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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.
November 13, 1998 -- Vol. 2 Number 46
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We have entered the cell, the mansion of our birth,
and have started the inventory of our acquired wealth.
-- Albert Claude (1899-1983)
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Contents of This Issue:
1. On the Tobacco Industry and Nicotine as an Addictive Drug
2. New Evidence for Subsurface Oceans in Europa and Callisto
3. Particle Physics: An Exchange Concerning Relevance
4. On Water and the Structures of Biological Molecules
5. Evidence that RNA Folding Causes Secondary Structure Changes
6. Neurobiology: Target Cell Modulation of Transmitter Release
7. Biology of Cancer: On Squamous Cell Carcinoma
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1. ON THE TOBACCO INDUSTRY AND NICOTINE AS AN ADDICTIVE DRUG
In 1994 the state of Minnesota filed suit against the tobacco
industry, and although this trial is now history, there are many
people who feel the legacy of the trial will carry on into the
21st century because of the revelations contained in the millions
of pages of previously secret internal tobacco industry documents
made public in the trial. ... ... R.D. Hurt and C.R. Robertson
now present an extensive review of the material in a medical
journal from the perspective of medical science, and the authors
make the following points: 1) The litigation tobacco industry
documents reveal that for decades the tobacco industry knew and
internally acknowledged that *nicotine is an addictive drug and
that cigarettes are the ultimate nicotine delivery device. The
following statements by executives, for example, are found in
tobacco industry documents: "Very few consumers are aware of the
effects of nicotine, i.e., its addictive nature and that nicotine
is a poison." (H.D. Steele, Brown and Williamson Tobacco Company,
1978). And in another Brown and Williamson memo: "Nicotine is the
addicting agent in cigarettes." (A.J. Mellman, Brown and
Williamson Tobacco Company, 1983). Concerning cigarettes as a
drug delivery device, the litigation documents reveal that C.E.
Teague Jr., assistant director of research at R.J. Reynolds
Tobacco Company, wrote in 1972 in an internal memorandum: "In a
sense, the tobacco industry may be thought of as being a
specialized, highly ritualized and stylized segment of the
pharmaceutical industry. Tobacco products, uniquely, contain and
deliver nicotine, a potent drug with a variety of physiological
effects... Thus a tobacco product is, in essence, a vehicle for
delivery of nicotine." 2) The authors report that perhaps their
most surprising finding in the document review was the evidence
of tobacco industry efforts spanning 3 decades to alter the
chemical form of nicotine to increase the percentage of freebase
nicotine delivered to smokers. Depending on pH, nicotine exists
as a diprotonated salt, a monoprotonated salt, or an uncharged
neutral species. The salt forms are called the "bound" forms, and
the neutral species is called the "freebase" form. Nicotine
favors the salt form at low values of pH (e.g., pH = 3) and the
freebase form at high values of pH (e.g., pH = 8). Freebase
nicotine apparently crosses biological membranes more easily than
the charged counterparts, and this affects the physiological
response to the drug. The tobacco industry was apparently well
aware of these properties of nicotine as far back as 1966, and
for 3 decades the tobacco industry had a focus on developing high
pH delivery of nicotine to increase its physiological effects.
The authors conclude: "When the breadth and depth of tobacco
industry actions are understood, it becomes evident that allowing
a tobacco settlement that honors the industry demands for legal
and financial immunity would be a public health disaster of epic
proportions and would allow the industry to continue to promote
its deadly product throughout the 21st century. Congress must use
its power to stop the carnage of more than 400,000 Americans
dying each year of cigarette-related diseases."
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R.D. Hurt and C.R. Robertson (2 installations, US)
Prying open the door to the tobacco industry's secrets about
nicotine.
(J. Amer. Med. Assoc. 7 Oct 1998 280:1173)
QY: Richard D. Hurt, Mayo Clinic, 200 First St. SW, Rochester, MN
55905 US.
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Text Notes:
... ... *nicotine: The alkaloid nicotine
[3-(1-methyl-pyrrolidyl)pyridine] is a tertiary amine composed of
pyridine and pyrrolidine rings. The current consensus among
neuropharmacologists is that nicotine is the psychoactive drug
primarily responsible for the addictive nature of tobacco use.
Nicotine is highly selective for so-called "nicotinic receptors"
for *acetylcholine in the peripheral and central nervous systems,
and activation of these receptors is the likely source of the
psychoactive effects of the drug. The nicotinic-acetylcholine
receptor is a molecularly well-characterized receptor, and its
activation evidently leads to conformation changes in its 5
subunits that result in a transient increase of permeability of
the neuron membrane to the sodium ion. The nicotinic-
acetylcholine receptor is therefore characterized as a
neurotransmitter-gated ion channel. Concentrations of nicotine in
blood rise quickly during cigarette smoking and peak at its
completion. Nicotine is also deposited in the lungs, spleen,
liver, and brain, where concentrations are typically twice those
of measurable blood concentrations. Nicotine readily crosses the
*blood-brain barrier, leading to the release of acetylcholine,
*norepinephrine, *dopamine, *serotonin, *vasopressin, *growth
hormone, *cortisol, *prolactin, *neurophysin 1, and
*adrenocorticotropic hormone, and release of these substances
causes various neuropharmacological effects. Apart from the
neuropharmacological effects of nicotine, nicotine and other
constituents in cigarette smoke elevate blood pressure, cause
*tachycardia, *arrhythmia, and *vasoconstriction in *cutaneous
tissue and skin; lower body temperature; inhibit *diuresis;
increase *gastrointestinal tonus; antagonize ulcer healing; and
decrease pain threshold.
... ... *acetylcholine: A prevalent *neurotransmitter substance,
both in the brain and in the peripheral nervous system, where it
controls the actions of skeletal and smooth muscle.
... ... *neurotransmitter substance: Neurotransmitters are
chemical substances released at the terminals of nerve axons in
response to the propagation of an impulse to the end of that
axon. The neurotransmitter substance diffuses into the synapse,
the junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell.
... ... *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 between cells. (Endothelial cells are flat cells
forming a layer lining blood vessels, lymphatic vessels, the
heart, etc.)
... ... *norepinephrine: The principal neurotransmitter substance
released from nerve endings of the sympathetic nervous system.
(The sympathetic nervous system is a part of the autonomic
nervous system involved in the mobilization of energy resources
during stress and arousal.
... ... *dopamine: A neurotransmitter substance.
... ... *serotonin: A neurotransmitter substance involved in
nearly everything occurring in the brain, including psychological
states such as anxiety and depression, and dysfunctions
producing
migraine and epilepsy.
... ... *vasopressin: A peptide hormone important in the
regulation of *diuresis.
... ... *growth hormone: A vertebrate polypeptide hormone that
regulates growth. In general, hormones are signaling molecules
secreted into the blood stream by endocrine cells and acting on
target cells that possess receptors for the hormone.
... ... *cortisol: A corticosteroid hormone secreted by the
adrenal gland.
... ... *prolactin: A polypeptide hormone synthesized and
released by the pituitary gland.
... ... *neurophysin 1: Neurophysins are a family of proteins
synthesized in the hypothalamus, and function as carriers in the
transport and storage of a number of hypothalamic-pituitary
hormones.
... ... *adrenocorticotropic hormone: (ACTH) A pituitary hormone.
... ... *tachycardia: Rapid beating of the heart, conventionally
applied to rates over 100 per minute.
... ... *arrhythmia: Irregularity of the heartbeat.
... ... *vasoconstriction: Narrowing of the blood vessels.
... ... *cutaneous tissue: In general, tissue associated with
skin.
... ... *diuresis: Excretion of large volumes of urine.
... ... *gastrointestinal tonus: In general, contraction of
gastrointestinal muscle.
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Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
2. NEW EVIDENCE FOR SUBSURFACE OCEANS IN EUROPA AND CALLISTO
The 4 largest of Jupiter's moons are called the Galilean moons,
and in order from outermost inward they are Callisto, Ganymede,
Europa, and Io. Callisto is a low-density moon 44 percent larger
than Earth's moon. Europa is denser than Callisto and slightly
smaller than Earth's moon, and it apparently contains a liquid
water mantle and a thick icy crust. Because of the presence of
large amounts of liquid water, Europa has been considered a
possible abode of life. Since 7 December 1995, the Galileo
spacecraft has been orbiting Jupiter and transmitting data
concerning the Jovian moons, and initial results from the
spacecraft's *magnetometer have indicated that neither Europa nor
Callisto have an appreciable internal magnetic field, in contrast
to Ganymede and possibly Io. ... ... K.K. Khurana et al now
report perturbations of the external magnetic fields (associated
with Jupiter's inner *magnetosphere) in the vicinity of both
Europa and Callisto. The authors interpret these perturbations as
arising from induced magnetic fields generated by the moons in
response to the periodically varying *plasma environment. The
authors suggest that *electromagnetic induction requires *eddy
currents to flow within the moons, and that their calculations
indicate that the most probable explanation is that there are
layers of significant electrical conductivity just beneath the
surfaces of both moons. The authors propose that these conducting
layers may be best be explained by the presence of salty liquid-
water oceans, for which there is already indirect geological
evidence in the case of Europa.
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K.K. Khurana et al (7 authors at 3 installations, US)
Induced magnetic fields as evidence for subsurface oceans in
Europa and Callisto.
QY: K.K. Khurana
(Nature 22 Oct 98 395:777)
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Text Notes:
... ... *magnetometer: In general, any instrument used to measure
the strength and direction of a magnetic field.
... ... *magnetosphere: In general, a region surrounding a planet
in which charged particles are controlled by the magnetic field
of the planet rather than by the magnetic field of the Sun. The
charged particles originate in the *solar wind (or stellar wind,
if the planet is extrasolar), and they form a tenuous ionized gas
(*plasma) surrounding the planet.
... ... *plasma: In general, a fully ionized gas consisting of
ions and electrons moving freely.
... ... *solar wind: The solar wind is the steady flow of charged
particles, consisting primarily of protons and electrons, from
the solar corona into interplanetary space. The solar wind
particles have energies high enough so they can escape the Sun's
gravitational field, but the wind is influenced by the Sun's
magnetic field, and the particles can be trapped by planetary
magnetic fields.
... ... *electromagnetic induction: In general, this refers to
the production of an electromotive force either by motion of a
conductor through a magnetic field so as to cut across the
magnetic flux (magnetic "lines of force") or by a change in the
magnetic flux that threads a conductor.
... ... *eddy currents: (Foucault currents) In general, an eddy
current is an electrical current induced within the body of a
conductor when that conductor either moves through a nonuniform
magnetic field or is in a region where there is a change in
magnetic flux.
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Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
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Related Background:
MOUNTING EVIDENCE FOR A SUB-SURFACE OCEAN ON JUPITER'S EUROPA
Europa is the smallest of Jupiter's so-called Galilean
satellites, with a diameter of 3138 kilometers. It has a smooth
crust of water-ice, criss-crossed by a network of light and dark
linear markings. It has been thought that beneath the crust there
may be an ocean of water, and a variety of ice tectonics has been
proposed to be operating on the surface. The Galileo spacecraft
is a US National Aeronautics and Space Administration mission to
Jupiter launched in 1989. ... ... Now Carr et al (22 authors at
12 installations, US DE) report high-resolution (54 meters per
pixel) Galileo spacecraft images of Europa that provide evidence
for mobile "icebergs", the detailed morphology of the terrain
strongly supporting the presence of liquid water at shallow
depths below the surface either at present or at some time in the
past. In a contiguous report, Pappalardo et al (11 authors at 7
installations, US) report an analysis of certain surface features
of Europa also revealed by high-resolution images from the same
spacecraft, and conclude the features are surface manifestations
of localized relatively warm ice masses that have risen through
the subsurface, and are consistent with a subsurface liquid water
ocean. Results from 2 other contiguous reports are also
interpreted as consistent with the idea of a subsurface liquid
water ocean on Europa.
QY: Michael H. Carr ; R.T. Pappalardo
; Robert Sullivan
(Nature 22 Jan 98) (Science-Week 6 Feb 98)
-------------------
Related Background:
NEW DETERMINATIONS OF INTERNAL STRUCTURE OF JUPITER'S MOON EUROPA
Data from the December 19, 1996 Galileo spacecraft encounter
with the Jovian moon Europa have now been published, and the
consensus is that Europa has a water ice-liquid outer shell
about 100 to 200 kilometers thick. Gravitational effects on the
spacecraft are consistent with two models of Europa. In one the
core is a mixture of rock and metal, and in the other it is
purely metallic. Further data concerning Europa's intrinsic
magnetic field is needed to distinguish between the two models.
Reports were provided by J. D. Anderson et al (California
Institute of Technology, Pasadena CA US; University of
California Los Angeles, CA US) and M. G. Kivelson et al
(University of California Los Angeles, CA US; Imperial College of
London UK; California Institute of Technology, Pasadena CA US).
Science 23 May 97)
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Related Background:
POSSIBILITY OF A DEEP OCEAN ON JUPITER'S MOON EUROPA
Jupiter's satellite system consists of at least 16 moons, the
four largest of which are called the Galilean moons, since they
were discovered by Galileo. They are Io, Europa, Ganymede, and
Callisto, in order of their orbital distance from Jupiter.
Europa, which is slightly smaller than Earth's moon, has a thick
icy crust, and may also have a liquid water mantle beneath this
crust. Very few craters are present on Europa, which suggests an
active surface that renews itself and thus erases craters as fast
as they form from impacts. The surface also shows numerous lines
about 30 km wide and 1000 km long, and these have been
interpreted to be breaks in the crust where water from below has
refrozen. The possible existence of a liquid water mantle beneath
the ice on Europa is of great interest to planetary scientists,
since such a mantle might contain life forms. Until recently,
most planetary scientists apparently doubted any contemporary
existence of a liquid water mantle. But new analyses have been
appearing, and at the meeting last week of the Division for
Planetary Sciences of the American Astronomical Society in
Boston, a consensus appears to have formed that a water mantle
probably existed in the recent past, and may even exist today. In
December, the Galileo spacecraft, as part of its extended
mission, will take an even closer look at Europa, with the resol-
ution of its best images expected to improve from 70 meters to 10
meters, and planetary scientists are hopeful the question of the
state of water on Europa will be answered. (Science 8 Aug 97)
3. PARTICLE PHYSICS: AN EXCHANGE CONCERNING RELEVANCE
In general, "reductionism" is the idea that macroscopic
phenomena can be explained in terms of microscopic entities
and/or events, but the specific meaning of the term depends upon
context and the conceptual identification within a particular
science of levels of understanding. In biology in general, for
example, "reductionism" is the term applied to attempts to
explain biological phenomena in the language of physics and
chemistry. In neurobiology, the term "reductionism" may be
applied to attempts to explain human cognitive behavior in terms
of the behavior of nerve cells and their connections. In
evolutionary biology, the term "reductionism" may be applied to
attempts to explain the dynamics of evolution in terms of
molecular genetics. In physics and chemistry, the term
"reductionism" may be applied to attempts to explain the
macroscopic behavior of physical or chemical systems in terms of
events at the level of atomic phenomena. Also in physics, the
term "reductionism" may be applied to attempts to explain both
the macroscopic behavior of a physical system and/or the
microscopic atomic behavior of the entities of the system in
terms of events at the still more microscopic level of
fundamental particles and fundamental forces.
The various sciences are split by scientists (not by nature)
into various levels of explanation, with researchers working at
the various levels using various techniques and concepts.
Ordinarily, in the practice of science, the working scientist
does not spend much time cogitating about whether a general
reductionist approach is useful or not useful, philosophically
valid or not valid, or whatever. The attitude essentially is that
here is a house, I choose to study in detail the nature of the
bricks, you choose to study in detail the nature of the
construction of the house, I enjoy what I'm doing, you enjoy what
you're doing, and each of us is making some contribution to a
general understanding of the nature of the entity "house". This
division of labor has been quite fruitful in science, and there
is never much of a problem concerning the existence of various
levels of investigation until the person who studies bricks says
that what he or she is doing is more important than what the
person who studies the construction of the house does, or when
the person studying the construction of the house says it is the
study of the construction of the house that is more important
than the study of bricks. From the standpoint of "nature", from
the perspective of the giant star *Betelguese, for example, a
relatively nearby stupendous and violent supergiant star
apparently 400 to 500 times the diameter of our Sun, any serious
bickering on the planet Earth about the relative merits of
various levels of understanding in science begins to smack of
farce. But science is a human enterprise, and occasionally the
bickering about reductionism and levels of understanding does get
serious and does occupy attention.
In 1996, in a most prestigious physics journal (*Reviews of
Modern Physics*), the physicist Robert Cahn stated that particle
physics is essential to the understanding of our everyday world,
that "particle physicists construct accelerators kilometers in
circumference and detectors the size of basketball pavilions not
ultimately to find the *t-quark or the *Higgs boson, but because
that is the only way to learn why our everyday world is the way
it is... Given the masses of the quarks and *leptons, and nine
other closely related quantities, [the current theory of particle
interaction] can account in principle for all the phenomena in
our daily lives."
In July 1998, in the journal *Physics Today*, Pablo Jensen,
a condensed matter physicist, took issue with Cahn's views and
suggested that Cahn's "reductionist vision seems to be shared by
many other particle physicists." Stating that he wished to
"reopen a debate in the physics community," Jensen made the
following points: 1) The reductionist ideas of Cahn and other
reductionist particle physicists are wrong: even if we knew all
the "fundamental" laws, we could not say anything useful about
our everyday world. Our everyday world is irremediably
macroscopic, and macroscopic concepts are needed to understand
it. 2) Contrary to the pretensions of particle physicists,
science is organized in decoupled layers, each with its own
elementary entities or concepts, which generally are not simply
derived from those of the lower level but constructed in creative
efforts... Particle physics is practically irrelevant to
understanding our everyday world... "If we learned tomorrow that
previous results and analysis had overlooked certain systematic
errors, and that the t-quark mass is near 195 *GeV and not 175
GeV, it is particle physics that would have to adjust to remain
in agreement with the rest of physics, and not vice versa." 3)
Considering, for example, the property of *chirality of large
molecules (e.g., a sugar or any biological molecule), for all
practical purposes, such molecules do not show the symmetry
expected from the fundamental laws -- in this case, quantum
mechanics. 4) In the study of phase transitions, there are
characteristics of such transitions that apparently depend on the
collective behavior of the system and are not determined by the
microscopic interactions. 5) Each level of complexity must be
studied with its own instruments, and requires the invention of
new concepts adapted to describe and understand its behavior...
Intermediate concepts such as *entropy, *dissipative structures,
cells, genes, etc., cannot be simply "deduced" from the
fundamental laws: such concepts are said to be "emergent" because
they arise at high levels of complexity and must be invented at
those levels to deal with specific situations... These emergent
concepts are as real and as fundamental as the concepts and
particles introduced by particle physicists. The author
concludes: "By all means let us each study our chosen "layer" of
reality, whether it involves quarks or convective cells. But let
us also remember that each layer is just one part of the greater
whole. Accounting for all the phenomena in our daily lives *in
principle* is entirely different from accounting for them in
actuality."
In the November 1998 issue of *Physics Today*, Robert Cahn
presents a rebuttal to the critique of Pablo Jensen, the author
making the following points: 1) The empirical parameters of the
*Standard Model of particle physics shape the most familiar
aspects of our physical surroundings... Given *these parameters,
the Standard Model, which subsumes the Maxwell and Schroedinger
equations, determines all the fundamental processes of
*electroweak and strong interactions. Changes in the basic
parameters would produce worlds quite different from our own. 2)
The stuff of daily life is made just of electrons and the
lightest quarks. However, we cannot understand these particles by
themselves, because they are intimately connected to others
accessible only in high energy collisions. 3) Concerning the
supposed irrelevance of particle physics, constructs that embody
the essential physical features of complex systems are
indispensable, but their success is not a reason for abandoning
the search for basic physical laws. 4) Nature is not neatly
partitioned into autonomous layers, as Jensen suggests. On the
contrary, the macroscopic makes manifest the microscopic... The
gross properties of the materials around us, their color,
conductivity, and strength, reflect the details of their quantum
mechanical states. Likewise the structure of atoms reflects
divisions in the subatomic world... "Only by willfully closing
our eyes can we miss the connection between the fundamental
interactions and their manifestations that surround us." The
author concludes: "We particle physicists share with all
physicists the goal of explaining the world. We differ by asking
ever more basic questions. Like young children who relentlessly
insist, Why?, particle physicists ask, Why is there light? Why
are electrons light and protons heavy? Why are there electrons or
protons, anyway? 'Just because' and 'Who cares?' will not
satisfy
the curious child, nor should they satisfy us."
The same issue of the journal includes a number of letters
on the subject from other physicists, and in one of these letters
Paul Roman suggests that perhaps the motivation for the debate is
that the physics research "grant pie is shrinking while the
number of pie-hungry individuals is still increasing." Perhaps
that is so, and perhaps that is also the motivation behind
debates concerning the reductionist approach in other sciences.
But perhaps such motivations are also part of science as a human
enterprise. Meanwhile, the enormous furnace of Betelguese
continues to roar.
-----------
R.N. Cahn (Lawrence Berkeley Natl. Lab., US)
(Rev. Mod. Phys. 1996 68:951)
QY: Robert N. Cahn, Lawrence Berkeley National Laboratory,
Berkeley, CA US
----------
P. Jensen (Claude Bernard University, FR)
Particle physics and our everyday world.
(Physics Today July 1998)
QY: Pablo Jensen, Claude Bernard University, Villeurbanne FR)
----------
R.N. Cahn (Lawrence Berkeley Natl. Lab., US)
"Particle physics and our everyday world": A reply
(Physics Today November 1998)
QY: Robert N. Cahn, Lawrence Berkeley National Laboratory,
Berkeley, CA US
-----------
Text Notes:
... ... *Betelguese: Also known as Alpha Orionis. It is the 10th
brightest star in the sky, with a luminosity 5000 times that of
the Sun, with an estimated distance of 400 light years. Some
astronomers believe its distance is 1400 light years, which would
make its luminosity 50,000 times that of the Sun. The star is a
variable, its size swelling and contracting with a period of
several years.
... ... *t-quark: (top-quark) A quark is a hypothetical
fundamental particle, having charges whose magnitudes are
one-third or two-thirds of the electron charge, and from which
the elementary particles may in theory be constructed. A t-quark
is one of the types of quarks and has an electrical charge of
+2/3.
... ... *Higgs boson: Higgs fields (named after Peter W. Higgs,
University of Edinburgh, UK) constitute a set of fundamental
theoretical fields that induce spontaneous symmetry breaking. In
general, spontaneous symmetry breaking occurs in systems whose
underlying symmetry state is unstable. A Higgs particle is
associated with a Higgs field in the same way that a photon is
associated with the electromagnetic field. Higgs bosons are
massive mesons whose existence is predicted by certain theories.
Mesons are apparently composed of quark and anti-quark pairs;
they are produced by various high-energy interactions and decay
into stable particles.
... ... *leptons: Leptons are a class of point-like fundamental
particles showing no internal structure and no involvement with
the strong forces. There are 6 leptons: the electron, the muon,
the massive tau lepton, and a specific neutrino associated with
each of the former (3 neutrino "flavors").
... ... *GeV: (Gev) Also written as Bev, a billion electronvolts.
An electronvolt is defined as the energy acquired by an electron
falling freely through a potential difference of one volt, and is
equal to 1.6022 x 10^(-19) joule.
... ... *chirality: In chemistry, chirality is a property of
certain asymmetric molecules, the property being that the mirror
images of the molecules cannot be superimposed one on the other
while facing in the same direction.
... ... *entropy: A measure of disorder in a system.
... ... *dissipative structures: In general, a dissipative system
is a system that loses energy by conversion of energy into heat.
... ... *Standard Model: In particle physics, the *Standard
Model is a theoretical framework whose basic idea is that all the
visible matter in the universe can be described in terms of the
elementary particles leptons and quarks and the forces acting
between them.
... ... *these parameters: The parameters referred to here are
the masses of the quarks, the masses of the charged leptons, the
strength of 3 forces, 4 numbers that describe the weak
transformations of one quark type into another, the mass of the
*W boson, and the mass of the Higgs boson.
... ... *W boson: Very massive charged particles (+ or -) that
convey part of the weak force between leptons and *hadrons. Bose-
Einstein statistics is the statistical mechanics of a system of
indistinguishable particles for which there is no restriction on
the number of particles that may simultaneously exist in the same
quantum energy state. Bosons are particles that obey Bose-
Einstein statistics, and they include photons, *pi mesons, all
nuclei having an even number of particles, and all particles with
integer *spin.
... ... *pi mesons: (pions) Pi mesons are subatomic particles
with masses approximately 270 times the mass of the electron.
... ... *spin: In quantum mechanics, "spin" is the intrinsic
angular momentum of a subatomic particle.
... ... *hadrons: Hadrons are particles with internal structure,
e.g., neutrons and protons.
... ... *electroweak and strong interactions: The fundamental
forces comprise the gravitational force, the electromagnetic
force, the nuclear strong force, and the nuclear weak force. The
electroweak interactions comprise the electromagnetic and nuclear
weak interactions, the latter involved in radioactive decay
processes.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
4. ON WATER AND THE STRUCTURES OF BIOLOGICAL MOLECULES
A prominent consideration in the minds of biologists who work at
the level of cells and molecules is that water is the most
prevalent chemical substance in all biological systems, and that
interactions of water with other biological molecules,
particularly with biological macromolecules, are not clearly
understood but are probably of considerable significance.
... ... M. Gerstein and M. Levitt present a review of some
aspects of the physical chemistry of water and an account of
their own computer simulations of biological macromolecules in
aqueous solutions. The authors make the following points: 1) At
the present time it is possible to model proteins and their
associated water molecules on a desktop computer in a few days.
Researchers have now simulated the aqueous structures of more
than 50 proteins and nucleic acids. 2) A single water molecule
has an essentially tetrahedral geometry, with an oxygen atom at
the center of the tetrahedron, hydrogen atoms at 2 of the 4
corners, and clouds of negative charges at the other 2 corners.
Reflecting the tetrahedral geometry of water, each molecule in
liquid water often forms 4 hydrogen bonds: 2 hydrogen bonds
between its hydrogens and the oxygen atoms of 2 other water
molecules, and 2 hydrogen bonds between its oxygen atom and the
hydrogens of other water molecules. The necessity of maintaining
a tetrahedral hydrogen-bonded structure gives water an "open"
loosely packed structure compared with that of most other liquids
[*Note #1]. 3) Present computer simulations are able to reproduce
quantitatively many of the bulk properties of water, such as its
average structure, rate of diffusion, and *heat of vaporization.
4) Biological molecules such as proteins and DNA contain both
hydrophilic and hydrophobic parts arranged in long chains. The 3-
dimensional structures of these molecules are determined by the
way these chains fold into more compact arrangements in which
hydrophilic groups are on the surface where they can interact
with water and hydrophobic groups are buried in the interior away
from water. These local macromolecule solubility considerations
were formulated in 1959 by Walter Kauzman as a "hydrophobic
effect" crucial for protein folding. 4) There are 3 types of
water molecules that must be considered in a computer model of a
biological molecule in aqueous solution: a) the ordered water
surrounding and strongly interacting with the macromolecule; b)
the bulk water beyond the ordered water; and, c) any water
molecules that may be buried within the macromolecule. 5)
Computer simulations of DNA in water have revealed that water
molecules are able to interact with nearly every part of the
double helix of DNA, including the nucleotide base pairs that
constitute the genetic code. In contrast, water is not able to
penetrate deeply into the structure of proteins, whose
hydrophobic regions are arranged on the inside into a close-
fitting core [*Note #2].
-----------
M. Gerstein and M. Levitt (2 installations, US)
Simulating water and the molecules of life.
(Scientific American November 1998)
QY: Mark Gerstein, Yale University, 203-432-4771.
-----------
Text Notes:
... ... *Note #1: In hydrated crystal structures, water molecules
generally donate two hydrogen bonds but may accept either one or
two. When water molecules are 3-coordinated (rather than 4-
coordinated as discussed by the authors in their review), the
geometry can be planar or pyramidal. But examples are known of
coordination as low as 2 and as large as 7.
... ... *heat of vaporization: The quantity of energy required to
evaporate 1 mole (or a unit mass) of a liquid at constant
pressure and temperature.
... ... *Note #2: Concerning the interaction of water molecules
with biological molecules, water molecules hydrogen-bonded to the
functional groups of biological molecules are apparently linked
in chains into extended networks, and some researchers have
suggested the *polarizability of these networks provides a
mechanism for long-range recognition between biological molecules
in aqueous solution.
... ... *polarizability: The electric dipole moment induced in a
system (such as an atom or molecule) by an electric field of unit
strength.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
5. EVIDENCE THAT RNA FOLDING CAUSES SECONDARY STRUCTURE CHANGES
Biological macromolecules such as proteins and nucleic acids
assume specific higher-order configurations (tertiary structures)
that are prerequisites for their function. The standard RNA
(ribonucleic acid) folding mechanism is believed to be a 2-step
process, the RNA first folding from a primary (simple linear
polymer) into a secondary structure (e.g., a helix), which then
folds into a 3-dimensional tertiary structure stabilized by
interactions between the preformed secondary structural motifs.
Divalent metal ions bound at a few specific locations appear to
be crucial for the tertiary folding. RNA secondary structures can
be deduced by various methods, but NMR spectroscopy and x-ray
diffraction are currently the major tools for high-resolution
structure determination of RNA. ... ... M. Wu and I. Tinoco, Jr.
now report a study of secondary and tertiary structure of a
domain of a *ribozyme by nuclear magnetic resonance (NMR).
Nucleotide base pairing in aqueous solution in the absence of
magnesium ions is significantly different from the RNA in a
crystal but is consistent with thermodynamic predictions. The
authors report that on addition of magnesium ions, the RNA folds
into a tertiary structure with greatly changed base pairing
consistent with the crystal structure. The authors suggest that
the common assumption that RNA folds by first forming secondary
structure and then forming tertiary interactions from the
unpaired bases is not always correct. ... ... In a short
commentary on the Wu and Tinoco paper, D. Thirumalai points out
the following: 1) The discovery of catalytic activity in RNA
(i.e., by ribozymes) has prompted serious attempts to decipher
the mechanisms of their assembly into functional *native states
starting from linear strands. 2) Implicit in all of the proposed
folding mechanisms is the assumption that there are 2 major
structural changes in RNA en route to the native state, starting
from an ensemble of unfolded molecules. It is proposed that
stable secondary structures form rapidly, perhaps on microsecond
time scales. The subsequent assembly leading to tertiary folding
takes place by bringing the secondary structural elements
together. 3) The evidence for the 2-step process (reminiscent of
framework-like models in protein folding), namely, fast secondary
structure formation followed by slower acquisition of tertiary
interactions, came from folding studies of *tRNA. Wu and Tinoco
now show that this commonly held picture of RNA assembly may not
always be correct.
-----------
M. Wu and I. Tinoco, Jr. (2 installations, US)
RNA folding causes secondary structure rearrangement.
(Proc. Natl. Acad. Sci. US 29 Sep 98 95:11555)
QY: Ignacio Tinoco, Jr.
-----------
D. Thirumalai (University of Maryland, US)
Native secondary structure formation in RNA may be a slave to
tertiary folding.
(Proc. Natl. Acad. Sci. US 29 Sep 98 95:11506)
QY: D. Thirumalai, University of Maryland 301-405-1000
-----------
Text Notes:
... ... *ribozyme: First discovered in 1981, ribozymes (not to be
confused with riboSOMES) are a small group of RNA molecules that
act as enzymes. They are found in the ciliate protozoan
Tetrahymena, and they are intriguing because they defy the usual
rule that enzymes are proteins.
... ... *native states: The "native" state or configuration of a
biological macromolecule is the functional state or configuration
ordinarily assumed by the molecule in the biological system in
which the molecule occurs.
... ... *tRNA: (transfer RNA) Transfer RNA is a class of small
RNA molecules that transfer individual amino acids to the locus
producing a growing polypeptide chain during protein synthesis.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
-------------------
Related Background:
MAGNESIUM ION CORE DETERMINES AN RNA FOLDING ARCHITECTURE
... In general, much more is known about the final folding
architecture of proteins than about the final folding architect-
ure of molecules like RNA. Final folding architecture in proteins
is important because a specific architecture is essential for
enzymatic activity. Now here are ribozymes, which are not
proteins, but which also have high-level folding and which are
also enzymes. This month Jamie H. Cate et al (Yale University,
US) report that the x-ray crystal structure of a major domain of
a large ribozyme (the Tetrahymena group I intron P4-P6) reveals
the molecule folds around a core of magnesium ions. At the center
of the domain, five magnesium ions are bound at a junction where
three RNA helices join, and single-atom changes in any four of
the five sites destroys the folding pattern of the entire domain.
So the ribozyme final folding architecture, like that of many
enzymatic proteins, depends on a metal cofactor. If one puts
together this information with that of the previous report on
metallo-enzymes, one gets a glimmer that the future rational
design of biological macromolecular configurations will not be
limited to proteins.
(Nature Structural Biology 1997 4:553)
(Science-Week 10 Jul 97)
6. NEUROBIOLOGY: TARGET CELL MODULATION OF TRANSMITTER RELEASE
Neurons in the mammalian central nervous system exhibit various
categories of diverging connections toward other neurons
("targets") belonging to distinct functional groups, with
divergent connections ("projections") of a single neuron
involving branching of the *axon of that neuron. For example, the
*Purkinje cells of the *cerebellum project to only a few other
cerebellar neurons; in contrast, in the mammalian brain region
called the *hippocampus, *CA3 pyramidal neurons each project to
tens of thousands of other nerve cells. In general, divergent
connectivity can be viewed as a potent means to coordinate the
behavior of neuronal populations in space and time, but there may
be other functional consequences. An important question in this
context is whether all *terminals of an axon have the same
properties, and during the past few decades it has become
apparent that this may not be so. There is evidence in
invertebrate nervous systems that indicates that presynaptic
terminals belonging to the same axon can exhibit different
properties of *neurotransmitter release, and that correlations
exist between the properties of the presynaptic terminal and the
type of target it impinges upon, suggesting that presynaptic
properties may be controlled by the target cell via a
postsynaptic to presynaptic ("retrograde") signal. There is also
some evidence that suggests that target cell specificity of
neurotransmitter release also occurs in the mammalian central
nervous system. ... ... M. Scanziani et al now report a study of
CA3 pyramidal cell neurons in *tissue slices from the hippocampus
of the rat. The authors report that with sequential paired
recordings from 3 connected cells, their observations indicate
that the presynaptic properties of CA3 pyramidal cell terminals
belonging to the same axon differ according to the type of target
cell. Furthermore, terminals contacting distinct target cells
show differing *facilitation frequencies. On the basis of their
results, the authors suggest that the pharmacological and
physiological properties of presynaptic terminals are determined,
at least in part, by target cells.
-----------
M. Scanziani et al (2 installations, FR CH)
Target cell-specific modulation of transmitter release at
terminals from a single axon.
(Proc. Natl. Acad. Sci. US 29 Sep 98 95:12004)
QY: Massimo S. Scanziani
-----------
Text Notes:
... ... *axon: In general, nerve cells have a single long
extension (the "axon") that propagates the electrical output (the
action potential) of the cell. In some types of nerve cells,
axons are extensively branched into a multitude of fine fibers
that make contact (synapses) with other nerve cells. The general
input extensions of nerve cells are called "dendrites", and they
may also be extensively branched. In general, dendrites are
considered to receive input and axons to propagate output, but
the electrical architecture of most neurons is complicated, and
in many types of nerve cells activation of the axon produces
electrical activity that not only propagates down the axon but
also propagates backward through the cell body and dendrites.
Action potentials are classically considered to occur only in
axons, but in some types of nerve cells, dendrites conduct action
potentials from a distal location to the cell body, and when the
axon fires, there is a back propagation of the action potential
along the dendrites. In addition to these complications, there
are also species differences in both the morphology and dynamics
of nerve cells, so that the delineation of "canonical" types of
nerve cells is usually difficult. Our views of relations between
morphology and dynamics in nerve cells have significantly changed
in the past few decades, and the electrical behavior of nerve
cells now appears to be considerably more complex than previously
believed. In summary, it is true that dendrites are concerned
with information input and axons are concerned with information
output, but that is only the beginning of the story of nerve
cells.
... ... *Purkinje cells: Large neurons of the cortex of the
cerebellum.
... ... *cerebellum: A large neural structure at the base of the
brain involved in motor coordination, posture, and balance.
... ... *hippocampus: A brain cortex structure in the medial part
of the temporal lobe. In humans, among other functions, the
hippocampus is apparently involved in short-term memory. Analysis
of the neurological correlates of learning behavior in the rat
indicates that the hippocampus is also involved in memory in that
species.
... ... *CA3 pyramidal neurons: CA3 is an anatomical region of
the hippocampus. Pyramidal neurons are the principal nerve cells
of the neocortex, olfactory cortex, and the cortex of the
hippocampus. The term "neocortex" refers to phylogenetically new
cerebral cortex.
... ... *terminals: The junction between the terminal of a
neuron's axon and another neuron is called a "synapse". When
studying the synapse, the first neuron is called the
"presynaptic" neuron, and the second neuron is called the
"postsynaptic" neuron.
... ... *neurotransmitter release: Neurotransmitters are chemical
substances released at the terminals of nerve axons in response
to the propagation of an impulse to the end of that axon. The
neurotransmitter substance diffuses into the synapse, the
junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell.
... ... *tissue slices: Tissue slices of brain cortex of less
than 1 millimeter thickness can sustain neural activity in vitro
in an appropriate medium. (The tissue slices in this report were
0.4 millimeters in thickness.) The basis of the viability of the
nerve cells is that in a thin tissue slice, and without vascular
input, the oxygen needs of the cells can be satisfied by free
diffusion of oxygen from the ambient solution. Electrical
recording of the activity of individual neurons can be made
without difficulty in such a preparation.
... ... *facilitation frequencies: In general, the term
"facilitation" refers to an increased neurotransmitter release
produced by an action potential that follows closely after a
preceding action potential. In this context, the term
"frequencies" refers to the interval between inputs.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 13Nov98
-------------------
Related Background:
RELEASE OF TWO DIFFERENT TRANSMITTERS BY THE SAME NEURON
*Synaptic transmission in the central nervous system is mediated
by the release of *neurotransmitters into the *synaptic cleft and
the subsequent activation of *postsynaptic receptors. It is
widely accepted that individual neurons in the central nervous
system release only a single *fast transmitter. A single
neurotransmitter can coactivate multiple *ionotropic and
*metabotropic receptor types, and a fast neurotransmitter can be
coreleased with *neuropeptides. In the spinal cord and brainstem,
both glycine and gamma-amino-butyric acid (GABA) mediate
*inhibitory synaptic transmission. It is not known, however,
whether glycine and GABA are released from separate or
overlapping populations of *interneurons. ... ... Jonas et al (3
authors at University of Freiburg, DE) now report a study of the
possible corelease of fast neurotransmitters from synaptically
connected neurons in spinal cord slices. The authors report that
unitary inhibitory postsynaptic electric currents generated at
interneuron-motorneuron synapses consist of a *strychnine-
sensitive glycine-receptor-mediated component, and a
*bicuculline-sensitive GABA-receptor mediated component. The
authors suggest their results indicate that spinal interneurons
release both glycine and GABA to activate functionally distinct
receptors in their postsynaptic target cells. They also report
that a subset of *miniature synaptic currents also showed both
components, consistent with corelease from individual synaptic
vesicles. The authors further suggest that glycine- and GABA-
mediated cotransmission could, among other possibilities, support
the precise regulation of the time course of postsynaptic
conductance by the relative amount of glycine and GABA released
from the presynaptic interneuron, and that this could be of
critical importance for motor coordination and the generation of
locomotor patterns.
QY: Peter Jonas
(Science 17 Jul 98 281:419) (Science-Week 7 Aug 98)
-------------------
Related Background:
... ... *Synaptic transmission: This is a general term referring
to the events mediating the membrane-to-membrane interaction
between a neuron and another neuron, or a neuron and a muscle or
gland cell, or a neuron and a sensory receptor cell. The input
cell is called "presynaptic" and the output cell is called
"postsynaptic", with the junction called the "synapse".
... ... *neurotransmitters: Neurotransmitters are chemical
substances released at the terminals of nerve axons in response
to the propagation of an impulse to the end of that axon. The
neurotransmitter substance diffuses into the synapse, the
junction between the presynaptic nerve ending and the
postsynaptic neuron, and at the membrane of the postsynaptic
neuron the transmitter substance interacts with a receptor.
Depending on the type of receptor, the result may be an
excitatory or an inhibitory effect on the postsynaptic nerve
cell. At present acetylcholine, 5 amines, 4 amino acids, 2
purines, and more than 28 peptides are known to be
neurotransmitters.
... ... *synaptic cleft: The space approximately 20 nanometers
wide between the presynaptic membrane and the postsynaptic
membrane. It is into this space that transmitter substances are
released by the presynaptic cell.
... ... *postsynaptic receptors: Postsynaptic membrane entities
for which neurotransmitters are the ligands.
... ... *fast transmitter: Fast neurotransmitters are
neurotransmitters that produce short-lived (on the order of
several milliseconds or less) electrical changes in the
postsynaptic membrane. In contrast, the electrical changes
produced by slow neurotransmitters are of the order of hundreds
of milliseconds.
... ... *ionotropic: Receptors whose activation by
specific ligands alters various ion permeabilities that control
the electrical activity of the nerve cell.
... ... *metabotropic receptors: Receptors whose activation by
specific ligands alters the metabolism of the nerve cell (which,
among other things, may have long-term effects on ion
permeabilities).
... ... *neuropeptides: A relatively large class of transmitter
substances, some of which (e.g., endorphins) are apparently
involved in the translation of emotions into bodily events, and
are suspected of an involvement in various neuropsychiatric
diseases.
... ... *inhibitory synaptic transmission: The electrical
dynamics at the synapse are such that if a neurotransmitter
produces an increase in the polarization of the postsynaptic
membrane (hyperpolarization), the result is an inhibiting
component as far as any subsequent production of a postsynaptic
action potential is concerned. In the classic paradigm, a neuron
receives a variety of inputs from other neurons, some of which
are inhibitory and some of which are excitatory, and it is the
total effect of these multiple inputs that conditions the output
of propagated action potentials.
... ... *interneurons: Combinations or groups of neurons between
sensory and motorneurons that govern coordinated activity. Some
interneurons are inhibitory, involved in local feedback circuits
that may be simple or elaborate.
... ... *strychnine: A central nervous system stimulant that
blocks the inhibitory action of glycine at several postsynaptic
receptors in several central nervous system locations,
particularly in the spinal cord.
... ... *bicuculline: An alkaloid naturally occurring in several
plant species, it is a powerful convulsant that acts by
antagonizing the inhibitory neurotransmitter GABA.
... ... *miniature synaptic currents: These are electric currents
produced by changes in the postsynaptic membrane resulting from
the release of neurotransmitter from a single *synaptic vesicle.
... ... *synaptic vesicle: *Synaptic vesicles are the packets of
neurotransmitter substance formed in the presynaptic axon
terminals, and when transmitter substances are released, they are
released as packets, the vesicle membrane dissolving in the
synaptic cleft to release the transmitter molecules.
7. BIOLOGY OF CANCER: ON SQUAMOUS CELL CARCINOMA
Epithelial tissue (also called epithelium) forms the outer layer
of the skin and the outer layers of some internal organs, the
inner lining of blood vessels, ducts, body cavities, and the
interiors of the respiratory, digestive, urinary, and
reproductive systems. 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. One of the most common forms
of skin cancer is squamous cell carcinoma. These cells usually
arise from preexisting lesions on sun-exposed skin, and they have
a variable tendency to metastasize. Approximately 90 percent of
the cells in the skin are keratinocytes, cells that produce the
protein keratin, which helps waterproof and protect the skin and
underlying tissues. ... ... N.M. Wikonkal and D.E. Brash present
a review of the cellular biology of squamous cell carcinoma, and
the authors make the following points: 1) Ultraviolet light
absorbed by DNA molecules in keratinocytes is the inciting cause
of squamous cell carcinoma of the skin. 2) Failure of DNA repair
enzymes to correct the UV-induced damage can lead to mutations
when cells divide. Particular mutations in the *tumor suppressor
gene p53 are characteristic of UV damage and are commonly found
in squamous cell carcinoma. 3) If mutations result in defective
p53 protein, the functions of this protein in *cell cycle control
and facilitation of *apoptosis will be absent, and this allows
*clonal expansion and eventual cancer. 4) A remarkable feature of
this type of cancer is that tumors closely resembling the human
clinical entity can be generated in the laboratory in mice,
allowing experiments that are not possible in humans. The
visibility and accessibility of squamous cell carcinoma of the
skin have made this tumor one of the best understood human
malignancies.
-----------
N.M. Wikonkal and D.E. Brash (Yale University, US)
Squamous Cell Carcinoma
(Science & Medicine Sep/Oct 1998)
QY: Norbert M. Wikonkal, Yale University, 203-432-4771.
-----------
Text Notes:
... ... *tumor suppressor gene: Tumor suppressor genes code for
proteins that apparently either prevent cell division or provoke
cell death in defective cells.
... ... *cell cycle control: In this context, the term "cell
cycle" refers to the entire life history of a single cell from
mitosis to mitosis, including the sequence of intervening phases.
... ... *apoptosis: In general, the term "apoptosis" refers to
programmed cell death, whether as a part of normal tissue
differentiation and development, or as a program activated in a
defective cell. In the molecular biology of cancer, apoptosis is
the name given to the programmed cell death provoked by the
proteins expressed by tumor suppressor genes. Thus, malignant
cells are defective cells with a deactivated apoptosis program,
and this allows malignant cells to survive and replicate.
... ... *clonal expansion: This refers to the expansion of a
population of cells all derived from repeated replications of
progeny of a single cell.
-------------------
Related Background:
MECHANISMS OF TUMOR SUPPRESSOR GENES
Cancer is fundamentally a genetic disease in which damage to
cellular DNA leads to disruption of the normal mechanisms that
control cellular proliferation. ... ... Ellisen and Haber (2
installations, US) review current knowledge concerning the genes
targeted in human cancer, and they make the following points: 1)
In general, cancer genes have been divided into 2 classes, proto-
oncogenes and tumor suppressor genes. 2) Proto-oncogenes are
genes that sustain activating changes in human cancer. These
changes may take the form of point mutations or gene
rearrangements that lead to increased or uncontrolled activity of
the encoded protein, or they make take the form of gene
amplification, which results in increased levels of protein
expression. 3) Tumor suppressor genes are characterized by
inactivating changes in human cancer, typically point mutations
that result in truncation or functional inactivation of the
encoded protein, or gross deletions of chromosomal fragments
carrying these genes. 4) Tumor suppressor genes are of particular
interest in cancer genetics because they are the genes most
commonly associated with hereditary predisposition to cancer. In
cases where familial cancer is linked to inheritance of a mutant
allele of a tumor suppressor gene, inactivation of the remaining
wild-type allele of that gene constitutes the critical genetic
event that initiates the development of cancer. 5) Although much
attention has focused on the initial tumor suppressor gene
mutation that initiates malignant transformation, cancer actually
results from the accumulation of a large number of genetic
events, both in tumor suppressor genes and in proto-oncogenes.
The authors tabulate 14 selected different tumor suppressor
genes, indicating the related familial syndrome, the types of
sporadic tumors containing mutations of these genes, and the
presumed normal function (mechanism of action) of these genes.
Mutations of the tumor suppressor gene p53 have been found in
approximately 50 percent of all cancers. The authors conclude:
"As the understanding of genetic heterogeneity evolves,
population studies are likely to uncover the contribution of
common subtle genetic variations to the risk of developing
different types of cancer. Together with societal and ethical
guidelines on the use of such genetic information, the study of
mutations in tumor suppressor genes and of their role in cancer
predisposition may provide important clues to the clinical
management of human cancer."
QY: Leif W. Ellisen, Dana-Farber Cancer Institute, Boston, MA US.
(Science & Medicine Jul/Aug 1998) (Science-Week 17 Jul 98)
-------------------
Related Background:
MECHANISM OF ACTION OF TUMOR SUPPRESSOR PROTEIN P53
Tumor suppressor genes apparently code for proteins that either
prevent cell division or provoke cell death, and since the
molecular mechanisms involved in these events are of great
importance in current efforts in cancer research, all the
elements in the sequences are of significance. Apoptosis is the
name given to the programmed cell death provoked by the proteins
expressed by tumor suppressor genes. Kornelia Polyak et al (Johns
Hopkins University, US) have investigated the genes whose
transcription is activated by protein p53, perhaps the most
important tumor suppressor protein, and they present a model for
the mechanism of apoptosis produced by this protein. The model
involves the transcriptional induction of redox related genes,
the formation of reactive oxygen species, and finally the
oxidative degradation of mitochondrial components, this sequence
then culminating in the death of the cell. [*Note #1].
QY: Kenneth W. Kinzler, Johns Hopkins Oncology Center, 424 N.
Bond St., Baltimore MD 21241 US.
(Nature 18 Sep 97) (Science-Week 3 Oct 97)
... ... *Note #1: A "redox" reaction is a chemical reaction
involving the simultaneous reduction and oxidation of two
compounds by a transfer of electrons between them. In biological
systems, the electrons involved in redox reactions are usually
those of hydrogen and oxygen. Loss of electrons is called
"oxidation"; gain of electrons is called "reduction". In general,
indiscriminate catalysis of redox reactions will corrupt
biological macromolecules and rapidly degrade biological systems.
The term "apoptosis" was initially used to described programmed
cell death as manifested with particular changes in cell
morphology: shrinkage of cytoplasm, membrane "blebbing"
(formation of blisters), chromatin condensation, and specific
changes in DNA superstructures. Recently, however, the term
"apoptosis" is being used to refer to programmed cell death of
all types. Since cell death and cell proliferation are under
genetic control, precisely balanced in each organ system to
maintain the proper number and types of cells, any disruption of
this balance can produce disease. Identifying the genes and
proteins involved in this balance, and the mechanisms that follow
protein expression, is an important research objective.
-------------------
Related Background:
DISCOVERY OF A POSSIBLE NEW TUMOR SUPPRESSOR GENE
Tumor suppressor genes are genes whose absence or loss of funct-
ion can cause a cell to become malignant. The normal function of
such genes is to restrain cell division and/or cause cell death,
and to thus retard cell proliferation. The most important of
these genes is perhaps the gene called p53, a tumor suppressor
gene whose protein product p53 is inactivated or deleted in
approximately half of all human malignancies. (Note: genes and
the proteins they express are often given the same name, except
the name of the gene is italicized. We use the brackets <> as a
substitute for italics.) The apparent function of the p53 protein
is to check the cell for DNA damage, and if such damage is
found,
to either prevent cell division or provoke apoptosis (programmed
cell death). A gene similar to p53 has been identified, called
p73, its expressed protein, p73, having significant structural
similarities to p53, and now Christine A. Jost et al (Harvard
University, US) have examined the function of p73 in cultured
cells, and they have found that at least when overproduced, p73
can act in a similar manner to p53, blocking cell division and/or
causing apoptosis. What cell types normally produce p73, and
whether inactivation of p73 plays a role in human cell cancer,
remains to be determined. The authors suggest there may be
additional p53 homologs yet to be identified. [*Note #1]
QY: W. G. Kaelin Jr., Harvard Medical School (617) 432-3307.
(Nature 11 Sep 97) (Science-Week 23 Sep 97)
-----------
Text Notes:
... ... *Note #1: The first tumor suppressor gene to be
identified was the gene involved in hereditary retinoblastoma, a
rare type of eye cancer that occurs in young children. These
children inherit a chromosomal deletion in a specific region of
one copy of chromosome 13. The deletion occurs in all cells, but
only a few cells in the retina actually become malignant, the
emergence of cancer requiring a subsequent mutation in the second
copy of chromosome 13. In other words, both alleles of the gene
must be eliminated. Since both alleles are coding for the same
protein, the implication is that particular protein must be
eliminated for the disease to occur. The gene that is lost is
called RB-1, and it is evidently a tumor suppressor gene coding
for the nucleoprotein pRB, which inhibits expression of a group
of genes whose products are required for cell division. Thus, if
the tumor suppressor gene RB-1 is missing or corrupted, the
protein pRB is not produced, and cell division is not inhibited.
Independent support for this scheme comes from studies involving
DNA tumor viruses such as adenovirus, SV40, and human
papillomavirus. These viruses possess an oncogene (a cancer-
producing gene) that produces a protein that apparently binds to
and inactivates the protein pRB. So cancers produced by a loss of
pRB can emerge via two routes: 1) mutations that delete or
corrupt both copies of gene RB-1 in the chromosomes 13, thereby
preventing the production of any of the protein pRB; and 2)
viral
encoded proteins that bind to and inactivate pRB even if one or
both alleles of gene 13 are intact. After the discovery of tumor
suppressor gene RB-1, other such genes were identified,
including the gene p53, which is now considered the most
important tumor suppressor gene, and which is mentioned in the
report.
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