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ScienceWeek
SCIENCE-WEEK
A Weekly Digest of the News of Science
August 14, 1998
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At the last dim horizon, we search among ghostly
errors of observations for landmarks that are
scarcely more substantial. The search will continue.
The urge is older than history. It is not satisfied
and it will not be oppressed.
-- Edwin Hubble (1889-1953)
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Contents of This Issue:
1. On Popular Culture and the Threat to Rational Inquiry
2. US Natl. Acad. of Sciences: Overwhelming Rejection of Religion
3. A Millisecond Pulsar in an X-Ray Binary System
4. A Tunable Kondo Effect in Quantum Dots
5. Combinatorial Chemistry in Insects
6. Confirmations of Wilmut Cloning Research
7. Neurobiology: High-Frequency Firing and Vesicle Replenishment
8. Activity-Dependent Cortical Target Selection by Growing Axons
9. A Successful Vaccine Against Lyme Disease
10. Combined Anti-Tumor Effects of Angiostatin and Radiation
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1. ON POPULAR CULTURE AND THE THREAT TO RATIONAL INQUIRY
In an essay on current popular attitudes toward science and
scientists, Douglas R. Hofstadter (Indiana University
Bloomington, US) makes the following points: 1) Science is
currently presented to children and teens combined with
irrelevancies such as action-packed stories, rock music, amusing
quipsters, sassy jokes, sexual innuendoes, or up-to-date teen
slang -- as if science is a "bitter pill" that needs sugar-
coating. 2) Society today seems to be pervaded by a deep,
unconscious, anti-science bias. Scientists are represented in
movies, television, and books as heartless, humorless nerds who
would sooner kill than smile, sooner write abstruse formulas than
make love. 3) There is a dismissive attitude toward science as an
explanatory framework for the world, and the welcoming of so-
called "mysteries" such as after-death experiences, alien
abductions, crystal channeling, crop circles, telekinesis,
clairvoyance, extrasensory perception, or remote viewing. 4)
Movie and television viewers and readers of serious literature
are given the tacit message that the line between the natural and
supernatural is blurry, and perhaps even nonexistent. 5) The
general public no longer views science with a sense of awe and
mystery, but instead considers it conservative and mundane,
"trapped" in logical thinking. 6) The implicit message of popular
culture is that science is boring, conservative, closed-minded,
devoid of mystery, and a negative force in society. The author
concludes: "I have no quick fixes. I do not know how to quickly
and easily repair decades of damage. I do not fully understand
why the sands have shifted so radically. All I can do is look on
in sadness and worry about the future of rational inquiry,
bemoaning the loss of awe toward genuine mysteries that our
society was once lucky enough to possess."
QY: Douglas R. Hofstadter, Indiana Univ. Bloomington 812-855-4848
(Science 24 Jul 98 281:512) (Science-Week 14 Aug 98)
2. US NATL. ACAD. OF SCIENCES: OVERWHELMING REJECTION OF RELIGION
Although the current popular US media are fond of informing the
public that science and religion are moving closer on a common
ground, the evidence is apparently the opposite. In a letter to
the journal *Nature*, Larson and Witham (University of Georgia
Athens, US) report the results of a recent survey of scientists
who are members of the US National Academy of Sciences (NAS). The
authors report "near universal rejection" of the transcendent by
NAS natural scientists. Overall, 93 percent of NAS scientists do
not profess a belief in God (72.2 percent disbelief, 20.8
agnostic), and 92.1 percent do not profess a belief in
immortality (76.7 percent disbelief, 23.3 percent agnostic).
Disbelief in God and immortality among NAS biological scientists
was 65.2 percent and 69.0 percent respectively, and among NAS
physical scientists it was 79 percent and 76.3 percent
respectively. As indicated, most of the rest define themselves as
agnostics, with only few believers. The highest percentage of
belief was found among NAS mathematicians: 14.3 percent belief in
God, 15 percent belief in immortality. Biological scientists had
the lowest rate of belief (5.5 percent in God, 7.1 percent in
immortality), with physicists and astronomers slightly higher
(7.5 percent in God, 7.5 percent in immortality). The authors
suggest that despite recent declarations by NAS president Bruce
Albert that many outstanding members of the academy are very
religious people, the present survey indicates otherwise.
QY: Edward J. Larson
(Nature 23 Jul 98 394:313) (Science-Week 14 Aug 98)
3. A MILLISECOND PULSAR IN AN X-RAY BINARY SYSTEM
A pulsar is a regularly pulsating source of radiation, the
pulsations believed to involve the magnetic field of a rotating
*neutron star. Pulsars were originally discovered at radio
wavelengths, but they have also been detected at optical and
gamma-ray wavelengths. They can be powerful gamma-ray emitters
(gamma-ray pulsars), and there is also a class of x-ray pulsars.
The periods of pulsars range from approximately 1.5 milliseconds
to 4 seconds and can typically be measured to accuracies of one
part in 10^(10). Pulsars with periods shorter than approximately
0.01 seconds constitute the distinct class of millisecond
pulsars. Most pulsars are single stars, but binary pulsars are
known, about half of which are millisecond pulsars. The
millisecond-pulsar neutron star is believed to be rotating
hundreds of times per second, and a large number of millisecond
binary pulsars have been discovered in globular clusters. The
origin and evolution of pulsars has not been clear, but it has
been thought that millisecond radio pulsars, which are often
found in binary systems, start as ordinary pulsars, then lose
most of their magnetic field and "spin up" to millisecond periods
by the accretion of matter (and transfer of angular momentum)
from a companion star in an x-ray binary system. Until now, there
has been no direct proof of this idea in the form of predicted
coherent millisecond x-ray pulsations in the flux of an x-ray
binary. ... ... Wijnands and van der Klis (2 installations, NL
US) now report the discovery of such a pulsar, confirming
theoretical expectations. The authors suggest the source will
probably become a millisecond radio pulsar when the accretion
turns off completely. ... ... In a contiguous paper, Chakrabarty
and Morgan (Massachusetts Institute of Technology, US) report
that the orbital period of this binary system is 2 hours, and
that the system seems closely related to "black-widow"
millisecond radio pulsars, a class of pulsars that completely
consume their binary companions.
QY: Michiel van der Klis
QY: Deepto Chakrabarty
(Nature 23 Jul 98 394:344,346) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *neutron star: If, following the terminal stages of its
evolution, the remnant mass of a star is between 1.4 and 2 to 3
solar-masses, the star will collapse into a neutron star, a body
with a radius of 10 to 15 kilometers, 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, and the weight of an object on the surface of a
neutron star would be 10^(11) its weight on the surface of the
Earth. Neutron stars apparently have an outer shell of iron, but
it is iron like no Earth iron, an iron of 4 orders of magnitude
greater density. Theory predicts that a neutron star should
rotate very rapidly, be extremely hot, and have an intense
magnetic field.
4. A TUNABLE KONDO EFFECT IN QUANTUM DOTS
Quantum dots are small electrically conducting regions, typically
less than 1 micron in diameter, that contain from one to a few
thousand electrons. Because of the small volume, the electron
energies within the dot are quantized, and the behavior of the
quantum dot is intermediate between that of an atom and that of a
classical macroscopic object. Such intermediate systems are
called "mesoscopic" systems, and in the past several years great
attention has been devoted to the physics of such systems, since
they apparently can provide insights into quantum systems in
general. The electronic states in quantum dots can be probed by
transport when a small *tunnel coupling is allowed between the
dot and nearby source and drain leads. ... ... Cronenwett et al
(3 authors at 2 installations, NL US) report the realization of a
tunable *Kondo effect in small quantum dots, with the capability
of switching a dot from a Kondo system to non-Kondo system as the
number of electrons on the dot is changed from odd to even. The
*Kondo temperature can be tuned by means of a gate voltage as a
single-particle energy state nears the *Fermi energy.
Measurements of the temperature and magnetic field dependence of
a *Coulomb-blockaded dot show good agreement with prediction of
both equilibrium and nonequilibrium Kondo effects.
QY: Sara M. Cronenwatt, Stanford University 415-723-0830.
(Science 24 Jul 98 281:540) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *tunnel coupling: This refers to tunneling, a quantum
mechanical phenomenon involving an effective penetration of an
energy barrier resulting from the width of the barrier being less
than the wavelength of the particle.
... ... *Kondo effect: The Kondo effect is a large anomalous
increase in the resistance of certain dilute alloys of magnetic
materials in nonmagnetic hosts as the temperature is lowered. In
general, the Kondo effect occurs when an impurity atom with an
unpaired electron is placed in a metal, producing an interaction
of localized electrons with delocalized electrons.
... ... *Kondo temperature: The temperature at which the Kondo
effect predominates.
... ... *Fermi energy: The average energy of electrons in a
metal.
... ... *Coulomb-blockaded: This refers to an effective blockade
of quantum mechanical tunneling produced by specific energy
barrier constraints.
-------------------
Related Background:
KONDO EFFECT IN A SINGLE ELECTRON TRANSISTOR
A transistor is essentially a semiconductor device in which it is
possible to control voltage or current in such a way as to
achieve gain or switching action, and a single-electron
transistor is a transistor of extremely small dimensions isolated
from its leads by potential barriers narrow enough to permit
electron tunneling, with a minute electron source that is
essentially a droplet of electrons. A single-electron transistor
switches on and off with the addition of each electron, in
contrast with the ordinary transistor which sustains a switched-
on state given a flow of added electrons. This quantized behavior
of the single-electron transistor is due to its dimensions, the
electron droplet essentially behaving as an artificial atom.
... ... Goldhaber-Gordon et al (6 authors at 2 installations, US
IL) report measurements on single-electron transistors smaller
than those previously made, and which exhibit all of the
predicted aspects of the Kondo effect in such systems. The
authors suggest the increased functionality of single electron
transistors may eventually be technologically important.
QY: M.A. Kastner
(Nature 8 Jan 98) (Science-Week 23 Jan 98)
5. COMBINATORIAL CHEMISTRY IN INSECTS
Insect *pupae, which are not mobile, should be vulnerable to
predators. Many types, however, benefit from concealment or
camouflage or from mechanical means of defense, and there are a
few documented cases of pupae that are protected chemically.
Pupae of coccinellid (ladybird) beetles of the genus Epilachna
bear a dense coating of glandular hairs that secrete oily
droplets deterrent to insects. ... ... Schroeder et al (6 authors
at 2 installations, US) now report that the pupal defensive
secretion of the coccinellid beetle Epilachna borealis is
composed principally of a *combinatorial library of macrocyclic
polyamines. These compounds constitute a previously unrecognized
family of natural products, characterized by extremely large ring
*lactonic structures (rings with up to 98 members) derived from a
small set of (2-hydroxyethylamino)alkanoic acids. The
combinatorial assembly of these simple building blocks generates
a high degree of structural diversity, which is further increased
by slow spontaneous intramolecular rearrangement of the
macrocycles. The authors suggest their study has revealed insects
to be capable of producing an unprecedented array of novel
macrocyclic structures. This particular library of alkaloids is
based on the oligomerization of only a few homologous building
blocks apparently derived from the *amination of simple fatty
acids. The authors conclude: "Ladybird beetles must be counted
among the pioneers of combinatorial chemistry."
QY: Frank C. Schroeder
(Science 17 Jul 98 281:428) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *pupae: The pupa (chrysalis) is the stage between larva
and adult in insects that undergo complete metamorphosis (which
occurs during the pupal stage).
... ... *combinatorial library: In general, a chemical
combinatorial library is any system capable of producing a large
number of different substances from a small number of building
blocks.
... ... *lactonic: These are ring compounds formed by the
intramolecular elimination of water between the hydroxyl and
carboxyl groups of hydroxy-acids.
... ... *amination: In this context, introduction of amino groups
into organic molecules.
6. CONFIRMATIONS OF WILMUT CLONING RESEARCH
The adult *somatic cell clone experiments of the Ian Wilmut group
in the UK have apparently now been unequivocally confirmed. Most
biologists expected this, but a few prominent doubters expressed
their doubts to the popular media and made newspaper headlines
(see related background below). Three reports have now appeared,
two reports establishing by DNA analysis that the probability of
fetal cell contamination or mistaken mixed cell cultures in the
Wilmut research is "vanishingly small", and the third report
presenting evidence of 22 healthy female mice from successfully
cloned cultured differentiated cells. ... ... Ashworth et al (11
authors at 3 installations, UK) report a more detailed *DNA
microsatellite analysis than was originally presented when the
cloned sheep Dolly was first announced. On the basis of their new
data, the authors estimate the probability that another sheep
from the same population would have the same genotype as the 6-
year old ewe (the proposed source of Dolly) as between 1.9 x
10^(-12) and 2.7 x 10^(-10), and they conclude that it is
"extraordinarily unlikely that Dolly was derived from a different
Finn Dorset animal," and therefore they reject the hypothesis of
Sgaramella and Zinder that "imagined and unimagined experimental
error" occurred. The authors then state that if Dolly were
derived from a fetal cell, she would have derived half of her
*alleles from the sire of the fetus and half from the 6-year old
ewe, and the authors calculate the chance of a fetal cell having
the same genotype as the 6-year old ewe to be between 1.1 x
10^(-6) to 9.2 x 10^(-6). They conclude that, as originally
proposed, "Dolly was derived from a mammary cell of the 6-year
old donor ewe." ... ... Signer et al (7 authors at 2
installations, UK) report a *DNA fingerprint analysis to
determine the origin of the donor cell used in the *nuclear
transfer that produced Dolly, and the authors state that on the
basis of their results they have "confirmed the authenticity of
Dolly." They state: "The probability that a second unrelated
sheep has by chance the same profile as the donor tissue can be
conservatively estimated at 6 x 10^(-10). We therefore reject the
possibility that Dolly was derived from a contaminating cell
culture." Concerning whether Dolly could have been derived from a
fetal cell, the authors calculated the probability as between 8.6
x 10^(-5) and 3.5 x 10^(-7), and they state: "We therefore
conclude that Dolly is derived from the nucleus of a cell from
the mammary gland of the adult donor." ... ... Wakayama et al (5
authors at 4 installations, US JP IT) report an investigation of
the factors governing embryonic development, the experiments
involving the introduction of nuclei from somatic cells (*Sertoli
cells, neuronal cells, and *cumulus cells) taken from adult mice
into enucleated mouse oocytes (egg cells). The authors report
they found that some enucleated oocytes receiving Sertoli or
neuronal nuclei developed in vitro and implanted following
transfer, but none developed beyond 8.5 days after implantation.
However, a high percentage of oocytes receiving cumulus nuclei
developed in vitro, and once transferred, many of these embryos
implanted, and 2 to 2.8 percent developed to term. The authors
conclude: "Our results suggest that, contrary to previous
opinion, mammals can be reproducibly cloned from adult somatic
cells. Furthermore, we believe that the success of these
experiments in the mouse provides an amenable model with which to
evaluate the molecular mechanisms that regulate the reprogramming
of somatic cell genomes, *genomic imprinting, embryonic *genome
activation, and cell *differentiation."
QY: Ian Wilmut
QY: Esther N. Signer
QY: R. Yanagimachi, University of Hawaii 808-956-8975.
(Nature 23 Jul 98 394:329,369) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *somatic cell: Somatic cells are cells other than
germline cells (egg cells and sperm cells).
... ... *DNA microsatellite analysis: Satellite DNA consists of
highly repeated DNA sequences that are present in the genome, are
not coded for proteins, and have utility as genetic markers and
elements in DNA profile analysis. Microsatellite DNA consists of
tandem repeats of short DNA sequences up to 6 nucleotides long.
Minisatellite DNA refers to similar larger repeat groups up to 30
nucleotides long.
... ... *alleles: An allele is one of two or more forms of a
given gene that control a particular characteristic, with the
alternative forms occupying corresponding loci on homologous
chromosomes.
... ... *DNA fingerprint analysis: This refers to DNA profile
analysis of *polymorphic loci. A profile compiled from a
sufficient number of rare alleles can be considered unique.
... ... *polymorphic: A genetic polymorphism is a naturally
occurring variation in the normal nucleotide sequence of the
genome within individuals in a population. Variations are denoted
as polymorphisms only if they cannot be accounted for by
recurrent mutation and occur with a frequency of at least about 1
percent.
... ... *nuclear transfer: The nuclear transfer technique
indicated involves the transfer of the nucleus of a somatic cell
(which contains the genome for the individual) to an enucleated
egg cell. The egg cell now has a new nucleus, and it is the
genome in the new nucleus that determines the development of the
egg cell.
... ... *Sertoli cells: Large cells in the vertebrate testis that
support and nourish developing sperm cells.
... ... *cumulus cells: Cells surrounding the ovulated mammalian
egg cell, and which quickly disperse in the presence of sperm.
... ... *genomic imprinting: Parental genetic imprinting. An
important genetic mechanism whereby some genes in an organism are
predominantly expressed from either the paternally or the
maternally inherited chromosome.
... ... *genome activation: Refers to regulated activation of
specific target genes during development, etc.
... ... *differentiation: Refers to developmental cell
specialization (morphology and biochemistry) resulting from
activation of specific parts of the cell genome.
------------------
Related Background:
SHEEP CLONING RESEARCH RESULTS: QUESTIONS AND ANSWERS
In a rare public exposure of what is usually a private or at
least specialist-restricted dispute between researchers,
Sgaramella and Zinder (2 installations, IT US), in a letter to
the journal Science and in interviews with various news media,
have extensively criticized the Roslin (Scotland, UK) sheep
cloning group headed by Ian Wilmut. Sgaramella and Zinder focus
on the cloning of the sheep Dolly from an adult ovine cell, and
state there has been a lack of any confirmation of this experi-
ment, that the original experiment was poorly controlled, the
interpretations untested, corollary mitochondrial data not
provided, and so on. Sgaramella and Zinder suggest that endless
debates about cloning are less than correct in the face of both
"the scientific weaknesses of the experiment and the possible
impact on the societal credibility of science itself" by debates
based on "facts" only presumed. In a contiguous reply, Campbell
et al (including Ian Wilmut) provide details explaining the
protocols used in the original Dolly cloning, say the Dolly
cloning was an unexpected and unplanned tangent from other
research, say the fact that Dolly is a Finn Dorset ewe restricts
the origin of Dolly to a single laboratory culture existing at
the time, that corollary data have indeed been provided to third
parties, that only 11 months have passed since publication of the
results, and since the gestation period in sheep is 5 months,
there has not yet been enough time to complete similar experi-
ments and publish data. Despite this public conflict, the
apparent consensus among embryologists is that the work of the
Wilmut group will be confirmed. QY: Norton D. Zinder, Rockefeller
University, 1230 York Avenue, New York, NY 10021 US; Ian Wilmut,
Roslin Institute, Roslin, Midlothian E-125 9PS, Scotland, UK.
(Science 30 Jan 98) (Science-Week 13 Feb 98)
7. NEUROBIOLOGY: HIGH-FREQUENCY FIRING AND VESICLE REPLENISHMENT
*Synapses in the central nervous system undergo various short-
term and long-term changes in the degree to which presynaptic
activity modulates or evokes postsynaptic activity, but it is
often difficult to distinguish whether presynaptic or
postsynaptic mechanisms are responsible for these changes. ...
... Wang and Kaczmarek (2 installations, CA US), in a study using
*patch-clamp recording from giant synapses in the mouse auditory
brainstem, report that short-term *synaptic depression can be
largely attributed to rapid depletion of a readily releasable
pool of *synaptic vesicles. Replenishment of this pool is highly
dependent on the recent history of synaptic activity: high-
frequency stimulation of presynaptic terminals significantly
enhances the rate of replenishment. The authors report that
broadening the presynaptic action potential with the *potassium-
channel blocker tetraethylammonium, which increases calcium ion
entry, further enhances the rate of replenishment. As this
increase can be suppressed by blockade of the calcium channel or
buffer sequestration of calcium ion, the authors conclude that
calcium ion influx through *voltage-gated calcium channels is the
key signal that dynamically regulates the refilling of the
releasable pool of synaptic vesicles in response to different
patterns of inputs.
QY: Leonard K. Kaczmarek
(Nature 23 Jul 98 394:384) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *Synapses: The junction between the terminal of a
neuron's axon and another neuron is called a "synapse". When
studying the synapse, the first neuron is called the
"presynaptic" neuron, and the second neuron is called the
"postsynaptic" neuron.
... ... *patch-clamp recording: This is a technique in which a
small patch of cell membrane containing a single or a small
number of *ionic channels is drawn up into a blunt hollow glass
microelectrode (micropipette) so that minuscule currents
(picoamperes) flowing through the single channel or through the
several channels can be recorded. The technique was first
perfected in the 1970s by Erwin Neher and Bert Sakmann, and in
1991 they shared the Nobel Prize in Physiology and Medicine for
their work.
... ... *synaptic depression: Any effective depression of the
response of the postsynaptic neuron to presynaptic input.
... ... *synaptic vesicles: Synaptic vesicles are the packets of
*neurotransmitter substance formed in the presynaptic axon
terminals. When transmitter substances are released, they are
released as packets, the vesicle membrane dissolving in the
synaptic space (synaptic cleft; the junction between the
presynaptic axon terminal and the postsynaptic neuron) to release
the transmitter molecules.
... ... *neurotransmitter substance: Neurotransmitters are
chemical substances released at the terminals of nerve axons in
response to the propagation of an impulse to the end of that
axon. The neurotransmitter substance diffuses into the synapse,
the junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell.
... ... *ionic channels: (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.
... ... *potassium-channel: A membrane ion channel with specific
permeability to the potassium ion.
... ... *voltage-gated: Refers to opening or closing of an ion
channel by changes in the electrical potential across the
membrane.
... ... *ligand-gated: Refers to opening and closing of an ion
channel by interactions between ligands and membrane receptors.
8. ACTIVITY-DEPENDENT CORTICAL TARGET SELECTION BY GROWING AXONS
Many of the connections between nerve cells (the "wiring" of the
nervous system) are programmed in mammals during development.
This is particularly true of the pathway connections of the
sensory systems and the basic motor output systems. During the
wiring of the connections between the *thalamus and *cortex in
mammals, there is an intermediate step in which thalamic axons
grow and interact with a special population of neurons (so-called
subplate neurons) before they contact their ultimate target
neurons within the cerebral cortex (cortical plate). Such
connections in the developing nervous system are thought to be
formed initially by a process not dependent on activity, the axon
pathfinding process and target selection only afterward refined
by neural activity. ... ... Now Catalano and Shatz (University of
California Berkeley, US) report that blockade of *sodium action
potentials by *intracranial infusion of *tetrodotoxin in cats
during the early period when axons from the *lateral geniculate
nucleus were in the process of selecting visual cortex as their
target altered the pattern and precision of this thalamo-cortical
projection. The majority of these neurons, rather than projecting
to visual cortex, elaborated a significant projection within the
subplate of cortical areas normally bypassed. Those axons that
did project to their correct target were *topographically
disorganized. The authors suggest that neural activity is thus
required for initial targeting decisions made by thalamic axons
as they cross the subplate, and that whatever the mechanisms, the
formation of connections between thalamus and *neocortex in
mammals be a special exception to the general rule that target
selection by developing axons is independent of neural activity.
QY: Carla J. Shatz
(Science 24 Jul 98) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *thalamus: The thalamus is a deep brain structure that
consists of groups of nerve cells that project to various other
regions of the brain. In general, these groups of nerve cells are
specific relay stations for sensory information (e.g., visual,
auditory, pain, temperature, etc.)
... ... *cortex: The term "cortex" is often used as the short
form for "cerebral cortex", but there are other anatomical
structures also called "cortex", so the meaning is context-
dependent.
... ... *sodium action potentials: In vertebrates, most action
potentials are "sodium action potentials", due to a transient
increase in sodium ion permeability that is propagated down the
axon to the axon terminal(s).
... ... *intracranial infusion: In general, the introduction of
any solution into the brain within the skull.
... ... *tetrodotoxin: A neurotoxin that specifically blocks the
change in sodium ion permeability necessary for the production of
an action potential. Tetrodotoxin acts on sodium ion channels in
the axon membrane.
... ... *lateral geniculate nucleus: A thalamic cell group that
acts as a relay station in the visual pathway from the retina to
the primary visual area of the cerebral cortex.
... ... *topographically disorganized: Ordinarily, the
topographical organization of visual (photon) input to the retina
is for the most part projected isomorphically to the primary
visual area of the brain for analysis. Any topographical
disorganization of information in the pathway or at its terminus
(a disruption of the "mapping") can thus have devastating effects
on the ability of the system to analyze visual inputs.
... ... *neocortex: The most recently evolved part of the
cerebral cortex.
9. A SUCCESSFUL VACCINE AGAINST LYME DISEASE
Lyme disease is caused by a spirochete bacterium, Borrelia
burgdorferi, a spirally coiled organism in which 2 to 100
flagella (contractile strands that are responsible for bacterial
motion) are wound beneath a flexible outer cell wall, enabling
the spirochete to move by rhythmic flexing that causes a cork-
screw motion through the surrounding medium. The pathogen that
causes syphilis is also a spirochete. In humans, Lyme disease is
contracted through the bite of small ticks such as the minute
tick Ixodes dammini. The disease was first recognized in 1975 as
a result of an unusual clustering of cases in the small community
of Lyme, Connecticut (US), and hence the name. It has since
appeared in more than half the states in the U.S., especially the
northeastern coast, and in California and Oregon, and it has also
appeared abroad. In the U.S., 18,461 cases of Lyme disease were
reported in 1996, a 41% increase over 1995. This disease is now
the most commonly reported tick-borne illness in the U.S., and it
is an insidious pathological entity that if not treated early may
lead to severe arthritis, various serious neurological complic-
ations when the organism invades the central nervous system, and
in some cases death. ... ... Sigal et al (20 authors at 11+
institutions, US) now report a study of the efficacy of a
*recombinant vaccine against Lyme disease, the vaccine consisting
of a pathogen outer surface protein without *adjuvant
administered to subjects at risk for Lyme disease. The study
involved a *double-blind trial with 10,305 subjects 18 years of
age or older in 14 sites in areas of the US where Lyme disease is
endemic. The authors report the efficacy of the vaccine was 69
percent in the first year of the study in the entire population,
and 92 percent in the second year among the 3745 subjects who
received the 3rd injection. The vaccine was well tolerated, and
with no significant side effects. The authors suggest this
vaccine, called OspA (outer surface protein A) is safe and
effective in the prevention of Lyme disease. They further suggest
that more studies will be needed to evaluate the vaccine in
children and adolescents, and that the optimal vaccination regime
remains to be determined: e.g., whether booster doses are
required beyond the 2nd year is as yet unresolved.
QY: Leonard H. Sigal, 1 Robert Wood Johnson Pl., MEB 484, New
Brunswick, NJ 08903-0019 US.
(New England J. Med. 23 Jul 98 339:216)
(Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *recombinant: In general, this means genetically
engineered -- in this case, the introduction of foreign DNA into
an organism's genome (here, E. coli) so that the organism
produces a particular protein.
... ... *adjuvant: In this context, a vehicle added to enhance
the immune response.
... ... *double-blind trial: Any experimental procedure in which
neither the subjects nor the experimenters know the makeup of the
test and control groups during the actual course of the
experiments.
-------------------
Related Background:
ACORNS, GYPSY MOTH OUTBREAKS, AND LYME DISEASE RISK
... Gypsy moths are large insects accidentally transported into
New England from Europe in the late 19th century. In a
metamorphosing insect, the pupa is the quiescent intermediate
form between the larva and the adult. ... ... Jones et al (5
authors at 3 installations, US) report that in eastern US oak
forests, both defoliation by gypsy moths and the risk of Lyme
disease are determined by interactions among acorns, white-footed
mice, moths, deer, and the black-legged ticks that carry the Lyme
disease pathogen. Experimental removal of mice, which eat moth
pupae, indicates that moth outbreaks are caused by reductions in
mouse density that occur when there are no acorns. Experimental
acorn addition increased mouse density. Acorn addition also
increased the densities of black-legged ticks, evidently by
attracting deer, which are key tick hosts. It is already known
that mice are primarily responsible for infecting ticks with the
Lyme disease agent. The authors suggest their results have
important implications for predicting and managing forest health
and human health, and clearly demonstrate that both gypsy moth
dynamics and Lyme disease risk have contingent outcomes arising
from a complex chain of strong pairwise interactions among
taxonomically diverse species that are all interconnected within
an ecosystem.
QY: Clive G. Jones
(Science 13 Feb 98) (Science-Week 27 Feb 98)
-------------------
Related Background:
COMPLETE GENOME SEQUENCE OF LYME DISEASE PATHOGEN
... Plasmids are small, often circular, extra-chromosomal genetic
entities that replicate independently of nuclear DNA. They are
common in bacteria and in certain eukaryotes. Translation is
protein synthesis, the process during which polypeptides are
synthesized on ribosomes. Fraser et al (38 authors at 3
installations, US) now report the complete genome sequence of B.
bergdorferi, the pathogen that causes Lyme disease. The genome is
comprised of a linear chromosome containing 910,725 base pairs
plus at least 17 linear and circular plasmids with a combined
533,000 base pairs. The chromosome contains 853 genes encoding a
basic set of proteins for DNA replication, transcription,
translation, solute transport, and energy metabolism, but no
genes for cellular biosynthetic reactions. Of 430 genes on 11
plasmids, most have no known biological function. The authors
suggest this elucidated genome sequence will provide a new
starting point for the study of the pathogenesis, prevention, and
treatment of Lyme disease.
QY: Claire M. Fraser
(Nature 11 Dec 97) (Science-Week 2 Jan 98)
-------------------
Related Background:
ORAL ANTIBIOTIC AN EFFECTIVE TREATMENT OF EARLY LYME DISEASE
... Antibiotics are the treatments of choice for Lyme disease,
particularly oral doxycycline and parenteral (non-oral)
ceftriaxone. For most clinical cases of Lyme disease, if the
patient is treated early enough, especially during the first
year, there is a high total cure rate (approximately 85%).
Treatment with the parenteral antibiotic is much more expensive
than treatment with the oral antibiotic (the estimate is approx-
imately $5,000 vs. $500), and for some time there has been a
public non-medical debate about health policy, with complaints
that more effective parenteral antibiotics for Lyme disease were
not being offered to enough patients. This week, Raymond J.
Dattwyler et al (12 authors at various installations, US) report
a carefully controlled study of 140 Lyme disease patients
indicates that early treatment of patients with acute
disseminated Lyme disease (in the absence of meningitis) with
oral antibiotic is just as effective as treatment with the more
expensive parenteral antibiotic. Whether these results will
reduce the decibels of the public health policy debate is
uncertain, but at least now there are some results that can be
used to make decisions.
QY: R. J. Dattwyler, Dept. of Medicine, State Univ. New York
Stony Brook (516) 632-6868.
(New England J. Medicine 31 Jul 97)
10. COMBINED ANTI-TUMOR EFFECTS OF ANGIOSTATIN AND RADIATION
Angiogenesis is the formation of new capillaries from pre-
existing blood vessels, and it is essential for the growth of
tumors. Angiostatin, a *proteolytic fragment of *plasminogen that
was first isolated from the serum and urine of tumor-bearing
mice, inhibits angiogenesis and thereby inhibits the growth of
primary and metastatic tumors. Radiotherapy is important in the
treatment of many human cancers, but it is often unsuccessful
because of tumor cell radiation resistance. ... ... Mauceri et al
(14 authors at 4 installations, US) now report a study combining
radiation with angiostatin to target tumor vasculature that is
genetically stable and thus less likely to develop resistance.
The study involved mouse tumors and human clone cell cultures.
The authors report there is an antitumor interaction between
ionizing radiation and angiostatin for 4 distinct tumor types at
radiation doses used in radiotherapy. The combination produced no
increase in toxicity towards normal tissue. In vitro studies
reveal cytotoxic effects of the combination on endothelial cells
but not tumor cells. In vivo studies show that these agents in
combination target the tumor vasculature. The authors suggest
their results provide support for combining ionizing radiation
with angiostatin to improve tumor eradication without increasing
deleterious effects. They also suggest that although angiostatin
is known to inhibit endothelial cell proliferation in vitro, this
to their knowledge is the first report of the killing of cloned
endothelial cells by angiostatin, and the first report of
synergistic antitumor effects using angiostatin as a radiation
modifier. They conclude that angiostatin has great potential to
enhance the *therapeutic ratio in combined modality cancer
treatment.
QY: Ralph R. Weichselbaum
(Nature 16 Jul 98 394:287) (Science-Week 14 Aug 98)
-------------------
Related Background:
... ... *proteolytic: A general term for the breakdown of
proteins via the hydrolysis of peptide bonds.
... ... *plasminogen: A precursor of plasmin, a proteolytic
enzyme enabling epithelial cells to invade new tissue.
... ... *therapeutic ratio: The ratio of the maximally tolerated
dose of a drug to the minimal curative or effective dose.
-------------------
Related Background:
SCIENCE NEWS, STOCK PRICES, AND BOOK DEALS
A cogent example of the interaction of science, medicine, the
media, the stock market, and personal riches came into public
view recently. The sequence of events in this episode was
apparently as follows: 1) On Sunday, May 3, 1998, *The New York
Times* ran a front page story by Gina Kolata, one of the chief
science writers of *The New York Times*, and a reporter who has
been writing about science for at least 30 years. The story
concerned the two chemicals angiostatin and endostatin that have
been known for some time to block angiogenesis in tumors in mice
(see background material following this report). The chemicals
have never been tested in humans, they are not the only chemicals
that achieve this effect, and they are not available as "drugs"
that can be administered by a physician. But the thrust of the
story was that this was new information, the headline, "A
Cautious Awe Greets Drugs That Eradicate Tumors in Mice." The
story quoted Nobel Laureate James Watson as telling Kolata that
Judah Folkman, one of the primary researchers in the field of
anti-angiogenesis chemicals, "will cure cancer within 2 years"
and "will be remembered along with scientists like Darwin as
someone who permanently altered civilization. Kolata also
reported that Richard Klausner, director of the US National
Cancer Institute said the two chemicals were "the single most
exciting thing on the horizon" for the treatment of cancer, and
that they were the top priority of the National Cancer Institute.
2) On the afternoon of the same day the story was published in
*The New York Times*, a New York book agent named John Brockman
telephoned reporter Gina Kolata about the story and apparently
told her he could get her a US$2 million advance for a book on
the subject. Kolata immediately began writing a book proposal,
and sent the proposal via Email to Brockman within hours. 3) That
evening, all major television networks highlighted the story that
had appeared in *The New York Times*. Brockman sent the proposal
to New York publishers at midnight of that first day, following
the network news reports. 4) At 9:30 the next morning (Monday),
Brockman informed Kolata that he already had the first offer from
a major New York publishing house. 5) Also on Monday morning, the
stock of EntreMed Inc. (US), the company that holds the rights to
turn the two chemicals angiostatin and endostatin into drugs,
rose immediately from a previous Friday closing of US$12 a share
to a Monday morning opening at US$83 a share. 6) Also beginning
Monday morning, oncologists and other physicians around the
country found themselves deluged with inquiries from cancer
patients, many of whom were saying they would be putting off
chemotherapy to wait for the new drugs. 7) By the end of the
week, the bubble had completely burst: Other reporters published
stories revealing the chemicals named in the May 3rd *New York
Times* story were already well-known, tested only on mice, and
not available at all as drugs. Both Watson and Klausner backed
off from their reported comments, saying they had been
misinterpreted. The price of EntreMed shares fell back to $30.
Kolata withdrew her revealed book proposal after a discussion
with her editors, and the agent Brockman already had a substitute
deal in the works for a book on the subject by a reporter at
another newspaper. Finally, around the country, physicians had
the task of explaining to their patients that no, a miracle
cancer cure was not yet available. As expected, much is being
written about this episode, with one question in the minds of
many people: Why does this happen? Well, one reason why it
happens is that these days news editors are prone to present
features to their readers as "news". This was a feature article,
and it should have appeared as an article in a magazine, and not
on the front news page of *The New York Times*. Secondly, the
habit that reporters have of using direct sound-bite quotes from
scientists to bolster the apparent importance of their stories
too often produces misinformation, inappropriate emphasis, and
whatnot, and certainly there is a tendency to avoid quotes that
reduce the significance of the "news". Science-news reporting
propped and hyped to be "exciting" does a disservice to the
public and can be dangerous as well. The James Watson comment,
apparently, actually occurred during a conversation Kolata had
with Watson *two months before* at a dinner table. In summary,
this so-called news story should never have appeared in the first
place as "news", should never have included quotes from
scientists with the quotes deliberately used to hype the material
beyond any significance attributed by specialists, should never
have been used as a prop for a quick lucrative book deal, should
never have been reported the way it was by television
broadcasters. The media, and in particular *The New York Times*,
have been deservedly embarrassed by this episode, and the
credibility of science-reporting by *The New York Times* has been
seriously and unfortunately compromised. [Editor's note:
concerning the science, we are appending here several relevant
reports from past issues of SCIENCE-WEEK. The reader will observe
that the anti-angiogenesis chemical endostatin was already noted
here in December 1997.]
(Science 15 May 98 280:996) (Science-Week 5 Jun 98)
-------------------
Related Background:
CANCER TREATMENT BY TARGETING TUMOR BLOOD VESSELS
Bacteriophage (phage) is a virus type that infects bacteria, and
it has been useful as a cloning vector in genetic engineering.
The phage injects its own DNA into the bacterium, effectively
assuming enough control of the bacterial genome to replicate
itself, with the ultimate disintegration of the bacterium and
liberation of the phage clones. A "phage library" is a collection
of genomic DNA fragments, each contained in a bacteriophage
cloning vector and propagated by infection of a host bacterium
(usually E. coli). The essential idea, in the context of this
report (and in many other research efforts), is to use the
genetic machinery of the phage to control the metabolic machinery
of the bacterium to produce (synthesize) particular complex
biomolecules (such as polypeptides) needed for testing. "Nude
mice" are a genetic variant of laboratory mice lacking a thymus
gland, which means they are unable to produce the T-cells
(Thymus-cells) necessary for various aspects of the mammalian
immune response. The origin and development of tumor blood
vessels (angiogenesis), is an important consideration in the
growth of cancerous tumors, since the tumor provokes directed
angiogenesis into itself with the end result that the tumor is
supplied with oxygen and nutrients. Without angiogenesis, tumors
can attain only a small size before becoming self-inhibiting. A
"xenograft" is a graft of tissue from one species into the body
of another species. ... ... Arap et al (3 authors at Burnham
Institute, US) report the use of in vivo selection of phage
libraries to isolate peptides that home specifically to tumor
blood vessels. When coupled to the anticancer drug doxorubicin,
two peptides were found that enhance the efficacy of the drug
against human breast cancer xenografts in nude mice and also
reduced the toxicity of the drug. The authors suggest their
results indicate it may be possible to develop targeted
chemotherapy strategies based on selective expression of
receptors in tumor blood vessels.
QY: Erkki Ruoslahti
(Science 16 Jan 98) (Science-Week 30 Jan 98)
-------------------
Related Background:
CANCER: NO ACQUIRED DRUG RESISTANCE TO ANTI-ANGIOGENIC AGENT
Angiogenesis is the generation of new blood vessels, a controlled
sequence of cell differentiation and tissue formation programmed
by the genome. It is of obvious importance during embryological
development, since new tissues need a blood supply in order to
continue macroscopic growth, and the angiogenesis process is also
of great importance during tissue trauma repair. Like new
embryological tissue, a neoplasm (a tumor) also needs a blood
supply, and one of the characteristics of tumor growth is the
provocation of angiogenesis by the cancer cells so that the mass
of such cells becomes supplied with adequate vascularization. It
is known, for example, that tumors will not grow beyond a few
millimeters in diameter in the absence of a newly forming blood
supply. Cancer cells apparently provoke angiogenesis by secreting
growth factor substances, and if this is prevented, tumor growth
will be severely limited. But attempts to chemically interfere
with the secretion of growth factors by cancer cells usually fail
because the high proliferation rate of cancer cells ultimately
results in drug resistance produced by a mutational selection
process. However, the normal epithelial tissue involved in
angiogenesis is not rapidly mutating. Recently, a substance named
endostatin, a 20,000 molecular weight fragment of a type of
collagen, has been found to be a specific inhibitor of
endothelial cell proliferation (which means also of new blood
vessel growth), and it was found that endostatin effects only
proliferating endothelial cells, not resting cells, and not
normal, transformed, or neoplastic cells. It has been shown that
systemic administration of endostatin to tumor bearing mice
results in the regression of tumors to a microscopic size, and
one important question has been whether drug resistance to
endostatin would develop. ... ... Now Boehm et al (4 authors at
Harvard Univ., US) report that endostatin causes three tumor
types in mice to regress without the production of drug
resistance, and that repeated cycles of anti-angiogenic therapy
are followed by prolonged tumor dormancy without further therapy.
The authors suggest that angiogenesis inhibitors that do not
induce drug resistance may be valuable for long-term maintenance
therapy. This is important work, and one expects much will be
heard about endostatin in the future.
QY: Thomas Boehm
(Nature 27 Nov 97) (Science-Week 19 Dec 97)
-------------------
Related Background:
MOLECULAR TARGET OF ANTI-ANGIOGENESIS COMPOUNDS DISCOVERED
... Any clinically useful anti-angiogenesis compound is of
great interest to cancer specialists (oncologists). There are 10
or so anti-angiogenesis agents presently undergoing clinical
trials. One of these (TNP-470) is a derivative of the natural
fungal product fumagillin, whose anti-angiogenesis activity was
first discovered in 1985. Now the cellular target of fumagillin
and TNP-470 has been discovered, a specific protein which appears
to play an important role in the proliferation of endothelial
cells, the cells that line blood vessels. The work was reported
by Craig M. Crews et al (Yale University, US), who suggests the
identification of this protein target will open new avenues of
research for the understanding of tumor-induced neo-vascular-
ization. The results have been independently confirmed by Jun O.
Liu et al (Massachusetts Institute of Technology, US).
(Proc. U. S. National Academy of Sciences, 94:6099 1997)
(Chemistry & Biology June 1997) (Science-Week 26 Jun 97)
----------------------------------------------------------------
CORRECTIONS:
In SW issue of 31 July 1998:
----------------------------
In Report #3:
approximately 13 Jupiter mass
should read:
approximately 13 Jupiter-mass
In Report #5
Dnase, Rnase, endonuclease
should read:
DNase, RNase, endonuclease
----------------------------------------------------------------
|