain is
marching up the ladder of resistance... It is not a cause for
panic, but it is a cause for concern." (UPI 28 May 97)
-------------------
Related Background:
REDUCED ANTIBIOTIC USAGE LOWERS BACTERIAL RESISTANCE
To understand the mechanism of the worldwide increase in
bacterial resistance to antibiotics one need only consider that
for all biological organisms most chemical aspects are more or
less displayed as a Gaussian distribution, the so-called "normal"
or "bell-shaped" curve. What this means in the context of
applying an antibiotic to a population of a particular bacterial
species is that something like 10% or 15% of the population will
show much lower than average resistance to the drug, about 60%
will have close to the average resistance to the drug, and about
10% to 15% will show above average resistance to the drug, all
because of the way the chemistry responsible for resistance to
the drug is distributed in the population. These numbers are
variable from one species of bacteria to another, and they also
vary with the antibiotic used, but the general idea is the same.
The result of all of this is that if we use an antibiotic against
a specific bacterial population, those members of the population
that have superior resistance to the antibiotic will survive to
reproduce their genome, most of the others will be killed, and
before long we will have on our hands populations of that species
which are more or less totally resistant to the antibiotic. This
is nothing more than a concrete instance of the idea of
"selection pressure" in evolution. In 1946 about 90% of
Staphylococcus aureus (a common and dangerous pathogen bacterium)
in hospitals were killed by the antibiotic penicillin, which
first became widely available at about that time. By only 6 years
later, 75% of S. aureus caught and cultured in hospitals were
resistant to penicillin, and by the 1970s, 90% of S. aureus,
whether in hospitals or in the community, were resistant to the
drug. There are similar stories concerning other bacterial
species and other drugs, the worst scenarios evidently occurring
in hospitals; but one cannot fault hospitals, because in both
hospitals and the community antibiotics have been routinely
needlessly administered and/or over-administered, with a
consequent selection pressure that produces antibiotic-resistant
pathogens. Can the process be reversed? There may still be some
hope against bacterial species which are not already overwhelm-
ingly resistant. This week Helena Seppala et al (about 100
authors in FI) report that in Finland, after an organized
nationwide reduction in the use of macrolide antibiotics
(macrolides are large-ring molecules with many functional side
groups) for outpatient therapy, the resistance of group A
streptococci to the common antibiotic erythromycin dropped by
half from 16.5 per cent in 1992 to 8.5 per cent in 1996. In an
editorial in the New England Journal of Medicine, Morton N.
Swartz (Massachusetts General Hospital, Boston US) calls this "an
impressive example of how an enlightened national policy on
antibiotic use can become an effective public health measure."
QY: H. S. Seppala, Antimicrobial Research Laboratory, PO Box 57,
20521 Turku, FI.
(New England J. Med. 14 Aug 97)
-------------------
Related Background:
NEW MULTI-DRUG RESISTANCE OF PLAGUE PATHOGEN
Plague, also called bubonic plague or "Black Death", is a disease
with a notorious history. It is caused by the bacillus Yersinia
pestis, which infects wild rodents. The bubonic variant of the
disease is transmitted to humans from rodents by the bite of an
infected flea. Human to human transmission occurs by inhalation
of respiratory droplets spread by the cough of patients with
plague who have developed pulmonary lesions, and the result of
this is "primary pneumonic plague", which differs from "bubonic
plague" in that bubonic plague affects the lymph nodes, among
other tissues (producing "buboes", lymph node swellings). The
last plague pandemic began in Hong Kong in 1894 and spread
throughout the world. Plague still exists as an endemic disease
in many parts of the world, including the southwestern U.S.
Prevention of plague is based on rodent control, and the use of
insect repellents to minimize flea bites. Early treatment after
infection with the antibiotics streptomycin, chloramphenicol, or
tetracycline reduces mortality to less than 5%. Nevertheless,
plague is now considered a reemerging disease, with recent
epidemics in a number of countries after an absence of as much as
3 decades. The incidence of the disease has also been spreading
in the U.S. Now Marc Galimand et al (World Health Organization
and the Pasteur Institute, FR) report high-level resistance of Y.
pestis in a clinical isolate in Madagascar to multiple
antibiotics, including resistance to all the drugs recommended
for plague prophylaxis and therapy. The resistant genes are
apparently carried by a plasmid that can conjugate to other Y.
pestis isolates. So this pathogen species, heretofore considered
universally susceptible to antibiotics, is now exhibiting high
and spreadable resistance to these drugs. Epidemiologists are
alarmed and are urging an international effort to deal with the
problem.
QY: Elisabeth Carniel, Institute Pasteur, 28 rue du Dr. Roux,
75724 Paris CEDEX 15, FR.
(New England J. Med. 4 Sep 97)
-------------------
Related Background:
APPARENT IRREVERSIBILITY OF BACTERIAL ANTIBIOTIC RESISTANCE
At a recent meeting of the European Society for Evolutionary
Biology (Arnhem NL), several research groups have apparently
independently confirmed the unhappy news that bacteria that have
mutated to exhibit resistance to specific antibiotics do not
evolve susceptible strains when they are no longer exposed to
these antibiotics. Bruce Levin and Bassam Tomah (Emory Univers-
ity, US) report that 25% of bacteria sampled from infant diapers
are strains of E. coli still resistant to the antibiotic strepto-
mycin, which has been rarely used during the past 30 years.
Richard Lenski (Michigan State University, US) has independently
shown that after 20,000 generations in the absence of strepto-
mycin, E. coli still carries the gene that confers resistance to
the antibiotic. The consensus is apparently that a compensatory
mutation has occurred, a mutation that compensates for the loss
of fitness produced by the gene that confers antibiotic
resistance, and which results in long-term survival of the
resistant strain. Levin suggests the same kind of compensatory
mutations "will almost certainly be found in other resistant
bacteria." The implication is that the evolutionary development
of bacterial resistance to antibiotics will not be reversed by
reducing the use of these antibiotics, which means the effective-
ness of these antibiotics is essentially irreversibly lost.
QY: B. Levin, Emory Univ., Population Genetics (404) 727-5660.
(Science 24 Oct 97)
10. DNA EVIDENCE FOR NEOLITHIC ANCESTRY OF EUROPEAN GENE POOL
According to the Ammerman and Cavalli-Sforza (1984) population
diffusion model, current European populations are descended
largely from ancestors who expanded from the Near East in the
*Neolithic age. Their westward and northward expansion, a
consequence of demographic increase, spread their genes over the
entire continent, along with novel technologies for farming and
animal breeding. In the process, Neolithic farmers mixed very
little with the preexisting hunting-gathering communities. Thus,
the genes of the hunting-gathering people should represent only a
small fraction of the present European gene pool. This Neolithic
diffusion model rests on a variety of evidence, both genetic and
archeological. In contrast to this model is a hypothesis based
primarily on recent *mitochondrial data, a *Paleolithic model
that proposes that the current European gene pool was established
in the Paleolithic age, with relatively few Near Eastern genes
incorporated during the Neolithic age, genetic diversities
(population splits) already established during the Paleolithic
age, and with the farming technologies mostly spread through
cultural transmission rather than by population movements.
... ... Chikhi et al (5 authors at 4 installations, IT) report an
analysis of existing molecular evidence to find support for
either of the above views of the origin and evolution of the
European gene pool. The authors collected data from published
literature and unpublished sources, analyzing chromosome gene
specifics from 65,280 individuals. The authors report that even
assuming low mutation rates and long generation times, they found
no evidence for population splits older than 10,000 years, with
the predictable exception of the Lapps (Saami). The authors
suggest the simplest interpretation of their results is that the
current European nuclear gene pool largely reflects the westward
and northward expansion of a Neolithic group. They further
suggest that many mitochondrial lineages whose origin has been
traced back to the Paleolithic period probably reached Europe at
a later time.
QY: Guido Barbujani, Dpt. Biologia, Universita di Ferrara, via
Borsari 46, 44100 Ferrara, IT.
(Proc. Natl. Acad. Sci. US 22 Jul 98 95:9053)
(Science-Week 21 Aug 98)
-------------------
Related Background:
... ... *Neolithic age: (New Stone Age) Characterized by first
domestication of animals, cultivation of plants, production of
sophisticated stone tools, etc. Considered to have begun
approximately 10,000 years ago.
... ... *mitochondrial data: Mitochondrial DNA has found
important uses in evolutionary studies. The mitochondria are cell
organelles that may have originated as separate organisms that
became resident in eukaryotic cells. Mitochondrial DNA is
independent of nuclear DNA. It consists of a circular molecule,
16,569 base pairs long in humans, with a known nucleotide
sequence. Mitochondrial DNA is inherited primarily through the
maternal lineage, and accumulates mutations at a rate an order of
magnitude greater than nuclear DNA, which facilitates
comparisons
between groups. In general, modern DNA sequencing techniques have
made possible the tracing of mitochondrial DNA differences among
individuals to reveal evolutionary relationships.
... ... *Paleolithic: (Old Stone Age) From approximately 10,000
to approximately 2 million years ago.
-------------------
Related Background:
ANTHROPOLOGICAL EVIDENCE FOR EARLIEST KNOWN NET HUNTERS
In anthropology, the Paleolithic Period, or the Old Stone Age, is
the name given to the earliest period of human development and
the longest phase of human history, beginning about 2 million
years ago and ending between 40,000 and 10,000 years ago,
depending on geographic location. The period between 40,000 and
10,000 years ago is called the Upper Paleolithic Period, and our
knowledge of the people of this period is derived from analysis
of fossil remains, and artifacts and fragments of artifacts found
in association with fossils. With radiocarbon dating techniques,
it is often possible to fix the date of any stratum in which
fossils and artifacts are found to within one or two thousand
years, which provides us with a rough calendar for the history of
Paleolithic groups of humans. One such group is the Gravettian
people, who apparently lived 29,000 to 22,000 years ago in a
region extending from Spain to southern Russia. Now Olga Soffer
et al (University of Illinois Urbana-Champaign), after detailed
microscopic analysis of clay impressions from two Gravettian
sites in Czechoslovakia, present convincing evidence that these
Gravettian groups not only wove basketry and textiles, but they
also apparently wove nets that were probably used for hunting
small animals. The latter evidence comes from the presence of
weaver's knots that are commonly used to make nets of secure
mesh. The idea is that the clay impressions of net fiber patterns
occurred in living quarters while the ground clay was not yet
baked by fire. This discovery has evidently caused some
excitement in the anthropology community, since the hunting of
small animals with nets was most likely a community effort rather
than the work of individual male hunters, and if this is true,
then our picture of the social structure of these Paleolithic
groups may need to be revised.
QY: O. Soffer, Univ. Illinois Urbana-Champaign (217) 333-0302.
(Science 29 Aug 97) (Science-Week 12 Sep 97)
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