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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.
October 23, 1998 -- Vol. 2 Number 43
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Between the fifth and tenth days the lump of stem cells
differentiates into the overall building plan of the mouse embryo
and its organs. It is a bit like a lump of iron turning into the
space shuttle. In fact it is the profoundest wonder we can still
imagine and accept, and at the same time so usual that we have to
force ourselves to wonder about the wondrousness of this wonder.
-- Miroslav Holub
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Contents of This Issue:
1. Report Urges Caution on Genetic Testing for Mental Disorders
2. Astrophysics: Formation of Substellar Objects
3. On Meteorite Impact and the K/T Mass Extinction
4. On the Chemical Physics of Protein Folding
5. On the Molecular Biology of Sperm-Egg Fertilization
6. On the Prion Hypothesis
7. Human Neurocognitive Architecture: A Plasticity Model
8. Gene Therapy Inhibition of Xenoreactive Antibody Production
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1. REPORT URGES CAUTION ON GENETIC TESTING FOR MENTAL DISORDERS
The continuing identification of specific gene mutations involved
in the pathogenesis of certain diseases will have as one
consequence an improvement in diagnostic and therapeutic
techniques that will considerably benefit patients with these
diseases. There is another consequence, however, a consequence
that is less certain to be uniformly beneficial: there are no
doubt many diseases whose pathogenesis involves one or more gene
mutations, but with the process such that the pathological
outcome is only more or less probable but not certain. The
identification of people with such probabilistic genetically
based pathologies is of great interest to commercial health
insurance and other interests, and there is thus a danger of a
type of branding of potential commercial insurance clients,
employees, children in various social contexts, and others on the
basis of genetic testing for "susceptibility genes". Britain's
main bioethics advisory panel has now issued a strong warning
against attempts to use genetic screening to predict an
individual's susceptibility to common mental health disorders
such as schizophrenia and Alzheimer's disease. There is concern
that commercial over-the-counter genetic tests for such diseases
will soon be available, and that the voluntary industry and
government constraints now in place will not be sufficient to
prevent the widespread use of such tests. The Nuffield Council on
Bioethics, Britain's national forum in this domain, has therefore
suggested in its recent report that regulations could be needed.
The report is titled: *Mental disorders and genetics: the ethical
context*. In a letter to the journal *Nature*, a group from the
Nuffield Council writes: "Even if a number of susceptibility
genes were identified for a particular disorder, the Nuffield
Council takes the view that, without an understanding of their
interaction, they would not be adequate for predicting individual
risk in a clinical setting. It has therefore recommended that
genetic testing for susceptibility genes which offer relatively
low predictive or diagnostic certainty be discouraged unless and
until there is clear medical benefit to the patient."
-----------
D. Dickson (*Nature*)
Panel urges caution on genetic testing for mental disorders.
(Nature 24 Sep 98 395:309)
QY: David Dickson
----------
S. Thomas (Nuffield Council on Bioethics)
Restrict genetic susceptibility tests.
(Nature 24 Sep 98 395:317)
QY: Sandy Thomas, Nuffield Council on Bioethics, 28 Bedford
Square, London WC1B 3EG, UK
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 23Oct98
2. ASTROPHYSICS: FORMATION OF SUBSTELLAR OBJECTS
The term "brown dwarf" refers to an astronomical entity with a
mass less than 0.08 solar-masses. Because of this low mass, these
entities never become hot enough to begin hydrogen fusion in
their cores, and thus they are considered to be not a star, but a
"substellar" object. An object below about 0.01 solar-masses
(about 10 Jupiter masses) is usually regarded as a planet. Brown
dwarfs have an extremely low luminosity and are difficult to
detect, and they have been considered possible components of
galactic *dark matter. ... ... D.N.C. Lin et al report that
numerical simulations between two protostars, each surrounded by
a relatively massive disk, resulted in the ejection of some of
the disk material into a *tidal tail. A portion of this tail
condensed into an object with a mass in the range of 5 to 10
Jupiter masses. The authors suggest this mechanism may explain
the existence of the single objects of substellar mass that have
recently been discovered. The authors further suggest that the
formation of substellar objects along tidal filaments requires
the protostars to have massive disks, and that since such disks
evolve rapidly, these events must occur during the earliest phase
of protostellar evolution.
-----------
D.N.C. Lin et al (4 authors at 3 installations, US PL)
The formation of substellar objects induced by the collision of
protostellar disks.
(Science 25 Sep 98 281:2025)
QY: G. Laughlin
-----------
Text Notes:
... ... *dark matter: In general, in this context, the term "dark
matter" refers to material whose presence can be inferred from
its effects on the motions of stars and galaxies, but which
cannot be seen directly because it emits little or no radiation.
It is believed that at least 90 percent of the mass in the
Universe exists as some form or dark matter.
... ... *tidal tail: In general, a "tidal force" is the ability
of a massive body to raise tides on another body, and in this
context a "tidal tail" is a long extrusion resulting from such a
force.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 23Oct98
-------------------
Related Background:
GIANT PLANETS VS. BROWN DWARFS
Filipe D. Santos (Centro de Fisica da Universidade de Lisboa, PT)
presents a short review of current ideas concerning giant
extrasolar planets and *brown dwarf stars. The author makes the
following points: 1) The recent discoveries of planets orbiting
nearby Sun-like stars have revealed that planetary systems can be
surprisingly diverse. The initial discovery in 1995 of the planet
around the star 51 Pegasi was a surprise because it is apparently
a planet with mass about that of Jupiter (at least 0.44 Jupiter-
mass) and an orbital period of only 4.2 days, which implies that
the planet is 20 times closer to its star than Earth is to the
sun. 2) Seven additional planets around solar-type stars have
since been discovered, with Jupiter-mass values ranging from 0.44
to 6.84. 3) Two critical questions are, a) Where should we set
the dividing line that distinguishes massive planets from brown
dwarfs? and, b) What are the mechanisms leading to the formation
of massive planets and brown dwarfs? 4) Brown dwarfs are expected
to have masses smaller than the hydrogen-burning limit of
approximately 0.075 solar-mass (approximately 75 Jupiter-mass),
but probably larger than the deuterium-burning limit of 0.013
solar-mass (approximately 13 Jupiter-mass). 5) Like the companion
massive planets mentioned, several companion brown dwarfs to
solar-type stars have also been identified. One method of
investigating brown dwarfs involves *astrometric measurements,
and in all cases of brown dwarfs investigated by the astrometric
method, the masses are above or very close to the hydrogen-
burning limit. The extant data thus suggest that the distribution
of mass of brown dwarfs does not extend to masses as small as
giant planets. Also, the new measurements indicate that brown
dwarfs orbiting solar-type stars are very rare. 6) The discovery
of Jupiter-mass planets with orbits very close to their stars
poses a considerable problem, because it is difficult to
understand how such planets could form in place. (Five known
Jupiter-mass planets have orbital radii smaller than the distance
from Mercury to the Sun.) The suggestion has been made that these
planets formed at larger distances and migrated inward, but the
proposed migration mechanisms are not yet empirically
distinguishable. The author concludes: "Clearly the discovery of
planetary systems outside our solar system has opened a Pandora's
box of startling phenomena and new questions." QY: Filipe D.
Santos
(Science 17 Jul 98 281:359) (Science-Week 31 Jul 98)
-------------------
Related Background:
... ... *brown dwarf stars: Brown dwarf stars are formed by the
contraction of a lump of gas with a mass too small for nuclear
reactions to begin in the core. Such a star has a relatively
short-lived luminosity (approximately 100 million years) as the
result of conversion of gravitational energy to radiation. The
surface temperature of a brown dwarf is below 2500 degrees
kelvin. As recently as 1994, brown dwarfs were "theoretical"
stars, with no brown dwarfs considered to be unambiguously
identified.
... ... *astrometric measurements: This method of detection
infers the presence of a companion to a star by measuring the
position of the star as it orbits the center of mass of the
entire system. From the orbital inclination, the real mass of the
companion can be derived.
3. ON METEORITE IMPACT AND THE K/T MASS EXTINCTION
The Cretaceous period is the geological period ranging approxi-
mately from 146 million years ago to 65 million years ago, and
was apparently characterized towards its end by the rapid
extinction of a number of species, including the dinosaurs. There
have been five major extinctions according to the fossil record,
the Cretaceous extinction one of them, and the consensus is that
these extinctions were related to violent geophysical events,
perhaps asteroid impacts. The Chicxulub impact crater in the
Yucatan peninsula of Mexico is a large impact crater apparently
caused by a 10 kilometer diameter asteroid, the impact area
extending at least 100 kilometers from the impact center. Using
Argon(40)/Argon(39) isotope dating methods, this impact crater
has been dated with high precision at 64.98 million years ago,
which places the impact at the end of the Cretaceous, and the
most popular hypothesis to explain the Cretaceous extinction is
the global effect of the Chicxulub impact on the extant life
forms. This hypothesis was first proposed by Luis and Walter
Alvarez in the 1970s on the basis of non-terrestrial dust of
presumed cosmic origin in deposits at the K/T boundary, but the
Yucatan crater was unknown at that time and was not discovered
until the 1990s. ... ... In a short review of the meteorite
impact hypothesis and the K/T extinction, K.O Pope et al make the
following points: 1) Confirmation of the impact portion of the
Alvarez hypothesis marks a turning point in the study of the K/T
mass extinction, a turning point away from speculations about
possible causes and toward linking the extinctions to a single
catastrophic event. 2) Advances in computer modeling of the
impact, coupled with knowledge of the target rocks and their
behavior under the high-pressure shock, have shed light on what
happened during the first few seconds after impact. A key aspect
of the Yucatan site is that the upper 3 kilometers of rock were
rich in water, carbonate, and sulfate, which upon impact produced
about 200 gigatons each of SO(sub2) and H(sub2)O vapor and other
gases that greatly altered the properties of the stratosphere. 3)
Early work predicted that smoke and dust from the impact plunged
the Earth into a freezing blackout. Recent computer simulations
and atmospheric models indicate that within a few weeks to months
temperatures and light levels would have begun to rebound due to
the release of heat stored in the oceans and the coagulation and
fall of the dust and soot. The major effects of the dust and soot
would last about 1 year or less, but SO(sub2) and water vapors
would remain in the stratosphere and ultimately produce sulfuric
acid aerosols. Models indicate that a global aerosol cloud would
be continuously produced for approximately 12 years, blocking out
over 50 percent of the sunlight during the first 10 years. The
authors conclude: "Now that we have a better understanding of the
dynamics of the impact, gleaned from the discovery of the crater
and the studies that followed, we can begin to address a wide
range of complex global effects. There is much work ahead, but
the course is clear."
-----------
K.O. Pope et al (3 authors at 3 installations, US)
Meteorite impact and the mass extinction of species at the
Cretaceous/Tertiary boundary.
(Proc. Natl. Acad. Sci. US 15 Sep 98 95:11028)
QY: Kevin O. Pope, Geo Eco Arc Research, 2222 Foothill Blvd., La
Canada, CA 91011 US.
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 23Oct98
-------------------
Related Background:
ANALYSIS OF THE CHICXULUB IMPACT CRATER
... An important parameter of the [Chicxlulub] impact is the
total area of the impact crater, since that area would be related
to the amount of debris thrown into the atmosphere. Until now,
the usual figure for the largest dimension of the impact crater
has been approximately 300 kilometers. Morgan et al (20 authors
at 8 installations, UK US MX CA) now report an analysis of
seismic data of the Chicxulub impact, determining the diameter of
the transient cavity at about 100 kilometers. The authors suggest
this parameter is critical for constraining any proposed impact-
related effects on the Cretaceous environment, and that the
seismic data indicate the morphology of the crater is similar to
large impact structures observed on other planets such as Venus.
QY: Mike Warner
(Nature 4 Dec 97) (Science-Week 26 Dec 97)
4. ON THE CHEMICAL PHYSICS OF PROTEIN FOLDING
Proteins are polymers consisting of long chains of amino acid
residues, but that is only the beginning of their functional
chemistry. In biological systems, proteins assume various complex
high-order configurations ("folding"), and it is these
configurations that usually determine the roles of proteins as
biochemical entities in the biological system. An important goal
of molecular biology is to understand the structural and
functional features of proteins, in particular the mechanisms
responsible for specific protein folding. ... ... C.L. Brooks et
al present a short review of protein folding from the perspective
of chemical physics, and with a focus on the work of their own
group, the authors make the following points: 1) The question of
the mechanism of protein folding was once thought to be entirely
analogous to the question of mechanism in intermediary metabolism
or classical organic chemistry: the essential classical idea was
that a protein folding pathway involves a series of discrete
intermediates. Such discrete intermediates do occur in the late
stages of protein folding, but to answer the practical questions
of structure prediction and design, a new viewpoint on folding is
required. 2) The authors suggest this new viewpoint is that of
chemical physics rather than that of classical chemistry, and
that the chemical physics view requires a new set of theoretical
ideas, computational techniques, and major advances in
experimental methodology. 3) The authors suggest the theoretical
framework for the new chemical physics approach to protein
folding should be that of "*energy landscape theory", which
asserts that "a full understanding of the folding process
requires a global overview of the energy landscape." 4) The
authors propose that the protein folding energy landscape
resembles a partially rough funnel riddled with energy traps
where the protein can transiently reside. There is no unique
pathway but a multiplicity of convergent folding routes toward
the native state... The authors state that the essence of the
funnel energy landscape idea is competition between the tendency
toward the folded state and trapping because of "ruggedness" of
the funnel. 5) Concerning theoretical modeling, the authors point
out that simulations with detailed atomic models are extremely
intensive numerically, so that the number and size of systems
that can be studied is limited. Simulation models of intermediate
complexity have therefore been used. 6) Concerning experimental
approaches to exploring the energy landscape of protein folding,
there are various new methods involving the physical monitoring
of folding from an unfolded state, for example, monitoring in the
microsecond range following initiation of folding by a
nanosecond-scale step-change in ambient temperature. The authors
conclude: "Experiments are beginning to build up a *phase diagram
of folding kinetics that can be used to test and refine
theoretical models."
-----------
C.L. Brooks et al (4 authors at 3 installations, US)
Chemical physics of protein folding.
(Proc. Natl. Acad. Sci. US 15 Sep 98 95:11037)
QY: Charles L. Brooks, Scripps Research Institute 619-784-1000.
-----------
Text Notes:
... ... *energy landscape: The "energy landscape" here refers to
the contours of what is essentially a classical energy/entropy
diagram, with the native configuration state positioned at the
bottom of a deep potential well, in this case a funnel with sides
containing miniature energy wells or "traps".
... ... *phase diagram: A classical graphical representation of
the equilibrium relationships between phases of a chemical
system.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 23Oct98
-------------------
Related Background:
ON THE THERMODYNAMIC HYPOTHESIS OF PROTEIN FOLDING
Proteins are macromolecules that assume specific high-order
configurations, with each type of protein molecule folding into
the specific configuration necessary for its function. There are
two central aspects of this folding: it occurs extremely rapidly,
on the order of milliseconds to minutes after first synthesis of
the polymer, and the final configuration achieved is always
identical for each type of protein. Thus, protein A rapidly folds
into the protein A-conformation, and protein B rapidly folds into
the protein B-conformation. The question is how does this happen?
What are the variables that control these events? Experimental
techniques in the study of protein folding often involve
"denaturation" and "renaturation" of proteins in vitro.
Denaturation is the elimination of the folding of a protein by
changing ambient conditions such as temperature and pH, and
renaturation is the refolding of the protein molecule into the
native state following restoration of the original ambient
conditions. ... ... Govindarajan and Goldstein (University of
Michigan, US) present a theoretical analysis of current ideas
concerning protein folding. In 1969, C. Levinthal pointed out
that it is impossible for an unfolded protein to find the native
state (its final configuration) by randomly searching through the
entire space of possible conformations. This led Levinthal to
postulate that a protein must follow a specific path to the final
configuration, and therefore folding must be under kinetic
control (i.e., under the control of a specific sequence of
reactions). According to Levinthal, if the final folded state
turned out to be one of lowest configurational energy, it would
be a consequence of the biological evolution of specific chemical
reaction sequences ("kinetic control"), and not of physical
chemistry and the laws of thermodynamics ("thermodynamic
control"). In contrast to this idea of Levinthal, C. Anfinsen in
1973 concluded from the results of his numerous denaturation-
renaturation experiments that the native state of the protein is
indeed the global minimum of free energy, a conjecture that he
called the "thermodynamic hypothesis" of protein folding. The
debate between these two viewpoints of kinetic control and
thermodynamic control has continued for more than two decades,
with numerous experimentalists and theoreticians investigating
whether proteins reach their global free energy minimum in a
pathway-independent manner under thermodynamic control, or
whether the protein molecule follows a specific pathway to a
possibly local free energy minimum under kinetic control.
Govindarajan and Goldstein now report an exploration of the
validity of the thermodynamic hypothesis of protein folding by
simulation of the evolution of protein sequences, investigating
whether what is proposed by the thermodynamic hypothesis could
result through the process of protein evolution, the approach
involving certain assumptions concerning the effects of random
mutations on protein evolution. The authors report that their
results suggest that even if protein folding is under kinetic
control, a specific kinetic sequence will evolve so that the
native state of the protein molecule is most often the state of
minimum free energy. They point out that one consequence of this
is that theoretical methods that predict protein structure by
means of algorithms and search strategies not apparently
available to the protein itself may still be relevant as long as
the model produces an eventual state of minimum free energy.
QY: Richard A. Goldstein (richardg@umich.edu)
(Proc. Natl. Acad. Sci. US 12 May 98 95:5545)
(Science-Week 26 Jun 98)
-------------------
Related Background:
ON SIMULATED EVOLUTION AND PROTEIN FOLDING
... The "bioinformatics" approach is based on the idea of
recognition and identification in a protein of a new sequence of
amino acids similar or identical to other sequences in other
proteins for which structure and function are known. But this
approach encounters difficulties because of a lack of
understanding of what features of sequences have evolved to
encode stability and fast folding in proteins, and a lack of
understanding of which features are functional and which features
are adventitious. Better understanding of general principles that
govern kinetics and thermodynamics of protein folding can help to
reveal the signatures of protein sequences that are related to
folding. ... ... Mirny et al (3 authors at Harvard University,
US) report a study of sequences of fast-folding model proteins 48
residues long, the sequences generated by an "evolution-like
selection" toward fast folding. They report that such fast
folding model proteins exhibit a specific folding mechanism in
which all transition state conformations share a smaller subset
of common contacts (folding nucleus). The authors suggest their
results and analysis imply that for each protein structure there
is a small number of positions that are most crucial for fast
folding into that structure. Protein sequences that fold fast
into that structure may have evolved by placing into those
strategic folding-nucleus positions amino acids that provide
stabilization of the folding-nucleus.
QY: Eugene I. Shakhnovich (shakhnov@chemistry.harvard.edu)
(Proc. Natl. Acad. Sci. US 28 Apr 98 95:4976)
(Science-Week 12 Jun 98)
-------------------
Related Background:
BROWNIAN DYNAMICS SIMULATIONS OF PROTEIN FOLDING
Protein folding occurs on a time scale ranging from milliseconds
to minutes for a majority of proteins. Computer simulation of
protein folding, from a random configuration to the native
structure, is nontrivial due to the large disparity between the
simulation and folding time scales. In order to overcome this
limitation, simple models with idealized protein subdomains,
e.g., the diffusion-collision model, have gained some popularity.
The diffusion-collision protein-folding mechanism postulates the
early-stage formation of fluctuating quasiparticles (micro-
domains), which may be incipient secondary structures (alpha-
helices and beta-sheets) or hydrophobic clusters. These micro-
domains move via diffusion, and their coalescence leads to the
formation of folded proteins. Thus, the diffusion-collision model
reduces the complexity of the folding process from a consider-
ation of individual amino acids to that of the properties of a
few microdomains and their interactions. ... ... Rojnuckarin et
al (3 authors at 2 installations, US) present an analysis of the
folding of a 4-helix protein bundle within the framework of a
diffusion-collision model. Even with the simplifying assumptions
of a diffusion-collision model, a direct application of standard
Brownian dynamics methods would consume 10,000 processor-years on
current supercomputers. The authors circumvented this difficulty
by invoking a special Brownian dynamics simulation. They report
that a coarse-grained (i.e., crude) model of the 4-helix bundle
can be simulated in several days on current supercomputers, and
that such simulations yield folding times that are in the range
of time scales observed in experiments.
QY: Sangtae Kim (kim01@aa.WL.com)
(Proc. Natl. Acad. Sci. US 14 Apr 98 95:4288)
(Science-Week 15 May 98)
-------------------
Related Background:
A MODEL FOR BETA-HAIRPIN FOLDING IN PROTEINS
To be biologically active, proteins must adopt specific tertiary
configurations, a specific "folding". Although many natural
proteins spontaneously refold once they have been forced to
unfold, synthetic proteins are often produced in an insoluble
unfolded state and are thus inactive and useless until correctly
folded. One important aspect of protein folding is the kinetic
process, the rate at which folding occurs. Were a single
conformation to be found by random searching of all the possible
conformations, the number of years required would range from
10^(7) to 10^(66). In actuality, protein folding occurs on the
scale of microseconds, so there is clearly much yet to be learned
about these macromolecules. Probabilistic analysis of the
kinetics and energetics of a system of entities can be made
within the framework of the theory of statistical mechanics, and
the application of this theory is an important part of current
research into protein folding. In general, protein chains fold
into alpha-helices or beta-sheet structures, and the minimal
beta-structural element is the "beta-hairpin", a turning of the
polypeptide chain that has the shape of a hairpin. As far as
experimental methods are concerned, analysis of folding kinetics
in response to temperature variation is one of the key experi-
mental procedures, and there are now sophisticated methods for
temperature control provided by the coupling of computers and
laser physics. One such method is laser "temperature jump"
spectroscopy, which involves jump-heating (jump-discontinuity
heating) of a small volume of aqueous solution in a short time
domain coupled with spectroscopy in some part of the electro-
magnetic spectrum. Munoz et al (4 authors: National Institutes of
Health, US) used a nanosecond laser temperature jump apparatus
coupled with laser fluorescence excitation to study the kinetics
of folding of a protein beta-hairpin consisting of 16 amino acid
residues, and they report that folding of the beta-hairpin occurs
at 6 microseconds at room temperature, which is 30 times slower
than alpha-helix formation. The authors offer a statistical
mechanical model that provides a structural explanation for their
observations.
QY: Victor Munoz
(Nature 13 Nov 97) (Science-Week 5 Dec 97)
-------------------
Related Background:
A SYNTHETIC OLIGOMER THAT MIMICS PROTEIN FOLDING
The existence of helical folding in polymers such as proteins and
nucleic acids is of extreme importance in biological systems, but
biological polymers are not the only polymers to assume such
special folding arrangements. Beta-peptides, for example, non-
biological polymers synthesized from beta amino acids, form
helices stabilized by hydrogen bonds. Now Jeffrey S. Moore et al
(University of Illinois Urbana-Champaign, US) report that syn-
thetic oligomers with an all-carbon backbone, linear phenyl-
acetylenes with ester-substituted benzene rings linked to one
another by acetylene groups, spontaneously fold into a stable
helical configuration in acetonitrile, and that this apparently
involves a "solvophobic" mechanism similar to the hydrophobic
collapse model of protein folding in water. In both systems, the
phenylacetylene oligomers and biological proteins, hydrophobic
groups associate to form a compact structure that excludes the
solvent. The phenylacetylene oligomers have longitudinal cavities
that might be used for binding metals and other reactive species.
The authors also suggest such systems could be used in the design
and construction of synthetic enzymes.
QY: J. S. Moore, Univ. Illinois Urbana-Champaign, Chemistry (217)
333-0722 (Science 19 Sep 97) (Science-Week 3 Oct 97)
-------------------
Related Background:
PROTEIN-FOLDING MECHANISMS IN PROKARYOTES VS. EUKARYOTES
In biological systems, proteins are the molecules that do most of
the biological work, and the various proteins are the ultimate
expression of the genome of any organism. As polymers, proteins
are similar to the polymers known to polymer chemists, but the
chemical activities of proteins (and their biological functions)
depend mostly on higher-order folding into specific configur-
ations rather than on quasi-crystalline backbone arrays, as is
often the case in non-biological polymer chemistry. It is these
specific configurations that are responsible for the important
specificity and high catalytic power of the proteins that are
enzymes. The configurations, in turn, are an ultimate result of
amino acid sequences which form the backbone of proteins,
sequences which are not simple, as are the backbone sequences of
most non-biological polymers, but are specific, cryptic (coded),
and heterogenous. It is now recognized that complex proteins
usually have more than one folding domain, each involving a
sequence of 100 to 300 amino acids. The entire folding
architecture of a complex protein must be precisely constructed
in order for protein functionality to exist. Which provokes the
question of how the specific folding of particular proteins is
ensured by the biological system. The answer is evident for
simple proteins in vitro: the final configuration is
predetermined by the amino acid sequence, there being a single
energetically favored configuration that will always be attained
at equilibrium. This is Anfinsen's Rule, first proposed by the
protein biochemist C. B. Anfinsen more than 30 years ago. In
vivo, however, and particularly for complicated proteins, the
situation is more involved. This week W. J. Netzer and F. U.
Hartl (Sloan Kettering Cancer Center, NY US; Max Planck Inst.
Biochemistry, Martinsried DE) report an analysis of the
differences between protein folding in prokaryotes (organisms,
such as bacteria, without membrane-bound organelles such as the
nucleus) and eukaryotes (organisms with membrane-bound
organelles). Perhaps the most interesting difference is that in
prokaryotes protein folding is delayed until translation (final
synthesis by the ribosome) is completed (post-translational
folding), while in eukaryotes folding of each protein domain
occurs as each domain is translated (co-translational folding).
One result is that new prokaryote proteins can often be
misfolded. There are helper proteins at work in both prokaryotes
and eukaryotes to chaperon the proteins to their final
configurations, but there is still more possibility for errors in
the prokaryotes. One important consequence of this analysis is
that when bacteria are genetically engineered to synthesize human
protein for clinical use, the susceptibility of prokaryote
protein synthesis to folding errors must be considered.
(Nature 24 Jul 97) (Science-Week 8 Aug 97)
5. ON THE MOLECULAR BIOLOGY OF SPERM-EGG FERTILIZATION
Sexual reproduction, defined in this context as the fusion of two
haploid cells (gametes) during fertilization to form a diploid
zygote, occurs in almost all eukaryotes. Fertilization is in
effect the cellular bridge between generations, but although it
has been studied for more than a century, it remains one of the
least understood fundamental biological processes [*Note #1]. In
general, most animal sperm have an *acrosomal vesicle anterior to
the nucleus. The opening (*exocytosis) of the vesicle is required
for fertilization. Animal eggs are contained within an egg
envelope, with a gelatinous matrix external to the envelope.
... ... V.D. Vacquier presents a review describing the molecular
diversity in the steps of sperm-egg interaction, with examples of
the apparent rapid evolution of fertilization molecules. The
author makes the following points: 1) A generalized scheme of
animal fertilization involves 5 steps in sperm-egg interaction.
Spermatozoa may be *chemotactically attracted to swim toward the
egg by egg-released molecules (step A). Depending on the species,
sperm bind to the egg envelope either before or after the opening
of the sperm acrosomal vesicle (steps B and C). Soon after
exocytosis of the acrosomal vesicle occurs (called the "acrosomal
reaction"), a hole is created in the egg envelope through which
the sperm passes (step D). Once the sperm is through the
envelope, the two cells fuse (step E) and the sperm nucleus is
incorporated into the egg cytoplasm. 2) One or more of the 5
steps can exhibit species specificity, meaning that if
spermatozoa and eggs are from the same species, their interaction
leading to fusion is more efficient than if two gametes are from
different species. 3) The author presents details of current
knowledge of the molecular events involved in each of the 5
steps. Concerning chemoattraction, the author notes that although
sperm chemoattraction to egg-derived factors has been
phenomenologically demonstrated in most invertebrate and some
vertebrate groups, the chemical nature of the attractants is
known in but a few species. The structures of known sperm
chemoattractants are chemically unrelated, indicating that they
evolved independently in different phyla. For example, in *brown
algae, female gametes release species-specific 11-carbon cyclo-
olefinic hydrocarbons, which in picomolar concentrations attract
male gametes. In the *ciliate protozoan Euplotes, small mating-
type-specific proteins control the cellular activities of
chemotaxis, *conjugation, and growth. In marine invertebrates,
sperm swim up gradients of an egg-derived peptide... Although
human sperm are attracted to the *follicular fluid surrounding
the human egg cell, the chemoattractant remains unknown.
-----------
V.D. Vacquier (University of California San Diego)
Evolution of gamete recognition proteins.
(Science 25 Sep 98 281:1995)
QY: Victor D. Vacquier, Univ. of Calif. San Diego 619-534-2230
-----------
Text Notes:
... ... *Note #1: When sperm were first discovered by Leeuwenhoek
and others in 1678, sperm were thought to be parasites living in
semen (the term "spermatozoa" literally means "sperm animals").
Although Leeuwenhoek soon came to believe that each sperm
contained a preformed embryo, most investigators did not accept
this idea and continued to regard sperm as unimportant in
reproduction. The first experimental evidence suggesting the
importance of sperm in reproduction came from experiments by
Lazzaro Spallanzani in the 18th century. Spallanzani demonstrated
that filtered toad semen devoid of sperm would not fertilize
eggs. But he concluded that the viscous fluid retained by the
filter paper -- and not the sperm -- was the agent of
fertilization. Like those who preceded him, Spallanzani believed
the sperm cells were parasites. His experiment stands, but not
his conclusion. It was not until 1824 that sperm cells were
proposed as the active agents in fertilization by J.L. Prevost
and J.B. Dumas, but several decades would pass before the idea
was generally accepted by most biologists. The involvement of
sperm cells in the fertilization of egg cells is therefore a
relatively modern idea.
... ... *acrosomal vesicle: (acrosome) The acrosome is a
specialized penetrating vesicular organelle at the tip of a
spermatozoan. It contains several enzymes (e.g., hyaluronidase)
that are released when the sperm contacts the egg cell, and which
effectively puncture the egg cell envelope and/or egg cell
membrane.
... ... *exocytosis: In general, any process in which an
intracellular vesicle fuses with the plasma membrane of the cell
with a resultant release of the contents of the vesicle into the
extracellular phase.
... ... *chemotactically attracted: In general, the term
"chemotaxis" refers to any movement of an organism in response to
chemical concentration gradients.
... ... *brown algae: (Phaeophyta) Mostly brown seaweeds of
coastal and marine environments. Brown algae produce *flagellated
motile sperm cells that fertilize egg cells.
... ... *flagellated: A flagellum is a long threadlike extension
providing locomotion for a cell.
... ... *ciliate protozoan: (Ciliophora) Cilia are short
threadlike extensions, hundreds usually present on an individual
ciliated cell, the cilia undergoing synchronized movements to
produce locomotion of the protozoan (e.g., the common
Paramecium).
... ... *conjugation: This is the usual reproductive process in
ciliated protozoa, but it also occurs in some species of
bacteria. The essential process is physical contact of two cells
with transfer of genetic material between them.
... ... *follicular fluid: In this context, the liquid
environment of the mammalian egg-cell containing follicle.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 23Oct98
6. 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 TRANSMEMBRANE FORM OF THE PRION PROTEIN
A transgenic mouse is a mouse into which genetic material from
another organism has been transferred, the transferred and
incorporated new mouse genes then being expressed with the
resultant production of specific proteins. 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"). The "endoplasmic reticulum" is an extensive
system of flattened membranous sacs in the cytoplasm of cells,
important in protein and lipid biosynthesis, translocation of
synthesized molecules, and continuous with the nuclear envelope.
... ... Hegde et al (9 authors at Univ. of California San
Francisco, US) report a study with transgenic mice expressing
prion protein mutations that alter the relative ratios of the
topological forms of the molecule. Expression of a particular
endoplasmic reticulum transmembrane form (Ctm) of the protein
produced neurodegenerative changes in mice similar to those of
some genetic prion diseases, and brains from these mice contained
this form of the protein but not the isoform responsible for
transmission of prion diseases. The authors suggest that aberrant
regulation of protein biogenesis and topology at the endoplasmic
reticulum can result in neurodegeneration, and that proteins
undergoing topological regulation such as Ctm-prion protein may
be involved in neurogenerative diseases besides those currently
attributed to prions.
QY: Vishwanath R. Lingappa ; Stanley B.
Prusiner, Univ. of Calif. San Francisco 415-476-4044.
(Science 6 Feb 98) (Science-Week 20 Feb 98)
-------------------
Related Background:
ON PROTEIN FOLDING IN PRION AND AMYLOID DISEASES
What is remarkable about prions is that although they behave as
infectious agents, they are 100 times smaller than viruses and
their mechanism of replication is unknown. All the prion diseases
are apparently associated with the accumulation in the brain of
an abnormal protease-resistant isoform of the prion protein PrP.
In other words, an abnormal variant of the normal PrP is somehow
copied or produced by the disease process, which can be initiated
by introducing infectious prion into the system. Denaturation is
an irreversible change in solubility and other properties of
proteins when they are exposed to various conditions, including
heat and an acidic environment. The denatured protein essentially
loses all its higher order structure and becomes a simple
uncoiled/unfolded polymer. A lysosome is a cytoplasmic
membrane-bound vesicle 5 to 8 nanometers in diameter and
containing a variety of glycoprotein hydrolytic enzymes used to
digest foreign material or defective organelles. The term
"amyloid" refers to a group of chemically diverse proteins
composed of linear nonbranching aggregated fibrils that occur as
pathological extracellular deposits in various diseases
(including several neurodegenerative diseases).
... ... J. Kelly (Scripps Research Institute, US), in a comment-
ary on prion proteins, suggests that the conversion of normal to
pathogenic prion protein likely occurs in the partially denatur-
ing environment of a cellular compartment such as a lysosome,
where the lower pH environment (or another factor-environment)
"effects the conformational changes that facilitate amyloid and
prion self-assembly". The author suggests that using the
structure of normal prion protein to design high-affinity ligands
to what appear to be critical higher-order molecular structure
regions may lead to an understanding of the structural changes
required for pathogenic amyloid fibril formation.
QY: Jeffrey W. Kelly, Scripps Research Institute 619-784-1000
(Proc. Natl. Acad. Sci. US 3 Feb 98)
(Science-Week 20 Feb 98)
-------------------
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 (cf. background material
below). ... ... 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 hypo-
theses of the nature of the causative agent of the transmissible
spongiform encephalopathies are being misrepresented and dismiss-
ed. 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 protect-ive 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
(Nature 22 Jan 98)
-------------------
Related Background:
MORE EVIDENCE THAT PRION PROTEIN BINDS COPPER IN VIVO
... A chelate is a metal coordination complex in which one ligand
coordinates at two or more points to the same metal ion, and a
glycine chelate is a chelate involving the amino acid glycine.
Brown et al (13 authors at 4 installations, DE CA UK) report that
the amino-terminal domain of normal prion protein exhibits 5 to 6
sites that bind copper presented as a glycine chelate, that
genetically engineered mice deprived of prion protein show severe
copper reductions in various cell membrane fractions and altered
electrophysiological responses to excess copper. The authors
suggest their findings indicate that normal prion protein can
exist in a copper-metalloprotein form in vivo, and that like
other cuproproteins implicated in the pathogenesis of neurolog-
ical disease, prion proteins may regulate copper distribution.
QY: Hans Kretschmer
(Nature 18/25 Dec 97)
-------------------
Related Background:
AN APPARENT INVOLVEMENT OF PRION PROTEIN IN COPPER BINDING
Copper is essential as a trace metal for the function of certain
enzymes and other biomolecules, but even a moderate excess can be
highly toxic in certain tissues. ... At a recent meeting of the
Society for Neuroscience (24-30 Oct New Orleans, US) David Brown
(Univ. of Cambridge, UK) reported that normal prion protein
apparently binds copper ions and thus protects neurons against
the cytotoxic effects of the metal. He suggests the transformed
disease-causing prion protein might not be able to perform this
important function. But this idea is not without problems, since
there is evidence that in genetically engineered mice without
normal prion protein there is no resulting pathology -- which in
turn suggests it is the transformed protein that is directly
pathogenic. (Science 21 Nov 97)
-------------------
Related Background:
PRION DISEASES AND BOVINE SPONGIFORM ENCEPHALOPATHY
... Prions are apparently able to induce certain other proteins
into pathogenic conformations, and these proteins in turn can
cause the same effect in other proteins of the same class. None
of this is yet well understood. One human disease in which prions
have been strongly implicated is Creutzfeldt-Jakob disease (CJD),
which appears to have a genetic basis in about 15% of the cases.
Recently, there has been much concern in Europe concerning the
possible infection of humans who might eat meat from prion-
infected cows. The fears were at first dismissed by the medical
community because of lack of evidence to support the idea, but
recently some evidence has appeared, and the level of concern has
increased significantly. Stanley B. Prusiner, who recently
received the Nobel Prize in Physiology and Medicine for his work
with prions, reviews the relation between prion diseases and the
current bovine spongiform encephalopathy crisis. The author urges
more attention to the fatal disorders of protein conformation
that are apparently involved in prion diseases, and he suggests
studies of prion proteins may have important applications to
understanding Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis.
QY: S. B. Prusiner, Univ. of Calif. San Francisco, Neurology
(415) 476-4044.
(Science 10 Oct 97)
-------------------
Related Background:
... Andrew F. Hill et al (8 authors at 3 installations, UK)
report that the biological and molecular transmission charac-
teristics of a variant of human Creutzfeldt-Jakob disease are
consistent with it being the human counterpart of bovine spongi-
form encephalopathy; and M. E. Bruce et al (13 authors at 4
installations, UK) report that interim results of transmissions
of sporadic classical Creutzfeldt-Jakob disease and the new
variant Creutzfeldt-Jakob disease to mice, such transmissions
producing effects apparently identical to those produced by
transmissions of bovine spongiform encephalopathy to mice,
provide strong evidence that the same agent strain is involved in
both bovine spongiform encephalopathy and Creutzfeldt-Jakob
disease.
QY: John Collinge, Prion Disease Group, Imperial College, London
UK; M. E. Bruce
(Nature 2 Oct 97)
-------------------
Related Background:
... Rudi Glockshuber et al (Swiss Federal Institute of Tech-
nology) report the first complete determination of the
structure of a full-length prion protein: 208 amino acids,
including a trio of helices and an unfolded tail 97 amino acids
long. Evidence indicates it is the unfolded tail that may be
involved in disease processes. Chemical techniques were used to
reconstitute the folding of the full-length protein, and then
nuclear magnetic resonance was used to determine the structure.
This may be an important step to understanding how prions become
pathogenic. (F.E.B.S. Letters 18 Aug 97)
-------------------
Related Background:
... Thomas Blattner et al (University of Zurich, CH) report that
mutant mice that do not produce normal PrP cannot be infected by
the scrapie producing prion variant that ordinarily infects mice
that do produce the normal protein. They conclude that transfer
of infectivity to the central nervous system, the major event in
the disease process, is crucially dependent on the expression of
PrP in some as yet unknown tissue compartment. The fact that
there is at least a useful laboratory animal model for the study
of these poorly characterized infectious agents leaves one
optimistic that an understanding of the essentials of prion
pathogenesis may soon be forthcoming. QY: Adriano Aguzzi
(Nature 4 Sep 97)
7. HUMAN NEUROCOGNITIVE ARCHITECTURE: A PLASTICITY MODEL
In human neurobiology, the term "cognition" refers to
intellectual functions that include perceiving, remembering,
imagining, conceiving, understanding, judging, and reasoning. And
one of the central problems of human neurobiology is to
understand the neurological substrates for all of these aspects,
and also to understand the evolution of these aspects where such
evolution can be delineated. In other words, from a neurological
standpoint, the questions in this context are how does the mind
work and how did it get that way? From any research perspective,
that is what is called a tall order. One view, proposed by
evolutionary psychologists, is based on the presumption that the
demands on *hunter-gatherer life during the *Pleistocene epoch
generated a vast array of evolutionary cognitive adaptations that
determine current human cognition and behavior. But many
neurobiologists disagree with this approach, and instead focus on
the intrinsic *plasticity of the human brain, and in particular
on the intrinsic plasticity of the human neocortex, an intrinsic
plasticity manifested during individual development -- a response
to the individual's physical and psychological environment. These
two approaches are in essence restatements of the classical
nature vs. nurture controversy, but the classical character of
the question does not make the question less important. ... ...
P. La Cerra and R. Bingham present a critique of the evolutionary
psychology approach to the understanding of cognitive processes
and offer an alternative model which they propose is more in
agreement with the current evidence in neurobiology. The authors
make the following points: 1) An extensive literature underscores
the enormous functional plasticity of the *neocortex, a
distinguishing characteristic of mammals. This evidence supports
the position that cortical representational features are
systematically constructed by the dynamic interaction between
environmentally derived neural activity and intrinsic neural
growth mechanisms. 2) The information-processing capacities of
the neocortex are largely constructed in response to the problem
domains confronting the individual throughout development, and
these constructions remain modifiable throughout the life
history. 3) This neurobiological account of the ongoing
construction of the human neurocognitive architecture contrasts
sharply with the account of evolutionary psychologists, who
conceive of the mind as a confederation of information-processing
adaptations, each of which evolved in response to a problem posed
by Pleistocene selection pressures. 4) Numerous methodological
problems and theoretical flaws call the validity of the
evolutionary psychological paradigm into question... Evolutionary
psychologists have suggested that investigation of the neural
correlates of behavior is not mandatory for the study of
cognitive adaptations. This failure to reconcile theoretical
claims with neurobiological data has veiled from evolutionary
analyses the functional organization of the information-
processing circuits that comprise the human neurocognitive
architecture. 5) The authors propose that the problems faced by
ancestral *hominids and their mammalian predecessors would have
required an adaptively flexible online information-processing
system, and would have driven the evolution of a functionally
plastic neural substrate, the neocortex, rather than a
confederation of evolutionary prespecified social cognitive
adaptations. 6) The authors propose that human cognitive
processes result from the activation of constructed cortical
representational networks, which reflect probabilistic
relationships between sensory inputs, behavioral responses, and
adaptive outcomes. The construction of these networks throughout
development, and their modification throughout experience, are
mediated by subcortical circuits that are responsive to the life
history regulatory system. The authors conclude: "The model we
have outlined emphasizes individual differences as the product of
an evolved self-adapting system, a neurocognitive architecture
that is unique by design." In summary, the La Cerra and Bingham
idea is essentially that human neurocognitive systems (the
neurocognitive "architecture") are "constructed" during
individual development and experience, rather than inherited as
preformed circuits (structures) selected by evolutionary
pressures during and before the Pleistocene epoch. The authors
term their approach "constructivist".
-----------
P. La Cerra and R. Bingham (Calif. Inst. of Tech., US)
The adaptive nature of the human neurocognitive architecture: An
alternative model.
(Proc. Natl. Acad. Sci. US 15 Sep 98 95:11290)
QY: Roger Bingham
-----------
Text Notes:
... ... *hunter-gatherer life: The consensus among
paleoanthropologists is that sometime between the beginning of
*hominid bipedalism (the "hominini") and the appearance of Homo
sapiens, perhaps about 2 to 3 million years ago, there occurred a
divergence from essential ape-like behavior and the emergence of
a hunter-gatherer existence, the hunting of animals and the
gathering of plants, both for food.
... ... *hominids: In general, any primate in the human family.
... ... *Pleistocene epoch: A geological epoch with the time-
frame 2.5 million years ago to 11,000 years ago. This was the
epoch of rapid hominid evolution, and the appearance of cattle
and the modern horse.
... ... *plasticity: In neurobiology, the term "plasticity" is
the name given to the capacity of neural tissue to adjust to
change. One variant of this concerns the dependence of the
"wiring" of the nervous system on its input. Another variant
concerns the degree to which one region can under certain
conditions assume the function of another region. Plasticity does
not occur everywhere in the nervous system, but it is often
evident in the cerebral cortex of the brain, the cortex being the
thin layer of cells apparently responsible for higher analysis of
sensory input, language, ideation, and other so-called higher
functions lumped together in the category "cognitive processes".
... ... *neocortex: The most recently evolved part of the
cerebral cortex.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 23Oct98
8. GENE THERAPY INHIBITION OF XENOREACTIVE ANTIBODY PRODUCTION
Antigens are chemical moieties, often proteins, that provoke
immune responses, and the "epitope" is the small region of the
antigen apparently involved in binding or recognition of the
antigen by antibodies of the immune system. Xenotransplantation
is the transplanting of non-human organs into humans. Since human
donor organs for transplantation to patients with failed or
failing organs are scarce, xenotransplantation has been
considered as an alternative. Pigs are the most likely species to
serve as donors for clinical xenotransplantation because of their
similarity to humans. The major barrier to transplantation across
discordant species, such as from pig to human, is rejection of
the graft mediated by xenoreactive natural antibodies that bind
the carbohydrate epitope known as alpha-Gal on donor tissues.
This epitope is synthesized by a glucosyl transferase enzyme
called "alpha-GT".... ... J.L. Bracy et al now report that
introduction of a functional alpha-GT gene by *retroviral gene
transfer into *bone marrow cells of mice resulted in the
cessation of production by the mice of antibodies to alpha-Gal.
The authors suggest their results indicate that genetic
engineering of bone marrow may overcome *humoral rejection of
discordant xenografts and may be useful for inducing *B-cell
tolerance. The authors further suggest that similar approaches
may also be applicable to induction of tolerance in other
disorders, including *autoimmune diseases.
-----------
J.L. Bracy (3 authors at 2 installations, US)
Inhibition of xenoreactive natural antibody production by
retroviral gene therapy.
(Science 18 Sep 98 281:1845)
QY: John Iacomini
-----------
Text Notes:
... ... *retroviral gene transfer: Retroviruses are single-
stranded RNA viruses that have an enzyme called reverse
transcriptase, and with this enzyme the viral RNA is used as a
template to produce viral DNA from cellular material. This DNA is
then incorporated into the host cell's genome, where it codes for
the synthesis of viral components. Most approved gene therapy
trials involve the use of retroviral vectors (carriers) for gene
transfer into cultured cells later administered to patients. The
retroviral vectors that are used are altered retroviruses that do
not replicate or produce infection, so the retroviruses are
merely carriers of genetic material into target cells, where the
genetic material is incorporated into the host cell genome.
... ... *bone marrow cells: In general, bone marrow is the
fibrous and cellular tissue filling the cavities of bones. Red
marrow produces red blood cells, white blood cells, and the cell
fragments called "platelets". There are several types of immune
system-related white blood cells, some of which are first formed
in bone marrow and mature elsewhere (e.g., T-cells mature in the
thymus gland). B-cells are white blood cells that mature in bone
marrow and which are directly responsible for the production of
antibodies.
... ... *humoral rejection: Refers to any graft rejection
involving antibody action by immune system components of blood or
other body fluids.
... ... *B-cell: (see above) White blood cells that mature in
bone marrow and which are directly responsible for the production
of antibodies.
... ... *autoimmune diseases: In general, any pathology that
involves a self-immunological process against the individual's
own cells or tissues. Classified as human autoimmune diseases are
rheumatoid arthritis, systemic lupus erythematosus, rheumatic
fever, Addison's disease, multiple sclerosis, type 1 diabetes
mellitus, etc.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 23Oct98
-------------------
Related Background:
XENOTRANSPLANTATION: A GROUP OF LETTERS
Xenostransplantation involves the surgical replacement of
defective human organs by animal organs. There are at present two
primary concerns in this area: 1) The use of genetically
engineered animal organs is of great appeal because human organs
are usually rejected by the human immune system, and a patient
receiving a human organ must be on a lifetime regimen of immune-
system-suppressant drugs; and 2) the possibility that the genome
of the animal cells may contain the sequences of endogenous
viruses, and these sequences may result in the appearance of
pathogenic viral forms dormant in the animal but suddenly active
in the human, and then be transmitted from human to human with
pandemic consequences. ... ... In a group of 3 letters from 5
authors in the journal Nature, various views are presented
concerning potential benefits and dangers of xenotransplantation.
A.S. Daar (Sultan Qaboos University, OM) suggests that
containment of xenotransplantation induced viral diseases may
work in the US, but any epidemic that starts may involve
countries other than the US, and that the problem is therefore
global rather than national. Salomon et al (3 installations, US),
representing the American Society of Transplant Physicians and
the American Society of Transplant Surgeons reject the call for a
moratorium on clinical trials of xenotransplantation in the US.
P. Macchiarini (Hopital Marie-Lannelongue Paris-Sud, FR) suggests
that virologists opposed to xenotransplantation clinical trials
have never been at the bedside of patients, and "cannot feel the
frustration of patients who die while waiting for an organ..."
(Nature 5 Mar 98) (Science-Week 20 Mar 98)
-------------------
Related Background:
US REJECTS MORATORIUM ON XENOTRANSPLANTATION TRIALS
Organ xenotransplantation is the transplantation of organs from
one species into another species, and in particular the
transplantation of animal organs into humans. In the context of
this report, "xenotransplantation" refers to animal-to-human
organ transplantation. As immunologists and molecular biologists
achieve increasing control over the biology of the transplant-
ation process, there has been a running debate about the relative
weights of the benefits and dangers of animal-to-human trans-
plantation. Despite mounting criticism from a number of
researchers, including vociferous opposition by the journal
Nature and its subsidiary Nature Medicine, US health officials
will apparently allow limited clinical trials of xenotransplant-
ation to proceed. At a meeting on 21 and 22 January (1998),
officials from the Food and Drug Administration, the Centers for
Disease Control and Prevention, and the National Institutes of
Health outlined plans involving stringent safeguards. There will
be rigorous standards to maintain disease-free donor animals, a
national registry of organ recipients, a tissue bank of samples
from donor animals and recipients, and a national policy advisory
committee. The guidelines are expected to be in final form by
this coming summer. QY: Gretchen Vogel
(Science 30 Jan 98)
-------------------
Related Background:
MORE CONTROVERSY CONCERNING POLICY ON XENOTRANSPLANTS
... In an editorial and several associated articles, the journal
Nature is now calling for an international moratorium on clinical
trials involving xenotransplantation, saying "a well-organized
and informed public debate should precede any action by
regulatory agencies." In a letter in the same issue of the
journal, Bach and Fineberg (Harvard University, US) also call for
a moratorium "on all forms of clinical xenotransplantation". QY:
Fritz H. Bach
(Nature 22 Jan 98) (Science-Week 6 Feb 98)
-------------------
Related Background:
XENOTRANSPLANTATION CONFLICT BETWEEN SURGEONS AND VIROLOGISTS
... This week the U.S. Food and Drug Administration hosted a
meeting to reduce an apparent conflict between surgeons and
virologists over how to proceed [re xenotransplantation]. In
brief, the surgeons want accelerated research to produce
genetically engineered animal organs that will not be rejected by
the human immune system, while the virologists are not at all
happy with the idea, and are urging extreme caution in the use of
animal tissues in transplantation surgery. The animal organs of
most relevance are those from the pig, and it has already been
demonstrated that pig retrovirus can be infectiously transmitted
to human cells. On the other hand, it has also been demonstrated
that the surfaces of pig cells can be easily genetically
engineered so that organ rejection might be eliminated. Despite
the conflict, and the real danger of endogenous virus infections,
the need for artificial organs is so great there is a consensus
that the field of xenotransplantation will move forward no matter
what the obstacles.
(Nature 31 Jul 97) (Science-Week 8 Aug 97)
-------------------
Related Background:
ENDOGENOUS RETROVIRUSES A DANGER IN XENOTRANSPLANTATION
... An initial problem [in xenotransplantation] was hyperacute
rejection of pig tissue caused by preexisting human antibodies to
a specific sugar (alpha-gal) on the surface of all pig cells.
These antibodies will target any alpha-gal coated cells for
destruction. Chemical methods were then devised to either remove
these specific antibodies or decrease the expression of alpha-gal
in the donor cells. Now C. Patience et al report that pigs harbor
endogenous retroviruses that are capable of infecting human cells
in vitro. Since endogenous retroviruses are incorporated into the
genome, where they act as molecular parasites that are capable of
producing disease, there is now the disturbing possibility that
pig retroviruses might infect human cells following
xenotransplant- ation. Even more disturbing is the possibility
that yet unidentified pig DNA or RNA viruses exist in a human
transmissible form.
(Nature Medicine 3:282 1997) (Science-Week 26 Jun 97)
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