ScienceWeek

SCIENCEWEEK
Briefs in the Sciences
May 9, 2003
Vol. 7 - Number 19B

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Contents:

1. On Misconceptions Concerning Descriptive Science
2. On Ockham's Razor
3. On Innate Immunity
4. Molecular Architecture of Voltage-Gated Ion Channels
5. On the Miller Prebiotic Soup Experiment
6. Massive Black Holes and Galaxy Formation
7. On Revisions Concerning Postmenopausal Hormone Treatment
8. On Severe Acute Respiratory Syndrome (SARS)

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1. ON MISCONCEPTIONS CONCERNING DESCRIPTIVE SCIENCE

The following points are made by Donald A. Fischman (The
Scientist 2003 May 5):

1) The author points out that description is the essence of all
physical and biological science. A careful and accurate
description provides a true-to-life and faithful representation
of a scientific observation. In fact, one cannot imagine any
field in the physical or life sciences that does not depend on
solid observations providing the foundation for all subsequent
conceptualization in that discipline. But descriptive input does
not end when conceptualization begins; tests of any hypothesis
must contain precise observational analyses. Thus, in the
author's view, it is naive and shortsighted to artificially
separate hypothesis-driven research from descriptive studies;
both must be integrated in productive experimental science.

2) More to the point, however, is the unstated presumption that
morphological studies of a cell, tissue, organ, or a whole
organism are less creative, conceptual, hypothesis-driven, or
experimental than deriving a gene sequence, a protein crystal
structure, a gene array scan, or the creation and analysis of a
transgenic animal. These are all descriptive, differing only in
their limits of resolution and the current fashions of scientific
research. Unfortunately, the adjectives descriptive, dull, and
nonmechanistic have become lumped negatively together in the
minds and actions of too many colleagues, especially in the field
of biomedical research.

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2. ON OCKHAM'S RAZOR

The following points are made by Phil Mole (Skeptic 2003 Vol.10
#1):

1) The principle of Ockham's Razor is named after William of
Ockham (1285-1349), a distinguished medieval philosopher and
theologian. Contrary to popular assumptions, Ockham did not
invent the principle that has become associated with him. The
idea that simplicity and efficiency are important advantages of a
theory dates back at least to Aristotle, who stated that "the
more perfect a nature is, the fewer means it requires for its
operation." Centuries after Ockham's time, Isaac Newton would
also cite the principle of simplicity in his Principia
Mathematical: "We are to admit no more causes of natural things
than such as are both true and sufficient to explain their
appearances."

2) Ockham emphasized the principle of parsimony as an antidote to
the various unwarranted assumptions he perceived in the
philosophy of his time. He used a number of different
formulations of the principle in his writings. He stated, for
example, that "it is futile to do with more what can be done with
fewer," and perhaps most famously, that "plurality should not be
assumed without necessity." A common term for this concept is
parsimony. Ockham's formulations match up quite well with modern
definitions of parsimony, which state that the most parsimonious
models are those requiring the fewest assumptions.

3) The author points out that science is always provisional.
Theories currently meeting all of the criteria of selection may
be unsatisfactory for future applications. Still, science
progresses through the careful amending and acquisition of
knowledge and the use of empirically validated methods. Ockham's
Razor is an important method of improving this knowledge
acquisition. Even safe use of Ockham's Razor will not eliminate
error altogether, but it will at least minimize the errors
relative to other, less reliable methods of evaluating theories.

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3. ON INNATE IMMUNITY

The following points are made by Peter Parham (Nature 2003
423:20):

1) Immunology ostensibly began with ancient Greek physicians, who
marvelled at their observation that patients who had survived a
bout of plague were resistant to the disease when it came around
again. From this germ was born the idea of vaccination -- a small
controlled infection, like a sort of immunological rehearsal,
designed to confer future resistance to full-blown infection
while causing only mere discomfort, rather than disease. What
those Greeks also initiated was the tendency for immunologists to
tackle their subject in a backward manner. They had become
captivated by immunological memory, a late-acting feature of the
immune response that only becomes useful if and when the first
battle between person and pathogen -- the primary infection --
has been won by other means.

2) Memory is the end point for adaptive immunity, the part of
defence that is mediated by white blood cells called B cells and
T cells. Although fascinating to immunologists for their strength
and specificity, these soldiers are not speedy. Typically found
in a state of suspended animation, B and T cells only become fit
to fight about a week after combat begins. During this first week
of a primary infection, defence is in the hands of innate
immunity. One of several paths can be followed: the infection can
gain the upper hand, leading to death or chronic debilitating
disease; alternatively, an acute infection can cause a temporary
state of disease, which ends when innate immunity calls up
reinforcements in the guise of adaptive immunity. Patients who
experience either of these outcomes have been carefully studied
by physicians ever since the time of the ancient Greeks.

3) A third possibility is that the infection will be terminated
quickly by innate immune mechanisms without the involvement of
adaptive immunity and with no major symptom of disease. In this
happy circumstance, in which health is maintained or only mildly
perturbed, neither ancient Greeks nor their modern counterparts
would be likely to consult a physician. Consequently, this most
desirable of outcomes, in which the war is won with little
collateral damage, remains understudied and poorly appreciated.

Notes:

All biological organisms are subject to invasive attack by
microbial pathogens, and the survivability of biological
organisms depends on the activation of various protective
mechanisms (immune responses) when a microbial invasion occurs.
In biology, the "immunity" of organisms to infection by various
pathogens is functionally characterized into 2 types: The term
"innate immunity" refers to non-specific antimicrobial systems of
response (e.g., phagocytosis: engulfment and digestion of
microbes by "killer" cells) that are innate and not intrinsically
affected by prior contact with the infectious agent; the term
"adaptive immunity" refers to immune responses which involve an
enhanced ability to respond to specific molecular *antigens
presented by the invading pathogenic entity, the enhancement
dependent on prior contact with the same pathogen. In addition,
the concept of innate immunity generally refers to the first-line
host defense that serves to limit infection in the early hours
after exposure to microorganisms. Recent data have highlighted
similarities between pathogen recognition, signaling pathways,
and *effector mechanisms of innate immunity in both the fruit fly
Drosophila and in mammals, pointing to a common ancestry of these
defenses. In addition to its role in the early phase of defense,
innate immunity in mammals appears to play a key role in
stimulating the subsequent clonal response of adaptive immunity.

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4. MOLECULAR ARCHITECTURE OF VOLTAGE-GATED ION CHANNELS

The following points are made by Fred J. Sigworth (Nature
423:21):

1) The membranes of living cells, from bacteria to humans,
contain protein macromolecules that behave rather like field-
effect transistors. In transistors, the flow of electrons through
a semiconductor "channel" is governed by the voltage applied to a
"gate" electrode. With the protein equivalents -- voltage-gated
ion channels -- an appropriate voltage, imposed across the cell
membrane, causes the channels to open and allows a current of
ions to cross the membrane. The molecular structures within ion
channels that sense the membrane voltage have remained obscure
for the 50 years since Hodgkin and Huxley first described their
function. But the voltage sensors have at last been made visible,
in the X-ray structure of a potassium ion channel (Jiang et al
(Nature 2003 423:33).

2) The functional unit of a voltage-gated channel is an assembly
of four proteins, or subunits; in each, the polypeptide chain
snakes back and forth across the membrane six times. This "six-
transmembrane" structure is seen in the voltage-gated potassium,
sodium, and calcium channel families, and also in other channel
types. As voltage-sensing devices, these channels can perform
much better than their electronic counterparts. Their high
sensitivity to voltage is important, because cellular voltage
changes are small.

Notes:

The regulated permeabilities of the biological cell membrane to
various ions are important factors in a number of crucial
cellular mechanisms. In general, these permeabilities involve
specific ion-selective pores constructed of proteins, the pores
called "ion channels", with ion channels of different types
available for any one ion species. Evidence suggests that an ion
channel protein spans the membrane and has a central water-filled
pore open to both the intracellular and extracellular
compartments. On each side, the pore widens to form a vestibule,
with the restricted region within the plane of the membrane
containing an effective "gate" that can open or close to control
the passage of ions.

Ion channels are highly regulated, linked to key cellular
processes, and during the past two decades, an intensive effort
in many laboratories has led to identification of the proteins of
some ion channels, studies of the configuration of these
proteins, and an improved understanding of the complex events
associated with the passage of simple ions such as sodium,
potassium, calcium, and chloride into and out of biological
cells. A very powerful technique used in much of this work
involves genetic engineering of ion channels. The essential idea
is to isolate a DNA sequence that encodes the protein for a
particular ion channel, then transfect this DNA sequence into the
genome of a host cell type amenable to detailed electrical and
transport measurements. When the ion channel protein is expressed
in this host cell and becomes part of the host cell plasma
membrane, the various properties of the ion channel become open
to investigation. Although the results of such experiments must
be carefully interpreted, the ability to make specific and
discrete alterations in channel protein membrane structure has
led to important insights into the relation between the
structures of ion channel proteins and their control of ion
permeabilities.

Of the ions that diffuse back and forth across cell membranes,
calcium ions are of great importance in many physiological
processes. In biological cells, extracellular and intracellular
concentrations of calcium ion differ by several orders of
magnitude, and cells are therefore exposed to a steep calcium ion
gradient across their membranes. In general, the control of
cellular calcium ion is maintained by an elaborate system of
channels, exchangers, and pumps located both in the plasma
membrane and in intracellular membranes.

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5. ON THE MILLER PREBIOTIC SOUP EXPERIMENT

The following points are made by J. Bada and A. Lazcano (Science
2003 300:745):

1) In 1953 Stanley L. Miller raised the hopes of understanding
the origin of life when on 15 May the journal Science published
his paper on the synthesis of amino acids under conditions that
simulated primitive Earth's atmosphere (Science 1953 117:528).
Miller had applied an electric discharge to a mixture of CH4,
NH3, H2O, and H2 -- believed at the time to be the atmospheric
composition of early Earth. Surprisingly, the products were not a
random mixture of organic molecules, but rather a relatively
small number of biochemically significant compounds such as amino
acids, hydroxy acids, and urea. With the publication of these
dramatic results, the modern era in the study of the origin of
life began.

2) The origin of Miller's experiment can be traced to 1950, when
Nobel laureate Harold C. Urey (1893-1981), who had studied the
origin of the solar system and the chemical events associated
with this process, began to consider the emergence of life in the
context of his proposal of a highly reducing terrestrial
atmosphere. Urey presented his ideas in a lecture at the
University of Chicago in 1951, followed by the publication of a
paper on Earth's primitive atmosphere. (Proc. Nat. Acad. Sci.
1952 38:349).

3) Almost a year and a half after Urey's lecture, Miller, a
graduate student in the Chemistry Department who had been in the
audience, approached Urey about the possibility of doing a
prebiotic synthesis experiment using a reducing gas mixture.
After overcoming Urey's initial resistance, they designed three
apparatuses meant to simulate the ocean-atmosphere system on
primitive Earth. The first experiment used water vapor produced
by heating to simulate evaporation from the oceans; as it mixed
with methane, ammonia, and hydrogen, it mimicked a water vapor-
saturated primitive atmosphere, which was then subjected to an
electric discharge. The second experiment used a higher pressure,
which generated a hot water mist similar to that of a water
vapor-rich volcanic eruption into the atmosphere, whereas the
third used a so-called silent discharge instead of a spark.

4) Miller began the experiments in the fall of 1952. By
comparison with contemporary analytical tools, the paper
chromatography method available at the time was crude. Still,
after only two days of sparking the gaseous mixture, Miller
detected glycine in the flask containing water. When he repeated
the experiment, this time sparking the mixture for a week, the
inside of the sparking flask soon became coated with an oily
material and the water turned a yellow-brown color.
Chromatographic analysis of the water flask yielded an intense
glycine spot; several other amino acids were also detected.
Experiments with the second apparatus produced a similar
distribution and quantities of amino acids and other organic
compounds, whereas the third apparatus with silent discharge
showed lower overall yields and much fewer amino acids (primarily
sarcosine and glycine).

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6. MASSIVE BLACK HOLES AND GALAXY FORMATION

The following points are made by C. L. Carilli et al (Science
2003 300:773):

1) Establishing a link between galaxy formation and massive black
hole formation has become of paramount importance to
observational astronomy since the correlation between black hole
mass and stellar bulge mass in nearby [redshift (z) < 0.1]
galaxies was discovered. This correlation suggests a causal
connection between the formation and evolution of the black hole
and the galactic bulge and has led to the hypothesis of coeval
formation at high redshift (z > 2) of massive black holes and
spheroidal galaxies. Supermassive black holes [10^(9) solar
masses (M)] at high redshift manifest themselves as optically
luminous quasi-stellar objects (QSOs), powered by mass accretion
onto the hole.
 
2) Observations of high-redshift QSOs have shown that 30% are
luminous infrared (IR) sources, with far infrared luminosities
10^(13) times the luminosity of the sun, corresponding to thermal
emission from warm dust. The key question for these far infrared
luminous QSOs is: What is the dominant dust-heating mechanism:
star formation or the active galactic nucleus? If the dust is
heated by star formation, the star formation rates must be on the
order of 10^(3) M/year, supporting the idea of coeval formation
of the stars and black holes in these systems.

3) The authors report observations that imply a massive star
formation rate of 900 solar masses per year. At this rate, a
substantial fraction of the stars in a large elliptical galaxy
could form on a dynamical time scale of 10^(8) years. The
observation of active star formation in the host galaxy of a
high-redshift QSO supports the hypothesis of coeval formation of
supermassive black holes and stars in spheroidal galaxies.

Notes:

Redshift (symbol: z) is a lengthening of the wavelengths of
electromagnetic radiation from a source caused either by the
movement of the source (Doppler effect) or by the expansion of
the universe (cosmological redshift). Redshift is defined as the
change in wavelength of a particular spectral line divided by the
unshifted wavelength of that line. Large redshifts imply large
radial velocities (which imply large distances, according to
current cosmological theory), but at redshifts greater than about
0.2 there is a relativistic divergence from a linear relation. A
redshift of 4.0 corresponds to an object receding with a radial
velocity 92% that of the velocity of light. The largest
astrophysical redshifts so far observed are of the order of z =
4.9. The furthest galaxy on record is at a redshift z = 4.92),
which implies a distance of approximately 13 billion light years.

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7. ON REVISIONS CONCERNING POSTMENOPAUSAL HORMONE TREATMENT

The following points are made by Deborah Grady (New Engl. J. Med.
2003 348:1835):
 
1) Over the past two decades, multiple observational studies have
suggested that postmenopausal hormone therapy reduces the risks
of osteoporotic fractures and coronary heart disease. On the
basis of this evidence, hormone therapy was often recommended for
women who were at high risk for fractures and coronary disease.
But these recommendations were based entirely on observational
evidence, which can sometimes be misleading if the groups being
compared have different risk patterns and lifestyles.

2) In the early to mid-1990s, several large, randomized trials
were initiated to provide definitive evidence concerning the
risks and benefits of hormone therapy for the prevention of
disease. The largest of these trials, the Women's Health
Initiative (WHI), included more than 27,000 older, generally
healthy postmenopausal women; those with an intact uterus were
randomly assigned to receive estrogen plus progestin or placebo,
and those without an intact uterus were randomly assigned to
receive estrogen alone or placebo.

3) The estrogen-plus-progestin segment was stopped last summer
when results showed that hormone therapy caused small increases
in the risks of coronary events, stroke, pulmonary embolism, and
breast cancer. There were also small decreases in the risks of
hip fracture and colon cancer, but the overall harm outweighed
these benefits. The investigators examined the net effect on
these six potentially deadly conditions and reported that hormone
therapy results in two such serious adverse events per 1000 women
treated for one year. After five years of treatment, the risk was
one serious adverse event per 100 women treated. 

4) In summary: Postmenopausal therapy with estrogen and progestin
results in increased risks of disease, does not make asymptomatic
women feel better, and does not improve cognition (New Engl. J.
Med. 2003 348:1839). There is no role for hormone therapy in the
treatment of women without menopausal symptoms. Women with
vasomotor symptoms must weigh the risks associated with treatment
against the benefit of symptom relief. Vasomotor symptoms occur
in about two thirds of women and are very distressing in 10 to 20
percent. The author suggests we clearly need to identify new
treatments that are highly effective and safe. 

Notes:

Hormones are signaling molecules secreted into the blood stream
by endocrine cells (i.e., cells that secrete internally) and
acting on target cells that possess receptors for the hormone.
Estrogen is a collective term for the female hormones, the most
powerful of which is estradiol. They control female secondary
sexual characteristics, and prepare and maintain the uterine
lining. Estrogen affects the growth, differentiation, and
function of peripheral tissues of the reproductive system,
including the mammary gland, uterus, vagina, and ovary. Estrogens
also play an important role in bone maintenance and exert
cardioprotective effects. In the brain, estrogens modulate
physiological parameters important for regulating procreation,
including reproductive behavior, gonadotropin production and
release from the pituitary, and mood. In general, there are two
estrogen receptors, estrogen receptor alpha and estrogen receptor
beta, both of which are members of the superfamily of steroid
hormone receptors. Estrogen receptors alpha and beta have
considerable amino acid sequence similarities and, like all
steroid hormone receptors, are transcription factors that alter
gene expression when they are activated. Estrogen receptors are
activated by estrogen binding, but they can also be activated by
growth factors in the absence of estrogen.

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8. ON SEVERE ACUTE RESPIRATORY SYNDROME (SARS)

The following points are made by Centers for Disease Control (J.
Am. Med. Assoc. 2003 289:2203):

1) CDC and the World Health Organization (WHO) are continuing to
investigate the multicountry outbreak of severe acute respiratory
syndrome (SARS). Infection with a novel coronavirus has been
implicated as a possible cause of SARS.

2) Laboratory diagnostic tests used at CDC to test clinical
specimens for evidence of this novel coronavirus are still in
development and are not available outside a research setting.
Serologic testing for coronavirus antibody consists of indirect
fluorescent antibody testing and enzyme-linked immunosorbent
assays that are specific for antibody produced after infection.
Although some patients have detectable coronavirus antibody
within 14 days of illness onset, definitive interpretation of
negative coronavirus antibody tests is possible only for
specimens obtained >21 days after onset of fever. For other
suspected SARS cases in the United States, a second serum
specimen collected >21 days after fever onset will be necessary
to determine whether infection with the novel coronavirus can be
documented. A reverse transcriptase-polymerase chain reaction
(RT-PCR) test specific for RNA from the novel coronavirus has
been positive within the first 10 days after fever onset in
specimens from some SARS patients, but the duration of detectable
viremia or viral shedding is unknown, and RT-PCR tests on samples
collected during convalescence might be negative. Viral culture
followed by RT-PCR also has been used to detect the novel
coronavirus in some specimens. 

3) Although evidence is accumulating that a novel coronavirus is
the primary causative agent of SARS, more laboratory and
epidemiologic data are needed before this link is established
fully. Once definitive identification of the cause of SARS has
been achieved, an intensive focus on development of effective
treatment regimens might reduce morbidity and mortality of
patients with SARS. However, specific measures to prevent
transmission (e.g., vaccination programs, prophylactic drugs, or
hyperimmune globulin) might require more time to develop and
implement. In the interim, strengthening traditional public
health functions such as collection and rapid analysis of
surveillance and epidemiologic data, and implementing essential
infection-control measures for suspected SARS patients and their
contacts, will be the mainstay of SARS control. A sustained and
cooperative global public health response will be necessary to
limit further dissemination of SARS and to prepare for emerging
global microbial threats.

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