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ScienceWeek
SCIENCE-WEEK
A Weekly Digest of the News of Science
September 4, 1998
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It took a million years to move from counting
pebbles to the elaborations of quantum mechanics.
Certainly this was an arduous migration of the
multitude -- not a private party of physicists,
but the Long March of the entire human race.
-- Anonymous
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Contents of This Issue:
1. On the Chasm Between Scientists and Non-Scientists
2. Corporate Payments to Scientists for Letters to Journals
3. On Planetary Nebula and the Death of Stars
4. On Neutron Stars and the Fluid Properties of Hot Atomic Nuclei
5. Molecular Archeology of the E. Coli Genome
6. Molecular Biology of Muscle: Coupled Calcium Ion Channels
7. Circadian Oscillators: Resetting by Temperature Changes
8. Biology of Aging: On Telomeres and Replicative Senescence
9. Embryogenesis: The Area Code Hypothesis Updated
10. On Anti-Angiogenic Gene Therapy
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1. ON THE CHASM BETWEEN SCIENTISTS AND NON-SCIENTISTS
In an essay in the journal *Science* on the gap between scientist
and non-scientist, the science journalist Takashi Tachibana makes
the following points: 1) In 1959 C.P. Snow presented the idea
that the chasm between scientists and literary intellectuals was
so vast that they could not communicate with each other. After
nearly 40 years, the situation has only grown worse. 2) The
current level of basic scientific knowledge is so low that it is
difficult to interest even the brightest layman or non-science
student in what modern science is doing. The chasm between
scientist and non-scientist has widened to become a gulf. 3) The
impact of the 20th century revolutions in physics and molecular
biology has been profound: the Universe looks different, Life is
different. But this impact has not been as thorough as it might
have been, because while those with a more comprehensive
scientific education can recognize that something important has
happened, the great majority of people do not even realize that a
fundamental shift has occurred. 4) Most non-scientists who like
to think of themselves as knowledgeable about modern science
really know only about technologies -- and specifically those
technologies considered likely to bring economic profits in the
short term. This is also the mind-set of most government
officials and lawmakers who consider themselves sympathetic to
science and technology budget requests. Science for homo
economicus and homo faber is flourishing, while science for Homo
sapiens is diminishing. 5) We may one day wake up to find
barbarians at the gate in the form of an upsurge in "new" science
-- that is, not science at all -- promoted by one or the other
fundamentalist religion or occultist group ready to lead us into
a new Dark Age. The author concludes: "What we must urgently do
is renovate education and significantly raise the basic level of
scientific knowledge, for, as C.P. Snow warned four decades ago,
we must 'educate ourselves or perish'".
QY: T. Tachibana, 2-18-12 Koishikawa, Bunkyo-ku, Tokyo 112 JP.
(Science 7 Aug 98 281:778) (Science-Week 4 Sep 98)
2. CORPORATE PAYMENTS TO SCIENTISTS FOR LETTERS TO JOURNALS
A blatant instance of corporate pressure in science was recently
revealed when a newspaper, the *St. Paul Pioneer Press* of St.
Paul, Minnesota (US), reported that more than a dozen scientists
received US$156,000 from the tobacco industry to write letters to
scientific journals disputing the carcinogenic effects of second-
hand smoke. The report was based on confidential industry
documents produced in a current litigation. Among the scientific
journals involved were the *Journal of the National Cancer
Institute*, *Journal of the American Medical Association*, *The
Lancet*, and *Pediatrics*. The authors were paid US$2250 to
US$10,000 per letter by the Tobacco Institute, and apparently two
law firms representing the industry revised some letters before
submission to the journals. According to the examined documents,
the strategy of the Tobacco Institute focused on recruiting
scientists "at or near retirement with no dependence on grant-
dispensing bureaucracies." Some of the journal editors involved
are apparently unconcerned, stating that what is important is
whether the content of a letter is solid. However, Richard
Horton, editor of *The Lancet*, says his reaction is one of
"disgust", and that the writing of such letters is "at best
unethical and at worst an example of research misconduct."
Cardiologist Stanton Glantz (University of California San
Francisco, US) says of the tobacco industry letters: "They are
basically building up a record they could use for political and
legal purposes." One now wonders what corporate groups aside from
the tobacco industry have been promoting by generous financial
inducements the writing of letters by scientists to scientific
journals on other scientific topics of legal, political, or
commercial significance.
(Nature 13 Aug 98 394:609) (Science 14 Aug 98 281:895)
(Science-Week 4 Sep 98)
-------------------
Related Background:
NEW STUDY FINDS CORPORATE GIFTS IMPLY CORPORATE CONTROL
Blumenthal et al (2 installations, US) report an anonymous survey
of 2167 scientists working at 50 research-intensive universities
in the US. More than half of the university scientists who
received gifts of research material from pharmaceutical companies
or biotechnology companies report that the donors expect to exert
influence over their work, including review of academic papers
before publication, and retention of patent rights for commercial
discoveries. This is apparently the first study to examine
relations between commercial interests that give gifts of
research materials and the scientists who receive them. Unlike
research grants and contracts, gifts to US scientists are largely
unregulated by universities and are usually dismissed as
insignificant. Christopher Scott, director of research
development for the Stanford University Medical Center, says:
"There has been, in essence, a gray market of research based on
gifts for many, many years."
QY: Christopher Scott, Stanford University 415-723-2300.
(J. Amer. Med. Assoc. 1 Apr 98) (New York Times 1 Apr 98)
(Science-Week 10 Apr 98)
-------------------
Related Background:
INTIMIDATION OF RESEARCHERS BY SPECIAL INTEREST GROUPS
A recent issue of the highly respected New England Journal of
Medicine includes a 5 page exchange of letters on the subject of
intimidation of researchers by special interest groups. The
letters concern three different special interest-clinical science
entanglements: 1) a research study of multiple chemical sensit-
ivity; 2) the public health hazard of a marketed chemical
(tryptophan) product; 3) a clinical investigation of the outbreak
of interstitial lung disease among workers in a nylon flocking
plant. The first situation involves an accusation of attacks
against a researcher by special interests opposed to the
researcher's published results; the second situation involves an
accusation of peer review corruption by a large corporate entity
confronted with a billion-dollar damage suit; the third situation
involves an accusation of censorship and harassment of a medical
specialist by a manufacturing plant, a medical school
administration, and a hospital. These are all complicated
entanglements, and one cannot do full justice to them in a few
hundred words. But all parties on both sides of the issues
present their views, and these 5 pages of letters provide a
textbook illustration of the problems existing at the societal
interfaces of science. The letters are in response to an article
on the subject by Richard A. Deyo et al that appeared in NEJM on
April 14, 1997 (336:1176).
QY: R. A. Deyo, Univ. Washington Seattle (206) 543-7212
(New England J. Med. 30 Oct 97)
-------------------
Related Background:
ACADEMIC JOURNAL REVISITS CORPORATE CORRUPTION OF SCIENCE
*Lingua Franca*, a highly respected general academic journal, has
published a review of some recent history in the arena of
corporate corruption of science and scientific research. The
fundamental problem is simply stated: Some corporations fund
scientific research with expectations, often contractual, of
control of publication and the final wording of conclusions in
the resultant papers. Several prestigious journals still do not
require scientists who report research results to reveal any
connections to interests that might profit from their
conclusions. But most of the scientific community is determined
to put an end to any corruption. The story is still to be played
out. (Lingua Franca June/July 1997)
3. ON PLANETARY NEBULA AND THE DEATH OF STARS
In astronomy, the term "nebula" was originally applied to any
astronomical object that appeared fuzzy and extended in a
telescope, and over 100 such objects had already been catalogued
in the 18th century. The majority of these objects were later
identified as galaxies and star clusters. At the present time,
the term "nebula" (i.e., cloud) refers to a region of
interstellar gas and dust. "Emission" nebulae are bright diffuse
nebulae that emit light and other radiation as a result of
ionization and excitation of gas atoms by ultraviolet radiation,
the source of the UV usually one or more hot stars. A "planetary"
nebula is an emission nebula formed when a *red giant or
*supergiant star sheds its outer layers in the last stage of its
evolution, leaving a hot core that excites the expunged gas. The
size of planetary nebulae range from approximately the diameter
of our solar system to a light year across. Their lifetime is
only about 10,000 years, and they are all expanding with speeds
of approximately 20 kilometers/second. In this context, the term
"planetary" has nothing to do with planets: the term is
historical, the first planetary nebulae discovered so named
because they gave the impression of planetary disks around stars
when viewed in small telescopes. ... ... In a review of planetary
nebulae, Sun Kwok (University of Calgary, CA) makes the following
points: 1) During the final 10,000 years of their life, stars
with masses up to 8 times the mass of the Sun pass through a
stage in which they produce planetary nebulae. Such nebulae are
not only bright in visible light, but they are also radio,
infrared, and x-ray sources. Immediately preceding the first
planetary nebula formation, there is a progenitor phase called
the "proto-planetary nebula", and this entity has recently come
into its own as a focus of research. 2) A full-grown planetary
nebula is completely ionized by the UV light from its central hot
star. The central star of a proto-planetary nebula, however, is
relatively cool and does not emit UV radiation, so the nebula is
unionized and shines by reflected light only (i.e., the proto-
planetary nebula is not yet an emission nebula). 3) The first
proto-planetary nebulae were observed in the 1970s, when it
became apparent that many terminal stage stars are obscured by
dust and can be found only by searching for emissions at mid-
infrared wavelengths. More than 2000 mid-infrared stars in our
Galaxy were thus identified. 4) The classification of planetary
nebula is based not on appearance by on their emission spectra.
Because planetary nebula expand with time, their radio surface
brightness decreases as the nebula ages and becomes more diffuse.
The youngest planetary nebula are thus small and radio bright. 5)
While all proto-planetary nebula have similar infrared
characteristics, they differ greatly from one another in their
visual brightness. But since proto-planetary nebula are not
ionized, whatever brightness they possess arises from starlight
reflected off the surrounding dust. A bright central star
typically outshines the small faint proto-planetary nebula, so
that proto-planetary nebulae are best identified when the system
is observed edge-on. 6) Planetary nebula often have bipolar
shapes, and the origin of this form has been a focus of research.
In 1978, Kwon et al proposed a stellar fast wind hypothesis which
has been successful in simulations and has had some observational
support. The author concludes: "While planetary nebulae have been
well-known objects for more than 200 years and have fascinated
generations of astronomers, the nature of their immediate
progenitors [proto-planetary nebulae] was not known until
recently. At last, we are now filling in this missing-link in our
understanding of stellar evolution."
QY: Sun Kwon, University of Calgary, CA.
(Sky & Telescope October 1998) (Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *red giant: A red giant star is a star in a late stage of
evolution, having exhausted the hydrogen fuel in its core. It
has
a surface temperature of less than 4700 degrees Kelvin and a
diameter 10 to 100 times that of the Sun.
... ... *supergiant star: A supergiant star is an extremely
luminous star of large diameter and low density. The diameter can
be as large as 1000 times that of our Sun.
-------------------
Related Background:
BIRTH AND EARLY EVOLUTION OF A PLANETARY NEBULA
White dwarf stars are extremely dense and compact stars that have
undergone gravitational collapse. White dwarfs are of great
interest to cosmologists, because it is believed their masses and
luminosities have little variance and they can thus be used as
"standard candles" to estimate distances. The final expulsion of
a gas by a star as it forms a planetary nebula (the ionized shell
of gas often observed surrounding a young white dwarf star) is
one of the most poorly understood stages of stellar evolution.
Particularly puzzling is how a spherical star can produce a
highly asymmetric nebula with collimated outflows (outflows
aligned parallel to a particular axis). ... ... Bobrowsky et al
(4 authors at 4 installations, US IN ES) now report optical
observations of the nebula surrounding the star He3-1357 (called
by the authors the "Stingray nebula"), a nebula that has
evidently become an ionized planetary nebula within the past few
decades. The authors find that the collimated outflows are
already evident, and they have identified the nebular structure
that focuses the outflows, and have also found a companion star,
which reinforces previous suspicions that binary companions play
an important role in shaping planetary nebulas and in changing
the direction of successive outflows. The authors suggest the
Stingray nebula demonstrates how far the nebular structure can
develop by the time the nebula becomes ionized, and that no other
planetary nebula in this phase of its evolution has been
previously identified.
QY: Matthew Bobrowsky (mattb@cta.com)
(Nature 2 Apr 98) (Science-Week 24 Apr 98)
4. ON NEUTRON STARS AND THE FLUID PROPERTIES OF HOT ATOMIC NUCLEI
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 10 to 15 kilometers,
with a core so dense that its component protons and electrons
have merged into neutrons. (If the terminal stages of star death
leave a remnant star mass greater than 3 solar-masses, the
ultimate gravitational collapse will produce a black hole.) 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. ... ... Viola and Kwiatkowski (Indiana University
Bloomington, US), in a review of a current experimental approach
to understanding the dynamics of neutron star structure, make the
following points: 1) During the catastrophic collapse of stellar
material in the core of a star destined to become a neutron star,
gaseous nuclear matter is believed to condense to the liquid
phase. A giant nucleus, or neutron star, is formed in this
nuclear phase transition. 2) In order to understand the formation
of neutron stars and black holes, it is essential to know the
conditions under which nuclear matter changes from the gas phase
to the liquid phase. These conditions are expressed, both for
nuclear matter and for ordinary matter, in terms of an equation
of state -- the thermodynamic equation that describes the phase
behavior of a substance as a function of temperature, pressure,
and composition. 3) In the case of the neutron star, the only
accessible approach is to study the reverse process, the
expansion and vaporization of heavy atomic nuclei, which approach
a neutron star's density and, in the intranuclear domain, share
many of its fluid properties. 4) The authors review their work
using ISiS (the Indiana Silicon Sphere detector), an apparatus
designed to study fragments ejected from an atomic nucleus after
the nucleus is "boiled" by the energy of a light-ion collision in
a particle accelerator. In the "soft explosions" analyzed by
ISiS, the nucleus vaporizes. By measuring the charges,
velocities, and flight paths of nuclear fragments, ISiS has
provided evidence that atomic nuclei indeed behave like droplets
of a liquid that expand as they are heated until they reach a
boiling point of approximately 10^(11) degrees Kelvin. 5) Various
tests distinguish between the extremes of boiling and shattering.
For example, a signature of phase transition (in this case,
boiling) is that fragments are emitted randomly in all
directions, rather than preferentially emitted in the direction
of the incident projectile. 6) Essentially, the result of these
experiments is that a class of collision events has been observed
that exhibits many characteristics expected for a phase
transition in nuclear matter. The major task is now to make a
quantitative connection between the data and nuclear
compressibility, in particular the nuclear compressibility of the
core of neutron stars and black holes.
QY: Vic Viola
(American Scientist October 1998) (Science-Week 4 Sep 98)
5. MOLECULAR ARCHEOLOGY OF THE E. COLI GENOME
The lack of complex morphological characteristics coupled with
the lack of a robust fossil record have impeded efforts to
understand *differentiation and *speciation in *prokaryotes.
Although vast numbers of mutations are introduced into bacterial
populations in each generation, it is difficult to account for
the ability of bacteria to respond to new *selection pressures
and to exploit new environments if the model involves only the
accumulation of *point mutations. Thus, the rapid adaptation of
bacteria to novel environments is often ascribed to genes
acquired through *horizontal interspecies gene transfer. The
recent availability of the complete genome sequence of
Escherichia coli (strain MG1655) has provided the first
opportunity to assess the overall impact of horizontal genetic
transfer on the evolution of bacterial genomes. ... ... Lawrence
and Ochman (2 installations, US) now report an analysis of the
complete nucleotide sequence of the E. coli genome, providing an
appraisal of the rate of horizontal gene transfer on an
evolutionary time scale. With certain assumptions concerning the
calendar of species divergence and the rate of evolution of
horizontally transferred DNA, the authors report that 755 of 4288
*open reading frames (547.8 kilobases) have been introduced into
the E. coli genome in at least 234 lateral transfer events since
this species diverged from the Salmonella lineage 100 million
years ago. The average age of introduced genes was 14.4 million
years, yielding a rate of transfer of 16 kilobases per million
years since divergence. Although most of the acquired genes were
subsequently deleted, the sequences that have persisted
(approximately 18 percent of the current chromosome) have
conferred properties permitting E. coli to explore otherwise
unreachable ecological niches. The authors suggest their results
support the hypothesis that the diversification of *enteric
bacteria into discrete species occurs by a very different process
than that proposed for *eukaryotes. The authors suggest bacterial
speciation is likely to be driven by a high rate of horizontal
transfer, which introduces novel genes, confers beneficial
*phenotypic capabilities, and permits the rapid exploitation of
competitive environments.
QY: Howard Ochman
(Proc. Natl. Acad. Sci. US 4 Aug 98 95:9413)
(Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *differentiation: In this context, varieties within a
species caused by external variables acting on expression of the
genome.
... ... *speciation: Refers to the origin of species.
... ... *prokaryotes: Unicellular or filamentous organisms in
which cells lack internal membrane compartments such as a
nucleus. E.g., bacteria.
... ... *selection pressures: The term "selection pressure"
essentially refers to differential gene transmission resulting
from environmental constraints.
... ... *point mutations: Minor changes in the genome, i.e.,
single base-pair substitutions.
... ... *horizontal interspecies gene transfer: As opposed to
vertical transfer between parent and progeny. There are several
possible pathways for this in bacteria. For example, certain
bacteria undergo a modified type of sexual reproduction called
"conjugation" in which chromosomal DNA from one bacterium is
injected into another bacterium of the same species.
... ... *open reading frames: The term "reading frame" refers to
a specific permutation of nucleotide triplets in DNA as "framed"
by a preceding start triplet (start codon), and an "open reading
frame" is any DNA sequence of triplets that potentially encodes a
protein.
... ... *enteric bacteria: Bacterial species normally resident in
the intestine.
... ... *eukaryotes: Cells with internal membrane compartments,
e.g., a nucleus.
... ... *phenotypic: In general, the phenotype is the individual
organism as determined by the interaction of the genetic
constitution (genotype) and the environment. (The term is
sometimes also used to describe discrete expressions of the
genome, rather than the entire individual organism.)
6. MOLECULAR BIOLOGY OF MUSCLE: COUPLED CALCIUM ION CHANNELS
In biological cells, extracellular and intracellular
concentrations of calcium ion differ by several orders of
magnitude, and cells are therefore exposed to a steep calcium ion
gradient across their membranes. In general, the control of
cellular calcium ion is maintained by an elaborate system of
channels, exchangers, and pumps located both in the plasma
membrane and in intracellular membranes. Intracellular calcium
ions are intimately involved in the contraction of skeletal
muscle. The shortening of skeletal muscle fibers during
contraction apparently involves the one-dimensional sliding of
protein filaments past one another ("sliding filament
mechanism"), and it is an increase in calcium ion concentration
in the cytoplasm of muscle cells (the "sarcoplasm") that starts
filament sliding, while a decrease in calcium ion concentration
in sarcoplasm turns off the sliding filament process and produces
a relaxation to the original arrangement of filaments. The
essential neuromuscular process in skeletal muscle involves an
incoming nerve action potential initiating neuromuscular junction
events that produce a muscle action potential, and as the muscle
action potential propagates rapidly along the muscle fiber, it
causes the opening of calcium ion release channels in
intracellular structures (calcium ion release channels). The
result is a flood of calcium ion from within around the protein
filaments involved in the contractile process, and the subsequent
sliding of the filaments and production of muscle fiber
shortening. In general, the intracellular calcium ion release
channels, present in the endoplasmic (or sarcoplasmic) reticulum
of virtually all eukaryotic cells, are integral to various
signalling pathways that require translation of electrical or
biochemical extracellular signals into intracellular activation
of calcium-dependent molecules. The calcium ion release channels
in skeletal muscle apparently comprise 4 565-kilodalton type 1
*ryanodine receptor subunits and four molecules of a 12-
kilodalton accessory protein (known as FKBP12), the latter
stabilizing the ryanodine complex and enabling the 4 subunits to
open and close in coordination. Half of the ryanodine receptor
channels are activated by *voltage-dependent calcium ion channels
in the plasma membrane. ... ... Marx et al (3 authors at 2
installations, US SK) now report that in *planar lipid bilayers,
ryanodine receptor channels exhibit simultaneous openings and
closings, termed "coupled gating". Addition of the channel
accessory protein FKBP12 induced coupled gating, and removal of
the accessory protein uncoupled the channels. The authors suggest
coupled gating provides a mechanism by which ryanodine channels
that are not associated with voltage-dependent calcium ion
channels can be regulated. Through coupled gating, activation of
one ryanodine channel may activate all of the ryanodine channels
in a locus -- a mechanism for the concerted activation of calcium
release channels during skeletal muscle excitation-contraction
coupling.
QY: Andrew R. Marks
(Science 7 Aug 98 281:818) (Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *ryanodine receptor: Ryanodine is an alkaloid compound
with a disruptive effect on calcium storage in cardiac and
skeletal muscle where it produces sustained contractions. The
substance is used as insecticide.
... ... *voltage-dependent calcium 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.
... ... *planar lipid bilayers: Lipid bilayers are spontaneously
forming self-organizing bimolecular layers of certain molecules
(lipids) with long nonpolar chains terminated by a polar group.
Such molecules are found in cell membranes, and also in soaps. A
variety of artificial lipid bilayer membrane systems can be
investigated in the laboratory.
-------------------
Related Background:
ROTATION OF MYOSIN LIGHT CHAIN DOMAIN ON MUSCLE CONTRACTION
Actin is a family of ubiquitous structural proteins present in
all eukaryote cells, and myosin is the predominant structural
protein found in muscle and other contractile structures. In
muscle cells, myosin is in association with actin, and myosin
"heads" are essentially bridges between myosin filaments and the
actin complex. Muscle contraction results from the relative
sliding between actin and myosin filaments, and most models
suggest that filament sliding is driven by a large structural
change of actin-bound myosin heads. However, resolving distinct
myosin structural states has been difficult, since active muscle
contains an apparently heterogeneous population of myosin heads
that independently cycle through different structural states.
... ... Baker et al (5 authors at University of Minnesota, US),
using electron paramagnetic resonance techniques, report
observing two distinct orientations of spin label attached
specifically to a single site on the light chain domain of myosin
in relaxed scallop muscle fibers. The results indicate that a
fraction of myosin heads undergoes a large (at least 30 deg.)
axial rotation of the myosin light chain domain upon force
generation and muscle contraction. The authors suggest the
resulting model helps explain why this observation has been so
elusive and provides insight into the mechanisms by which motor
protein structural transitions drive molecular motility. They
also suggest that these results support a new framework for
exploring energy transduction systems, in which molecular engines
work by modulating a distribution between existing structural
states through ligand binding and protein-protein interactions,
rather than by driving new structures that are directly coupled
to the bound ligand.
QY: David D. Thomas (ddt@ddt.biochem.umn.edu)
(Proc. Natl. Acad. Sci. US 17 Mar 98 95:2944)
(Science-Week 24 Apr 98)
7. CIRCADIAN OSCILLATORS: RESETTING BY TEMPERATURE CHANGES
Many organisms exhibit daily (circadian) rhythms, cyclical
variations in various bodily functions, metabolisms, etc., the
variations having considerable endurance even in constant light
or constant darkness. Such biological clocks are most easily
studied in simple organisms. Recent research has resulted in the
identification of common elements in the molecular mechanisms of
circadian rhythms and in the ways that these mechanisms respond
to environmental cues such as light and temperature. Phase
resetting by light is understood in terms of rapid light-induced
responses of central clock biochemical components. However, a
description of how small, naturally occurring temperature cycles
can reset a clock is lacking. ... ... Liu et al (4 authors at
Dartmouth Medical School, US) now report a study of the clock
protein FRQ in *Neurospora. Levels of FRQ were measured at
various temperatures. At higher temperatures, the amount of FRQ
oscillated around higher levels. Absolute FRQ amounts thus
identified different times at different temperatures, so
temperature shifts corresponded to shifts in clock time without
immediate synthesis or turnover of components. Moderate
temperature changes could dominate light-to-dark shifts in the
influence of circadian timing. The authors suggest their results
provide insight into how physiologically and ecologically
relevant temperature steps and pulses act to reset a day-phase
circadian oscillator. They further suggest their results provide
another example in which highly conserved and plainly adaptive
behaviors of a circadian system can be understood in terms of the
straightforward responses of clock components to factors in the
environment of the organism.
QY: Jay C. Dunlap
(Science 7 Aug 98 281:825) (Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *Neurospora: (pink bread mold) A genus of fungi grown in
culture and widely used in research in genetics and biochemistry.
-------------------
Related Background:
CIRCADIAN RHYTHMS IN HUMANS: EXTRA-VISUAL PHOTOTRANSDUCTION
In biology, a circadian rhythm is a daily cyclical process, be it
biochemical, or physiological, or behavioral. The human sleep-
wake cycle is the most familiar example. Circadian rhythms are
often described in terms of endogenous "biological clocks", with
the thrust of research to reduce some particular behavioral or
physiological circadian rhythm to biochemical events. These
clocks are usually set by environmental cues such as the light-
dark cycle, and what is characteristic of an endogenous clock is
that if one removes the environmental cue, keeps the organism in
constant light, for example, the endogenous rhythm will continue,
but will tend to drift out of synch. Restoring the external
light-dark cue will reset the clock to its normal intrinsic
rhythm. ... ... Campbell and Murphy (Cornell Univ., US) report
measurements of the response of the human circadian clock to
extraocular light exposure involving light pulses presented to
the popliteal region (the area behind the knee). They report a
systematic relation between the timing of the light pulse and the
magnitude and direction of clock phase shifts. The authors
suggest their findings challenge the belief that mammals are
incapable of extraretinal circadian phototransduction, and that
the findings also have implications for the development of more
effective treatments of sleep and circadian rhythm disorders.
QY: Scott S. Campbell, Cornell Univ. Medical College 212-746-1067
(Science 16 Jan 98) (Science-Week 30 Jan 98)
-------------------
Related Background:
DISSEMINATED INDEPENDENT CIRCADIAN CLOCKS IN THE FRUIT FLY
Drosophila melanogaster is a fruit fly that has been extensively
used in research in genetics, development, and molecular biology.
A transgenic Drosophila is a fruit fly into which genetic
material from another organism has been transferred, the trans-
ferred and incorporated new genes then being expressed with the
resultant production of specific proteins. Bioluminescence is the
production of light in biological organisms, the process usually
involving the protein luciferin and the enzyme luciferase. In
molecular biology, a "promoter" is a DNA sequence essential for
the initiation of the transcription of RNA from a particular gene
sequence. Many organisms exhibit daily (circadian) rhythms,
cyclical variations in various bodily functions, metabolisms,
etc., even in constant light or constant darkness. Such
biological clocks are most easily studied in simple organisms,
but several clock genes have been identified that have apparently
been conserved in evolution and are present in both simple
organisms and higher forms such as mammals. Now Plautz et al (4
authors at 2 installations, US) report that using transgenic
Drosophila expressing either luciferase or a green fluorescent
protein derived from the promotor of the clock gene period to
monitor the circadian clock in various explanted body parts
reveals that such tissues show rhythmic bioluminescence that can
be reset by light. The authors suggest their results show that
autonomous circadian oscillators are present throughout the body
of Droso-phila, that individual cells in Drosophila are capable
of supporting their own independent clocks, and that the idea of
a master oscillator controlling all other oscillators may need to
be revised.
QY: Steve A. Kay, Scripps Research Inst. 619-784-1000
(Science 28 Nov 97) (Science-Week 19 Dec 97)
-------------------
Related Background:
IDENTIFICATION OF A MAMMALIAN CIRCADIAN RHYTHM GENE
Circadian rhythms are *biological rhythms based on a 24-hour
cycle apparently controlled by an endogenous biochemical clock.
The essential aspect is that if the environmental cues are
removed, the rhythm will continue for some time before the
periodicity degenerates. These rhythms are observed in both
primitive organisms and in mammals including humans, and in
primitive organisms as well as in insects, several genes have
been isolated that apparently are involved in the endogenous
clock process. Cheng-Chi Li et al (Baylor College of Medicine,
Houston TX US) have now isolated a gene in mice and humans that
is apparently similar to the "period" per gene of the fruit fly
Drosophila melanogaster. Previous evidence shows the fruit fly
gene is switched on and off in a daily cycle, and with several
other genes produces the oscillating mechanism responsible for
the organism's diurnal clock. This is apparently the first
evidence that clock genes have been conserved through the course
of evolution.
QY: C-C. Li, Baylor College of Medicine (713) 798-4841
(Cell 19 Sep) (Science-Week 10 Oct 97)
-------------------
Related Background:
... ... *biological rhythms: Cyclic behaviors of various kinds
have been observed in organisms ranging from single-celled
protozoans and primitive plants to the most recently evolved
primates. In animals, an endogenous clock apparently exists in
the brain, and the light- sensitive production of the hormone
melatonin is evidently involved in this brain clock. Many
biologists believe primeval 13-hour tidal rhythms and monthly
lunar cycles influenced the clocks of primitive seashore
creatures, beginning the evolution of related biological clocks.
But of course the most significant periodicity to which the Earth
biosphere has always been exposed is the day-night light cycle,
and the term "circadian" technically applies only to this 24-hour
cycle.
-------------------
Related Background:
ANALYSIS OF MELATONIN ROLE IN HUMAN CIRCADIAN RHYTHMS
... In mammals, including humans, the biological clock apparently
resides in a group of neuron clusters in a part of the brain
called the hypothalamus, a region that responds to many chemical
inputs, including the hormone melatonin, an indole derived from
the metabolism of serotonin. Melatonin is secreted by another
hypothalamic brain structure, the pineal gland, which in turn is
stimulated by neurons in a nearby cluster (the suprachiasmatic
nucleus) that receives input from the retina of the eye. So this
is the apparent pathway in mammals: light on the retina,
electrical activity in the retino-hypothalamic tract, activity in
a hypothalamic region called the suprachiasmatic nucleus,
electrical signals to the pineal gland, secretion of the hormone
melatonin, action of melatonin on other neural structures in the
hypothalamus and elsewhere. In some insects, the biological clock
may be located in the optic lobes of the brain, and biological
clocks of one sort or another have been found at nearly all
levels of organism complexity. In humans, there is some evidence
that our biological clocks can be implicated in psychiatric
entities known as mood disorders, which is not surprising, since
the hypothalamus and nearby structures are known to play a key
role in emotions. But more generally, the biological clock is
apparent to anyone who has experienced jet- lag upon travelling
long distances east or west, the jet-lag effects resulting from
the body's biological clock being out of synch with the
light-dark cycle. The key question, of course, is that if
melatonin is involved in the workings of the human biological
clock, exactly how does it function? A number of laboratories
have been concerned with this problem, and this week Steven
Reppert et al (installations in MA, CT US) report that melatonin
apparently has two receptors, a major and a minor, and that the
result of binding to the minor receptor is a lowering of activity
in the suprachiasmatic nucleus, which seems to indicate a
chemical negative feedback loop. Identification of such feed-
back loops are the key to understanding brain function. The
studies were carried out on genetically altered mice lacking the
major melatonin receptor.
QY: S. Reppert, Harvard Med. School, Boston MA US (617) 432-1000
(Neuron 25 Jul 97) (Science-Report 1 Aug 97)
-------------------
Related Background:
IDENTIFICATION OF A CLOCK GENE IN THE MOUSE
The unraveling of the molecular mechanisms of biorhythmicity
received new impetus recently. Two weeks ago Loros and Dunlap
reported the identification of two new clock genes in the bread
mold Neurospora, the genes chemically related to those already
known in Neurospora and also in the fruit fly, and now Joseph
Takahashi and his colleagues (Northwestern Univ., Evanston IL
US) report the identification of the first mammalian clock gene
in the mouse. Circadian rhythms in mice are precise, animals
kept in darkness beginning exercise on a treadmill each night
with a 23.7 hour cycle. The method used by Takahashi and his
group was to produce random chemical mutations of the entire
mouse genome until one mouse was found that had its clock
altered. Proceeding from there, the damaged gene was identified.
The gene's function was proved by repairing the clock in mutant
mice by substituting a correct piece of DNA. Of great interest
is the news that one domain of the mouse clock protein is the
same as a domain in the clock proteins of the fruit fly and
Neurospora, which supports the idea that circadian rhythms in
mammals have evolved from biochemical feedback loops in
primitive organisms.
(Cell 16 May) (Science-Week 22 May 97)
-------------------
Related Background:
CLOCK GENES: RESPONSES TO LIGHT AND CIRCADIAN RHYTHMS
... Now Susan K. Crosthwaite et al (Dartmouth Medical School, US)
have shown that certain clock genes in the fungus Neurospora are
also involved in the production of proteins necessary for the
organism's response to light, suggesting that circadian
oscillators in more complex organisms evolved from light-
regulated pathways in simpler organisms.
(Science 2 May) (Science-Week 8 May 97)
8. BIOLOGY OF AGING: ON TELOMERES AND REPLICATIVE SENESCENCE
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are essential for normal chromosome
replication, and since their length shortens a bit with each
replication, they are believed to be involved in the aging of the
cell. Telomerase is an enzyme that repairs damage to telomeres,
and it is thought by some that cancerous cells may have mutant
telomerase, the mutant enzyme conferring immortality on the
cancer cell. ... ... In a review of cell senescence, the aging of
cell cultures, and the immortalization of mammalian cells, John
M. Sedivy (Brown University, US) makes the following points: 1)
Finite replicative lifespan (senescence) of mammalian cells in
culture is a phenomenon that has generated much curiosity since
its description. The obvious significance of senescence to
organismal aging and the development of cancer has engendered a
long-lasting and lively debate about its mechanisms. 2) Three
classical observations are usually cited to argue that in vitro
replicative senescence is a phenomenon with biological
significance: a) the correlation of in vitro lifespan with the
age of the donor; b) the correlation of in vitro lifespan with
the average life expectancy of species; and, c) the reduced in
vitro lifespan of cells from patients afflicted with premature
aging syndromes. 3) Two major theories have been used to explain
limited replicative capacity. The first hypothesis invokes the
gradual accumulation of mutations, and the second hypothesis
invokes the existence of a molecular clock (or clocks) that can
keep track of cell divisions. The second theory is now believed
to be generally true. 4) It is known that cell senescence can be
overcome, because many cell lines in common laboratory use are
quite obviously immortal. Rodent cells can overcome senescence
spontaneously. Human, chicken, bovine, and horse cells rarely, if
ever, immortalize spontaneously. 5) Certain viral or biochemical
interventions in human cell cultures can overcome cell
senescence, typically by causing 20 to 30 extra population
doublings. At the end of this extended lifespan, there is a
decline and death of the culture in 4 to 6 weeks, which has been
termed "crisis". Senescent cells, on the other hand, can be
maintained in vitro in a viable non-proliferative state for very
long periods of time (reports of from 4 to 6 months, and up to 2
years). 6) The author suggests it is amazing that in spite of
very long periods of apparent "immortality", the senescent
program in cells remains intact in cells in which senescence has
been overridden, so that on removal of the overriding agent, the
program is capable of establishing rapid growth arrest. 7) The
current prevailing hypothesis for the nature of the molecular
clock involved in cell senescence is the attrition of telomeres.
*Germ cells, and some key *stem cells, are known to express
telomerase catalytic activity, whereas the majority of somatic
cells lack it. Murine (mouse) embryonic stem cells express
telomerase and are functionally immortal, and elimination of
telomerase eventually results in loss of proliferation. 8) The
author proposes that immortalization of human cells requires a
bypass of both cell senescence and crisis, whereas in rodent
cells cell crisis does not exist and culture lifespan is limited
only by senescence. 9) Evidence indicates that, at least in human
cells, telomere length appears to be linked critically to the
triggering of senescence. The author suggests that although it
remains to be rigorously demonstrated, this strongly implies that
activation of telomerase can result in one-step immortalization.
In conclusion, the author states the two most significant
questions in this field: a) Does cell senescence limit organismal
lifespan? And, b) Is telomerase expression necessary for cancer
progression in vivo?
QY: John M. Sedivy
(Proc. Natl. Acad. Sci. US 4 Aug 98 95:9078)
(Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *Germ cells: Any cell from which gametes (sperm cells and
egg cells) are derived. All other cells are called "somatic"
cells.
... ... *stem cells: In general, a stem cell is any precursor
cell, a form prior to cell differentiation. E.g., stem cells in
bone marrow that give rise to blood cells.
-------------------
Related Background:
ROLE OF MOUSE TELOMERASE IN HIGHLY PROLIFERATIVE ORGANS
Telomeres are guanine-rich repeat sequences that form the
physical ends of the chromosomes of cells containing membrane-
bound organelles, and there is evidence these terminal structures
may be important in chromosome function. Synthesis and
maintenance of telomeric repeats are mediated by the specialized
ribonucleoprotein complex "telomerase". ... ... Lee et al (6
authors at 4 installations, US ES) report a study of the role of
the enzyme telomerase in highly proliferative organs in
successive generations of mice lacking telomerase RNA. Late
generation animals exhibited defective spermatogenesis, with
increased programmed cell death (apoptosis) and decreased
proliferation in the testis. The proliferative capacity of
hematopoietic cells in bone marrow and spleen was also
compromised. These progressively adverse effects coincided with
substantial erosion of telomeres and fusion and loss of
chromosomes. The authors suggest their findings indicate an
essential role for telomerase, and hence telomeres, in the
maintenance of genomic integrity and in the long-term viability
of high-renewal organ systems. They also suggest that the high
proliferation index of most cancer cells compared with the more
sporadic cycling of normal stem-cell populations indicates that
telomerase inhibition should be well tolerated in clinical
settings. QY: Ronald A. DePinho, Albert Einstein College of
Medicine 718-430-2106.
(Nature 9 Apr 98 392:569) (Science-Week 1 May 98)
-------------------
Related Background:
EXTENSION OF MITOTIC LIMITS BY TELOMERASE EXPRESSION
Somatic cells are all cells other than germline cells such as egg
cells and sperm cells and their progenitors, and the term
"cellular replicative senescence" refers to the observation that
somatic cells, in contrast to germline cells, can proliferate
(divide) only a fixed number of times, the actual number
dependent on the organism from which the somatic cells derive.
Since there is a general correlation between cellular replicative
senescence in vitro and the average life-spans of various animals
(including humans), cellular replicative senescence has been
implicated in aging and age-related pathologies. Telomeres are
regions at the ends of chromosomes consisting of repeats of
particular nucleotide sequences, and with each somatic cell
division a small part of the telomere is ordinarily lost. What
has been observed is that in germline cells the lengths of
telomeres are maintained constant by repair, while in somatic
cells this repair does not occur, and this difference has led to
the idea that the finite proliferative capacity of somatic cells
is related to the ultimate depletion of telomere lengths. The
enzyme telomerase is the enzyme that causes repair of telomeres,
and this enzyme is active in germline cells, but it is not
expressed in most somatic cells. In animals, epithelial cells
compose the cell layers that form the interface between a tissue
and the external environment, for example, the cells of the skin,
the lining of the intestinal tract, and the lung airway passages,
and fibroblasts are a type of connective tissue cell that secret
structured proteins such as collagen. Transfection is the uptake
of exogenous (foreign) DNA fragments in solution directly into
animals cells in laboratory culture, and is one method of
introducing foreign genes into cells. The term "vector", in the
context of DNA cloning, is any DNA fragment used in a
transfection process. ... ... Bodnar et al (10 authors at 2
installations, US) now report that two normal human cell types
(retinal pigment epithelial cells and foreskin fibroblasts) that
do not ordinarily express telomerase, can be transfected with
vectors encoding the human telomerase catalytic subunit, the
transfected cells (as opposed to controls) then exhibiting
elongated telomeres, dividing vigorously and exceeding their
normal life-span by at least 20 doublings. The authors suggest
their results establish a causal relationship between telomere
shortening and in vitro cellular replicative senescence, and that
the ability to maintain normal human cells in a youthful state
can have important applications in research and medicine. QY:
Serge Lichtsteiner
(Science 16 Jan 98) (Science-Week 30 Jan 98)
-------------------
Related Background:
NEW DATA AGAINST IMPORTANT TELOMERASE ROLE IN CANCER
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are essential for normal chromosome
replication, and since their length shortens a bit with each
replication, they are believed to be involved in the aging of the
cell. Telomerase is an enzyme that repairs damage to telomeres,
and it is thought by some that cancerous cells may have mutant
telomerase, the mutant enzyme conferring immortality on the
cancer cell. Now M. A. Blasco et al (Cell 91:25 1997) have
genetically engineered telomerase-deficient mice and have shown
that after 6 generations these mice are both viable and fertile.
Commenting on this research, David Wynford-Thomas and David
Kipling (University of Wales College of Medicine, Cardiff UK)
suggest that telomerase inhibitors that have been envisaged for
cancer therapy will therefore not have any acute toxicity against
cancer cells or other cells. Blasco et al have suggested that
current dogma that telomerase facilitates tumor growth may be
wrong, with telomerase nothing more than a "passive bystander" in
oncogenesis. (Nature 9 Oct 97) (Science-Week 24 Oct 97)
-------------------
Related Background:
ANALYSIS OF PROTEIN COMPONENT OF TELOMERASE
... Toru M. Nakamura et al (University of Colorado, US;
Geron Corp., Menlo Park CA US) report that telomerase catalytic
subunits are identical in yeast and humans, indicating the
molecular biology of telomere maintenance is evidently phylo-
genetically conserved.
QY: Thomas R. Cech, Univ. Colorado Boulder (303) 492-6301
(Science 15 Aug 1997) (Science-Report 29 Aug 97)
9. EMBRYOGENESIS: THE AREA CODE HYPOTHESIS UPDATED
The area code hypothesis of cell migration and tissue assembly
during embryogenesis was first formulated by William J. Dreyer in
1977. This hypothesis proposes that cells assemble organisms,
including their brains and nervous systems, with the aid of a
molecular-addressing code that functions much like the country,
area, regional, and local portions of the current telephone
dialing system. Because of the complexity of the information
required to code cells for the construction of entire organisms,
the hypothesis assumes that the code must make combinatorial use
of members of large multi-gene families, the system reusing the
same receptors as molecular digits in various regions of the
embryo, thus greatly reducing the total number of genes required.
... ... William J. Dreyer (California Institute of Technology,
US) now reviews the area code hypothesis and presents new data to
amplify the proposed coding scheme, the data accumulated from the
published literature and from databanks of gene sequence tags.
The author states that previous studies have already succeeded in
identifying a large number of cell surface molecules that are
involved in cellular interactions and assembly and that seem to
play a role more or less analogous to country, area, and prefix
codes, although until now the predicted highly specific final
part of the code has been elusive. The author now proposes that
members of the very large families of olfactory receptors and
*vomeronasal receptors fulfill the criteria postulated for area
code molecules and could serve as the last (local) digits in such
a code. The author discusses the evidence that the receptors of
these families are expressed in many parts of developing embryos,
and suggests that they play a key functional role in cell
recognition and targeting not only in the olfactory system but
also throughout the brain and numerous other organs as they are
assembled. The author states that his hypothesis (which proposes
the irreversible loss of genetic totipotentiality in fully
differentiated cells) predicts that cells from fully
differentiated tissues cannot be used to clone new individuals,
and he suggests the Wilmut sheep cloning experiments have not
been proven to have been accomplished from a differentiated cell
type. The author concludes: "As a good heuristic model, this
updated area code hypothesis makes predictions and suggests
experimental tests that can be carried out using currently
available methods. The implications and potential applications of
the knowledge to be gained from such experiments will be
profound." [Editor's note: This paper was received by the journal
March 9, 1998 and approved May 27, 1998]
QY: William J. Dreyer
(Proc. Natl. Acad. Sci. US 4 Aug 98 95:9072)
(Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *vomeronasal: The vomer is a flat bone of trapezoidal
shape forming the inferior and posterior portion of the nasal
septum, and term "vomeronasal" refers to the vomer and the nasal
bone.
-------------------
Related Background:
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.
10. ON ANTI-ANGIOGENIC GENE THERAPY
Angiogenesis, the origin and development of blood vessels, 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. ... ... In a commentary on 2 recent
reports of anti-tumor therapy in mice based on inhibition of
angiogenesis by gene therapy, Judah Folkman (Children's Hospital
Boston, US) makes the following points: 1) These 2 recent
reports, taken together with other recent reports by other
investigators of different types of experimental anti-angiogenic
gene therapy, reveal the emergence of a new branch of gene
therapy directed at tumor angiogenesis. 2) Of approximately 200
gene therapy clinical trials now underway, at least 50 percent
are for the treatment of cancer, and virtually all of these
strategies target the cancer cell. These trials include the
introduction of genes that, a) permit tumor cells to express
toxic molecules; b) prevent or correct genetic defects; c)
increase the immunogenicity of tumor cells; and d) increase the
sensitivity of tumor cells to drugs. 3) Although gene therapy of
cancer may inherently be less toxic than conventional
chemotherapy, it must still overcome other fundamental obstacles
that hinder conventional chemotherapy, e.g., limited access to
tumor cells, heterogeneity of tumor cells, and emergence of
resistant tumor cells. In contrast, anti-angiogenic therapy is
directed specifically against *microvascular endothelial cells
that have been recruited into the tumor bed. Specific anti-
angiogenic therapy has little or no toxicity, does not require
that the therapeutic agent enter any tumor cells nor cross the
*blood-brain barrier, controls tumor growth independently of
growth fraction or tumor cell heterogeneity or even tumor cell
type, and does not induce acquired drug resistance. The author
concludes that the recent reports by Lin et al (Proc. Natl. Acad.
Sci. US 95:8829 1998) and Goldman et al (Proc. Natl. Acad. Sci.
US 95:8795 1998) provide experimental evidence that translation
of anti-angiogenic gene therapy from laboratory to clinic may
soon become a reality.
QY: Judah Folkman, Children's Hospital, Boston MA 02115 US.
(Proc. Natl. Acad. Sci. US 23 Jun 98 95:9064)
(Science-Week 4 Sep 98)
-------------------
Related Background:
... ... *microvascular endothelial cells: Refers to the cells
that form new blood capillary vessels. Endothelial cells are flat
cells forming a layer lining blood vessels, lymphatic vessels,
the heart, etc.
... ... *blood-brain barrier: A selective mechanism opposing the
passage of most ions and large molecular-weight compounds from
the blood to brain tissue, the mechanism operating in a
continuous layer of endothelial cells connected by tight
junctions.
-------------------
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)
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