ScienceWeek

SCIENCE-WEEK

A Weekly Email Digest of the News of Science

A journal devoted to the improvement of communication
between the scientific disciplines, and between scientists,
science educators, and science policy makers.

January 29, 1999 -- Vol. 3 Number 5

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We still stand in the presence of riddles, but not
without hope of solving them. And riddles with the
hope of solution -- what more can a scientist desire?
-- Hans Spemann (1869-1941)

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Contents of This Issue:

1. US Physicists Forbidden to Meet in India
2. Research Use of Stem Cells Approved by NIH
3. On Models for the Development of Solar Systems
4. On the Use of Antibody Catalysis in Organic Chemistry
5. Embryonic Alterations by Strong Magnetic Fields
6. Telomerase Activity and Immortal Cells

Following the main text: Notices, subscription information,
editorial contacts, etc.

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1. US PHYSICISTS FORBIDDEN TO MEET IN INDIA
A controversy has apparently erupted in the physics community in
the US, resulting from the refusal of the US Department of Energy
to allow physicists at its national laboratories to travel to a
major particle physics conference in India during the week of 15
January. At least 7 physicists from the Fermi National
Accelerator Laboratory (Fermilab) and the Argonne National
Laboratory were apparently denied requests for travel to the 13th
Topical Conference on Hadron Collider Physics at the Tata
Institute for Fundamental Research in Mumbai (Bombay). John
Peoples, Director of Fermilab, said: "We never even did this with
the Russians at the worst part of the Cold War. This is a
precedent." Peoples also says that the US Department of Energy
ordered him in writing to remove the flag of India from the
United Nations-like display in front of the main building of
Fermilab. The Tata Institute, one of India's most prestigious
scientific institutes, was evidently placed on a list of
restricted sites because it conducts joint research with the
Bhabha Atomic Research Center, which is said to be "at the heart
of India's nuclear weapons program."
-----------
James Glanz: DOE blocks physicists from Indian meeting.
(Science 15 Jan 99 283:307)
QY: James Glanz 
-------------------
Summary by SCIENCE-WEEK  29Jan99
-------------------
Related Background:
NUCLEAR TEST EXPLOSIONS AND SCIENTISTS IN INDIA
G. Padmanaban, Director of the Indian Institute of Science
(Bangalore, IN), in a letter to the journal *Science*, comments
about the Indian science community and the recent nuclear test
explosions in India. The author makes the following points: 1)
The recent nuclear test explosions have created a "tremendous
euphoria" in India. The average Indian does not associate the
test with security concerns or power politics. "Right-thinking
Indians know that our priorities are such things as health,
education, and containment of population." 2) The author says
that India, despite having an ancient culture and a functioning
and stable large democracy, and being a hunting ground for
technically qualified people, has been persistently represented
in the US and the West as the home of poverty, filth, disease,
and backwardness. 3) The author says a feeling of alienation
permeates those segments of Indian society that have anything to
do with the West, and with the US in particular, and that the
general perception among Indian scientists in leading institut-
ions, most of whom are US-trained, is that they are being
discriminated against. Research papers sent to top international
journals from India seem to be reviewed with a bias. "Even if I
manage to publish one of my papers in one of the best journals,
it will seldom be quoted or have an impact, unless I have a US-
Western pedigree or a connection with an inner circle... Even if
I am invited to deliver a lecture at an international research
conference, I am made to feel like an outsider..." 4) The author
says India was denied a Cray computer for more than a decade, and
that Indian scientists "are appalled by how the US, which values
intellectual challenges and academic freedom, can have such a
discriminatory attitude toward a country struggling to develop
its science." 5) The author states: "India has many, many
problems, but we are tired of being depicted in the West as
having negative qualities. Given this treatment, one clutches at
any 'victory' that makes one feel like an entity to be counted.
It can be a win in cricket, a chess match, or a beauty contest,
or even a nuclear blast."
QY: G. Padmanaban 
(Science 10 Jul 98 281:175) (Science-Week 31 Jul 98)
-------------------
Related Background:
SEISMOLOGY: EARTHQUAKES AND NUCLEAR TEST BANS
US seismologists and some US politicians are evidently in a
dispute concerning the effectiveness of the international nuclear
device explosion detection system. The disagreement specifically
concerns the report by India of nuclear device explosions in
India on this past May 11th and May 13th. Eliot Marshall, in a
review of the dispute, makes the following points: 1) The web of
sensors that encircles the globe, programmed to monitor
compliance with the Comprehensive Test Ban Treaty, detected the
May 11th explosion but did not detect the May 13th explosion. 2)
Politicians who oppose the treaty are arguing that since
monitoring is ineffective, the treaty is useless and money
appropriated for the detection system wasted. 3) However, a
consensus has emerged among seismologists that the system in fact
worked well, and that the May 13th nuclear device explosion
reported by India either did not occur or was of too low yield to
be detectable by the present system. India reported a blast of
800 tons, and most seismologists evidently believe a blast of 100
to 200 tons would have been detected by the system that is place.
4) The international detection system, which is managed by the
United Nations, involves 35 primary seismic monitoring stations
supported by 58 auxiliary stations that can be queried for data
as needed. Plans are underway for considerable expansion of this
detection system. Marshall concludes: "The only way to resolve
the debate about blast yields may be through independent studies
of the bomb test sites. These might provide a clear indication of
just how well the seismic watchdog performed. But at the moment,
neither India nor Pakistan is ready to invite such inspections."
QY: Eliot Marshall 
(Science 26 Jun 98 280:2039) (Science-Week 24 Jul 98)
-------------------
Related Background:
A CONFLICT BETWEEN SEISMOLOGISTS AND DEFENSE ANALYSTS
It is an old adage that politics uses science, but a regrettably
frequent and insidious aspect of that use is the distortion of
science for political ends. On August 16, 1997 a geological event
occurred approximately 130 kilometers off the coast of Novaya
Zemlya. That Arctic island has been a Russian test site for
nuclear weapons, and politicians opposed to ratification of what
is called the Comprehensive Test Ban Treaty with the Russians are
claiming that geological event was a nuclear explosion and thus
evidence that the Russians are cheating. A press report suggest-
ing the geological event had "explosive characteristics" was
"leaked" from the U.S. Department of Defense to the Washington
Times, a conservative newspaper. But apparently most seismolog-
ists consider the geological event a seismic event -- in other
words, an earthquake -- and they are quite upset over the
distorted interpretation of the scientific evidence by the U.S.
Government. Whereas explosions produce predominantly compression
waves, earthquakes have a significant shear wave component, and
the August event apparently has the clear signature of an
earthquake. Greg van der Vink of the Incorporated Research
Institutions for Seismology, a collaboration of 90 universities
supported by the U.S. National Science Foundation to operate
seismology research facilities, says, "I don't know of any
seismologist who does not think that this was an earthquake."
Evidently Jesse Helms, Chairman of the U.S. Foreign Relations
Committee, disagrees. And evidently many seismologists are afraid
to be more vociferous because their research funding originates
with the U.S. Department of Defense.
(Nature 2 Oct 97) (Science-Week 17 Oct 97)


2. RESEARCH USE OF STEM CELLS APPROVED BY NIH
It is probable that one of the major public debates in the coming
months will concern the use of human stem cells in research (see
related background report below). On 19 January 1999, the US
Department of Health and Human Services announced that a
Congressional ban on human embryo research does not apply to
human stem cells, and federally financed researchers will may
soon be able to work on these cells. In its ruling, the Office of
the General Counsel of the US health department said that because
stem cells by themselves do not have the capacity to develop into
a human being, they cannot be considered embryos. Deriving the
cells from human embryos is legal, provided it is not done with
federal money. Harold E. Varmus, director of the US National
Institutes of Health, has stated it would still be illegal for
researchers to use federal money to derive their own stem cells
from human embryos, but they can now use federal money to work on
the cells obtained by others, in particular the stem cells
obtained by James Thompson (University of Wisconsin, US) from
human embryos created in surplus amounts in a fertility clinic.
The new US government ruling on the use of human stem cells is
opposed by the US National Conference of Catholic Bishops, and
the ruling is still subject to modification or elimination by the
new US Congress.
(New York Times 20 Jan 1999)
-------------------
Summary by SCIENCE-WEEK  29Jan99
-------------------
Related Background:
EMBRYONIC STEM CELLS DERIVED FROM HUMAN BLASTOCYSTS
*Embryonic stem cells are derived from *totipotent cells of the
early mammalian embryo and are capable of *unlimited and
undifferentiated proliferation in vitro. In *chimeras with intact
embryos, mouse embryonic stem cells contribute to a wide range of
adult tissues, including *germ cells, providing a powerful
approach for introducing specific genetic changes into the mouse
*germ line. ... ... J.A. Thompson et al now report the production
of human *blastocyst-derived *pluripotent cell lines that have
normal chromosome characteristics, express high levels of
*telomerase activity, and express *cell surface markers that
uniquely characterize primate embryonic stem cells. The authors
report that after undifferentiated proliferation in vitro for 4
to 5 months, these cells still maintained the developmental
potential to form *trophoblast, and to form derivatives of *all 3
embryonic germ layers, including gut *epithelium (mesoderm) and
neural epithelium, embryonic *ganglia, and *stratified squamous
epithelium (ectoderm). The authors suggest these cell lines
should be useful in human developmental biology, drug discovery,
and transplantation medicine. ... ... In a related commentary in
the same journal, J. Gearhart makes the following points: 1) A
renewable tissue-culture source of human cells capable of
differentiating into a wide variety of cell types would have
broad applications in basic research and transplantation
therapies. A major step in realizing this goal has now been taken
with the demonstration that human embryonic stem cells can be
grown in culture. 2) In the work of J.A. Thompson et al, four
cell lines tested produced *teratomas when grown in
*immunosuppressed mice. Histology of the tumors revealed
differentiated cells derived from all 3 embryonic germ layers
(ectoderm, mesoderm, and definitive endoderm) -- a result
consistent with pluripotency. 3) The derivation of human
embryonic stem cells now raises a whole new set of expectations.
On the basis of the already completed use and study of mouse
embryonic stem cells, the research and clinical potential for
human embryonic stem cells is enormous. They will be important
for in vitro studies of normal human embryogenesis, abnormal
development (through the generation of cell lines with targeted
gene alterations and engineered chromosomes), human gene
discovery, drug and *teratogen testing, and as a renewable source
of cells for tissue transplantation, cell replacement, and gene
therapies. These latter applications could eventually make
unnecessary the direct use of fetal tissue in transplantation
therapies [*Note #1].
-----------
J.A. Thompson et al (7 authors at 2 installations, US IL)
Embryonic stem cell lines derived from human blastocysts.
(Science 6 Nov 98 282:1145)
QY: James A. Thompson, University of Wisconsin 608-262-3961.
-----------
J. Gearhart (Johns Hopkins University, US)
New potential for human embryonic stem cells.
(Science 6 Nov 98 282:1061)
QY: John Gearhart 
-----------
Text Notes:
... ... *Embryonic stem cells: In general, the term "stem" cells
refers to undifferentiated cells that upon differentiation can
give rise to various specialized cell lines such as blood cells,
skin cells, nerve cells, etc. Adult bone marrow, for example,
contains stem cells that are the precursors of the various
specialized types of blood cells. "Embryonic" stem cells are
specifically stem cells derived from the embryo only.
... ... *totipotent cells: Cells that have the ability to
differentiate into any type of cell and thus form a new organism
or regenerate any part of an organism.
... ... *unlimited and undifferentiated proliferation in vitro:
In general, differentiated "normal" cells in tissue culture
produce a limited number of replications. In contrast, embryonic
stem cells and many types of cancer cells in tissue culture show
unlimited replications, and are thus called "immortal" cell
lines. In this context, "undifferentiated" proliferation is
simply proliferation without cell differentiation
(specialization).
... ... *chimeras: In this context, an animal that has received a
transplant of genetically and immunologically different tissue.
In this report, the transplant involves the injection of human
cultured stem cells into mice.
... ... *germ cells: In general, reproductive cells. All other
cells are "somatic" cells.
... ... *germ line: In general, this refers to the line of
differentiated germ cells.
... ... *blastocyst: A mammalian egg in the later stages of
*cleavage but before implantation in the uterus. The blastocyst
consists of a hollow fluid-filled ball of cells and an inner cell
mass (embryonic stem cells) from which the embryo develops.
... ... *cleavage: The early and rapid division stage that
divides the fertilized egg into smaller and smaller cells
(blastomeres) while retaining the same overall size of the
embryo.
... ... *pluripotent cell: A cell that has the potential,
depending on conditions, to give rise to many differentiated cell
lines but which lacks complete totipotency.
... ... *telomerase: 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.
... ... *cell surface markers: Cell surface proteins or protein
components that can be chemically identified.
... ... *trophoblast: In the early vertebrate embryo, the outer
ectodermal cell layer of the blastocyst. In mammals, it is the
trophoblast that attaches to the uterus and forms the placenta.
... ... *all 3 embryonic germ layers: In the embryos of higher
animals, there occurs the transformation of a single-layer
blastula into a 3-layered gastrula consisting of ectoderm,
mesoderm, and endoderm surrounding a cavity with one opening. The
3 layers are called the "germ layer", and these layers, via
further cell differentiation and proliferation, determine the
development of all the major body systems and organs.
... ... *epithelium: In animals, epithelial cells (epithelium)
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.
... ... *ganglia: (singular: ganglion) In the context of cells,
the original meaning of "ganglion" was any cluster of nerve cell
bodies in the central or peripheral nervous system. Currently,
the term "ganglion" refers to a aggregation of nerve cell bodies
located in the peripheral nervous system. Unfortunately, many
neuroanatomy texts still label certain neuron clusters in the
central nervous system in the old way (e.g., basal ganglia).
... ... *stratified squamous epithelium:  The cells of the
epithelium are for the most part closely packed cells with little
extracellular material between adjacent cells, the cells arranged
in continuous sheets in either single or multiple layers. The
cells may be flat, cubelike, columnar, or a combination of
shapes, and "squamous" cells are flattened and scalelike. In this
context, "stratified squamous epithelium" refers to a structure
consisting of distinctly layered epithelial cells (layers varying
in size and shape of cells), the top layer of which are squamous
cells.
... ... *teratomas: A teratoma is a neoplasm (tumor) composed of
multiple tissues, including tissues not normally found in the
organ in which it arises. A teratoma in the adult human ovary,
for example, can contain hair, teeth, skin, heart muscle, nerve
cells, and so on -- all a result of "wild" cellular
differentiation of neoplastic cells, but with enough regulation
so that distinct tissues are formed. In the context of this
report, the teratomas occurred in mice after injection of
cultured human stem cells, thus demonstrating the ability of
those stem cells to differentiate into organized specific tissue-
producing cells.
... ... *immunosuppressed mice: In general, this refers to mice
whose immune system response has been suppressed by chemical,
biological, or physical means. In this report, the purpose of the
immunosuppression was to allow the development of a mouse
teratoma provoked by injection of human stem cells. Without
immunosuppression, the human stem cells would be immediately
attacked and possibly destroyed by the mouse immune system before
the stems cells could differentiate.
... ... *teratogen: Any drug or other agent that causes abnormal
fetal development.
... ... *Note #1: We repeat here a quotation that appeared at the
head of a recent issue of SW: "Between the fifth and tenth days
the lump of stem cells differentiates into the overall building
plan of the mouse embryo and its organs. It is a bit like a lump
of iron turning into the space shuttle. In fact it is the
profoundest wonder we can still imagine and accept, and at the
same time so usual that we have to force ourselves to wonder
about the wondrousness of this wonder." -- Miroslav Holub
-------------------
Summary & Notes by SCIENCE-WEEK  27Nov98


3. ON MODELS FOR THE DEVELOPMENT OF SOLAR SYSTEMS
Recent discoveries of extrasolar giant planets are challenging
standard ideas about planet formation. Astronomers are now faced
with increasing numbers of apparently unusual planetary systems,
and simulation models are being developed to explain these giant
planets around Sun-like stars. ... ... Brett Gladman
(Observatoire de la Cote d'Azur, FR) presents a brief review of
present extrasolar planetary system simulation model research,
the author making the following points: 1) A bewildering variety
of extrasolar planetary systems are now known. The systems that
have been discovered are heavily biased by the methods used to
detect them, with the bias towards planets at least as large as
Jupiter and relatively near their stars, but the observations
have provided evidence of the apparent diversity of solar
systems. 2) Concerning the formation of these giant planets, one
general theoretical scheme involves the aggregation of kilometer-
size *planetesimals from the disk-like gas nebula surrounding a
young star. But the details are vague: the physics of these
processes is poorly known. We do not understand how planetesimals
form, and we do not understand the physical conditions
(temperature, mass, and density as a function of solar distance)
of the nebula. 3) Simulation models produce a wide variety of
final planetary systems. Some of these model systems have a few
widely spaced planets, others have many Uranus-sized planets
evenly spaced, while yet others have large planets closely packed
together... The variety found in these simulations may be due to
the fact that the range of physical parameters used in these
models (due largely to our ignorance) is far wider than the range
of parameters apparently present in protoplanetary nebulae.
Another cause of the variety of simulation results is that the
models involve a highly chaotic dynamical evolution of a small
number of planetary embryos, and this results in variable
locations and numbers of planets. Stable systems, for example,
have been found to range from 1 to 7 planets. Thus it is
unreasonable to demand that planet-formation theories produce our
own Solar System in detail. This is in contrast to the
"regularist" thinking of several decades ago, when it was popular
to postulate that most planetary systems would have a Jupiter
analogue just beyond the distance at which the temperature is low
enough so that icy solids condense and local accretion rates
increase. 4) The author states: "The near future holds the
promise of a doubling or tripling of the number of extraplanetary
systems known, with reasonable chances of detecting systems with
planets both smaller and further from their stars [than the giant
planets so far detected]."
-----------
[Editor's note: In addition to the related background material
below, other background material can be found in the SW Focus
Report "Astrophysics: Extrasolar Planets" available at URL
.]
-----------
Brett Gladman: Twenty-Eight ways to build a solar system.
(Science 10 Dec 98 396:513)
QY: Brett Gladman 
-----------
Text Notes:
... ... *planetesimals: Planetesimals are bodies with dimensions
of 10^(-3) to 10^(3) meters that are believed to form planets by
a process of accretion. The term "accretion" refers to an
aggregation, an increase in the mass of a body by the addition of
smaller bodies that collide and adhere to it, provided the
relative velocities are low enough for coalescence. As the mass
of the agglomerate increases, so does the rate of accretion, and
this accretion process is believed to generally occur in the form
of a disk. A stellar accretion disk is a swarm of dust grains
that evolve into planetesimals and then planets.
-------------------
Summary & Notes by SCIENCE-WEEK  29Jan99
-------------------
Related Background:
A MYSTERIOUS DUST CLUMP IN A BINARY STAR SYSTEM DISK
The current nebula theory of planet formation proposes that
star-planet systems begin as a contracting cloud of gas and dust
that flattens into a rotating disk. The center of this cloud
becomes the star, and the planets eventually form in the disk of
the nebula. In the inner part of the nebula, the hottest part,
only high density minerals can form solid grains. The outer
regions are cooler, and in those regions icy materials of lower
density are formed. Planets grow from these solid materials,
beginning as dust grains, which grow by condensation and
accretion into planetesimals that range from a few centimeters to
a few kilometers in diameter. These planetesimals settle into a
thin plane around the star and accumulate into larger bodies, the
largest of which grow the fastest and eventually become
protoplanets. Once the star becomes a luminous object, the
remaining nebula is cleared as the star's radiation and the
stellar-wind (powerful streams of charged particles from the
star's surface) push the remnants out of the system. Thus ends
the phase of planet-building. As might be expected, the above
theory is also the current view of the history of our own solar
system. Since the details of disk formation, and the physical
properties of protoplanetary disks, can be modelled by
quantitative theory, the general idea is to investigate such
disks that are apparent around stars to test the theoretical
models. There is no way to do that with our own solar system,
because the protoplanetary disk is long gone. One needs young
stars, or such was the thinking until recently. The discovery in
1992 of apparent planets in orbit around a *pulsar has suggested
that planets may form around *post-Main Sequence stars and not
just around young stars. Gravitationally bound orbiting dust
disks are now known to be present around evolved stars other than
pulsars, an example being HD44179, an evolved star (probably
evolving into a *white dwarf) that is part of the binary system
that has expelled the gas and dust that constitute what is called
the Red Rectangle nebula. ... ... M. Jura and J. Turner now
report *high-angular-resolution observations at *millimeter and
submillimeter wavelengths of the dust disk associated with the
Red Rectangle. The authors report evidence for a dust clump with
an estimated mass near that of Jupiter in the outer regions of
the disk. The clump is larger than our Solar System, and is far
beyond where planet formation would normally be expected, which
leads the authors to suggest the nature and fate of the apparent
clump are a mystery.
-----------
M. Jura and J. Turner (University of California Los Angeles, US):
A mysterious dust clump in a disk around an evolved binary star
system.
(Nature 10 Sep 98 395:144)
QY: M. Jura 
-----------
Text Notes:
... ... *pulsar: A pulsar is a pulsing source of stellar
radiation believed to originate with a *neutron star. They were
originally discovered at radio wavelengths, but there are
optical, gamma-ray, and x-ray pulsars, and some of the gamma-ray
pulsars are extremely powerful gamma-ray emitters.
... ... *neutron star: If at the terminal stages of a star's
evolution the remnant mass of the 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.
... ... *post-Main Sequence stars: The Hertzsprung-Russell
diagram is a plot of stellar absolute magnitude against spectral
type, and is perhaps the most useful diagrammatic aid in
astrophysics. The Main Sequence is a region on the Hertzsprung-
Russell diagram where most stars lie, including our own sun. The
evolution of a star can be diagrammed as a movement along the
Main Sequence and an eventual branching off the Main Sequence to
regions associated with various types of old stars. The phrase
"post-Main Sequence stars" thus refers to old stars, i.e., stars
whose position on the H-P diagram is off the Main Sequence.
... ... *white dwarf: White dwarf stars are extremely dense and
compact stars that have undergone gravitational collapse. They
are the final stage in the evolution of low-mass stars after they
have lost their outer layers. White dwarf stars are about the
size of Earth, but with a mass about that of the Sun.
... ... *high-angular-resolution: In general, "resolution" is a
measure of the ability of an instrument to distinguish fine
detail, and the spatial or angular resolution of a viewing
instrument is the smallest angle between two point objects that
produces distinct images. The angular resolution depends on both
the wavelength at which the observations are made and on the
effective diameter or aperture of the viewing instrument.
... ... *millimeter and submillimeter wavelengths: The
submillimeter band lies between the microwave band (above 1
millimeter) and the far-infrared band (at about 0.1 millimeter). 
Submillimeter wavelengths trace directly the emission from
dust that has been warmed by massive star-formation activity.
-------------------
Summary & Notes by SCIENCE-WEEK  9Oct98
-------------------
Related Background:
DUST DISKS AND EXTRASOLAR PLANETS
Paul Kalas (Max-Planck Institute for Astronomy Heidelberg, DE)
reviews current investigations concerning dust disks around stars
and the implications of the data for the existence of planets
around these stars. The author makes the following points: 1) One
of the important discoveries of the 1980s was the existence of
circumstellar disks of dust around some stars, the disks
apparently replenished by unseen parent bodies such as comets and
asteroids. 2) Some of these disks have recently been spatially
resolved by a new generation of ground-based instruments. An
example is the disk surrounding the star HR 4796, discovered in
1991 to have thermal emission from warm circumstellar dust. Two
observing teams have now mapped the emission from this dust disk
and revealed a peanut-shaped disk with the waist of the disk due
to an apparent central cavity (papers by Jayawardhana et al and
Koerner et al, in press). The data are interpreted by the authors
as indicating the existing of planets in formation around the
star, and so announced in news headlines (press releases by US
Harvard-Smithsonian Center for Astrophysics, US Jet Propulsion
Laboratory). Kalas, however, says the interpretation is premature
and not warranted by the data. 3) At about the same time as the
previous reports, maps of dust around the stars Vega, Fomalhaut,
and Beta Pictoris were published (Holland et al, *Nature*,
392:788 1988), and these maps were also interpreted as indicating
the presence of planets, but with differing bases for the
interpretations. Of the four stars, the data from HR 4796 and
Fomalhaut are interpreted as indicating planets creating central
cavities in dust formation, whereas the data from Vega and Beta
Pictoris are interpreted as indicating planets producing local
concentrations in their dust disks. The two interpretations are
apparently inconsistent. 4) Kalas asks: "Could the apparent
discrepancy result from 'planet mania', a bias among astronomers
in which every cavity and blob, even a wiggle, in circumstellar
dust disks is taken as evidence for extrasolar planets? Which
dust-planet relation does theory favor?" 5) Kalas says
theoretical arguments are available for both interpretations: one
can show that gravitational perturbations from a planetary object
will eventually create a cavity in a dust disk, but one can also
show that a planet can create a dust wake that looks like a large
blob following the planet in its orbit. 6) Kalas says: "At
present, therefore, we cannot uniquely identify the cause of the
dust blobs and dust cavities near these four stars. Planet-mass
objects are just one of the physically possible ideas."
QY: Paul Kalas 
(Science 10 Jul 98 281:182) (Science-Week 31 Jul 98)


4. ON THE USE OF ANTIBODY CATALYSIS IN ORGANIC CHEMISTRY
An antibody is a protein molecule (immunoglobulin) produced by
vertebrates that binds with high specificity to a "foreign"
entity (*antigen) that has entered the system by one means or
another (for example, via bacteria, tissue grafts, or blood
transfusions). Antibodies are therefore key elements in all
vertebrate immune systems. That is the first point. The second
point is that we now know that enzymes work the way they do
mostly because they bind *transition state entities in chemical
reactions, this binding lowering the energy barrier to the
transition state, and thereby increasing the reaction rate
many-fold. Which provokes the notion that it might somehow be
possible to use the high specificity of antibodies in catalysis.
And the notion is correct. A catalytic antibody, sometimes called
an "abzyme", is an antibody capable of catalyzing specific
chemical reactions. The general strategy in producing catalytic
antibodies has been to 1) design and synthesize a molecule whose
charge and shape closely resemble those of the transition state
of the reaction to be catalyzed; 2) attach this molecule to a
larger molecule and provoke an immune response in a living system
to this complex; and 3) isolate the resultant antibodies for
catalytic activity of the type desired. These resultant
antibodies are highly specific for binding to the transition
state, and they will be potentially capable of catalyzing the
reaction. Antibody catalysis has become a multifaceted field of
research involving many bridges between the biological and
chemical sciences. ... ... Peter G. Schultz (University of
California Berkeley, US) presents a short review of past and
recent research in the field, the author making the following
points: 1) The use of catalytic antibodies in organic chemistry
began with the idea that chemists should be able to use the
complex machinery of the immune system, which is capable of
generating enormous chemical diversity through the processes of
*recombination and *somatic mutation, to create new molecular
functions, specifically highly selective catalysts. 2) The
earliest examples involved the use of transition state analogues
to select antibodies with maximal binding affinity toward the
rate-limiting transition state for a given reaction. Other
strategies then emerged, strategies in which many of the basic
concepts of biological catalysis (e.g., strain, proximity,
general acid/base catalysis) were used in the design of molecules
that could guide the generation of catalytic antibodies for a
wide variety of reactions. 3) More recently, efforts have focused
on detailed studies of catalytic antibodies to gain new insights
into the molecular mechanisms of biological catalysis and of the
immune response itself. For example, structural studies of
catalytic antibodies have resulted in important new perspectives
concerning the *combinatorial processes involved in the immune
response. 4) Another direction the field has taken involves
efforts to recapitulate the combinatorial processes of the immune
system in vitro. For example, strategies are now being developed
to directly select *bacteriophage mutants with enhanced catalytic
activities from large libraries of such mutants. Such strategies
are designed to provide a direct linkage between catalysis and
biological amplification in order to produce protein catalysts
for a broad range of chemical reactions. 5) A new strategy for
generating antibody catalysis involves "reactive immunization" --
a designed covalent interaction between immunogen and antibody,
and this technique has now been used to carry out the synthesis
of key intermediates that in turn simplify the synthesis of the
natural product epothilone, a powerful cytotoxic agent of
considerable biomedical interest [*Note #1].
-----------
Peter G. Schultz: Bringing biological solutions to chemical
problems.
(Proc. Natl. Acad. Sci. US 8 Dec 98 95:14590)
QY: Peter G. Schultz, Univ. of Calif. Berkeley 510-642-6000.
-----------
Text Notes:
... ... *antigen: In general, an antigen is any substance or
moiety that produces an immune response.
... ... *transition state: (activated state) In general, in any
chemical reaction, the "transition state" is the high energy
configuration through which the reactants must pass before
becoming products.
... ... *recombination: In general, integration of DNA fragments
into a particular site in a genome.
... ... *somatic mutation: In general, a mutation occurring in
non-germ cells, which means the mutation is not transmitted to
the next generation.
... ... *combinatorial processes: Certain aspects of the immune
response and its production of antibodies apparently mimic a
"combinatorial process" in the sense that many factors are
involved in various combinations, rather than one factor involved
as a predominant determinant. (Combinatorial analysis is a branch
of mathematics involving analysis by means of combinations,
permutations, etc.) Combinatorial chemistry is a recent
technology involving the automated rapid production and screening
of thousands of compounds for specific properties, the population
of compounds consisting of a large number of possible
permutations of chemical constituents. One method, for example,
produces thin-film "libraries" of up to 25,000 different
substances on a 3-inch diameter substrate. The methods are
increasingly used in molecular biology for the production and
screening of large libraries of antibodies, peptides, DNA
ligands, and so on. A random peptide library synthesis may
involve as many as 100 million different peptides, with
subsequent screening of the library for the purposes of drug
discovery.
... ... *bacteriophage: Bacteriophage is a virus that
infects bacteria, the virus essentially consisting of a naked
strand of DNA surrounded by a complex polyhedral shell ("capsid")
composed mainly of glycoproteins.
... ... *Note #1: The Schultz review is a commentary on a
research report appearing in the same issue of the journal: S.C.
Sinha et al: The antibody catalysis route to the total synthesis
of epothilones. ((Proc. Natl. Acad. Sci. US 8 Dec 98 95:14603)
Epothilones are powerful cytotoxic agents isolated from
*myxobacteria (Sorangium cellulosum), the substances exhibiting a
*taxol-like effect on cellular *microtubules.
... ... *myxobacteria: An order of bacteria bearing extracellular
slime.
... ... *taxol: An anti-tumor and anti-leukemic agent isolated
from the bark of the yew tree.
... ... *microtubules: Microtubules are part of the cytoskeleton
of biological cells, the quasi-rigid matrix that among other
things determines cell shape. The microtubules are 25 nanometers
in diameter, and composed of the protein tubulin. They occur in
regular arrays in cilia, flagella, the mitotic spindle, and in
the cytoplasm in general, and they contribute not only to cell
shape, but also to cell motility. 
-------------------
Summary & Notes by SCIENCE-WEEK  29Jan99
-------------------
Related Background:
SELECTION OF BROAD-SCOPE ENZYMES BY ANTIBODY CATALYSIS
... "Reactive immunization" is a new term to describe a synthetic
antibody specificity that involves a covalent chemical reaction
with an antigen rather than weaker affinity bonds, and new
antigens specifically synthesized or selected for this reactive
process are called "reactive immunogens". In biological systems,
glycolysis (also known as Embden-Meyerhof pathway), involving the
breakdown of glucose, is one of the main energy producing
pathways in the cell, and anaerobic glycolysis is glycolysis in
the absence of oxygen. Decarboxylation is the removal of CO(2)
from organic compounds, and in biological systems often involves
the conversion of amino acids to amines. Lysine is one of the
amino acids found in biological systems. ... ... Barbas et al (11
authors at Scripps Res. Inst., US) report the preparation of
catalytic antibodies by reactive immunization, the process
yielding aldolase catalytic antibodies that approximate the rate
acceleration of the natural enzyme used in glycolysis. But unlike
the natural enzyme, the antibody aldolases catalyze a variety of
aldol reactions and decarboxylations. Crystal structure analysis
of one of the antibodies identified the lysine residue selected
in the immunization process, and the lysine residue is apparently
deeply buried in a hydrophobic pocket at the base of the binding
site. The authors suggest that an early defining event in the
evolution of some natural enzymes was an interaction with
reactive materials such as toxins in a process similar to the
induction of catalytic antibodies with a reactive immunogen.
QY: Richard A. Lerner, Scripps Research Institute 619-784-1000
(Science 19 Dec 97) (Science-Week 9 Jan 98)
-------------------
Related Background:
RELATING BOND ENERGY TO CATALYSIS IN CATALYTIC ANTIBODIES
A catalytic antibody, sometimes called an "abzyme", is an
antibody capable of catalyzing specific chemical reactions. 
These antibodies, which can be immunologically engineered, are
highly specific for binding to the transition states of react-
ions, and they are potentially capable of catalyzing such
reactions. Helle D. Ulrich et al (University of California
Berkeley, US) recently reported a study of the relationship
between binding energy and catalysis by catalytic antibodies, the
study involving the antibody AZ-28, which catalyzes a well-known
reaction in organic chemistry called an oxy-Cope rearrangement.
They found the catalytic rate depends on a complex balance of
several subtle stereo-electronic effects, so that increasing the
affinity for a catalytic antibody with its ligand may actually
reduce the reaction rate rather than increase it. The authors
suggest that catalytic antibodies can be useful to explore the
complex relationships between binding energy and catalysis in
biological enzymes.
QY: Peter G. Schultz, Univ. Calif., Chemistry (510) 642-5883
(Nature 18 Sep 97) (Science-Week 3 Oct 97)
-------------------
Related Background:
FIRST COMMERCIAL CATALYTIC ANTIBODY FOR CHEMICAL SYNTHESIS
... Now there has been announced the first catalytic antibody to
enter the marketplace, produced by Richard A. Lerner et al
(Scripps Research Institute, La Jolla CA US), and available to
anyone who wants it at a modest charge. The new entity, called
38C2, catalyzes a wide range of aldol condensation reactions at
high efficiency (accelerating the reaction by a factor of 3.6
million). Aldol condensations are among the reactions widely used
for the synthesis of steroids, terpenoids, and other natural
products, so this new catalytic antibody molecule will be of
great interest to organic chemists.
QY: R. Lerner, Scripps Research Institute 619-784-1000
(J. Amer. Chem. Soc. 119:8131 1997) (Science-Week 12 Sep 97)


5. EMBRYONIC ALTERATIONS BY STRONG MAGNETIC FIELDS
Most biological systems exhibit some form of polarity -- a
physiological or morphological difference between the two ends of
an axis. For example, in the eggs of most fish, amphibians,
reptiles, and birds there is found a species specific
characteristic asymmetric yolk distribution. The part of the egg
with less yolk is called the "animal" pole, and the opposite end
of the axis is called the "vegetable" pole [*Note #1]. After such
an egg is fertilized, it enters a "cleavage" phase characterized
by rapid division of the egg into smaller and smaller cells while
the same overall size of the embryo is retained. The planes of
cleavage division can be easily recognized and the sequence and
orientation of these planes precisely mapped.
... ... J.M. Denegre et al (5 authors at Brown University, US)
report a study of the embryos of Xenopus (a species of African
toad) in strong static magnetic fields (1.76 - 16.7 tesla). The
authors report that 3rd-cleavage planes, normally horizontal
(i.e., perpendicular to the Earth's gravity field) were seen to
orient to a vertical plane parallel with a vertical magnetic
field. 2nd-cleavages, normally vertical, could also be oriented
by applying a horizontal magnetic field. The authors suggest that
these changes in cleavage-furrow geometries result from changes
in the orientation of the *mitotic apparatus, and that the
magnetic fields act directly on the *microtubules of the mitotic
apparatus. The authors report that considerations of the *astral
microtubules, their *diamagnetic anisotropy, and flexural
rigidity predict the required field strength for an effect that
agrees with the data. The authors conclude: "This observation
provides a clear example of a static magnetic-field effect on a
fundamental cellular process, cell division."
-----------
J.M. Denegre et al: Cleavage planes in frog eggs are altered by
strong magnetic fields.
(Proc. Natl. Acad. Sci. US 8 Dec 98 95:14729)
QY: Kimberly L. Mowry 
-----------
Text Notes:
... ... *mitotic apparatus: In general, the term "mitosis" refers
to the ordered process by which a cell nucleus and cytoplasm
divide into two progeny. In general, the term "mitotic apparatus"
refers to the dynamic cytoskeletal architecture involved in the
temporal staging of the process and actual physical separation of
components.
... ... *microtubules: Microtubules are part of the cytoskeleton
of biological cells, the quasi-rigid matrix that among other
things determines cell shape. The microtubules are 25 nanometers
in diameter, and composed of the protein tubulin. They occur in
regular arrays in cilia, flagella, the mitotic apparatus, and in
the cytoplasm in general, and they contribute not only to cell
shape, but also to cell motility and cell mitosis.
... ... *astral microtubules: An aster is a spherical array of
microtubules that appears during mitotic division of the cell
nucleus.
... ... *diamagnetic anisotropy: Diamagnetic substances such as
the alkalis and alkaline earth metals, the halogens, and the
noble gases are repelled by magnets and tend to position
themselves at right angles to the magnetic lines of force. In
this context, the term "diamagnetic anisotropy" refers simply to
direction-dependent variations diamagnetic properties.
-------------------
Related Background:
MAGNETIC LEVITATION OF ORDINARY OBJECTS
All substances can be influenced by applied magnetic fields.
In terms of magnetic properties, substances are usually divided
into 3 broad categories: 1) Ferromagnetic substances such as
iron, steel, cobalt, and nickel are able to become highly
magnetic in a relatively weak magnetic field. Such substances
contain substantial internal magnetic fields in the absence of an
applied magnetic field. 2) Paramagnetic substances such as liquid
oxygen have a capability to be magnetized which is slightly
greater than that of a vacuum and much less than that of iron.
When placed in a magnetic field, paramagnetic substances are
magnetized parallel to the lines of force of the field to an
extent proportional to the intensity of the field (but not at
extremely low temperatures or extremely high fields). When
removed from an applied magnetic field, the magnetization of
paramagnetic substances returns to zero. 3) *Diamagnetic
substances such as the alkalis and alkaline earth metals, the
halogens, and the noble gases are repelled by magnets and tend to
position themselves at right angles to the magnetic lines of
force. Like paramagnetic substances, when removed from an applied
magnetic field, the magnetization of diamagnetic substances
returns to zero. In the context of this report, "lifting" is
distinguished from "levitation", with levitation referring to
stable floating in an applied magnetic field. ... ... In a review
of the behavior of diamagnetic materials in laboratory magnetic
fields, Andrey Geim makes the following points: 1) All materials
can be lifted by magnetic fields that are currently standard. 2)
Due to the readjustment of electron orbits in a magnetic field,
all objects exhibit diamagnetism, which determines the lowest
possible limit of their magnetic response... Fields of
approximately 10 *tesla are sufficient to lift practically any
substance. 2) Magnetic fields strong enough to lift diamagnetic
materials became available during the mid 20th century, and
*superconductors were first levitated in 1947. It took 50 years
to rediscover the levitation of conventional room-temperature
diamagnetic materials. In 1991, Beaugnon and Tournier
magnetically lifted water and a number of organic substances.
Other researchers soon levitated liquid hydrogen, helium, and
frog eggs. The author's research group at the University of
Nijmegen (NL) has levitated practically everything at hand, "from
pieces of cheese and pizza to living creatures including frogs
and a mouse." (The article includes a photograph of a levitated
live frog in the bore of a 20 T magnet, the frog reported to
exhibit no adverse effects from exposure to the magnetic field.)
The magnetic fields used in these experiments have been available
for decades. 3) In contrast to diamagnetic substances,
paramagnetic substances cannot levitate. Only diamagnetic
substances can flaunt *Earnshaw's theorem, which states that no
stationary object made of charges, magnets, and masses can be
held in space by any fixed combination of electric, magnetic, and
gravitational forces. Diamagnetism involves electron motion
around nuclei, and thus is not a fixed configuration as required
by the theorem. 4) A diamagnetic substance can levitate only
close to an inflection point of the vertical component of the
magnetic field. This is a purely geometric condition independent
of the field strength. 5) The author suggests an example of the
exploitation of the diamagnetic force: the direction of growth of
germinating seeds, which ordinarily depends on gravity, can in
the absence of gravity (e.g., in a space ship) be determined by a
small permanent magnet (O.A. Kuznetsov and K.H. Hasenstein,
_Planta_ 1996 198:87).
-----------
A. Geim (University of Nijmegen, NL): Everyone's magnetism.
(Physics Today September 1998)
QY: Andrey Geim, University of Nijmegen, NL.
-----------
Text Notes:
... ... *Diamagnetic substances: Diamagnetism was discovered by
Michael Faraday in 1846.
... ... *tesla: International System unit of magnetic flux
density. 1 tesla = 1 weber per square centimeter.
... ... *superconductors: Superconductivity is a property of many
metals, alloys, and chemical compounds at temperatures near
absolute zero, at which temperatures their electrical resistivity
vanishes and they become strongly diamagnetic.
... ... *Earnshaw's theorem: The classic statement of this
theorem is that a charge cannot be held in stable equilibrium in
an electric field under the influence of electric forces alone.
The theorem as given in the text by Geim is a recent
reformulation by Michael Berry (M.V. Berry and A.K. Geim, Eur. J.
Phys. 1997 18:307)
-------------------
Summary & Notes by SCIENCE-WEEK  2Oct98


6. TELOMERASE ACTIVITY AND IMMORTAL CELLS
Tumors arise as the end product of a multistep process involving
successive rounds of mutation, selection, and *clonal expansion.
One obstacle to the completion of tumor development may be the
limited number of replication cycles apparently allowed normal
human cells. In vitro, normal human cells exhibit a limited
replicative potential, eventually succumbing to "senescence".
Premalignant cell populations evolving in vivo may exhaust this
apparent allotment of doublings before the population progresses
to a malignancy, and when that happens such progression to a
malignancy will only occur if the "replication clock" is
disrupted by the cells acquiring replicative immortality. 
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are apparently 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 addition to cell "senescence", there is a
phenomenon called "crisis" (proliferative crisis), which
essentially involves the following: Certain viral or biochemical
interventions in human cell cultures can overcome cell
senescence, typically by causing 20 to 30 extra population
doublings, but 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" (proliferative crisis). Cell culture crisis has
been proposed to be the result of telomeric shortening.
... ... C.M. Counter et al (8 authors at 4 installations, US CA)
now report that ectopic expression (i.e., "abnormal" expression)
of the telomerase catalytic subunit (human telomerase *reverse
transcriptase) and subsequent activation of telomerase can allow
post-senescent cells to proliferate beyond crisis. The authors
also report that alteration of the *carboxyl terminus of human
telomerase reverse transcriptase does not affect telomerase
enzymatic activity but does impede the ability of this enzyme to
maintain telomeres, and cells expressing this mutant enzyme fail
to undergo immortalization. The authors state: "Our results
formally demonstrate that acquisition of human telomerase reverse
transcriptase expression is sufficient to immortalize human cells
and [thus our results] validate the role of telomerase in
rescuing cells from crisis."
-----------
C.M. Counter et al: Dissociation among in vitro telomerase
activity, telomere maintenance, and cellular immortalization.
(Proc. Natl. Acad. Sci. US 8 Dec 98 95:14723)
QY: Robert A. Weinberg 
-----------
Text Notes:
... ... *clonal expansion: In this context, the term "clonal
expansion" refers to the replicative production of a population
of cells from a single originating parent cell.
... ... *reverse transcriptase: Transcription is the process by
which genetic information in DNA is converted into RNA, and
*reverse transcription, involving the enzyme reverse
transcriptase, is the synthesis of complementary DNA from an RNA
template. (Note: The terminological convention in biochemistry is
to identify an enzyme by use of the suffix "-ase")
... ... *carboxyl terminus: In general, since all proteins (and
all enzymes are proteins) are linear polymers consisting of amino
acid subunits connected by peptide bonds, one terminus of the
linear polymer is a carboxyl residue and the other terminus is an
amino residue.
-------------------
Summary & Notes by SCIENCE-WEEK  29Jan99
-------------------
Related Background:
CELLULAR AGING: DONOR AGE AND CELLULAR REPLICATION LIFESPAN
Fibroblasts are a type of connective tissue cell, secreting
structural proteins such as collagen, the proteins forming a
matrix in which the fibroblasts become embedded. These cells can
be easily obtained from skin, and they can be easily cultured
outside the body. Normal human fibroblasts have a finite
replicative lifespan in vitro (i.e., they divide a finite number
of times), and this has been postulated to be a cellular
manifestation of aging of the human organism. Several studies
have indeed shown an inverse relationship between donor age (the
age of the persons from which cultured cells are derived) and
fibroblast culture replicative lifespan. But in all cases the
correlation was weak, and with few exceptions the health status
of the donors was unknown. Thus, the relationship between the
replicative lifespan and the age of the donor from which the
cells are derived has remained equivocal (*Note #1).
... ... V.J. Cristofalo et al now report a study of the
replicative lifespan of 124 skin fibroblast cell lines
established from donors of different ages. All donors were
medically examined and were declared "healthy" (according to
Baltimore Longitudinal Study of Aging protocols) at the time the
biopsies were taken. The authors report that both long- and
short-lived cell lines were observed in all age groups, but no
significant correlation between the proliferative potential of
the cell lines and donor age was found. A comparison of multiple
cell lines established from the same donors at different ages
also failed to reveal any significant trends between
proliferative potential and donor age. The authors suggest their
results clearly indicate that if health status and biopsy
conditions are controlled, the replicative lifespan of
fibroblasts in culture does not correlate with donor age.
-----------
V.J. Cristofalo et al (5 authors at 2 installations, US)
Relationship between donor age and the replicative lifespan of
human cells in culture: A reevaluation.
(Proc. Natl. Acad. Sci. US 1 Sep 98 95:10614)
QY: Vincent J. Cristofalo, Center for Gerontological Research,
Alleghany University of the Health Sciences, Philadelphia, PA
19129 US.
-------------------
... ... *Note #1: The possibility that the process of cell aging
and death is under genetic control was first suggested by Leonard
Hayflick in 1961. Hayflick reported that normal human fibroblasts
apparently have an intrinsic limit to the number of times they
can proliferate, with human fibroblasts removed from an embryo
and grown in culture dividing approximately 50 times before they
deteriorate and die. In contrast, human fibroblasts removed from
adults multiply only 15 to 30 times before dying. Also,
fibroblasts removed from young children suffering from Werner's
syndrome (a rare disease that causes premature aging) divide only
2 to 10 times in culture. Further evidence for a relationship
between aging and the replicative capacity of cells was provided
by the discovery that the number of replications in culture is
apparently related to the lifespan of organism. For example,
cultured cells of the Galapagos tortoise, whose maximum life span
is approximately 175 years, divide more than 100 times in
culture, whereas cells from the mouse, whose maximum life
expectancy is only a few years, divide fewer than 30 times in
culture. The correlation roughly holds for other species as well.
-------------------
Summary & Notes by SCIENCE-WEEK  16Oct98
-------------------
Related Background:
BIOLOGY OF AGING: ON TELOMERES AND REPLICATIVE SENESCENCE
... ... 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: R.A. DePinho, Albert Einstein Coll. 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 97) (Science-Report 29 Aug 97)


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