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.

June 8, 2001 -- Vol. 5 Number 23

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Translation:
For: "handled with extreme care throughout the experiments"
Read: not dropped on the floor.
-- C.D. Graham Jr.

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Section 1
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Contents of this Issue (Full reports in Section 2):

1. MESOSCOPIC PHYSICS: ON MESOSCOPIC ELECTRONIC CIRCUITS
Mesoscopic electronics is the study of the movement of electrons
in extremely small circuits, circuits composed of conductors,
capacitors, and inductors but on the order of hundreds of
nanometers to several microns in scale. At these dimensions, and
at low temperatures, quantum mechanics dominates all of the
properties of circuit elements

2. CHEMICAL PHYSICS: ON FEMTOCHEMISTRY
The term "femtosecond spectroscopy" refers to a method for
analyzing transition states and intermediates in chemical
reactions, events that occur on the scale of 10 to 100
femtoseconds. Ahmed H. Zewail (California Institute of
Technology, US) was awarded the 1999 Nobel Prize for Chemistry
for his invention of the femtosecond spectroscopy technique.

3. ORGANIC CHEMISTRY: ON SOLID-STATE REACTIVITY
Although the solid state is the least reactive of the three forms
of matter, not all solids are chemically inert, and in recent
years chemists have made intensive studies of the chemical
reactions of crystals of organic compounds, and several important
principles of solid-state reactions have been formulated.

4. NEUROSCIENCE:
ON RETROVIRUSES AND THE PATHOGENESIS OF SCHIZOPHRENIA
Nearly every possible etiology has been proposed to explain the
pathogenesis of schizophrenia. The idea that viruses may be
involved in the etiology of schizophrenia is not new, but as
molecular biology continues to advance in techniques and
insights, evidence and considerations of a virus involvement in
schizophrenia continue to recur.

5. PHYSIOLOGY: ON PAIN AND INFLAMMATION
In mammals the limbs have a high density of sensory endings that
can detect touch, heat, and acute pain -- sensations that are
rapidly transmitted to the brain by the nerves. Drugs that
silence sensory nerves work well to relieve acute pain, but when
local inflammation has occurred, blocking nerve impulses produces
little pain relief.

6. MEDICAL BIOLOGY: A CLINICAL TEST OF THE PLACEBO EFFECT
The administration of a placebo to a patient is a psychological
input that may or may not produce a physiological effect
depending on the patient and on the circumstances. A recent study
of the placebo effect is being touted in the popular press
as proof that the placebo effect does not exist. The study,
however, does not demonstrate that at all.

7. IN FOCUS: ON THE HISTORY OF AMERICAN NEUROLOGY
American neurology came out of the American Civil War, attempted
to take over American psychiatry and failed, and then went off by
itself to focus on neurological diseases without psychiatric
symptoms.

8. FROM THE SCIENCEWEEK ARCHIVE:
CELL BIOLOGY: FUNCTIONAL MODULES IN BIOLOGICAL ORGANIZATION
Although living systems obey the laws of physics and
chemistry, the notion of function or purpose differentiates
biology from other natural sciences. A major challenge for
science in the 21st century is to develop an integrated
understanding of how biological cells and organisms survive and
reproduce.

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Section 2
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1. MESOSCOPIC PHYSICS:
ON MESOSCOPIC ELECTRONIC CIRCUITS AND QUANTUM COMPUTING
In general, the term "quantum computing" refers to the use of
quantum mechanical effects as the basis of computer processors.
One way to engage these effects is at the level of mesoscopic
physics, the physics of nanoscale and microscale interactions.
... ... Jan van Ruitenbeek (University of Leiden, NL) presents a
commentary on current research on mesoscopic electronic circuits
and quantum computing, the author making the following points:
     1) The author points out that mesoscopic electronics is the
study of the movement of electrons in extremely small circuits,
circuits composed of conductors, capacitors, and inductors but on
the order of hundreds of nanometers to several microns in scale.
At these dimensions, and at low temperatures, quantum mechanics
dominates all of the properties of circuit elements, so the
common laws used by engineers in the design and analysis of
electronic circuits are useless. An apparently complete quantum
field theory of mesoscopic circuits has recently been proposed,
but the theory is so complicated that it can only be applied to
simple systems.
     2) The author (van Ruitenbeek) points out that properties of
electrons cause three complications at mesoscopic scales:
... ... a) The motion of electrons at such scales must be
described in terms of quantum waves. Like light waves, quantum
waves are scattered by objects such as the edge of the metallic
conductor and defects or impurities present in its interior. This
scattering results in an interference pattern, making properties
such as resistance extremely sensitive to variations in the
circuit geometry.
... ... b) Another complication arises from the charge of the
electron, which results in a repulsive force between all of the
electrons in the circuit. For example, for very small capacitors,
adding a single electron to the many electrons already inside the
capacitor plates may be sufficient to raise the capacitor energy
to a level high enough to prevent the next electron from
entering. In general, the motion of any electron in a mesoscopic
circuit can influence all other electrons in the circuit, making
the calculations complicated.
... ... c) Finally, one must account for the correlations in the
motion of the electrons, correlations that give rise to phenomena
such as superconductivity.
     3) The author points out that one attractive application of
mesoscopic circuit analysis is quantum computing. The quest to
create a quantum computer has spread into many areas of physics,
including quantum optics and atomic physics, but the mesoscopic
physics approach has the advantage that one can design and
fabricate circuits consisting of many individual elements with
various properties. The author concludes: "The challenge of
developing a full-size quantum computer puts our ability to
fabricate circuits and our understanding of these systems to an
extreme test. It is becoming increasingly likely that to make a
quantum computer we will have to integrate the knowledge and
techniques from many fields, combining tools from mesoscopic
physics with those from quantum optics and molecular physics."
-----------
Jan van Ruitenbeek: Noisy times ahead.
(Nature 22 Mar 01 410:424)
QY: Jan van Ruitenbeek: ruitenbe@phys.leidenuniv.nl
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Summary by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
APPLIED SCIENCE: ON PHYSICS AND THE INFORMATION REVOLUTION
Since the dawn of the modern computer era, physicists and
computer technologists have been involved in a symbiosis --
physicists active in research in the fundamental science
underlying computer technology, and computer technologists
designing the high-speed machines that physicists use to solve
quantitative problems previously off-limits to physicists when
such machines were not available. Of course, this symbiosis is a
particular instance of the general interaction between science
and technology, but the interaction between physicists and
computer technologists is perhaps more direct and clear than any
other, and it continues to be mutually vital. Many people, both
physicists and computer technologists, believe that because of
intrinsic limitations in current computer technology, a new phase
in the "information revolution" will soon be required if advances
in computing power are to occur, and that this new phase will
depend on new contributions of fundamental physics, particularly
quantum physics.
... ... J. Birnbaum and R.S. Williams (Hewlett-Packard, US)
review the current state of computer technology and what must be
done to sustain the momentum of the past few decades. The authors
make the following points:
     1) The first stored-program electronic computer was ENIAC
(Electronic Numerical Integrator and Computer), built in 1946.
This was a vacuum-tube machine that could 5000 numbers in one
second. ENIAC could calculate the trajectory of an artillery
shell in only 30 seconds, compared to 40 hours required by a
human with a mechanical calculator. The machine contained 17,468
vacuum tubes, weighed 60,000 pounds, occupied 16,200 cubic feet,
and consumed 174 kilowatts (233 horsepower). The authors point
out that the amount of energy expended by ENIAC to compute a
single shell trajectory was comparable to that of the explosive
discharge required to actually fire the shell. In 1954, nine
years later, ENIAC was still the fastest computer on Earth, when
it was turned off because the US Army could no longer justify the
expense of running and maintaining it. In 1949, a panel of
experts confidently predicted that the future of computer
technology would involve a machine such as ENIAC with only 1500
vacuum tubes, weighing only 3000 pounds, requiring only 10
kilowatts of power, and about the size of an automobile. So much
for the experts: at the present time, a palmtop computer is
thousands of times more powerful than ENIAC.
     2) The authors point out that the reason for the now-
laughable error of the experts in 1949 was that their prediction
was based on the wrong foundation: reasonable extrapolation of
the in-place vacuum-tube technology. Although the transistor,
which represented a "disruptive technology" (i.e., a technology
that could replace vacuum tubes in computers), had already been
invented, the transistor was completely ignored. The authors
point out that even though transistors as discrete devices had
significant advantages over vacuum tubes and progress on
transistors was steady during the 1950s, the directors of many
large electronic companies believed that the vacuum tube held an
unassailable competitive position. These companies were
eventually eclipsed by companies that invested heavily in
transistor research and development and were thus poised to
exploit new advances. The authors state: "There are eerie
parallels with the situation today."
     3) "Moore's Law", first formulated by Gordon Moore of Intel
Corporation, states that the number of transistors that can be
built on a chip increases exponentially with time. During the
past 28 years, computer technology has exhibited a factor-of-four
increase every 3.4 years in the number of bits that can be stored
on a memory chip. But there is also "Moore's Second Law": the
cost of building fabrication facilities to manufacture chips has
also been increasing exponentially. Thus the cost of
manufacturing chips is increasing significantly faster than the
market is expanding. In 1995, to build a single fabrication
facility required approximately US$1 billion, or approximately 1
percent of the entire annual chip market. By the year 2010, a
fabrication facility could cost US$30 billion to US$50 billion,
or approximately 10 percent of the total annual market at that
time.
     4) The authors point out that by 2010 the individual
transistors in computer circuits will be turned on or off by the
addition or removal of only 8 electrons on the gate of a
transistor, compared to approximately 1000 electrons today. The
statistics of small numbers will become a significant factor, and
the ability to distinguish between zero and one in a digital
circuit will be severely compromised. By 2020, the continuation
of geometric scaling would mean that less than one electron would
be available to switch the transistor. The authors state: "That
would require getting around a fundamental physical limitation,
and not just an engineering obstacle. Yet, many researchers and
corporate executives seem to have a blind optimism that somehow
that will happen... If there is to be any hope of sustaining the
economic benefits to the national economy that come from
containing Moore's Law, then we have no choice but to develop
quantum switches and the means to interconnect them."
     5) Concerning nanostructured devices, the authors suggest
that perhaps the search for a way to make such devices should
concentrate on wires and switches, because those are the
components that will allow high-defect-tolerant systems to be
built. The most desirable types of wires would be those that
could conduct information without having to conduct electric
current (e.g., information conducted in the form of the phase of
a charge density wave). The switches should be a form of
nonvolatile memory that requires the expenditure of power only to
open or close a circuit, but not to maintain the state of the
switch.
     6) The authors conclude: "Today, we have the silicon field-
effect transistor, but we speculate that a quantum-state switch
could be better. Many laboratories are now engaged in basic
research on fabricating materials into arbitrary shapes and
sizes. They are searching for the device concept that will lead
to a disruptive new technology. Breakthroughs will significant
advances in the understanding of fundamental issues and will
undoubtedly act as the foundation for new mathematical and
scientific disciplines. Those companies that convert the
breakthroughs into a new manufacturable technology will be the
survivors of the quantum age of information processing."
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J. Birnbaum and R.S. Williams: Physics and the information
revolution.
(Physics Today January 2000)
QY: Joel Birnbaum, Chief Scientist, Hewlett-Packard, Palo Alto,
CA US.
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 31Mar00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
ON THE FUTURE OF QUANTUM COMPUTING
     The superposition principle in quantum mechanics derives
from the superposition principle in pure mathematics, which
states that for a linear homogenous differential equation, if
y(sub1)(x) and y(sub2)(x) are solutions, then so is y(sub1)(x) +
y(sub2)(x). In other words, for such a differential equation, the
sum of solutions is itself a solution. A corollary is that any
physical system which can be described by a linear homogeneous
differential equation (or a set of such equations) will obey the 
superposition principle.
     This principle produces various applications and
formulations in the physics of oscillating systems. In quantum
mechanics, where the time-independent Schroedinger equation is a
linear homogenous differential equation and systems are described
by oscillating probability amplitudes, the principle of
superposition results in the postulate that any state function of
a given quantum mechanical system corresponding to a given
observable (e.g., energy) can be expressed as a linear expansion
of the eigenstates of the system for the same observable, with
the term "eigenstate" referring to any one of the wave function
solutions (probability amplitude function solutions) to the
Schroedinger equation for the given boundary conditions.
     Another way to state the quantum mechanical principle of
superposition is as follows: If a physical state of a system can
be realized in a number of different but unknown distinct ways,
then the actual state of the system is a superposition for each
distinct way, and there is a distinct probability amplitude for
each way in which the physical state can be realized.
     This is essentially a restatement of Feynman's rule: The
probability amplitude of an event that can occur in two or more
indistinguishable ways is the sum of the probability amplitude
for each considered separately.
     And Feynman's rule, in turn, is an analog of Bayes' rule in
classical probability theory: The probability of an event which
can occur in two indistinguishable ways is the sum of the
probabilities for each way considered separately.
     The quantum mechanical principle of superposition is of
major importance in considerations of quantum computing,
particularly in connection with "decoherence". In this context,
the term "decoherence" refers to the observed destruction of the
superposition of pure quantum states, the destruction due to
interactions with uncontrolled or unknown physical effects (e.g.,
interactions with the environment of the system). It is currently
believed that quantum computers, which manipulate quantum states
rather than classical "bits", may someday be able to perform
tasks that would be inconceivable with conventional digital
technology.
... ... John Preskill (California Institute of Technology, US)
presents a review of current problems in the development of
quantum computers, the author making the following points:
     1) Formidable obstacles must be overcome before large-scale
quantum computers can become a reality. A major difficulty is
that quantum computers are highly susceptible to making errors.
The considerable theoretical power of a quantum computer derives
from its ability to process *coherent quantum states (i.e.,
quantum states obeying the principle of superposition), but the
coherence of such quantum states is very easily damaged by
uncontrolled interactions with the environment (decoherence). 
     2) The indivisible unit of classical information is the
"bit", which takes one of two possible values, 0 or 1. Any amount
of classical information can be expressed as a sequence of bits.
A classical computer executes a series of simple operations
("gates"), each of which acts upon a single bit or pair of bits.
By executing many gates in succession, the computer can evaluate
any *Boolean function of a set of input bits.
     3) Quantum information can also be reduced to elementary
units, called quantum bits or "qubits". A qubit is a two-level
quantum system (e.g., the spin of an electron). A quantum
computer executes a series of elementary quantum gates, each of
which is a *unitary transformation that acts on a single qubit or
pair of qubits. By executing many such gates in succession, the
quantum computer can apply a complicated unitary transformation
to a particular initial state of a set of qubits. Finally, the
qubits can be measured, the measurement outcome the final result
of a quantum computation.
     4) It was Richard Feynman (1982) who suggested that using a
quantum computer might enormously speed up finding solutions to
certain difficult computational problems. David Deutsch (1985),
developing the idea further, observed that a quantum computer can
invoke the equivalent of a massive parallelism by operating on a
coherent superposition of a vast number of classical states. In
fact, a single computation acting on just 300 qubits can achieve
the same effect as 2^(300) simultaneous computations acting on
classical bits, more than the number of atoms in the visible
Universe. It is not possible to build a conventional computer
with that many processors.
     5) There is, however, a problem of principle that is
potentially very serious for the future of quantum computers --
namely, decoherence. Unavoidable interactions with the
environment will cause the quantum information stored in a
quantum computer to decay, thus inducing errors in the
computation. Decoherence occurs very rapidly in complex quantum
systems, which is the reason we never observe macroscopic
superpositions. If quantum computers are ever to be capable of
solving difficult problems, a method must be found to control
decoherence and other potential sources of error.
     6) At present, quantum information technology remains in the
pioneering stage. It is currently possible to do experiments
involving a few qubits and a few quantum gates. For a quantum
computer to compete with a state-of-the-art classical computer,
we will need machines with hundreds or thousands of qubits
capable of performing millions or billions of operations. The
technology clearly has far to go before quantum computers can
assume their rightful place as the world's fastest machines. But
recent advances in the theory of quantum error correction suggest
there are no insurmountable obstacles, and quantum computers of
the 21st century may indeed unleash the vast computational power
woven into the fundamental laws of physics.
-----------
John Preskill: Battling decoherence: The fault-tolerant quantum
computer.
(Physics Today June 1999)
QY: John Preskill, Dept. of Theoretical Physics, California
Institute of Technology 818-395-6811.
-----------
Text Notes:
... ... *coherent quantum states: In order for a system to be
used to process and transfer information, the system must be
"coherent" in its parts. In quantum physics, coherence is a
matter of locking of phase differences between wave functions.
The wave functions of two or more particles are said to be
coherent if the phase difference between their wave functions
remains constant. So if new quantum electrodynamic information
processing devices are to be developed, methods must be found to
keep the quantum states of the parts of the system coherent long
enough for information to be processed and transferred from one
place to another. 
... ... *Boolean function: In general, a "Boolean function" is
any function assembled by the application of the operations AND,
OR, NOT to a set of variables and elements whose common domain is
a "Boolean algebra". The term "Boolean algebra" refers to a form
of symbolic logic devised by George Boole (1815-1864), such an
algebra providing a mathematical procedure for manipulating
logical relationships in symbolic form. In the realm of
computers, Boolean algebra is an important tool enabling the bits
0 and 1 to be related to logical functions of the computer.
... ... *unitary transformation: In this context, the term
"unitary transformation" refers to a linear operator whose
adjoint is equal to its inverse. The "adjoint" A* of an operator
A is an operator such that for all f and g in the domain of A:
(Af,g) = (f,A*g). If A* = A, then A is said to be self-adjoint.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 24Sep99
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
ON QUANTUM COMPUTING WITH MOLECULES
In general, in quantum mechanics, the "superposition principle"
holds that any two quantum mechanical states can be combined in
infinitely many ways to form states that have characteristics
intermediate between those of the two that are combined.
Entanglement is unique to quantum mechanics, and involves a
relationship (a "superposition of states") between the possible
quantum states of two entities such that when the possible states
of one entity collapse to a single state as a result of suddenly
imposed boundary conditions, a similar and related collapse
occurs in the possible states of the entangled entity no matter
where or how far away the entangled entity is located. The idea
of quantum computing received a significant impetus in 1994 when
Peter W. Shor of ATT (US) proposed that quantum entanglement and
superposition could in principle be used to accomplish many
numerical tasks, in particular the factoring of large numbers,
much faster than the best classical calculator. Since the
security of many important encryption systems depends on the
difficulty of factoring large numbers, quantum computing suddenly
became of great practical importance, and Shor's algorithm
provoked computer scientists to learn about quantum mechanics,
and physicists to begin serious considerations of the
requirements of a quantum computer science. ... ... Gershenfeld
and Chuang (2 installations, US), review the theoretical bases
and current status of quantum computing, in particular their own
work applying nuclear magnetic resonance techniques. The authors
point out the following: 1) In classical computation, the state
of a bit (the fundamental unit of information) is specified by
one number, 0 or 1. An n-bit binary word in a typical computer is
thus described by string of n zeroes and ones. In contrast, in a
quantum computer, the qubit (the fundamental unit of information)
might be represented by an atom in one of two different states, 0
or 1, but unlike classical bits, qubits can exist simultaneously
as 0 or 1, with the probability for each state given by a
numerical coefficient. 2) A quantum computer promises to be
immensely powerful because it can be in multiple states at once
(superposition), and because it can act on all its possible
states simultaneously. Thus, a quantum computer could naturally
perform myriad operations in parallel, using only a single
processing unit. This is the essence of the idea of quantum
computing, although one must understand the expression here is
quite general. 3) The authors have investigated the construction
of a quantum computer based on the nuclear magnetic resonance
behavior of a simple molecular liquid [chloroform, CHCl(sub3)],
with the 2 possible quantum mechanical "spin" states of atoms as
the basic qubit states. Since chloroform is a simple molecule,
the fundamental limitation in this particular system is the small
number of qubits. The authors and other researchers are actively
working to increase the size of the basic molecule in
experimental quantum computing systems, and thus increase the
number of available qubits. 4) The authors conclude: "All along,
ordinary molecules have known how to do a remarkable kind of
computation. People were just not asking them the right
questions."
QY: Neil Gershenfeld, Massachusetts Institute of Technology 617-
253-1000.
(Scientific American June 1998) (Science-Week 12 Jun 98)
[Editor's note: Experimental details of the method and algorithm
used in the above mentioned NMR quantum computing technique were
recently presented by Chuang et al (5 authors 4 installations,
US) in Nature 14 May 1998 393:143] 
-------------------
Related Background:
A SILICON-BASED NUCLEAR SPIN QUANTUM COMPUTER
B.E. Kane (University of New South Wales, AU) presents an
analysis of quantum computing and a new scheme for implementing a
quantum mechanical computer. The author proposes: 1) Although the
concept of information underlying all modern computer technology
is essentially classical, "physicists know that nature obeys the
laws of quantum mechanics." The idea of a quantum computer has
been developed theoretically over several decades in order to
understand the capabilities and limitations of machines in which
information is treated quantum mechanically. 3) Logical
operations carried out on the qubits and their measurement to
determine the result of the computation must obey
quantum-mechanical laws. 4) Quantum computation can in principal
only occur in systems that are almost completely isolated from
their environment and which consequently must dissipate no energy
during the process of computation, conditions that are extra-
ordinarily difficult to fulfill in practice. The author presents
a scheme for implementing a quantum computer on an array of
nuclear spins located on donors in silicon. Logical operations
and measurements can in principle be performed independently and
in parallel on each spin in the array. Specific electronic
devices are described for the manipulation and measurement of
nuclear spins, and the author suggests that the development of a
silicon-based quantum computer can benefit from already existing
highly developed silicon technology.
QY: B.E. Kane: kane@newt.phys.unsw.edu.au
(Nature 14 May 98 393:133) (Science-Week 12 Jun 98)
For more information: http://scienceweek.com/swfr.htm

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2. CHEMICAL PHYSICS: ON FEMTOCHEMISTRY
     The prefix "femto-" is from "femton", the Scandinavian word
for "fifteen". The term "femtosecond spectroscopy" refers to a
method for analyzing transition states and intermediates in
chemical reactions, events that occur on the scale of 10 to 100
femtoseconds. Ahmed H. Zewail (California Institute of
Technology, US) was awarded the 1999 Nobel Prize for Chemistry
for his invention of the femtosecond spectroscopy technique. In
this method, the molecules being studied are mixed together, and
an ultrafast laser then beams in two pulses, a "pump pulse" that
supplies energy to drive the molecules into a transition state,
and a second and weaker pulse, the "probe pulse", which is tuned
to the wavelength necessary for detecting the original molecules
or an altered form of the molecules. The pump pulse starts the
reaction; the probe pulse examines the ongoing reaction. By
studying characteristic spectra from the molecules, the structure
of the molecules at the transition state can be determined, as
well as the structure of intermediate products.
... ... J.S. Baskin and A.H. Zewail (California Institute of
Technology, US) present a review of current femtochemistry laser
techniques, the authors making the following points:
     1) The authors point out that atoms can now be seen,
observed in motion, and manipulated, bringing the microscopic
world and its language into a new age that covers domains of
length, time, and number. Resolutions of length down to the scale
of atomic distance (1 angstrom), and resolutions of time down to
the scale of atomic motion (femtoseconds) have been achieved. The
confinement ("trapping") and spectroscopy of a single ion or
electron and the trapping and cooling of neutral atoms have also
been achieved. All these achievements have been recognized by the
awarding of Nobel Prizes to *scanning tunneling microscopy
(1986), single-electron and single-ion trapping and spectroscopy
(1989), laser trapping and cooling (1997), and laser
femtochemistry (1999).
     2) The authors point out that before femtochemistry, the
actual atomic motions involved in chemical reactions had never
been observed in real time despite the rich history of chemistry
over 2000 years. Chemical bonds break, form, or change
geometrically with great rapidity, and whether in isolation or in
any other phase, this ultrafast transformation is a dynamic
process involving displacements of electrons and atomic nuclei.
The speed of atomic motion is approximately 1 kilometer per
second, so to record atomic scale dynamics over a distance of an
1 angstrom, the average time required is approximately 100
femtoseconds. The focus of femtochemistry is the very act of
atoms within molecules (reactants) rearranging themselves to form
new molecules (products). With femtosecond time resolution, one
can "freeze" atoms in motion and study the evolution of molecular
structures as reactions unfold and pass through their transition
states, thus providing a motion picture of the transformation.
     3) The authors point out that the requirements for
femtochemistry experiment are easily determined. For a molecular
structure in which atomic motions of a few angstroms typically
characterize chemical reactions, a detailed mapping of the
reaction process will require a spatial resolution of less than 1
angstrom, more than 8 orders of magnitude smaller than that
needed to photographically freeze, for example, the macroscopic
motion of a trotting horse. Therefore, the equivalent shutter
speed required to observe with high definition molecular
transformations in which atoms move at speeds of the order of
1000 meters per second is 0.1 angstroms divided by 1000 meters
per second, which equals 10^(-14) seconds or 10 femtoseconds.
While this time scale has been recognized theoretically as the
time scale for chemical reactions since the 1930s, it became
possible to directly see the detailed steps in molecular
transformations for the first time in the 1980s with the
development of femtosecond lasers. Such minute times and
distances mean that molecular-scale phenomena are governed by
quantum mechanical principles. Specifically, at the scale of
atomic masses and energies, the quantum mechanical particle-wave
duality of matter comes into play, and the notions of positions
and velocities common to everyday life must be applied with
caution.
-----------
J.S. Baskin and A.H. Zewail: Freezing atoms in motion: Principles
of femtochemistry and demonstration by laser stroboscopy.
(J. Chem. Ed. June 2001 78:737)
QY: J.S. Baskin, California Institute of Technology, Pasadena CA
91125 (US).
-----------
Text Notes:
... ... *scanning tunneling microscopy: In scanning tunneling
microscopy, an atomically sharp metal tip is brought in atomic
proximity (e.g., 0.5 to 1 nanometer) to a flat surface so that
electrons can *tunnel between the two systems. The probe is
slowly moved across the surface and raised and lowered so as to
keep the tunneling current constant. A computer-generated contour
map of the surface is thus produced. The technique can resolve
individual atoms, but requires electrically conducting materials.
... ... *tunnel: "Tunneling" is a quantum mechanical phenomenon
involving an effective penetration of an energy barrier by a
particle resulting from the width of the barrier being less than
the wavelength of the particle.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
OBSERVATION OF TRANSIENT STRUCTURES IN CHEMICAL REACTIONS
The term "femtochemistry" refers to the probing of chemical
reactions on the femtosecond [10^(-15) seconds] time scale. In
such experiments, nuclear motions on the time scale of bond
breaking and bond making are monitored by using an initiation
pulse to establish time-zero and probing pulses to view the
motion. Typical probes are optical and infrared spectroscopy,
*photoelectron spectroscopy, *mass spectroscopy, *nonlinear
optical techniques, and *diffraction methods. Ultrafast *electron
diffraction is considered a unique method for studies of the
structural changes of complex molecular systems.
... ... J. Cao et al (California Institute of Technology, US) now
report a direct ultrafast electron diffraction study of the
evolution of short-lived intermediates in the course of a
chemical change. The authors observed the transient intermediate
in the *elimination reaction of 1,2-diiodotetrafluoroethane
[C(sub2)F(sub4)I(sub2)] to produce the corresponding ethylene
derivative by the breakage of 2 carbon-iodine C-I bonds. The
authors report that the evolution of the *ground-state
intermediate [C(sub2)F(sub4)I radical] is directly revealed in
the population change of a single chemical bond, namely the
second C-I bond. The elimination of 2 iodine atoms was shown to
be nonconcerted, with a reaction time of the second C-I bond
breakage of 17 +- 2 picoseconds. The authors suggest this
apparent leap in the ability to record structural changes on the
picosecond and shorter timescales bodes well for many future
applications in complex molecular systems.
-----------
J. Cao et al: Ultrafast electron diffraction and direct
observation of transient structures in a chemical reaction.
(Proc. Natl. Acad. Sci. US 19 Jan 99 96:338)
QY: Ahmed H. Zewail: zewail@cco.caltech.edu
-----------
Text Notes:
... ... *photoelectron spectroscopy: This is a technique for
determining the *ionization potentials of molecules, the sample a
gas or vapor irradiated with a narrow beam of ultraviolet
radiation. The photoelectrons produced in accordance with the
"*photoelectric effect" (and Einstein's photoelectric equation)
are passed through a slit into a vacuum region to be deflected by
magnetic or electrostatic fields to exhibit an energy spectrum
with peaks corresponding to the ionization potential of the
molecule. The technique also provides information about the
vibrational energy level of the formed ions.
... ... *ionization potentials: In general, the ionization
potential is the energy required to produce an ionization of a
molecule. Specifically, the minimum energy required to remove an
electron from a specified atom or molecule to such a distance
that there is no electrostatic interaction between ion and
electron.
... ... *photoelectric effect: In general, the liberation of an
electric charge by electromagnetic radiation incident on a
substance.
... ... *mass spectroscopy: The mass spectrometer is a
device in which molecules are ionized and the accelerated ions
are separated according to their mass to charge ratio. The
relative abundance of isotopes or other ionized species can thus
be determined by measuring positive or negative ion currents.
... ... *nonlinear optical techniques: In general, nonlinear
optics is a branch of optics concerned with the optical
properties of matter subjected to intense electromagnetic fields.
In order for nonlinearity to be exhibited, the external field
must not be negligible with respect to the internal fields of the
atoms or molecules constituting the substance. The nonlinearity
concerns the relation between induced polarization and the
strength of the external electromagnetic radiation. In linear
optics, this relation is linear. The methods of experimental
nonlinear optics are highly dependent on the use of lasers to
generate sufficiently intense external fields.
... ... *diffraction methods: In general, in this context,
diffraction methods are any methods that utilize the wave
properties of radiation to analyze structure (e.g., x-ray
diffraction).
... ... *electron diffraction: In general, electron diffraction
is diffraction of a beam of electrons by atoms or molecules. The
fact that electrons can be diffracted in a manner similar to the
diffraction of x-rays and light is a demonstration that particles
can act as waves. Electrons show diffraction effects with
molecules and crystals in which the interatomic spacing is
comparable to the wavelength of the beam of electrons. The
advantage is that the electron beam wavelength can be set by
adjusting the voltage. Due to the fact that electron beams have
very low penetrating power, electron diffraction is not useful
for investigations of crystal structure but is instead used to
measure bond lengths and angles of molecules in gases.
... ... *elimination reaction: In general, an "elimination
reaction" is a chemical reaction involving elimination of some
portion of a reactant compound, with the production of a second
compound.
... ... *ground-state intermediate: In general, in this context,
the "ground state" is the lowest energy electronic, vibrational,
or rotational state of an atom, molecule, or ion.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 19Mar99
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
NEW LASER STUDIES OF ULTRAFAST REACTION DYNAMICS
Most chemical reactions involving two or more reactants occur in
the presence of a solvent, a significant presence, since the
solvent molecules are always interacting with the reactants
themselves in some important manner. To fully understand what
occurs between the main reactants, one must understand the
participation of the solvent in the reaction sequence. The
problem has been that these solvent-reactant events are of
extremely short duration, on the order of femtoseconds
[10exp(-15) sec], and it is only recently, with the availability
of laser pulse techniques, that physical chemists can observe
chemical bonds break and reform in real time. B. Jefferys
Greenblatt et al (University of California Berkeley, US) have now
described the use of such techniques to examine the influence of
a solvent on the photodissociation of a molecular cluster ion
(Iodine-Argon). Apparently, in a single experiment, they have
presented "a comprehensive picture of the recombination,
relaxation, and evaporation processes that follow
photodissociation of a diatomic molecular ion in a cluster."
(Science 13 June 97) (Science-Week 19 Jun 97)
For more information: http://scienceweek.com/swfr.htm

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3. ORGANIC CHEMISTRY: ON SOLID-STATE REACTIVITY
Although the solid state is the least reactive of the three forms
of matter, not all solids are chemically inert, and in recent
years chemists have made intensive studies of the chemical
reactions of crystals of organic compounds.
... ... J.R. Sheffer and C. Scott (University of British
Columbia, CA) present a commentary on current research in solid-
state organic chemistry, the authors making the following points:
     1) The authors point out that x-ray crystallography is the
key experimental technique that permeates and informs the entire
field of solid-state organic chemistry. Without detailed
knowledge of the shapes and packing arrangements of molecules in
crystals, solid-state behavior would be virtually impossible to
understand. But x-ray structures have been obtained on a routine
basis only since modern computing methods emerged in the early
1960s.
     2) The authors point out that in 1967, Gerhard M.J. Schmidt,
considered the father of modern solid-state organic chemistry,
was the first to systematically explore the relation between the
structure of organic crystals and their chemical behavior.
Schmidt formulated the "topochemical postulate", which states
that reaction in the solid state occurs with a minimum amount of
atomic or molecular movement. Bimolecular reactions are thus
expected to take place only between nearest neighbors, and the
molecular structure of the product(s) is expected to reflect the
geometric relation between these neighbors in the crystal
lattice. As a result of these restrictions, solid-state reactions
are generally more selective than those in solution: fewer
products are formed, and greater control is exerted over product
structure and stereochemistry.
     3) The authors point out that in 1975, M.D. Cohen, a
colleague of Schmidt, formulated the concept of the "reaction
cavity". According to this concept, molecules in crystals can be
visualized as existing in rigid 3-dimensional cavities formed by
their nearest neighbors. As the central molecule reacts, its
geometry changes within the cavity. Reactions that involve minor
changes in reactant geometry are topochemically allowed (i.e.,
they proceed without restriction from the cavity walls), whereas
reactions with transition-state geometries that do not fit within
the cavity will be strongly disfavored. The topochemical
postulate and reaction-cavity concept have stood the test of
time, with numerous studies confirming their validity.
     4) The authors conclude: "There will always be a need to
carry out organic chemical reactions in the liquid phase, not
least because not all organic compounds form solids at convenient
temperatures and pressures, but solid-state organic chemistry
represents a unique and rapidly growing interdisciplinary field
with important practical applications in materials science and
chemistry."
-----------
J.R. Scheffer and C. Scott: Stepping it up.
(Science 2 Mar 01 291:1712)
QY: John R. Scheffer: scheffer@chem.ubc.ca
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm

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4. NEUROSCIENCE:
ON RETROVIRUSES AND THE PATHOGENESIS OF SCHIZOPHRENIA
     The diagnoses of various behavioral disorders are for the
most part made in the absence of defined etiology, and because of
this there is a necessary focus on symptoms rather than causes,
and the diagnostic categories are consequently often ambiguous
and labile. Schizophrenia is a serious mental disease (or complex
of mental diseases) that occurs worldwide with a prevalence
ranging from 0.2% to 1%. Its chief characteristic is a chronic
impairment of function involving disturbances of thought,
perception, feelings, and behavior, particularly the appearance
of the classical psychotic symptoms of delusions, hallucinations,
and logic dysfunction. A major worldwide mental health problem,
schizophrenia has been the focus of an enormous number of
research studies during the past century, and nearly every
possible etiology has been proposed to explain its pathogenesis.
The idea that viruses may be involved in the etiology of
schizophrenia is not new, but as molecular biology continues to
advance in techniques and insights, evidence and considerations
of a virus involvement in schizophrenia continue to recur.
     When viruses are categorized in terms of their genomes,
there are two general types: a) viruses with a DNA genome (DNA
viruses), and b) viruses with an RNA genome (RNA viruses). RNA
viruses are unique: only in these viruses do we find genomes
consisting of RNA; all other biological entities, DNA viruses,
bacteria, plant cells, animal cells, etc., contain DNA genomes.
     There are more than 2500 groups of different viruses now
recognized and at least partially characterized. In each case,
for both DNA and RNA viruses, once it enters the host cell, the
general challenge for the virus is the same: directly or
indirectly, the viral genome must bring about the production of
the *messenger RNAs needed by the host ribosomes to produce the
specific proteins necessary for replication of the complete
virus.
     With DNA viruses, the DNA genome acts as the template for
the production of messenger RNA. With RNA viruses, however, the
process is more complicated.
     In general, with some types of RNA viruses, the RNA genome
("plus-sense"; "positive-strand") can itself act as messenger RNA
for host *ribosomes; while other types of RNA viruses, the RNA
genome ("minus-sense"; negative-strand) must first produce a
complementary RNA, which then acts as messenger RNA for the host
ribosomes. The replication process in minus-sense RNA viruses is
complex, since host cells do not carry enzymes that can
polymerize complementary RNA from an RNA template, and such
viruses therefore must carry their own special enzymes ("RNA-
dependent transcriptases") to achieve this synthesis.
     A third and special type of RNA virus is the so-called
"retrovirus", of which there are many versions. 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 host-cellular material. This
DNA is then incorporated into the host cell's genome, where it
codes for the production of messenger RNA and the ultimate
synthesis of viral components. The HIV virus, for example, is a
retrovirus.
     Concerning retroviruses, if the incorporation of the viral
DNA into the host cell DNA takes place in *germ-line cells
(oocytes) or early embryos, then the retroviral genes become
"endogenous" -- they become a permanent part of the organismic
genome and are reproduced from generation to generation. It is
believed by some researchers that all vertebrates, for example,
have endogenous retroviruses that are the "footprints" of ancient
retroviral infections. For the most part, the significance of
endogenous retroviruses is unclear, but there is some evidence
suggesting they may contribute to the development of diseases in
several animal species and possibly also in humans.
     It is important to emphasize that the nomenclature here is
not rigorous, since an endogenous retrovirus is not an actual
virus, but one or more pieces (complete or incomplete genes) of a
retroviral genome embedded in a host genome. These endogenous
retroviral genes may be eternally dormant, sporadically activated
and repressed, or always operational. A disease related to the
activation of an endogenous retrovirus is therefore not an
"infectious" disease in the classical sense, although the
original introduction into the host germ-line of the retroviral
genetic material may indeed have involved an infection. As a
further complication, there is evidence that in some diseases
interactions of endogenous retroviral genes and infectious
(exogenous) retroviral genes may occur.
... ... David A. Lewis (University of Pittsburgh, PA) presents a
commentary on some recent work (H. Karlsson et al: Proc. Natl.
Acad. Sci. US 2001 98:4634) connecting retroviruses to
schizophrenia, the author (Lewis) making the following points:
     1) The author (Lewis) points out that the contribution of
genetic factors to the risk of developing schizophrenia has been
demonstrated in family, twin, and adoption studies. In contrast
to the 1 percent lifetime incidence of schizophrenia in the
general population, the incidence of schizophrenia in the
relatives of affected individuals is approximately 2 percent in
3rd-degree relatives, 2 to 6 percent in 2nd-degree relatives, and
6 to 17 percent in 1st-degree relatives. When one member of a
twin pair has the illness, the risk of schizophrenia in the other
twin is approximately 17 percent for fraternal twins and
approaches 50 percent for identical twins. Furthermore, in
adoption studies, the risk of schizophrenia is related to the
presence of the illness in the biological but not in the adoptive
parents. Although regions on a number of chromosomes have been
implicated as sites of potential susceptibility genes, the
specific genes (or combination of genes) that confer risk for
schizophrenia have not yet been identified.
     2) The author (Lewis) points out that a number of
environmental factors, usually factors occurring early in life,
also seem to increase the risk for schizophrenia. For example,
severe maternal malnutrition during the first trimester or
maternal influenza during the second trimester of pregnancy are
apparently associated with a doubling of the relative risk of
schizophrenia, and *perinatal brain damage or maternal
*preeclampsia may increase the risk by 7- to 9-fold.
     3) The author (Lewis) points out that retroviruses have been
considered possible etiological agents in schizophrenia for some
time, at least since 1984, because retroviruses could apparently
explain some of the enigmatic aspects of the illness. For
example, the differential activation and reintegration of
endogenous retroviruses during early development may lead to
altered brain function later in life, providing a potential link
between risk factors identified in utero and perinatal risk
factors on the one hand, and the onset of clinical schizophrenia
during the late second and third decades of life on the other
hand. In addition, an endogenous retroviral etiology could
provide explanation for the continued prevalence of schizophrenia
despite the reduced fecundity associated with the illness, and
for the relatively uniform incidence of schizophrenia throughout
the world.
     4) Although evidence of an association between retroviruses
and schizophrenia has not been available, Karlsson et al (2001)
now report the identification of nucleotide sequences homologous
to retroviral "pol" (polymerase) genes in the cerebrospinal fluid
of 28.6 percent of subjects with schizophrenia of recent onset (N
= 35), and in 5 percent of subjects with chronic schizophrenia (N
= 20). In contrast, such retroviral sequences were not found in
any individual with non-inflammatory neurological illness (N =
22) or in normal control subjects (N = 30).
     5) The author (Lewis) states: "Although the observations of
the study of Karlsson et al are interesting, their potential
significance for our understanding of the etiopathogenesis of
schizophrenia rests on the replication of these findings in other
cohorts of subjects. Independent replication is an axiom in all
areas of medicine, but it is particularly important in studies of
schizophrenia, where the history of the field includes many
examples of exciting findings that subsequently either failed to
be confirmed in other cohorts of subjects with the disorder or
proved to lack specificity to the illness."
-----------
David A. Lewis: Retroviruses and the pathogenesis of
schizophrenia.
(Proc. Natl. Acad. Sci. US 10 Apr 01 98:4293)
QY: David A. Lewis: lewisda@msx.upmc.edu
-----------
Text Notes:
... ... *messenger RNA: (mRNA) The ribonucleic acid molecule
transcribed from DNA that carries the coded information
specifying the sequence of amino acids in a protein.
... ... *ribosomes: A ribosome (not to be confused with riboZYME)
is a small particle, a complex of various ribonucleic acid
component subunits and proteins that functions as the site of
protein synthesis. In general, ribosomes read the messenger RNA
template to produce specific polypeptide sequences by
polymerizing amino acids.
... ... *germ-line cells: In general, "germ-line" cells are
reproductive cells, or any cells giving rise to reproductive
cells such as oocytes (egg cells) or spermatocytes (sperm cells).
All other cells are called "somatic cells". Mutations (or
introduction of foreign genes) in germ-line cells are carried
from the parent generation to the offspring generation, while
mutations in somatic cells are not transferred to the next
generation.
... ... *perinatal: Refers to the time-frame before, during, and
immediately after birth.
... ... *preeclampsia: In general, the development of
hypertension during pregnancy.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm

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5. PHYSIOLOGY: ON PAIN AND INFLAMMATION
     In mammals, including humans, the receptors for pain, called
"nociceptors", are free nerve endings (i.e., endings not
terminating on other neurons or muscle fibers or specialized
sense receptors) found in almost every tissue of the body. These
free nerve endings may respond to any type of stimulus if the
stimulus is strong enough to cause tissue damage. When stimuli
for other sensations, such as touch, pressure, heat, and cold,
reach a certain intensity, they provoke the sensation of pain as
well as the relevant primary sensation. Excessive stimulation of
most sensory receptors causes pain, but pain is also caused by
excessive distension or dilation of a structure, prolonged
muscular contractions, muscle spasms, inadequate blood flow to an
organ, or the presence of certain specific chemical substances.
For example, tissue injury releases chemical entities (e.g.
prostaglandins and kinins [see below]) that stimulate
nociceptors. In general, pain persists even after an initial
tissue trauma occurs, since these substances linger and
nociceptors adapt to stimuli only slightly or not at all. Because
of their sensitivity to all excessive stimuli, pain receptors
perform a protective function as they respond to changes that
might endanger the organism.
     In general, the term "inflammation" refers to a fundamental
pathologic process consisting of a dynamic complex of cellular
and chemical reactions occurring in affected blood vessels and
adjacent tissues in response to an injury or abnormal stimulation
of a tissue caused by physical, chemical, or biological agents. A
primary stage of inflammation consists of vasodilation and
increased permeability of local blood vessels, the process
occurring within minutes after injury, and involving a number of
released substances, including various prostaglandins and kinins.
Prostaglandins (a group consisting of a variety of prostanoic
acids) are released by damaged cells and stimulate the migration
of certain immune system cells (phagocytes) through capillary
walls. Kinins (a varied group, some of which are polypeptides)
induce vasodilation and increased permeability and serve as
chemotactic agents for phagocytes. The term "cytokines" refers to
polypeptides that serve as local hormones, of which there are
many types, and the cytokine interleukin-1beta is an important
cytokine involved in the inflammatory response to tissue injury.
     The so-called "ventricles" of the vertebrate brain are
macroscopic spaces in the brain that comprise the remnants of the
embryonic neural tube. These spaces are filled with cerebrospinal
fluid (CSF), a clear colorless fluid that flows continuously in
the brain and spinal cord, the fluid containing proteins,
glucose, and various electrolytes. As a macroscopic fluid
compartment, cerebrospinal fluid is essentially continuous with
the microscopic extracellular space surrounding nerve cells in
the central nervous system. The same is not true of the blood
fluid compartment: the blood fluid system is separated from
central nervous system neural tissue by the "blood-brain
barrier", an arrangement of cell layers and tight cell junctions
surrounding blood capillaries that effectively prevents the
movement of proteins and other large molecules between central
nervous system neural tissue and blood. Thus, a substance found
in cerebrospinal fluid can be assumed to have access to central
nervous system neural tissue, whereas if the same substance is
found in blood, such access cannot be assumed. 
... ... Tamas Bartfai (Scripps Research Institute, US) presents a
commentary on some recent studies of the interaction of the pain
and inflammatory systems, the author making the following points:
     1) The author points out that in mammals the limbs have a
high density of sensory endings that can detect touch, heat, and
acute pain -- sensations that are rapidly transmitted to the
brain by the nerves. Drugs that silence sensory nerves work well
to relieve acute pain, but when local inflammation has occurred,
blocking nerve impulses produces little pain relief.
     2) The author points out that in humans when a tissue is
injured inflammation often occurs, and this inflammation usually
results in general feelings of illness, with symptoms such as
fever, lethargy, anorexia, general muscle and joint ache, and an
oversensitivity of nearby uninjured tissue to pain. These
consequences of injury have been thought to occur by a mechanism
coordinated by the brain and involving the transmission of nerve
impulses from the injured region, via the spinal cord, to the
brain. Now T.A. Samad et al (Nature 410:471 2001) have provided
evidence that suggests that nerve impulses are not involved, and
that the general feelings of illness following tissue injury
result from the production of inflammatory signals inside the
brain, the production of these signals provoked by tissue injury
via a chemical rather than a neural pathway.
     3) The author (Bartfai) points out that Samad et al have
found, in experiments in the rat, that local inflammation causes
a rapid, large, and long-lasting increase in the concentration of
interleukin-1beta in cerebrospinal fluid. Samad et al demonstrate
that when interleukin-1beta is blocked, either by injecting drugs
into the spine that inhibit the production of interleukin-1beta
in cerebrospinal fluid, or by using a drug to block the
interleukin-1beta receptor in brain cells, the hypersensitivity
to pain is strongly reduced. This inhibition is less effective
when these same drugs are injected directly into the bloodstream.
In other words, it is the increase in cerebrospinal fluid levels
of interleukin-1beta that informs the brain about local
inflammation. Related evidence by M. Ek et al (Nature 410:430
2001) demonstrates that following peripheral tissue injury
cerebral vascular cells express components enabling a blood-borne
cytokine to stimulate the production of prostaglandin E(sub2), an
inflammatory mediator whose small size enables it to pass through
the blood-brain barrier into neural tissue. Since receptors for
this prostaglandin are found in neural tissue, Ek et al propose
that the activated immune system controls central nervous system
reactions to peripheral inflammation through a prostaglandin-
dependent cytokine-mediated pathway.
-----------
Tamas Bartfai: Telling the brain about pain.
(Nature 22 Mar 01 410:425)
QY: Tamas Bartfai: tbartfai@scripps.edu
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm

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6. MEDICAL BIOLOGY: A CLINICAL TEST OF THE PLACEBO EFFECT
     In general, the term "placebo" (which in Latin means "I will
please") refers to a treatment that has no specific effects on
the condition being treated. Thus, a placebo is often a substance
or preparation without pharmacological activity, e.g., a pill
consisting of milk sugar (lactose) or a liquid consisting of
physiological saline solution. There are currently two general
uses of placebos in clinical medicine: a) an inert substance
administered as a "medicine" for its suggestive effect; b) an
inert compound identical in appearance to material being tested
in experimental research, with the placebo known or not known to
the physician and/or patient, the purpose to distinguish between
drug action and any suggestive effect of the material under
study. It is generally agreed that although a placebo may have no
effect on organic disease, it may have an effect on the patient's
subjective experience of disease
     The term "placebo effect" refers to something more complex,
a phenomenon in which a clinically significant response occurs
following administration of a therapeutically inert substance.
Such responses include both therapeutic and side effects of drugs
and are not limited to subjective reports: physiological
functions may be objectively influenced. Placebo effects also
include changes deriving from the nonspecific aspects of a
procedure, for example the treatment setting, patient
expectations, etc.
     For more than 50 years, the placebo effect has been
recognized as a distinct phenomenon, with many illustrations of
the effect. For example, in one classic study, 3 out of 4
patients suffering from postoperative wound pain reported
satisfactory pain relief after an injection of sterile saline
solution. Responders were indistinguishable from non-responders,
both in the apparent severity of their pain and in the nature of
their personalities. It has also been found that the placebo
effect in postoperative patients can be blocked by the drug
naloxone, a competitive antagonist of opiate receptors. In
general, a common misunderstanding about the placebo effect is
the view that patients who respond to a therapeutically
meaningless reagent are not suffering real pain but only
"imagining" the pain, and so therefore the pain can be relieved
by a placebo. In general, in the psychological, psychiatric, and
neurobiological communities, the placebo effect is considered to
be quite real. Many others in the medical community, however, are
not convinced.
     The general idea that psychological input can effect
physiological processes is well accepted by psychologists,
psychiatrists, and neurobiologists primarily because the pathways
that make such effects possible have been identified. However, in
the 19th century, the noted pathologist Rudolf Virchow (1821-
1902) uttered his famous dictum, "All diseases are diseases of
cells," and this attitude has colored much of biological medicine
since that time. Well, yes, all diseases are indeed ultimately
diseases of cells, but when fear causes sudden death in a cardiac
patient one is confronted with a salient instance of
psychological input producing a massive physiological response
via activation of the autonomic nervous system. Such activation
can produce pathological interactions between cells, including
ultimate tissue injury. In general, to neglect the psychological
input to the nervous system as a factor in pathologic
physiological function is not appropriate, no more appropriate
than the idea that all problems with a personal computer are
independent of user input. The administration of a placebo to a
patient is a psychological input that may or may not produce a
physiological effect depending on the patient and on the
circumstances.
     With that said, we now report a very recent study of the
placebo effect that is already being touted in the popular press
as proof that the placebo effect does not exist. The study,
however, does not demonstrate that at all.
... ... A. Hrobjartsson and P.C. Gotzsche (University of
Copenhagen, DK) present an analysis of clinical trials in the
literature, the analysis comparing placebo with no treatment. The
authors make the following points:
     1) The authors conducted a systematic review of reports of
clinical trials in which patients were randomly assigned to
either placebo or no treatment. A "placebo" could be
pharmacological (e.g., a tablet), physical (e.g., a
manipulation), or psychological (e.g., a conversation). The
authors identified 130 trials that met their inclusion criteria,
the study involving a total of 8525 patients in trials
investigating 40 different clinical conditions ranging from
anxiety to hyperglycemia.
     2) The authors report that as compared with no treatment,
placebo had no significant effect on binary outcome studies,
regardless of whether these outcomes were objective or
subjective. For trials with continuous outcomes, placebo had a
beneficial effect, but the effect decreased with increasing
sample size, indicating a possible bias related to the effects of
small trials. The pooled standardized mean difference was
significant for the trials with subjective outcomes but not for
the trials with objective outcomes. In 27 trials involving the
treatment of pain, placebo had a beneficial effect.
     3) The authors conclude: "We found little evidence in
general that placebos had powerful clinical effects. Although
placebos had no significant effects on objective or binary
outcomes, they had possible small benefits in studies with
continuous subjective outcomes and for the treatment of pain.
Outside the setting of clinical trials, there is no justification
for the use of placebos."
-----------
A. Hrobjartsson and P.C. Gotzsche: Is the placebo powerless? An
analysis of clinical trials comparing placebo with no treatment.
(New England J. Med. 24 May 01 344:1594)
QY: Asbjorn Hrobjartsson: a.hrobjartsson@cochrane.dk
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
MEDICAL BIOLOGY:
ANALYSIS OF A MASS PSYCHOGENIC ILLNESS IN A HIGH SCHOOL
Epidemic hysteria, also called "mass psychogenic illness" or
"mass sociogenic illness" or "transient situational disturbance"
was first described in the Middle Ages, and it has been reported
in a variety of cultures and settings. In general, in an actual
acute situation, mass psychogenic illness may be difficult to
distinguish from a bioterrorist event, a rapidly spreading
infection, or acute exposure to toxic substances. Epidemics of
psychogenic illness often attract intense media attention and may
have profound public health, social, and economic repercussions.
... ... T.F. Jones et al (8 authors at 4 installations, US)
present a detailed analysis of a particular outbreak of mass
psychogenic illness, the authors (who essentially comprised a
medical and environmental team) making the following points:
     1) On November 12, 1998, a teacher at Warren County High
School in McMinnville, Tennessee (US) noticed a "gasoline-like"
smell in her classroom, and soon thereafter she had a headache,
nausea, shortness of breath, and dizziness. The school was
evacuated, and 80 students and 19 staff members went to the
emergency room at the local hospital, where 38 persons were
hospitalized overnight. Five days later, after the school had
reopened, another 71 persons went to the emergency room. An
extensive investigation was performed by government agencies.
     2) The authors report they were unable to find a medical or
environmental explanation for the reported illnesses. The persons
who reported symptoms on the first day came from 36 classrooms
scattered throughout the school. The high school population
consisted of 1825 students and 140 staff members. The building
was 4 years old and situated on land that had previously been
farmed. The property was located outside the town of McMinnville,
which has a population of approximately 11,000 persons. The
county has one high school and one hospital. The most frequent
symptoms (both in this group and in the group of people who
reported symptoms 5 days later) were headache, dizziness, nausea,
and drowsiness. Blood and urine specimens showed no evidence of
carbon monoxide, volatile organic compounds, pesticides,
polychlorinated biphenyls, paraquat, or mercury. There was no
evidence of toxic compounds in the environment. A questionnaire
administered 1 month later indicated that the reported symptoms
were significantly associated with female sex, seeing another ill
person, knowing that a classmate was ill, and reporting an
unusual odor at the school.
     3) The authors conclude: "This illness, attributed to toxic
exposure, had features of mass psychogenic illness -- notably,
widespread subjective symptoms thought to be associated with
environmental exposure to a toxic substance in the absence of
objective evidence of an environmental cause."
     4) In a critical commentary on this report in the same
journal, Simon Wessely (Guy's School of Medicine, UK) states:
"One of the less welcome aspects of the Freudian tradition has
been the widespread acceptance of the existence of symptoms that
are, in that destructive phrase, "all in the mind". Yet
psychogenic symptoms are physiologic experiences that are based
on identifiable physiologic processes that cause pain and
suffering. The children at McMinnville High School experienced
genuine symptoms. That the cause of these symptoms was probably
anxiety about toxic exposure, rather than any exposure itself,
does not detract from their reality. By labeling the episode
psychogenic or hysterical, however, that is precisely what we are
doing."
     [Editor's note: Wessely's point is that although mental
health professionals are aware that physiologic symptoms in
psychogenic illness are real symptoms that can cause pain and
suffering, the public (and many professionals outside the field
of mental health) has a tendency to consider symptoms of
psychogenic illness as "imagined" and not worthy of attention.
Such symptoms, however, are indeed real, as real as the
psychogenic blushing of an individual's face (an opening of blood
capillary beds in the face), when that individual perceives (or
imagines) a social embarrassment, or as real as the increase in
heart rate that can be produced by a real or imagined physical
threat, or even by merely watching an action film. All the
symptoms in the reported high school case can be shown to be
produced by specific activations of the autonomic nervous system,
activations affecting the vascular system, heart rate,
respiration, etc., and these activations can follow specific
activations of the central nervous system by psychological
anxiety states. The biologic paradigm is simply stated: the
central nervous system receives (perceives) psychological input,
and, in addition to the effect of that input on other central
nervous system activity, that input, if capable of provoking
certain emotional states, is complexed, filtered, and converted
to activation of the autonomic nervous system, which in turn
activates physiologic output by controlling various involuntary
muscle groups and glandular secretions. In summary, the symptoms
of the high school population should be considered as most
definitely real; it was the source of the anxiety that was
evidently imagined.]
-----------
T.F. Jones et al: Mass psychogenic illness attributed to toxic
exposure at a high school.
(New England J. Med. 13 Jan 00 342:96)
QY: Timothy F. Jones, Tennessee Dept. of Health, Nashville TN
37247 US.
-----------
Simon Wessely: Responding to mass psychogenic illness.
(New England J. Med. 13 Jan 00 342:129)
QY: Simon Wessely, Guy's School of Medicine, London SE5 8AF UK
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 28Apr00
For more information: http://scienceweek.com/swfr.htm

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7. IN FOCUS: ON THE HISTORY OF AMERICAN NEUROLOGY
"Neurology came out of the Civil War, inspired by examination of
war-related head injuries; and when it organized in the late
1860s and early 1870s it tried to take over psychiatry. It was a
fascinating fight, a bitter battle in the professional journals
and the New York Herald Tribune using some of the most
vituperative language I have ever seen in print. Basically, what
the neurologists said was "Both of us are dealing with the same
brain. But you guys off in your asylums are hopeless. You're not
doing any research, your asylums have gone downhill, and we
demand a state investigation." They got the investigation; they
carried on the fight, mostly in New York State, a little in
Massachusetts; and they made a very strong attempt to take over
psychiatry. In the end they failed, but not by much. They failed
because the asylums were then growing very fast. And when push
came to shove and they were asked what should be happening, they
didn't have really good answers. They didn't have an alternative
plan other than to say "You ought to take the jobs away from
those guys because they don't know what they're doing and give
the jobs to us." And the state people correctly said "You have
something of a vested interest here, don't you, so why should we
believe you?" And neurology then went off and became very much
what it is today, taking care of all the brain diseases not
presenting psychiatric symptoms."
-----------
E. Fuller Torrey: "Why are there so many homeless mentally ill?"
Harvard Medical School Mental Health Letter, August 1989.
In J.A. Hobson and J.A. Leonard: _Out of Its Mind: Psychiatry in
Crisis_
(Perseus Publishing, Cambridge MA 2001, p.38)
http://www.amazon.com/exec/obidos/ASIN/0738202517/scienceweek
-----------
SCIENCE-WEEK http://scienceweek.com 8Jun01
For more information: http://scienceweek.com/swfr.htm

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8. FROM THE SCIENCEWEEK ARCHIVE:
CELL BIOLOGY: FUNCTIONAL MODULES IN BIOLOGICAL ORGANIZATION
     The term "phenomenology" has a variety of meanings, but in
this report we are concerned with only one meaning of the term:
we take the term "phenomenology" to refer to a scientific
approach that focuses on explanations based on formal
relationships among observed entities or processes, as opposed to
an approach ("reductionist") that focuses on explanations based
on analysis of the fundamental constituents of such entities or
processes. Using the terms in this way, we have the following
examples: a) Thermodynamics is a phenomenological approach to the
behavior of a gas; statistical mechanics is a reductionist
approach to the behavior of a gas. b) Mendelian genetics is a
phenomenological approach to the inheritance of traits; molecular
genetics is a reductionist approach to the inheritance of traits.
One can think of similar dichotomies in almost every field in
science.
     The term "reductionist" has had an unfortunate history in
biology, where it has been used to characterize the idea that any
biological entity or process can be "explained" in terms of the
laws of physics and chemistry. Certainly, the behavior of every
entity or process in the natural world is ultimately totally
dependent on the laws of physics and chemistry (which leads to
the idea that the behavior can "in principle" be derived
["explained"] from such laws), but the actual practical
possibility of any explanations of the behavior of observable
entities or processes in terms of the laws of physics and
chemistry depends on the current state of our knowledge
concerning both the observables and the fundamental laws. In the
practice of science, it can be argued that it does not matter
much which approach is used, phenomenological or reductionist,
provided the approach produces results that are useful, or which
help in understanding the behavior of the entity or process, or
which suggest new and intriguing questions. Beyond this, the
discussion properly belongs in the domain of philosophy and not
science.
     The above preamble is necessary in the context of the
present report, since the report concerns a recent article in
which a group of authors (2 molecular biologists, a biophysicist,
and a physiologist) call for a more "phenomenological" approach
to cell biology, an interesting idea, since cell biology is not
one of those areas of biology where such appeals are common.
During the last 50 years, in fact, cell biology has experienced a
remarkable flowering based on the application of fundamental
biochemistry, biophysics, and molecular biology to entities and
processes recognizable at the cellular level (i.e., micron-scale
objects).
... ... L.H. Hartwell et al (4 authors at 3 installations, US)
present an essay calling for a transition from molecular to
"modular" cell biology, the authors making the following points:
     1) The authors begin their essay with the following
statement: "Although living systems obey the laws of physics and
chemistry, the notion of function or purpose differentiates
biology from other natural sciences. Organisms exist to
reproduce, whereas, outside religious belief, rocks and stars
have no purpose. Selection for function has produced the living
cell, with a unique set of properties that distinguish it from
inanimate systems of interacting molecules." [Editor's note:
Contrast with this the remarks in the relevant background
material below.]
     2) The authors propose that a major challenge for science in
the 21st century is to develop an integrated understanding of how
biological cells and organisms survive and reproduce. The authors
suggest that cell biology is in transition from a science that
was preoccupied with assigning functions to individual proteins
or genes, to a science that is now attempting to cope with the
complex sets of molecules that interact to form "functional
modules".
     3) The authors define a "functional module" as a discrete
entity whose function is separable from those of other modules.
This separation depends on chemical isolation, which can
originate from spatial localization or from chemical specificity.
For example, a ribosome, the module that synthesizes proteins,
concentrates the reactions involved in making a polypeptide into
a single particle, thus spatially isolating its function. Modules
can be insulated from or connected to each other. The authors
suggest that in the future, the higher-level properties of cells,
such as their ability to integrate information from multiple
sources, will be described by the pattern of connections among
their functional modules.
     4) The authors point out that the number of cellular
functional modules that have been analyzed in detail is very
small, and each of these efforts has required intensive study.
The authors suggest that biologists need to study more functions
at the modular level and develop methods that make it easier to
determine the relationship of inputs to outputs of modules, their
biochemical connectivity, and the states of key intermediates
within them.
     5) The authors suggest that the best test of our
understanding of cells will be to make quantitative predictions
about their behavior and test them. This will require detailed
simulations of the biochemical processes occurring within the
modules. "But making predictions is not synonymous with
understanding. We need to develop simplifying, higher-level
models and find general principles that will allow us to grasp
and manipulate the functions of biological modules."
     6) The authors summarize their essay: "Cellular functions,
such as signal transmission, are carried out by 'modules' made up
of many species of interacting molecules. Understanding how
modules work has depended on combining phenomenological analysis
with molecular studies. General principles that govern the
structure and behavior of modules may be discovered with help
from synthetic sciences such as engineering and computer science,
from stronger interactions between experiment and theory in cell
biology, and from an appreciation of evolutionary constraints."
-----------
Editor's note: The essential idea here can be presented as
follows: Consider a computer, a machine with a "purpose" -- to
compute. A computer operates on its inputs in specific ways to
produce specific outputs. A "flow diagram" of computer dynamics
is a phenomenological description of the behavior of the machine.
A complete "wiring diagram" of electrical entities and events in
the machine is a reductionist description of the behavior of the
machine. (Of course, from the perspective of quantum mechanics,
the wiring diagram is itself phenomenological.) Suppose we are
given a machine and know nothing about it except that it operates
on inputs to produce outputs. If our problem is to predict the
behavior of the machine in response to particular inputs, there
will come a time when a flow diagram, albeit "phenomenological",
will be of immense value in understanding how the machine works.
What the authors propose is that much of the future of cell
biology will lie in the construction of the equivalent of
detailed and predictive flow diagrams for the internal operations
of biological cells.
-----------
L.H. Hartwell et al: From molecular to modular cell biology.
(Nature 2 Dec 99 402supp:C47)
QY: Leland H. Hartwell, Fred Hutchinson Cancer Center, Seattle,
WA 98109 US.
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 11Feb00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
IN FOCUS: ON FUNCTION AND TELEOLOGY IN BIOLOGY
"Biology, and especially evolutionary biology, is rife with
claims concerning what various characteristics are "for". The
heart exists for the purpose of pumping blood. Bears have fur in
order to ward off the cold. Functional claims of this sort have
quite disappeared from physics. Whereas Aristotle thought that
planets, no less than living things, have goals, this
teleological conception of the physical world is now a relic of a
bygone age. Planets move as they do because of the laws of
motion; they do not act as they do for the good of anything.
Darwin is rightly famous for having introduced an important
materialist element into the science of life. But rather than
banishing functional notions from biology, he showed how they can
be domesticated within a materialist framework. Organisms are
goal-directed systems because they have evolved. Their behaviors
are suited to the tasks of survival and reproduction because
natural selection has allowed some traits, but not others, to be
passed from ancestors to descendants. Even if Darwinism
legitimates talk of goal and purpose within biology, the question
of what such talk means remains to be addressed. The heart does
many things. It pumps blood, but it also makes noise and takes up
space in our chests. Why are we inclined to say that pumping
blood is part of the heart's function, but making noise and
taking up space are not?"
-----------
Elliott Sober: _Conceptual Issues in Evolutionary Biology_
(MIT Press, Cambridge 1995, p.x)
(Science-Week 9 Jul 99)

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