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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.
March 5, 1999 -- Vol. 3 Number 10
-----------------------------------------------
There is no doubt that great revolutions of human
scientific thought will occur in the next century,
and in the century after that, and in thousands of
centuries afterward. So which of our current pet
scientific dogmas will be among the first washed
away by new facts and sudden clarities?
-- Anonymous
-----------------------------------------------
Contents of This Issue:
1. More Protest Concerning a Nobel Prize
2. On the Ether Concept in Physics
3. Interaction Between Like-Charged Colloidal Spheres
4. Structure of a Gated Mechanosensitive Ion Channel
5. Human Longevity and Family Size
6. On Creutzfeldt-Jakob Disease and Related Encephalopathies
In Focus: On Living Organisms and Energy Flow
-----------------------------------------------------------
1. MORE PROTEST CONCERNING A NOBEL PRIZE
Last October, the Nobel Prize in Physiology or Medicine for 1998
was awarded to pharmacologists Robert Furchgott, Louis Ignarro,
and Ferid Murad (3 installations, US), the prize given for
pioneering work of the 3 researchers on nitric oxide as a
signaling molecule in the cardiovascular system [*Note #1]. A
debate among researchers in the field immediately erupted. No one
disputed the contributions of Furchgott, Ignarro, and Murad, but
many people apparently felt that Salvador Moncada (University
College London, UK) should also have been recognized. In 1987,
Ignarro published a paper confirming the identity of what was
called "endothelium-derived relaxing factor" and nitric oxide, an
identity whose possibility had previously been suggested
separately by himself and Furchgott. But that publication
appeared 6 months after a similar report in _Nature_ by Moncada
and colleagues, who had already concluded that endothelium-
derived relaxing factor and nitric oxide were identical. Moncada
was elected a foreign associate of the US National Academy of
Sciences in 1994, the citation stating that Moncada "discovered
that mammalian vascular tissues generate nitric oxide that is
biosynthesized from L-arginine," and that Moncada "elucidated the
relevance of this pathway as a universal transduction mechanism
for the regulation of cell function and communication." One of
the people who in October 1998 protested the neglect of Moncada
by the relevant Nobel Committee was Nobel Laureate (1984) Cesar
Milstein, who apparently characterized the decision of the Nobel
Committee to ignore Moncada as "scandalous". More recently, in a
letter to _Nature_, the University of El Salvador and its Faculty
of Medicine and the National University of Honduras and its
Faculty of Medical Sciences expressed their "deep regret and
strong protest at the exclusion of Salvador Moncada from the 1998
Nobel Prize in Physiology or Medicine." The letter states: "To
distinguish earlier research, which can only be deemed part of
this field with hindsight and in the light of Moncada's work,
without recognizing his work, is tantamount to an attempt to
rewrite the history of this discovery." In an appended comment on
a group of letters on the subject, the Editor of _Nature_ states:
"The most troublesome aspect of the Nobel process is the
apparently unchangeable fact that the prizes are distributed
according to the terms of Nobel's will, which states that the
number of recipients in each category shall be limited to three."
This is, of course, not the first time that debates and protests
have resulted from particular awards of the Nobel Prize in this
field or in other fields. In this case, the problem concerns not
the merit of the prize, but the exclusion of others because the
prize is limited to 3 recipients in a category. Alfred Nobel
(1833-1896) lived during a time quite different than our own, a
time when the practice of science was a more casual and
individual undertaking than it is now. Currently, nearly every
specialty in science is a fast-moving, international,
collaborative effort of many researchers at different
installations, and it seems apparent that some of the
stipulations of Alfred Nobel's will may no longer be sensible.
Which provokes the question: Were Nobel alive today, what would
he think of all of this?
-----------
J.B.L. Guillen et al: Protest at Nobel omission of Moncada.
(Nature 17 Dec 98 396:614)
QY: Jose B.L. Guillen, Universidad de El Salvador, Ciudad
Universitaria, Final 25 Avenida Norte, San Salvador, El Salvador.
-----------
Text Notes:
... ... *Note #1: Details on terminology and research appear in
the appended background material below.
-------------------
Summary by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
NITRIC OXIDE FUNCTION IN SKELETAL MUSCLE
Endothelial cells are flat cells forming a layer lining blood
vessels, lymphatic vessels, the heart, etc., and the term
"relaxing factor" refers to any chemical entity that promotes the
relaxation of muscle fibers. The discovery of an endothelial-
derived relaxing factor by Furchgott in 1980 initiated studies
that ultimately led to the identification of nitric oxide as an
endogenous signaling molecule [*Note #1]. In the classical
pathway described by Furchgott, nitric oxide is synthesized by
vascular endothelial cells and the substance then diffuses into
the underlying *smooth muscle cells to mediate vascular
relaxation. Although this pathway plays a major role in vascular
control, subsequent work has revealed that endothelium-dependent
relaxation is not the only mode for nitric oxide to regulate
blood flow. In certain vascular beds, regulation of vessel tone
by nitric oxide does not require the endothelium but instead
relies on neuronal activity, specifically on neurons involved in
the synthesis of nitric oxide. (This is the basis for the action
of sildenafil [Viagra].) ... ... David S. Bredt presents a short
review of recent work demonstrating that nitric oxide is also
produced by contracting *skeletal muscle cells, and that nitric
oxide is also vasoactive in this system and is involved in the
regulation of blood flow to skeletal muscle fibers. In this
pathway, the released nitric oxide opposes *adrenergic
vasoconstriction, resulting in the continued dilation of local
blood vessels to maximize the blood supply to active skeletal
muscle fibers. As this protective nitric oxide-synthesis pathway
is apparently disrupted in *Duchenne muscular dystrophy, the
author suggests these new results have important implications for
both the pathophysiology and possible treatment of muscle
disease. The new work on nitric oxide release by skeletal muscle
is reported in the same issue of the journal by G.D. Thomas et al
(6 authors at 2 installations, US), and these authors also
suggest that nitric oxide deficit may be implicated in Duchenne
muscular dystrophy.
-----------
David S. Bredt: NO skeletal muscle derived relaxing factor in
Duchenne muscular dystrophy.
(Proc. Natl. Acad. Sci. US 8 Dec 98 95:14592)
QY: David S. Bredt [bredt@phy.ucsf.edu]
-----------
G.D. Thomas et al: Impaired metabolic modulation of alpha-
adrenergic vasoconstriction in dystrophin-deficient skeletal
muscle.
(Proc. Natl. Acad. Sci. US 8 Dec 98 95:15090)
QY: Gail D. Thomas [gthom1@mednet.swmed.edu]
-----------
Text Notes:
... ... *Note #1: See the notes to the related background report
below for details concerning nitric oxide.
... ... *smooth muscle cells: Smooth muscle was originally
differentiated from striated muscle on the basis of microscopic
appearance, but there are important other differences both
functional and molecular, and in general smooth muscle is
specialized for slow sustained contractions such as those
involved in the control of the diameters of blood vessels.
... ... *skeletal muscle cells: (striated muscle cells) Voluntary
muscle in which cross striations occur in the fibers as a result
of regular overlapping of thick and thin filaments. Although
cardiac muscle is not "voluntary" muscle, it is also striated in
appearance. In general, striated muscle is involved in rapid
transient contraction, while smooth muscle is involved in slow
sustained contraction.
... ... *adrenergic vasoconstriction: Vasoconstriction produced
by adrenergic neurons, nerve cells that secrete norepinephrine
or epinephrine as neurotransmitters.
... ... *Duchenne muscular dystrophy: The most common type of
childhood muscular dystrophy, typically affecting boys. A genetic
disorder that results in the absence of the gene product
dystrophin, a protein normally localized in the cell membranes of
muscle cells. Most patients die by the age of 20 years. The
disease is chromosome X-linked: it affects males and is
transmitted by females. The role of dystrophin in muscle cells is
not clear.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 5Feb99
-------------------
Related Background:
A CRITIQUE OF THE NOBEL PRIZE
There are supreme awards in nearly all the branches of science,
but none of them have acquired the popular interest of the Nobel
prizes, and certainly no science prizes except the Nobel prizes
have had even a remotely comparable portrayal in melodrama.
... ... E. Crawford, a sociologist and historian of science,
presents a critique of the Nobel prizes and the Nobel prize
system, the author making the following points: 1) Nobel intended
his prizes to encourage promising young scientists, so it would
no doubt be a surprise for him to see the prizes become the
standards for the highest achievements of modern science. 2) The
notion that the Nobel prizes parallel the history of modern
science ignores the fact that the awards cover only a small part
of modern science, neglecting a number of important fields such
as technology, astronomy, meteorology, and psychiatry. Thomas
Edison, the Wright brothers, the astrophysicists G.E. Hale and
Arthur Eddington, the meteorologist Vilhelm Bjerknes, Sigmund
Freud -- all did not receive a Nobel prize. Before the 1920s,
even theoretical physics and theoretical chemistry were
neglected, and Arnold Sommerfeld, G.N. Lewis, Ludwig Boltzmann,
Josiah Willard Gibbs, Oliver Heaviside, and Henri Poincare also
did not receive a Nobel prize. 3) The manner in which attention
has focused on the prize winners -- never on the candidates -- is
one reason for the extraordinary success of the prizes. Another
reason is the wholesale acceptance of the justification provided
by the prize awarders for the choices. Major eligible discoveries
have indeed received prizes, but for the most part, the awarders
of the prize "have been engaged in the rather humdrum business of
choosing among works produced by what Kuhn called 'normal'
science." 4) From the beginning, secrecy has been at the heart of
the Nobel system, the statutes of the Nobel Foundation adopted in
1901 stipulating that no part of the prize deliberations could be
made public, nor could a prize decision be appealed. But in 1974
the statutes of the Nobel Foundation were changed to authorize
the four institutions that award Nobel prizes to permit access to
archival documents at least 50 years old for purposes of
historical research. 5) Myths are necessary for the cohesion of
institutions and groups, and the myth of the Nobel laureate as
the lone discoverer may appear to be one that preserves some of
the innocence of science in an age of multimillion dollar
research projects and research teams involving hundreds of
collaborators. But the winner-take-all mentality masks the
realities of doing science in the 20th century. 6) It is
important to bear in mind that prize winners are chosen from a
large pool of worthy candidates, and that the choices are
conditioned not only by the predilections of the Swedish prize
awarders but also by their ties to international networks that
so far have centered almost exclusively in Europe and North
America, allowing for few prize winners residing in Russia,
India, and Japan, and none in China.
-----------
E. Crawford (Universite Louis Pasteur, FR)
Nobel: Always the winners, never the losers.
(Science 13 Nov 98 282:1256)
QY: Elisabeth Crawford, Institut d'Histoire des Sciences,
Universite Louis Pasteur, 7 rue de l'Universite, 67070
Strasbourg, FR.
-------------------
Summary by SCIENCE-WEEK [http://scienceweek.com] 27Nov98
-------------------
Related Background:
AN EXPECTED REPERTOIRE OF IMPOTENCE DRUGS
According to the US National Institutes of Health, 20 to 30
million men in the US suffer from some form of penile erectile
dysfunction, and these numbers are apparently confirmed by the
phenomenal commercial success of Viagra, the brand name for the
drug sildenafil citrate. At the annual meeting of the American
Urological Association in San Diego (US) early in June, the drug
apparently dominated discussions. Elizabeth K. Wilson reviews
these discussions and makes the following points: 1) Viagra is
the first oral medication approved in the US for penile erectile
dysfunction, but other treatments working by different modes of
action are evidently on the way. 2) A variety of compounds have
been used to treat impotence: papaverine, prostaglandin E1,
sildenafil, phentolamine, apomorphine. And several other
compounds have been investigated as impotence remedies: L-
arginine, colforsin, trazodone. 3) The intracellular messenger
molecule cyclic guanosine monophosphate (cGMP) apparently plays a
key role in producing the physiological changes that lead to an
erection. 4) The process begins when *nitric oxide, released by
nerve cells or endothelial cells, diffuses into smooth muscle
cells in the walls of penile arteries and penile spongy erectile
tissue. 5) Nitric oxide binds to the heme component of the enzyme
guanylate cyclase, stimulating that enzyme to synthesize cGMP
from guanosine triphosphate. Increased levels of cGMP lead to
decreased calcium ion concentrations in the muscle cells, causing
the muscles to relax and blood to flow into the penis. The
concentration of cGMP is regulated by the activity of a second
enzyme, phosphodiesterase-5, which hydrolyzes cGMP to GMP
(guanosine monophosphate). 6) The consensus at the urology
meeting was apparently that within the next few years there will
appear a new generation of Viagra-like drugs, and that during
this time attention will also turn to biochemical remedies for
sexual dysfunction in women.
QY: Elizabeth K. Wilson
(Chem. & Eng. News 29 Jun 98) (Science-Week 24 Jul 98)
-------------------
Related Background:
... ... *nitric oxide: The gas nitric oxide is the prime member
of an entirely new class of neurotransmitters discovered only in
the 1990s. In the brain, the enzyme that synthesizes nitric oxide
(nitric oxide synthase) is localized in discrete populations of
neurons. In the peripheral autonomic nervous system, the enzyme
occurs in neurons that regulate the adrenal medulla, the
posterior pituitary, and the smooth muscle cells of the intestine
involved in *peristalsis. In all of these systems, nitric oxide
acts as a neurotransmitter released as a consequence of neural
activity. Nitric oxide has also been implicated as a messenger in
the response of macrophages (immune system cells) to cancer cells
and invading bacteria. It is also released from *endothelium in
response to acetylcholine and other vasodilators, with a
resultant relaxation of blood vessels. And, as noted in the
report, it is involved in penile erection. Nitric oxide is a free
radical with a half-life of only a few seconds, and its
concentration in tissues is difficult to establish
quantitatively. It should not be confused with nitrous oxide
("laughing gas"), which is an analgesic gas used as an auxiliary
in anesthesia in dentistry and surgery.
... ... *peristalsis: This refers to the regulated waves of
alternating contraction and relaxation of the intestine that move
its contents onward.
... ... *endothelium: A layer of flat cells lining blood vessels,
lymphatic vessels, the heart, etc.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 24Jul98
-------------------
Related Background:
REVELATIONS CONCERNING LISA MEITNER AND THE NOBEL PRIZE
Science is a human activity, and the prizes that are awarded to
individuals in science are perhaps a necessary element in scient-
ific progress. Nearly everyone wants approval and accolades for
one's work, and if there is not that motive, there is always the
rationalization that receiving an important prize is an aid to
getting more funds for research, more equipment, more time, and
so on. One of the most prestigious prizes is the Nobel Prize in
the various sciences, and now an article has appeared in the
journal Physics Today that tells a sad story. Based on recently
available documents of the Royal Swedish Academy of Sciences,
official records of Nobel Prize deliberations, Elizabeth Crawford
et al (3 installations, FR and US) review the details of the
Nobel Prize awards in physics and chemistry in the years 1945 and
1946, in particular the long-puzzling failure of the physicist
Lise Meitner (1878-1968), acknowledged as one of the central
discoverers of atomic fission, to win either the prize in physics
or the prize in chemistry for those years. Meitner was a long-
time collaborator of Otto Hahn (who received the 1945 Nobel Prize
in Chemistry); she barely escaped the Nazis in 1938 to work in
Sweden. The conclusions of the authors: Meitner did not share the
chemistry prize in 1945 because of "a mixture of disciplinary
bias, political obtuseness, ignorance and haste." As for the
physics prize of 1946, for which Meitner was also nominated, the
authors conclude the failure to then award her the prize was "a
rare instance in which personal negative opinions apparently led
to the exclusion of a deserving scientist." Meitner received the
U.S. Atomic Energy Commission Fermi Award in 1966.
QY: E. Crawford, CNRS, Pasteur Univ., Strasbourg FR.
(Physics Today Sep 97) (Science-Week 17 Oct 97)
2. ON THE ETHER CONCEPT IN PHYSICS
In the late 19th century, what we now call "classical" physics
incorporated the assumed existence of the "ether", a hypothetical
medium believed to be necessary to support the propagation of
electromagnetic radiation. The famous *Michelson-Morley
experiment of 1887 was interpreted as demonstrating the
nonexistence of the ether, and this experiment became a
significant prelude to the subsequent formulation of Einstein's
*special theory of relativity. Although it is often stated
outside the physics community that the ether concept was
abandoned after the Michelson-Morley experiment, this is not
quite true, since the classical ether concept has been
essentially reformulated into several modern *field concepts.
... ... Frank Wilczek (Institute for Advanced Studies Princeton,
US) presents a short review of the recent history of the ether
concept, and the relation of the ether concept to modern field
concepts. The author makes the following points: 1) Isaac Newton
(1642-1727) believed in a continuous medium filling all space,
but his equations did not require any such medium, and by the
early 19th century the generally accepted ideal for fundamental
physical theory was to discover mathematical equations for forces
between indestructible atoms moving through empty space. 2) It
was Michael Faraday (1791-1867) who revived the idea that space
was filled with a medium having physical effects in itself... To
summarize Faraday's results, James Clerk Maxwell (1831-1879)
adapted and developed the mathematics used to describe fluids and
elastic solids, and Maxwell postulated an elaborate mechanical
model of electrical and magnetic fields. 3) The achievement of
Einstein (1879-1955) in his paper on special relativity was to
highlight and interpret the hidden symmetry of Maxwell's
equations, not to change them. The Faraday-Maxwell concept of
electric and magnetic fields, as media or ethers filling all
space, was retained by Einstein. Later, Einstein was dissatisfied
with the particle-field dualism inherent in the early atomic
theory, and Einstein sought, without success, a unified field
theory in which all fundamental particles would emerge as special
solutions to the field equations. 4) Following Einstein, Paul
Dirac (1902-1984) then showed that photons emerged as a logical
consequence of applying the rules of quantum mechanics to
Maxwell's electromagnetic ether. This connection was soon
generalized so that particles of any sort could be represented as
the small-amplitude excitations of quantum fields. Electrons, for
example, can be regarded as excitations of an electron field, an
ether that pervades all space and time uniformly. Our current and
extremely successful theories of the *strong, electromagnetic,
and weak forces are formulated as *relativistic quantum field
theories with *local interactions. 5) The author states:
"Einstein first purified, and then enthroned, the ether concept.
As the 20th century has progressed, its role in fundamental
physics has only expanded. At present, renamed and thinly
disguised, it dominates the accepted laws of physics."
-----------
Frank Wilczek: The persistence of ether.
(Physics Today January 1999)
QY: Frank Wilczek [wilczek@ias.edu]
-----------
Text Notes:
... ... *Michelson-Morley experiment of 1887: Conducted by Albert
Michelson (1852-1931) and Edward Morley (1838-1923), the
experiment attempted to measure the velocity of the Earth through
the "ether" by using an interferometer to detect a difference in
the speed of light in the direction of Earth's rotation from the
speed perpendicular to this direction. No difference was
observed, indicating the absence of an ether "wind".
... ... *special theory of relativity: Proposed by Einstein in
1905, the special theory refers to inertial (non-accelerated)
frames of reference. It assumes physical laws are identical in
all frames of reference and that the speed of light in a vacuum
is constant throughout the Universe and is independent of the
speed of the observer. In general, the special theory gives a
unified account of the laws of mechanics and electromagnetism
(including optics). The companion theory, the general theory of
relativity (1915), deals with general relative motion between
accelerated frames of reference, and it is the general theory
that led to Einstein's analysis of gravitation.
... ... *field: In this context, in general, the term "field"
refers to a physical quantity (e.g., electric or magnetic field)
that varies from point to point in space.
... ... *strong, electromagnetic, and weak forces: The
fundamental forces currently identified in physics are the
gravitational force, the electromagnetic force, the nuclear
strong force, and the nuclear weak force. The nuclear strong
force is the dominant force that acts between hadrons (e.g., the
force that binds neutrons and protons in nuclei). (A "hadron" is
any object made of *quarks and/or antiquarks). The weak force
occurs between leptons (particles without internal structure,
e.g., electrons, neutrinos) and hadrons (particles with internal
structure, e.g., neutrons and protons); In general, the weak
force is responsible for radioactivity.
... ... *quarks and antiquarks: 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. The
antiquark is the antimatter quark entity. In general,
antiparticles are homologs of elementary particles but with
opposite charge. The positron, for example, is the antimatter
particle homologous to the electron. Matter composed entirely of
antiparticles is called "antimatter".
... ... *relativistic quantum field theories: In general, a
"quantum field theory" is any quantum mechanical theory in which
particles are represented by fields whose normal modes of
oscillation are quantized. The term is also used to refer to a
quantum mechanical theory applied to systems having an infinite
number of *degrees of freedom. Quantum electrodynamics, for
example, is a particular quantum field theory describing the
emission or absorption of photons by charged particles.
"Relativistic quantum field theories" are used to describe
fundamental interactions between elementary particles (which
exhibit relativistic velocities, i.e., velocities approaching the
speed of light).
... ... *local interactions: In this context, a local interaction
is an interaction between particles whose quantum mechanical wave
functions are confined to a small region of a large system rather
than being extended throughout the system.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
ON FIELD THEORY IN PHYSICS
In physics, a field is an entity that acts as intermediary in
interactions between particles, and which is distributed over
part or all of space, and whose properties are functions of space
coordinates, and except for static fields, also functions of
time. There is also a quantum-mechanical analog of this entity,
in which the function of space and time is replaced by an
operator at each point in space-time. ... ... Roman Jackiw
reviews present theoretical work in the theory of elementary
particles and forces, and the author makes the following points:
1) Present-day theory for fundamental processes (i.e.,
descriptions of elementary particles and forces) is phenomenally
successful. Experimental data confirms theoretical prediction,
and where accurate calculation and experiments are attainable,
agreement is achieved to 6 or 7 figures. Two examples: a) The
helium atom ground state energy (*Rydbergs) is experimentally
measured as -5.8071394 and theoretically calculated as
-5.8071380. b) The muon magnetic dipole moment is experimentally
measured as 2.00233184600 and theoretically calculated as
2.00233183478. 2) The theoretical structure within which this
success has been achieved is *local field theory, which offers a
wide variety of applications, and which provides a model for
fundamental physical reality as described by our theories of
*strong, electroweak, and gravitational processes. No other
framework exists in which one can calculate so many phenomena
with such ease and accuracy. 3) But is spite of these successes,
today there is little confidence that field theory will advance
our understanding of nature at its fundamental workings beyond
what has already been achieved. Although in principle all
observed phenomena can be explained by present-day field theory,
these accounts are still imperfect, requiring ad hoc inputs.
Moreover, because of conceptual and technical obstacles,
classical gravity theory has not been integrated into the
*quantum field description of nongravitational forces:
*quantizing the *metric tensor of Einstein's theory produces a
quantum field theory beset by infinities that apparently cannot
be controlled. 4) These shortcomings are actually symptoms of a
deeper lack of understanding concerning *symmetry and symmetry
breaking... Physicists are happy in the belief that Nature in its
fundamental workings is essentially simple, but observed physical
phenomena rarely exhibit overwhelming regularity. Therefore, at
the very same time that we construct a physical theory with
intrinsic symmetry, we must find a way to break the symmetry in
physical consequences of the model. 5) These problems have
produced a theoretical impasse for over two decades, and in the
absence of new experiments to channel theoretical speculation,
some physicists have concluded that it will not be possible to
make progress on these questions within field theory, and they
have turned to a new structure, "*string theory". In field
theory, the quantized excitations are point particles with point
interactions, and this gives rise to the infinities. In string
theory, the excitations are extended objects -- strings -- with
nonlocal interactions; there are no infinities in string theory,
and that enormous defect of field theory is absent. 6) Yet in
spite of its positive features, until now string theory has
provided a framework rather than a definite structure, and a
precise derivation of the *Standard Model has yet to be given.
The author concludes: "On previous occasions when it appeared
that quantum field theory was incapable of advancing our
understanding of fundamental physics, new ideas and new
approaches to the subject dispelled the pessimism. Today we do
not know whether the impasse within field theory is due to a
failure of imagination or whether indeed we have to present
fundamental physical laws in a new framework, thereby replacing
the field theoretic one, which has served us well for over 100
years."
-----------
Roman Jackiw (Massachusetts Institute of Technology, US)
Field theory: Why have some physicists abandoned it?
(Proc. Natl. Acad. Sci. US 27 Oct 98 95:12776)
QY: Roman Jackiw, Mass. Inst. of Technology 617-253-1000.
-----------
Text Notes:
... ... *Rydbergs: A unit of energy used in atomic physics,
value = 13.605698 electronvolts.
... ... *local field theory: In this context, "locality" is the
condition that two events at spatially separated locations are
entirely independent of each other, provided that the time
interval between the events is less than that required for a
light signal to travel from one location to the other. For
example, the quantum mechanical wave function is a "local" field.
... ... *strong, electroweak, and gravitational processes: The
fundamental forces comprise the gravitational force, the
electromagnetic force, the nuclear strong force, and the nuclear
weak force. The "electroweak" interactions are a unification of
the electromagnetic and nuclear weak interactions, and are
described by the Weinberg-Salam theory (sometimes called "quantum
flavordynamics"; also called the Glashow-Weinberg-Salam theory).
... ... *quantum field description: In general, a quantum field
theory is a quantum mechanical theory applied to systems having
an infinite number of *degrees of freedom. The term is also used
to refer to any quantum mechanical theory in which particles are
represented by fields whose normal modes of oscillation are
quantized (see below).
... ... *degrees of freedom: In general, the number of
independent parameters required to specify the configuration of a
system.
... ... *quantizing: In experimental physics, a quantized
variable is a variable taking only discrete multiple values of a
quantum mechanical constant. In theoretical physics, "quantizing"
means the consistent application of certain rules that lead from
classical to quantum mechanics. In general, "quantization" is a
transition from a classical theory or a classical quantity to a
quantum theory or the corresponding quantity in quantum
mechanics.
... ... *metric tensor: The mathematical statement (involving a
set of quantities) that describes the deviation of the Pythagoras
theorem in a curved space.
... ... *symmetry and symmetry breaking: If a theory or process
does not change when certain operations are performed on it, the
theory or process is said to possess a symmetry with respect to
those operations. For example, a circle remains unchanged under
rotation or reflection, and a circle therefore has rotational and
reflection symmetry. The term "symmetry breaking" refers to the
deviation from exact symmetry exhibited by many physical systems,
and in general, symmetry breaking encompasses both "explicit"
symmetry breaking and "spontaneous" symmetry breaking. Explicit
symmetry breaking is a phenomenon in which a system is not quite,
but almost, the same for two configurations related by exact
symmetry. Spontaneous symmetry breaking refers to a situation in
which the solution of a set of physical equations fails to
exhibit a symmetry possessed by the equations themselves.
... ... *string theory: In particle physics, string theory is a
theory of elementary particles based on the idea that the
fundamental entities are not point-like particles but finite
lines (strings), or closed loops formed by strings, the strings
one-dimensional curves with zero thickness and lengths (or loop
diameters) of the order of the Planck length of 10^(-35) meters.
... ... *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. Leptons are a class of point-like fundamental
particles showing no internal structure and no involvement with
the strong forces. 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.
-------------------
Summary & Notes by SCIENCE-WEEK 4Dec98
3. INTERACTION BETWEEN LIKE-CHARGED COLLOIDAL SPHERES
The interactions between *colloidal particles in electrolyte
solutions play an apparently central role in the *phase behavior
and agglomeration kinetics of colloidal dispersions. These
interactions are thus of fundamental importance for understanding
the properties of inorganic materials (e.g., ceramics composed of
nanoparticles), foods such as milk, and solutions of
biomacromolecules such as globular proteins. After decades of
theoretical and experimental efforts, the long-accepted theories
for describing the interactions of colloidal particles in
electrolyte solutions have been challenged by results from recent
experiments. Included in this challenge is the issue of apparent
attractive electrostatic forces between like-charged colloidal
particles in an electrolyte solution. ... ... J. Wu et al
(University of California Berkeley, US) now report *Monte Carlo
simulation studies that indicate the existence of a short-range
attractive force between identical macroions in electrolyte
solutions containing divalent counterions. The authors report
strong evidence (complementing recent and related results by
others) of attraction between a pair of spherical macroions in
the presence of added salt ions for the conditions where the
interacting macroion pair is not affected by any other macroions
that may be in the solution. The authors state that classical
theories fail to describe the attractive interactions found in
their simulations, with one set of classical theories (Derjaguin-
Landau-Verwey-Overbeek) predicting only repulsive interactions
and another set of theories (Sogami-Ise) predicting a long-range
attraction that is too weak and that occurs at too large macroion
separations. The authors suggest their simulations provide
fundamental "data" for an improved theory of colloidal
interactions in electrolyte solutions.
-----------
J. Wu et al: Interaction between like-charged colloidal spheres
in electrolyte solutions.
(Proc. Natl. Acad. Sci. US 22 Dec 98 95:15169)
QY: John M. Prausnitz [lindar@cchem.berkeley.edu]
-----------
Text Notes:
... ... *colloidal particles: In general, a colloid is a system
of particles 1 to 1000 nanometers in diameter dispersed in
another phase.
... ... *phase behavior: In this context, the term "phase" refers
to any part of a system which is uniform in chemical composition
and physical properties and separated from other homogeneous
parts of the system by boundary surfaces. Also in this context,
the term "phase behavior" refers to the equilibrium relationships
between water, the dispersed colloid, and dissolved non-colloidal
electrolytes.
... ... *Monte Carlo simulation studies: In general, a "Monte
Carlo method" is any method for obtaining a statistical estimate
of a desired quantity by random sampling. In the most successful
applications, the desired quantity is a statistical parameter,
and the sampling is made from an artificial population that may
be a model of the physical system itself. The method is of
considerable utility in handling certain intractable applied
mathematical problems.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
ATTRACTION BETWEEN LIKE-CHARGED SPHERES IN A CHARGED PORE
A colloid is a system of particles 1 to 1000 nanometers in
diameter dispersed in another phase, and such systems,
particularly systems of electrically charged colloids, have
important practical significance and are also of considerable
theoretical interest. The existence of long-range attractive (as
opposed to the expected repulsive) electrostatic forces between
particles of like charge is one of the current major
controversies of colloid science. The established classical
theory (Derjaguin-Landau-Vervey-Overbeek) of colloidal
interactions predicts that an isolated pair of like-charged
colloidal spheres in an electrolyte should experience a purely
repulsive *screened electrostatic (coulombic) interaction. Direct
measurements of such interactions have shown quantitative
agreement with the classical theory, but recent experiments have
provided evidence that the effective interparticle potential can
have a long-range attractive component in more concentrated
suspensions and for particles confined by charged glass walls.
This long range attraction in concentrated systems is apparently
due to multi-body interactions. Theoretical explanations have
been proposed but remain the subject of controversy.
... ... Bowen and Sharif (University of Wales, UK) now present a
quantitative theoretical explanation of the attractive forces
between confined colloidal particles, the theory based on direct
solutions of the classical nonlinear Poisson-Boltzmann equation
for two like-charged spheres confined in a cylindrical charged
pore. The calculations show that the attraction may be explained
by the redistribution of the electric double layer of ions and
counterions in solution around the spheres, owing to the presence
of the wall. The authors suggest there is thus no need to revise
the established concepts of underlying theories of colloidal
interactions. [Editor's Note: The theoretical result in this
paper is unequivocal: the calculation shows that for the given
boundary conditions, the force between two particles of like
charge dips below zero (i.e., becomes attractive) before
returning to zero at infinite distance.]
QY: W. Richard Bowen (r.bowen@swansea.ac.uk)
(Nature 18 Jun 98 393:663) (Science-Week 3 Jul 98)
... ... *screened: Screening is a reduction of the effective
electric field at a point, the reduction due to the space charge
of ambient charged particles of sign opposite to the source of
the field.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 3Jul98
4. STRUCTURE OF A GATED MECHANOSENSITIVE ION CHANNEL
Ion channels are protein channels in cell membranes that allow
ions to pass from extracellular solution to intracellular
solution and vice versa. Most ion channels are selective,
allowing only certain ions to pass, and an individual cell has
ion channels with various ion selectivities. The selectivity of
an ion channel can be "gated", the channel effectively opened or
closed, and ion channels are said to voltage-gated or ligand-
gated, depending on how the change in selectivity is provoked.
Concerning physical forces in the environment of a biological
cell that are significant for the cell, the sensing of such
forces is primarily mediated by a specialized class of membrane
proteins known as mechanosensitive ion channels. Such channels
have evolved the ability to transduce mechanical strain into an
electrochemical event that enables cells to respond to stimuli
such as sound, touch, gravity, and pressure. Although several
types of supposed mechanosensitive ion channels have been cloned,
the large ion-conductance mechanosensitive channels of
*prokaryotes have been most extensively characterized, and a
major objective is to better understand the structural basis for
the function of these channels. ... ... G. Chang et al (5 authors
at California Institute of Technology, US) now report an x-ray
crystallographic analysis (resolution to 3.5 angstroms) of the
large conductance mechanosensitive channels (MscL) in the
prokaryote Mycobacterium tuberculosis. The authors report that
this channel is organized as a homopentamer (i.e., 5 identical
subunits), with each subunit containing 2 transmembrane *alpha-
helices and a 3rd cytoplasmic alpha-helix. From the extracellular
side, a water-filled opening approximately 18 angstroms in
diameter leads into a pore lined with hydrophilic residues, the
pore narrowing at the cytoplasmic side to an occluded hydrophobic
apex that may act as the channel gate. The authors suggest this
structure may serve as a model for other mechanosensitive
channels, as well as for the broader class of pentameric ligand-
gated ion channels exemplified by the *nicotinic acetylcholine
receptor.
-----------
Editor's note: For General background material on biological
membranes, see the SW Focus Reports "Biological Membranes (1)"
and "Biological Membranes (2)" at
[http://scienceweek.com/swfr001.htm] and
[http://scienceweek.com/swfr004.htm].
-----------
G. Chang et al: Structure of the MscL Homolog from Mycobacterium
tuberculosis: A gated mechanosensitive ion channel.
(Science 18 Dec 98 282:2220)
QY: Douglas C. Rees [dcrees@caltech.edu]
-----------
Text Notes:
... ... *prokaryotes: Unicellular or filamentous organisms in
which cells lack internal membrane compartments such as a
nucleus. E.g., bacteria.
... ... *alpha-helices: In general, protein chains fold into
either alpha-helices or beta-sheet structures. The alpha-helix is
a configuration of a polypeptide chain in which successive turns
of the helix are held together by hydrogen bonds between the
amide (peptide) links, the carbonyl group of any given residue
being hydrogen-bonded to the imino group of the 3rd residue
behind it in the chain. The alpha-helix was first described by
Pauling and Corey in 1951.
... ... *nicotinic acetylcholine receptor: The nicotinic
acetylcholine receptor is a molecularly well-characterized
receptor in the neuron membrane, its activation evidently leading
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".
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
STRUCTURAL ANALYSIS OF VOLTAGE-GATED CHLORIDE ION CHANNELS
In the context of studies of biological cell membranes, the term
"ion selectivity" refers to the ability of all cell membranes to
distinguish between various ions such as Na(+), K(+), Ca(++),
Cl(-), etc. There is much evidence that this ion selectivity
involves specific pores or channels in the cell membrane, with
certain channels specific for certain ions, the channels capable
of being opened or closed (gated) depending on conditions and
various interactions with ligands binding to receptors. These
receptors are in some cases part of the channel itself and in
other cases neighboring entities that control channel dynamics.
Since the movement of ions is by definition an electric current,
ion-selective channels can be viewed as involved in "conductance"
pathways. Fahlke et al (5 authors at Vanderbilt Univ., US) report
they have identified regions of a human skeletal muscle chloride
channel that contribute to formation of its anion-selective
conduction pathway. A core structural moiety evidently spans the
cell membrane and is conserved in evolution. The authors suggest
the conserved motif may be a critical sequence for anion
selectivity of ion selective membrane pores.
QY: Alfred L. George Jr. [al.george@mcmail.vanderbilt.edu]
(Nature 4 Dec 97) (Science-Week 26 Dec 97)
5. HUMAN LONGEVITY AND FAMILY SIZE
What is called the "disposable soma theory" in the biology of
ageing states that longevity of the organism requires investments
in somatic maintenance (i.e., maintenance of the body) that
reduce the resources available for reproduction. A possible
corollary of this is that avoidance or prevention of reproduction
will tend to increase longevity, and there are experiments with
the fruit fly Drosophila melanogaster that indicate this trade-
off exists. ... ... R.G.J. Westendorp and T.B.L. Kirkwood (2
installations, NL UK) now report a study of the interrelationship
between longevity and reproductive success in humans using
historical data from the British aristocracy. The records used in
the study involve the years 740 to 1875, and data concerning
19,830 male and 13,667 female aristocrats. The authors report
that the number of progeny was small when women died at an early
age, increased with the age of death, reaching a plateau through
the 6th, 7th, and 8th decades of life, but decreased again in
women who died at an age of 80 years or over. Age at first
childbirth was lowest for women who died early and highest for
women who died at the oldest ages. When account as taken only of
women who had reached menopause, who were aged 60 years and over,
female longevity was negatively correlated with number of progeny
and positively correlated with age at first childbirth. The
authors suggest the findings show that human life histories
involve a trade-off between longevity and reproduction.
Commenting on this paper, in the same issue of the journal,
Daniel E.L. Promislow (University of Georgia, US) states:
"Although childless women benefit from a decreased incidence of
heart disease and cervical cancer later in life, they have an
increased risk of breast cancer and respiratory disease. Clearly,
many factors influence lifespan..."
-----------
Editor's note: In addition to the background material below, see
the SW Focus Report "Biology of Aging" at URL
[http://scienceweek.com/swfr041.htm]
-----------
R.G.J. Westendorp and T.B.L. Kirkwood: Human longevity at the
cost of reproductive success.
(Nature 24/31 Dec 98 396:743)
QY: Rudi G.J. Westendorp [RudiWestendorp@compuserve.com]
-----------
Daniel E.L. Promislow: Longevity and the barren aristocrat.
(Nature 24/31 Dec 98 396:719)
QY: Daniel E.L. Promislow [promislow@bscr.uga.edu]
-------------------
Summary by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
AN ANALYSIS OF DEMOGRAPHIC TRAJECTORIES OF HUMAN LONGEVITY
Human old-age survival has increased substantially since 1950,
and this evidence of extended post-reproductive survival is
apparently puzzling biodemographers. Vaupel et al (14 authors at
10 installations, DE US DK MX CN) review current questions and
results in this field, presenting data from various sources. The
reduction in death rates at older ages has increased the size of
the elderly population considerably. In developed countries in
1990 there were about twice as many nonagenarians and 4 to 5
times as many centenarians as there would have been if mortality
after age 80 had stayed at 1960 levels. Reliable data for various
developed countries indicate that the population of centenarians
has doubled every decade since 1960, mostly as a result of
increases in survival after age 80. Here are selected data for
people 60 years and older in 1997 and projections for 2025:
----------------------------------------------------------------
1997 2025 percent of pop. in 2025
World 530 million 1200 million 15
Italy 13 18 33
Sweden 2 2.7 29
Germany 18 28 32
Japan 27 40 33
US 44 83 25
China 118 290 20
India 64 165 12
Mexico 6.5 18 13
----------------------------------------------------------------
QY: James W. Vaupel [jwv@demogr.mpg.de]
(Science 8 May 98 280:855) (Science-Week 29 May 98)
-------------------
Related Background:
ON GRANDMOTHERING, MENOPAUSE, AND HUMAN EVOLUTION
Hawkes et al (5 authors at 2 installations, US) present a
hypothesis that the long postmenopausal lifespans that disting-
uish humans from all other primates may have evolved with mother-
child food sharing, a practice that allowed aging females to
enhance the fertility of their daughters, the practice thereby
increasing selection against senescence. The authors suggest
their hypothesis also accounts for human late maturity, small
size at weaning, and high fertility, and that the hypothesis has
implications for past human habitat choice and social organiz-
ation, and for ideas about the importance of extended learning
and paternal provisioning in human evolution.
QY: E.L. Charnov, Univ. of Utah, Dept. of Biology 801-581-5636
(Proc. Natl. Acad. Sci. US 3 Feb 98)
(Science-Week 20 Feb 98)
6. ON CREUTZFELDT-JAKOB DISEASE AND RELATED ENCEPHALOPATHIES
Until 30 years ago, Creutzfeldt-Jakob disease was an obscure form
of dementia unknown to most physicians. The name is now familiar
to the medical community as the major *transmissible spongiform
encephalopathy (or prion disease) in humans, and familiar to
research scientists because of its strange causative agent
(*prions) that exhibit apparently novel modes of replication and
transmission. ... ... R.T. Johnson and C.J. Gibbs (Johns Hopkins
University, US) present a review of some of the biological
aspects and most of the clinical aspects of this disease and
related animal transmissible spongiform encephalopathies, the
authors making the following points: 1) A number of transmissible
spongiform encephalopathies have been described in animals and
humans [*Note #1]. All have incubation periods of months to
years, and all gradually increase in severity and lead to death
over a period of months. None evoke an immune response, and all
share a common *noninflammatory pathologic process restricted to
the central nervous system. The only macromolecules thus far
associated with infection are *isoforms of a host membrane
*sialoglycoprotein called "prion protein". 2) Studies of animal
and human prions indicate that the agents are resistant to
treatments that inactivate nucleic acids and viruses (e.g.,
alcohol, *formalin, ionizing radiation, *proteases, *nucleases),
but they are inactivated by treatments that disrupt proteins
(e.g., *autoclaving, phenol, detergents, and extremes of pH). 3)
Creutzfeldt-Jakob disease was first described clinically and
pathologically in the 1920s. The disease occurs worldwide with an
incidence of 0.5 to 1.5 cases per million population per year.
There is no seasonal distribution, no evidence of changing
incidence over the years, and no convincing geographic clustering
except for areas with large numbers of familial cases. 80 percent
of sporadic cases (i.e., non-familial cases) of Creuzfeldt-Jakob
disease are diagnosed in persons 50 to 70 years of age, with a
mean survival time of only 5 months. 80 percent of patients with
sporadic disease die within one year. 4) Surgical transmission of
Creuzfeldt-Jakob disease in humans has been documented. A
dramatic demonstration occurred when two young patients developed
the disease 16 and 20 months after they underwent surgery to
excise *epileptic foci. At the time of surgery, *stereotactic
electroencephalographic exploration was undertaken with silver
electrodes that had been previously implanted in a patient with
known Creutzfeldt-Jakob disease, the electrodes having been
"sterilized" with 70 percent alcohol and formaldehyde vapor. Two
years later, after recognition of the possible transmission of
Creutzfeldt-Jakob disease to the epilepsy patients, the
electrodes were retrieved and implanted into a chimpanzee in
which the disease subsequently developed. Contaminated
neurosurgical instruments have been suspected as modes of
transmission in other patients. 5) The authors conclude: "Despite
clues provided by *iatrogenic and familial cases of Creutzfeldt-
Jakob disease and by the possible transmission of *bovine
spongiform encephalopathy to humans, the cause of the sporadic
instances of Creutzfeldt-Jakob disease that make up 85 to 90
percent of cases remains a mystery. Past exposures, dietary
eccentricities, occupation, contact with others with the disease,
recreational activities, pets, and a myriad of other factors
provide no aid in establishing the diagnosis and no clue to
causation."
-----------
Editor's note: In addition to the related background material
below, see the SW Focus Report "Medical Biology: Prions"
available at URL [http://scienceweek.com/swfr034.htm].
-----------
R.T. Johnson and C.J. Gibbs: Creutzfeldt-Jakob disease and
related transmissible spongiform encephalopathies.
(New England J. Med. 31 Dec 98 339:1994)
QY: Richard T. Johnson, Meyer 6-181, Johns Hopkins Hospital,
Baltimore, MD 21287 US.
-----------
Text Notes:
... ... *transmissible spongiform encephalopathy: In general, an
encephalopathy is any disorder of the brain. In this context, the
term "spongiform" refers to the sponge-like texture or appearance
of the brain upon autopsy. In this context, the term
"transmissible" means capable of being transmitted from one
individual to another.
... ... *prions: Prions are a class of poorly understood proteins
implicated in a number of exotic human neurological diseases and
in some common animal diseases such as sheep scrapie and bovine
spongiform encephalopathy in cattle ("mad cow disease"). (See
below.)
... ... *Note #1: The following are currently recognized as prion
diseases:
-- Animal diseases: Scrapie (sheep and goats); transmissible mink
encephalopathy; wasting disease of deer and elk; bovine
spongiform encephalopathy; transmissible spongiform
encephalopathy of captive wild ruminants (e.g., kudu, bison);
feline spongiform encephalopathy (e.g., domestic cat, puma,
cheetah, ocelot, tiger).
-- Human diseases: Kuru; sporadic Creutzfeldt-Jakob disease;
familial Creutzfeldt-Jakob disease; Gerstmann-Straussler-
Scheinker disease; fatal familial insomnia; new-variant
Creutzfeldt-Jakob disease.
... ... *noninflammatory pathologic process: In general, the term
"inflammation" refers to a complex of cytological and chemical
reactions that occur in affected blood vessels and adjacent
tissues in response to an injury or abnormal stimulation caused
by a physical, chemical, or biological agent. A "noninflammatory"
pathological process" is essentially a disease process without
inflammation of tissues.
... ... *isoforms: In this context, an "isoform" is any one of
multiple forms of a functional protein that differ in amino acid
sequence and *electrophoretic mobility.
... ... *electrophoretic mobility: In general, electrophoresis is
a laboratory technique used to separate macromolecules on the
basis of electric charge and size, the technique involving
application of an electric field to a population of
macromolecules dispersing according to their electric mobilities.
... ... *sialoglycoprotein: Glycoproteins are a group of protein-
carbohydrate compounds, sometimes called "conjugated" proteins.
(In this context, the term "conjugated" merely means linked
together and does not concern double bond structure.)
Sialoglycoproteins are glycoproteins with sialic acid as a
component.
... ... *formalin: (formol) A 37 percent aqueous solution of
formaldehyde.
... ... *proteases: Any enzyme which splits proteins and
therefore degrades them. These enzymes catalyze the hydrolysis of
peptide bonds.
... ... *nucleases: Refers to any enzyme that degrades nucleic
acids, e.g., DNase, RNase, endonuclease, etc. These enzymes
catalyze the cleavage of phosphodiester bonds.
... ... *autoclaving: In this context, an autoclave is any
apparatus designed for sterilization by steam under high
pressure.
... ... *epileptic foci: In general, an epileptic focus is a
localized brain region involved in the onset of epileptic
seizures. In certain cases, excision of the focus prevents
subsequent seizures in the patient.
... ... *stereotactic electroencephalographic exploration: A
stereotaxic device is a rigid metal coordinate frame into which
the head of a patient is fixed so that microscale positioning of
electrodes at any particular coordinate position can be effected
without displacement caused by movement of the patient. In this
context, electroencephalographic exploration is used to localize
an epileptic focus in order to excise it.
... ... *iatrogenic: In general, this denotes any result produced
by surgery or other treatment. In this context, and in the usual
usage, the term is used for a result that is unwanted and
injurious to the patient (e.g., an infection due to contaminated
surgical instruments).
... ... *bovine spongiform encephalopathy: "Mad cow" disease.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 5Mar99
-------------------
Related Background:
ON PRIONS AND PRION DISEASES: A NOBEL LECTURE
Prions are defined as proteinaceous infectious particles that
lack nucleic acid, and in 1997 Stanley B. Prusiner was awarded
the Nobel Prize in Physiology or Medicine for his discovery of
prions, an entirely new genre of disease-causing agents.
... ... In a recently published abbreviated version of Prusiner's
Nobel Lecture (the lecture comprising an extensive review of
prion research), Prusiner makes the following points: 1) Prions
are unprecedented infectious pathogens that cause a group of
invariably fatal neurodegenerative diseases by an entirely novel
mechanism. 2) Prion diseases may appear as genetic, infectious,
or sporadic (i.e., non-familial) disorders, all of which involve
modifications of the prion protein. Bovine spongiform
encephalopathy ("mad cow disease"), scrapie of sheep, and
Creutzfeldt-Jakob disease of humans are among the most notable
prion diseases. 3) Prions are transmissible particles that are
devoid of nucleic acid and seem to be composed exclusively of a
modified protein. The normal cellular prion protein is converted
into modified protein through a *post-translational process
during which it acquires a high *beta-sheet content. The variety
of a particular prion is determined by the sequence of the
chromosomal prion protein gene of the mammals in which the prion
protein last replicated. 4) In contrast to pathogens carrying a
nucleic acid genome, prions appear to encode strain-specific
properties in the *tertiary structure of the modified prion
protein. *Transgenetic studies suggest that modified (pathogenic)
prion protein acts as a template upon which normal prion protein
is refolded into a nascent modified protein through a process
facilitated by another protein. 5) While knowledge about prions
has profound implications for studies of the structural
plasticity of proteins, investigations of prion diseases suggest
that new strategies for the prevention and treatment of these
disorders may also find application in the more common
degenerative diseases. The author concludes: "The discovery of
prions and their eventual acceptance by the community of scholars
represents a triumph of the scientific process over prejudice.
The future of this new and evolving area of biology should prove
even more interesting and productive as a multitude of
unpredicted discoveries emerge."
[SW note: For extensive background, see the SW Focus Report
"Medical Biology: Prions" at URL:
]
-----------
Stanley B. Prusiner: Prions
(Proc. Natl. Acad. Sci. US 10 Nov 98 95:13363)
QY: S. B. Prusiner, Univ. of Calif. San Francisco 415-476-4044.
-----------
Text Notes:
... ... *post-translational process: Translation is protein
synthesis, the process during which polypeptides are synthesized
in accordance with RNA code.
... ... *beta-sheet: In general, protein chains fold into
alpha-helices or beta-sheet structures. The beta-sheet is a
protein structure where the peptide is extended and stabilized by
hydrogen bonding between NH and CO groups of different
polypeptide chains or of separate regions of the same chain.
... ... *tertiary structure: In general, the structures of
biopolymers are denoted as follows: 1) Primary structure: The
sequence of subunits that comprise the macromolecule (e.g., the
amino acid sequence of a protein). 2) Secondary structure: The
localized arrangement in space of regions of a biopolymer (e.g.,
the alpha-helix). 3) Tertiary structure: The 3-dimensional
configuration of a biopolymer. 4) Quaternary structure: The 3-
dimensional arrangement and constitution of a multimeric
macromolecule (i.e., a substance containing more than one
biopolymer; an entity consisting of biopolymer subunits.
... ... *Transgenetic studies: (transgenic) In general, studies
involving the transfer of genetic material from one organism to
another, and subsequently the second organism expressing the
transferred genes with a resultant production of specific
proteins.
-------------------
Summary & Notes by SCIENCE-WEEK 1Jan99
-------------------
Related Background:
ON THE PRION HYPOTHESIS
Prions are a class of poorly understood proteins implicated in a
number of exotic human neurological diseases and in some common
animal diseases such as sheep scrapie and bovine spongiform
encephalopathy in cattle ("mad cow disease"). One human disease
in which prions have been strongly implicated is Creutzfeldt-
Jakob disease, which appears to have a genetic basis in about 15%
of the cases. The prion protein (denoted as PrP) is encoded by
the host's chromosomal DNA, and an abnormal *isoform of the
protein is the only known component associated with disease
transmissibility. This abnormal isoform differs physically from
the normal "cellular" protein form by its high *beta-sheet
content, its insolubility in detergents, its propensity to
aggregate, and its relative resistance to proteolysis.
... ... In a short review of the present status of research on
prions, D. Westaway et al make the following points: 1) The
benign cellular prion form, called Prp(supC) is a molecule that
is most probably present in all mammals and expressed on the
surfaces of neurons via a glycophosphatidylinositol anchor. The
pathogenic form of the prion protein is called Prp(supSc) (Sc =
scrapie) or Prp(sup res) (res = resistant to protease), and the
cellular form apparently serves as a necessary precursor to the
pathogenic form. 2) It is presently unclear whether subtypes of
pathogenic prion protein are the true infectious agent, or
whether such preparation harbor cryptic agents such as viruses or
proviruses (nonviral or previral nucleic acid entities). 3) The
simplest form of the "protein only" prion hypothesis proposes
that infectious molecules can be produced by coercing the normal
protein to adopt pathogenic conformations. 4) At least 11
possible prion ligands have been identified by in vitro binding
and other techniques, but the situation concerning ligands is
unclear: a) in no case have independent methods identified the
same ligand in an unequivocal fashion; b) in no case have binding
sites been mapped on prion proteins; c) in no case have ligand-
prion binding affinities been estimated; and, d) in no case have
any genetic methods been used to demonstrate binding in vivo. 5)
In summary, although the prion hypothesis is not universally
accepted, even skeptics concede that the prion protein is somehow
involved in the control of disease susceptibility. At the other
theoretical extreme, prion proteins are believed to comprise the
prototype of a new class of infectious pathogens, with protein
misfolding as a novel mechanism of pathogenesis, and with the
suggestion that simple organisms may use prion-like mechanisms to
switch physiological states and thereby adapt to new
environments.
-----------
D. Westaway et al (3 authors at 3 installations, CA UK US)
Prions.
(Proc. Natl. Acad. Sci. US 15 Sep 98 95:11030)
QY: David Westaway, University of Toronto 416-979-4901
-----------
Text Notes:
... ... *isoform: Any one of the multiple forms of a functional
protein that differ in amino acid sequence and
electrophoretic mobility.
... ... *beta-sheet: (beta-conformation) One type of protein
secondary structure.
-------------------
Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 23Oct98
-------------------
Related Background:
A CRITICISM OF THE PRION HYPOTHESIS
Spongiform encephalopathies are a type of brain disease found in
humans and animals and are characterized by macroscopic vacancies
produced by the disease process (the brain has a sponge-like
appearance). "Transmissible spongiform encephalopathies" such as
bovine spongiform encephalopathy ("mad cow disease") and human
Creutzfeldt-Jakob disease are diseases that apparently involve an
infectious agent. Prions are a class of poorly understood
proteins implicated in transmissible spongiform encephalopathies,
but there is controversy about this, since the details of the
prion infectious process are unknown. ... ... Now C. Farquhar
(Institute for Animal Health Edinburgh, UK), in a letter to the
journal Nature, notes that the prion hypothesis is far from
proven, and that alternative hypotheses of the nature of the
causative agent of the transmissible spongiform encephalopathies
are being misrepresented and dismissed. The "virino" hypothesis,
for example, which is not a conventional virus hypothesis,
proposes an agent-specific replicable informational molecule, yet
to be identified, bound to a protective host prion protein. The
author emphasizes that the precise nature of a prion still eludes
identification, and that the prion hypothesis has yet to explain
satisfactorily the many strains of transmissible spongiform
encephalopathies. In conclusion, the author suggests that the
discovery of an informational molecule with strain-specific
properties, for example a nucleic acid, would refute a prion
protein-only hypothesis, and that until the matter is settled, it
should be recognized there may be more to the biological
diversity of transmissible spongiform encephalopathies than prion
protein.
QY: Christine F. Farquhar [christine.farquhar@bbsrc.ac.uk]
(Nature 22 Jan 98) (Science-Week 6 Feb 98)
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IN FOCUS: ON LIVING ORGANISMS AND ENERGY FLOW
"A living organism is something extremely improbable, and not
only because you hardly find any in the universe at large. Mainly
it is improbable because it represents a highly complicated,
ordered structure, while the fundamental laws of thermodynamics
(the science of energy conversions) tell us that disorder of the
universe (or any other closed system) must increase with time.
The secret of living beings -- why they can exist for a given
lifespan despite the universal trend toward disorder -- lies in
their energy consumption. Living beings use up energy, the
production of which creates an amount of disorder elsewhere that
outweighs the order created by the organism. This is why life is
so dependent on energy flow. Even a very energy-efficient
organism that does not move and only replicates once in one
hundred years will permanently need energy to defend the ordered
state against the natural tendency for disorder."
-- Michael Gross: _Life on the Edge_
(Plenum Press, New York 1998, p.3)
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