ScienceWeek August 18, 2007
Dan Agin
August 18, 2007
Vol. 11 - Number 32
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The world little knows how many of the thoughts
and theories which have passed through the mind
of a scientific investigator have been crushed in
silence and secrecy; that in the most successful
instances not a tenth of the suggestions, the hopes,
the wishes, the preliminary conclusions have been
realized.
-- Michael Faraday (1791-1867)
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Contents (full text below):
1. Cell Biology: Aneuploidy in the Balance
2. Neuroscience: Synapses Here and Not Everywhere
3. Books: Science And Society: To Arbitrate or to Advocate?
4. Books: Neuroscience: Wittgenstein and the Brain
5. Biological Chemistry: Enzymes Line Up For Assembly
6. Astrophysics: Photons From A Hotter Hell
7. Obituary: Anne McLaren (1927-2007)
8. The Common Biology of Cancer and Ageing
9. Biochemistry: Designer Enzymes
10. Science In Culture: Left To Digest
11. Microbiology: Labs Not So Secure After All
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1.
Science 17 August 2007: Vol. 317. no. 5840, pp. 904 - 905 DOI:
10.1126/science.1146857
Cell Biology: Aneuploidy in the Balance
Prasad V. Jallepalli and David Pellman
A central principle of genetics is that cells within an organism
contain the same complement of chromosomes. The presence of too
many or too few chromosomes, called aneuploidy, is associated
with disease, and accounts for the majority of spontaneous
miscarriages in humans, as well as hereditary birth defects such
as Down syndrome (1). Precisely how aneuploidy affects cells is
not well understood. Extra chromosomes cause a proportionate
increase in gene expression (2), potentially altering a cell's
dosage of proteins in damaging ways. On the other hand, most
cancer cells are aneuploid, suggesting that some patterns of
chromosome gain and loss enable cells to escape normal growth
restraints and develop into malignant tumors--for example, by
acquiring extra copies of an oncogene, or losing a tumor
suppressor gene (3, 4). But are the effects of aneuploidy
strictly specific to a given over- or underrepresented
chromosome, or does aneuploidy evoke a generalized physiological
response regardless of what chromosome is affected? A new study
by Torres et al. (5) on page 916 of this issue uncovers
characteristics shared by all aneuploid cells, identifying a
broad cellular response to aneuploidy that has ramifications for
better understanding aneuploidy-linked diseases in humans.
Torres et al. analyzed the budding yeast Saccharomyces
cerevisiae, a well-established and tractable system for studying
chromosome segregation errors (6). In general, aneuploid yeast
cells are at a substantial competitive disadvantage relative to
cells with a normal complement of chromosomes (euploids) because
they are eventually overtaken by spontaneously arising euploid
revertants (7, 8). However, aneuploidy can be beneficial in the
presence of strong selective pressure (9, 10). For example, where
yeast has two similar genes on different chromosomes, cells in
which one of these paralogs is deleted may compensate by the
chance gain of an extra copy of the chromosome bearing the other
paralog (10). Torres et al. engineered yeast strains to contain
two copies of specific chromosomes (disomes) on an otherwise
haploid genetic background. By varying the identity of the extra
chromosome, the authors generated disomic strains encompassing 13
of the 16 yeast chromosomes. As expected, genes present on
disomic chromosomes were transcribed at about twice their normal
levels. However, after correcting for this effect, two groups of
genes were coordinately up-regulated in many different aneuploid
strains. One cluster, previously characterized as part of the
environmental stress response, is also induced in many slow-
growing but euploid strains. However, the other cluster, whose
expression increased in aneuploid strains independently of growth
rate, includes genes involved in ribosome biogenesis. Ribosome
biogenesis consumes roughly half of the metabolic energy of a
proliferating yeast cell, and it is tightly coupled to signaling
pathways that regulate progress through the G1 phase of the cell
division cycle (11). Indeed, a substantial fraction of the
aneuploid strains examined by Torres et al. exhibited a delay in
cell cycle entry and an increase in cell size, demonstrating a
functional impact of supernumerary chromosomes on cell
proliferation. Identifying the molecular nature of this signal
will be of considerable interest.
The authors found that aneuploidy also strongly affects cell
metabolism. The aneuploid strains avidly take up glucose, and
many also undergo amplification of genes encoding glucose
transporters. However, glucose is used less efficiently in these
cells, resulting in lower accumulated biomass per unit of
glucose. This is intriguing given that many tumor cells exhibit
the "Warburg effect" (12), in which glycolysis (anaerobic
metabolism) is emphasized at the expense of mitochondrial
(aerobic) respiration. Although S. cerevisiae has a unique
physiology that emphasizes fermentation relative to respiration,
it will be interesting to determine whether aneuploidy elicits a
similar metabolic effect in mammalian cells.
What is the basis for the increased glucose requirement in the
yeast aneuploids? Torres et al. propose a simple and intuitive
explanation. Although transcripts from the disomic chromosome
doubled in abundance, steady-state levels of many proteins
encoded by these transcripts did not. The aneuploid strains are
also sensitive to compounds that inhibit protein translation or
block protein degradation by proteasomes. Thus, the gene
expression imbalance leads to compensatory proteolysis, which
demands more energy (see the figure). Furthermore, analysis of
strains harboring large human genomic DNA fragments as yeast
artificial chromosomes, which are not expected to be transcribed
or translated to any great extent, did not exhibit a growth delay
or drug sensitivities associated with authentic yeast disomes,
indicating that these phenotypes are triggered by increases in
gene expression rather than the presence of extra DNA.
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2.
Science 17 August 2007: Vol. 317. no. 5840, pp. 907 - 908 DOI:
10.1126/science.1147570
Neuroscience: Synapses Here and Not Everywhere
David M. Miller
Brain function depends on a vast array of synapses, or
connections, between neurons. The overall architecture of these
networks is defined by the creation of specific synapses as well
as by the removal or pruning of excess connections. Pruning is
particularly dramatic in the human brain, in which an estimated
40% of synapses generated during postnatal growth are eliminated
by adulthood (1). The scope of this phenomenon argues for robust
mechanisms that select synapses for preservation or destruction,
but the molecular details are obscure. For instance, how is this
choice regulated in a single neuron that initially synapses with
multiple partners? On page 947 of this issue, Ding et al. (2)
provide an intriguing model of this process in which the creation
of adult synapses triggers the destruction of developmentally
transient synapses forged by the same neuron.
These findings are derived from studies of a motor neuron circuit
that regulates egg laying in the nematode Caenorhabditis elegans.
The hermaphrodite-specific neuron (HSNL) synapses with muscles
and with VC-class motor neurons adjacent to the vulva, an opening
through which fertilized embryos are expelled from the uterus
(see the figure). Specialized structures assemble at these
synapses for the release of neurotransmitter signals from the
presynaptic membrane to stimulate receptors at the postsynaptic
surface. Ding et al. expressed presynaptic proteins (labeled with
green fluorescent protein) in nematodes and observed that HSNL
synapses near the vulva in the primary synapse region are
accompanied by a distal set of HSNL connections in the secondary
synapse region during larval development. However, by the adult
stage, these secondary synapses were removed as the primary
synapse region matured. The authors propose that a local cue
directs the maturation and elimination events simultaneously, and
that synapse removal results from the destruction of presynaptic
proteins by the ubiquitin-proteasome system.
The ubiquitin-proteasome system uses the enzyme E3 ubiquitin
ligase to attach the peptide ubiquitin to specific protein
substrates. These ubiquitin-labeled targets are dismembered in a
barrel-shaped structure called the proteasome. The SCF (Skp1-
Cullin-F-box) type of E3 ubiquitin ligase is composed of multiple
subunits and achieves target selectivity with an interchangeable
set of F-box adaptor proteins (3).
Earlier work by Shen and colleagues revealed that intercellular
contact between a pair of immunoglobulin membrane proteins, SYG-1
and SYG-2, directs assembly of the primary synapse region (4, 5).
Remarkably, SYG-2, the instructive signal that stimulates synapse
formation in this location, is presented by a nearby epithelial
cell (guidepost cell) rather than by postsynaptic vulval muscle
or VC motor neurons. Complementary expression of SYG-1 in the
HSNL neuron tethers presynaptic components to this spot.
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3.
Science 17 August 2007: Vol. 317. no. 5840, pp. 900 - 901 DOI:
10.1126/science.1145781
Books: Science And Society: To Arbitrate or to Advocate?
Nathan E. Hultman (Reviewer)
The Honest Broker Making Sense of Science in Policy and Politics
by Roger A. Pielke Jr. Cambridge University Press, Cambridge,
2007. 198 pp. Paper, $29.99. ISBN 9780521694810.
Perhaps there was a time when scientists found it easy to
maintain a dispassionate separation from the big political
questions of their day, toiling with utmost focus on formulating
and investigating questions of theoretical importance without
being asked by journalists, politicians, bureaucracies, and
interest groups to interpret the "broader impact" of their
inquiry and discovery. Although the reality of misty visions of
past times can be debated, it is clear that present-day issues of
science and society--climate change, stem cell research,
genetically modified organisms, space research, and biofuels, to
name just a few--challenge many scientists to contextualize their
research in a wider social matrix. Yet navigating a path of
responsible engagement in a loud and contested political context
can try the integrity of even the most seasoned researchers;
indeed, science is of course sometimes used as a shield for
advancing individual political agendas, even by scientists
themselves. Moreover, scientists often justify, sometimes under
duress, their requests for funding by linking their research to
broader societal benefits, even if their research has no such
goal. In The Honest Broker: Making Sense of Science in Policy and
Politics, Roger Pielke Jr. successfully illuminates these
challenges to science and scientists. He also poses several
reflexive questions that enable researchers to improve their
contributions to the public interest.
Pielke (a professor in the Environmental Studies Program,
University of Colorado) has contributed extensively to debates on
climate change science and policy, especially on hurricane and
storm damages. His perspectives on the scientific process and
climate change also draw on his training as a political
scientist, his familiarity with academic views of the role of
scientists in policy, and his experience collaborating with his
father, Roger Pielke Sr., an atmospheric scientist. The author's
background gives him a broad vantage point from which to assess
the problems that can arise when bringing scientific expertise
into democratic debates.
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4.
Science 17 August 2007: Vol. 317. no. 5840, p. 901 DOI:
10.1126/science.1144965
Books: Neuroscience: Wittgenstein and the Brain
Barry Dainton (Reviewer)
Neuroscience and Philosophy: Brain, Mind, and Language by Maxwell
Bennett, Daniel Dennett, Peter Hacker, and John Searle. Columbia
University Press, New York, 2007. 227 pp. $25.50, £16. ISBN
9780231140447.
"Whereof one cannot speak, thereof one must be silent." With this
now-famous line Ludwig Wittgenstein brought to a close Tractatus
Logico-Philosophicus, his first great work (1). The lines that
bring to a close his second great work, Philosophical
Investigations (2), are rather less well known; they include:
"The confusion and barrenness of psychology is not to be
explained by calling it a 'young science'... in psychology there
are experimental methods and conceptual confusion." The alleged
confusion stems from certain prevalent ways of thinking about the
mental realm that Wittgenstein held to be disastrously misguided.
These same ways of thinking are also prevalent, to equally
disastrous effect, in contemporary neuroscience, or so
philosopher Peter Hacker and neuroscientist Maxwell Bennett argue
over the 450 or so Wittgenstein-inspired pages of Philosophical
Foundations of Neuroscience (3). Neuroscience and Philosophy, the
present (and much briefer) work, is a useful introduction to
their position. It contains several extracts from Foundations,
together with critical surveys by John Searle and Daniel Dennett-
-derived from an "authors and critics" session at the 2005
American Philosophical Association meeting--and responses from
Bennett and Hacker (henceforth "B&H").
There are several strands to B&H's case, some more contentious
than others. Quoting from the like of Blakemore, Crick, Edelman,
Frisby, Marr, and Young, they show that neuroscientists commonly
talk of subsystems within the brain storing maps,
representations, and information; forming hypotheses; or passing
"symbols" and "messages" to each other. Much of this talk, they
argue, is disguised nonsense. To take just one example, for
something to be a map in the ordinary sense of the term, in
addition to certain similarities of structure between the map and
what it depicts, there are also rules and conventions that allow
someone who understands them to know what parts or aspects of the
world the map is representing. Because so-called neural maps are
typically not associated with such conventions, it is wrong to
suppose they "represent" in the way of ordinary maps, although
some neuroscientists talk as if they do. Dennett complains that
B&H are too conservative by far when it comes to recognizing
legitimate and fruitful extensions to the way terms are normally
used--such extensions are commonplace in all sciences. He may
well be right. But B&H are also right to insist that such
extensions must be carefully considered. (Indeed, Dennett's own
willingness to ascribe beliefs and intentions to systems as
simple as thermostats strikes some as an ill-considered extension
of ordinary usage.)
So far so good, but what B&H themselves describe as their main
line of argument is more problematic and less obviously of
potential use to practicing neuroscientists.
Although Sherrington, Eccles, and Penfield may have subscribed to
variants of mind-body dualism, contemporary neuroscientists are
generally of the opinion that our mental lives are material in
nature and completely dependent upon neural goings-on in our
brains. Yet B&H claim that the field remains committed to a
pernicious form of dualism. Why so? Because these same
neuroscientists hold that brains can think thoughts, have
experiences, take decisions, hold grudges, remember past events,
and so forth. B&H claim this too is just nonsense. For it is not
brains that have thoughts and experiences, it is human beings--
i.e., whole human animals. B&H do not deny that our mental lives
depend on our brains, but they insist that to ascribe mental
powers to brains is as senseless as ascribing mental powers to
numbers.
This claim will strike many as bizarre in the extreme. What are
their grounds for making it? Their reasoning derives from
Wittgenstein, who wrote: "Only of a human being and what
resembles (behaves like) a living human being can one say: it has
sensations; it sees, is blind; hears, is deaf; is conscious or
unconscious." Like Wittgenstein, B&H hold that when it comes to
the correct ascription of mental states and processes, it is a
subject's capacities for publicly observable behavior that are
significant, not what is going on inside the subject (or her or
his mind or consciousness). Simplifying only a little, because
brains are incapable of the relevant forms of behavior--they
can't walk, talk, flinch, point, or run around--it is senseless
to ascribe mental attributes to them.
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5.
Nature 448, 755-756 (16 August 2007) | doi:10.1038/448755a;
Published online 15 August 2007
Biological Chemistry: Enzymes Line Up For Assembly
Nicholas M. Llewellyn & Jonathan B. Spencer
Many enzymes have a series of catalytic sites, lined up like
beads on a string. A previously unknown link in one of these
molecular assembly lines involves an unexpected approach to a
common biochemical reaction.
Nearly 100 years ago, Henry Ford demonstrated the full strength
of economist Adam Smith's insights into productivity and the
division of labour when he established the first moving assembly
line. By shuttling partially constructed cars mechanically from
one worker to the next, each performing a single specific task,
Ford's assembly line could issue a new Model T every three
minutes. This manufacturing method provided the foundation of
modern mass production. But nature employed much the same
approach for constructing molecules long before humans existed to
ponder questions of economy and efficiency. On page 824 of this
issue, Walsh and colleagues1 identify a previously unrecognized
link in one such biological assembly line - an enzyme that could
some day be exploited by chemists to modify complex, naturally
occurring compounds.
The enzymes that form the polyketide synthase (PKS) and non-
ribosomal peptide synthetase (NRPS) families are responsible for
the biosynthesis of many useful compounds, including the
antibiotics erythromycin and vancomycin, and the antitumour drug
epothilone. These multi-subunit enzymes are the molecular
equivalents of moving assembly lines: growing substrate molecules
are handed, bucket-brigade style, from one specialized catalytic
site to the next, with each site performing a specific and
predictable function (Fig. 1)2, 3. The catalytic domains that
make up these complex biosynthetic machines are so well studied
that the likely product of a newly discovered PKS or NRPS gene
cluster can often be predicted from the gene sequence alone.
The PKS assembly line starts by recruiting small building-blocks
(such as acetate and propionate molecules, which contain 'acyl'
chemical groups) onto carrier proteins. The building-blocks are
then bonded together in reactions catalysed by a 'ketosynthase'
region of the PKS. The resulting substrate may then be chemically
tailored by various other enzyme domains, before being passed on
to another ketosynthase for a further round of extension and
modification. The cycle is repeated until the finished molecule
is finally offloaded. The various catalytic domains may exist as
discrete enzymes (as in type II PKS), or be connected end to end,
like beads on a string (as in type I PKS), but in both cases the
biosynthetic strategy remains the same.
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6.
Nature 448, 760-762 (16 August 2007) | doi:10.1038/448760a;
Published online 15 August 2007
Astrophysics: Photons From A Hotter Hell
Trevor Weekes
Blazars are massive black holes sending out particle jets at
close to the speed of light. Stupendously fast, intense bursts of
highly energetic gamma-rays indicate that the blazar environment
is even more extreme than was thought.
Serendipity has always played a large part in astronomy.
Detecting the short-lived, violent phenomena characteristic of
high-energy astrophysics is a case in point. Catching these
transient signals as they appear, dominate the sky briefly, and
disappear again - perhaps never to be repeated - requires not
only the right telescope, but also the luck of pointing it in the
right direction. When technology and serendipity do come
together, dramatic results can follow.
An example of such an auspicious conjunction is given by two
papers from the Astrophysical Journal1, 2, in which two separate
teams of astronomers report the detection of powerful bursts of
teraelectronvolt (TeV) gamma-rays lasting just minutes, the
shortest time ever observed. The sources, billions of light years
away, are two 'blazars' - black holes of more than 100 million
solar masses that signal their presence through jets of charged
particles emitted at almost the speed of light.
The detection of high-energy gamma-ray emission from blazars is
not new. The gamma-ray telescope EGRET, on NASA's Compton gamma-
Ray Observatory, was sensitive to photons 100 million times more
energetic than optical photons, and reported the detection of
some 70 blazars3 almost a decade ago. The new generation of
telescopes, with acronyms such as CANGAROO-III, HESS, MAGIC and
VERITAS, is sensitive to TeV gamma-rays 1,000 times more
energetic again, and has already catalogued some 60 sources,
including 15 blazars4, 5. In the Universe that is being revealed
by these telescopes, violent, high-energy phenomena are
commonplace.
The new findings1, 2 are based on the atmospheric S caronerenkov
technique, in which a gamma-ray is detected indirectly through a
shower of secondary particles that initiates an optical shock
wave as it passes through the atmosphere. The blue light produced
in this process can be easily detected by large, relatively crude
optical telescopes coupled with fast, sensitive electronic
cameras.
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7.
Nature 448, 764-765 (16 August 2007) | doi:10.1038/448764a;
Published online 15 August 2007
Obituary: Anne McLaren (1927-2007)
Azim Surani & Jim Smith
Inspiring reproductive biologist and mammalian geneticist.
On 6 July, Anne McLaren spent a busy day at the Gurdon Institute
in Cambridge, where she had worked since 1992. She prepared a
talk for a meeting in Germany and answered a large number of e-
mails. In the afternoon, she attended a group leaders' meeting,
as always paying close attention and ready to offer sensible
advice. Towards the end of the day, she chatted with colleagues
and asked questions about some recent stem-cell publications. She
left promising to continue the discussion. Sadly, this was to be
her last working day.
Anne McLaren had an extraordinary life, both personally and
professionally. The daughter of industrialist Henry McLaren,
Second Baron Aberconway, and his wife Christabel McNaughten, in
1945 she embarked on the study of zoology at the University of
Oxford because for her this was an easier option than reading
English, for which the entrance examination required too much
reading in too little time. She completed her doctoral studies in
1952, and moved to University College London. There she began her
studies on mouse genetics and reproduction with her colleague
Donald Michie, whom she married that same year.
Initially, McLaren's research interest was in the interactions
between genes and the environment. One of her findings - now
often ignored in bioassays and drug testing in mice -
demonstrated that, compared with the offspring of a cross-strain
mating, inbred strains of mice showed greater variability in
their response to stress. These ideas were elegantly recaptured
in a review, "Too late for the midwife toad", written more than
40 years later. The article encompasses not only Conrad
Waddington's theories of canalization and the inheritance of
apparently acquired characteristics, but also the recent
molecular explanations for morphological evolution based on
studies in flies.
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8.
Nature 448, 767-774 (16 August 2007) | doi:10.1038/nature05985
The Common Biology of Cancer and Ageing
Toren Finkel, Manuel Serrano & Maria A. Blasco
At first glance, cancer and ageing would seem to be unlikely
bedfellows. Yet the origins for this improbable union can
actually be traced back to a sequence of tragic-and some say
unethical-events that unfolded more than half a century ago. Here
we review the series of key observations that has led to a
complex but growing convergence between our understanding of the
biology of ageing and the mechanisms that underlie cancer.
Like so many areas of science, our subject is one that has no
true beginning, and as yet, no clear ending. However, if we must
begin somewhere, it would be in the winter of 1951, when a 31-yr-
old woman and mother of five small children underwent a seemingly
routine biopsy for a suspicious cervical mass. A portion of that
biopsy went as usual to the pathology lab for diagnosis;
unbeknownst to the patient, another portion was diverted to the
research laboratory of two investigators at Johns Hopkins, George
and Martha Gey. The Geys had spent the better part of the
preceding twenty years attempting to find a human cell that could
grow indefinitely in laboratory culture conditions. That search
would end with the arrival of this particular biopsy sample.
Unfortunately for the patient, the pathology laboratory quickly
confirmed that the mass was indeed cancer and, despite surgery
and radium treatment, the patient succumbed to her disease a mere
eight months later. On the day of her death, in October 1951,
George Gey appeared on national television in the United States
to announce that a new era in medical research had begun. For the
first time, he explained, it was now possible to grow human cells
continuously in the laboratory. He termed the cell line he had
created the 'HeLa cell', in memory of Henrietta Lacks, the
unfortunate young mother whose biopsy sample made all this
possible.
Over the next 50 years, researchers would slowly strip away many
of the secrets of how a cancer cell achieves and maintains its
immortality. Here we review those efforts in an attempt to give
both a historical perspective and an update on the more recent
experimental highlights. In particular, we will focus on five
aspects of cancer biology that appear to be particularly
informative about normal ageing: the connection between cellular
senescence and tumour formation; the common role of genomic
instability; the biology of the telomere; the emerging importance
of autophagy in both cancer and ageing; and the central roles of
mitochondrial metabolism and energetic-dependent signal
transduction in both processes. Together, these findings seem to
indicate that both cancer and ageing represent complex biological
tapestries that are often-but not always-woven by similar
molecular threads.
The Geys' success in cultivating human cancer cells spurred a
huge interest in isolating as many types of human cells as
possible. These early 'cell culturists' quickly recognized that
few, if any, of the isolated cell lines maintained a diploid
status. This problem led Leonard Hayflick and Paul Moorhead to
turn their attention to a particular source of tissue that is now
off limits to many scientists. Using human fetal explants, these
investigators found that it was possible to grow and maintain
normal diploid fibroblasts. Hayflick and Moorhead emphasized that
such isolates were not clonal cell lines, but polyclonal pools or
strains1. Despite their success in growing these cell lines for
several months, they soon stumbled upon another curious
phenomenon: cells could not be subcultivated more than about 50
times. They noted that the culture medium was not to blame
because if they took early passage cells and transferred them to
the conditioned media from late passage cells "luxurious growth
invariably results." On the basis of this and other arguments,
such as the fact that frozen cells retained the memory of their
subcultivation history, they concluded that some intrinsic
factor/s (later termed 'Hayflick factors') accumulated in these
cells until they 'senesced'1. In a further leap of speculation,
they proposed that this cellular phenomenon could be relevant for
organismal ageing. The degree of that relevance remains hotly
debated, although it is now clear that the senescent response can
be triggered by a wide variety of cellular stresses including the
loss of telomeres, the de-repression of the cyclin-dependent
kinase inhibitor 2a (CDKN2a, also known as INK4a or ARF) locus,
or the accumulation of DNA damage and the subsequent activation
of the DNA damage response. Furthermore, the critical
executioners of senescence in response to the above factors seem
to include the well known tumour suppressor pathways that are
controlled by retinoblastoma 1 (RB1) and P53, proteins that have
been widely implicated in tumorigenesis.
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9.
Nature 448, 757-758 (16 August 2007) | doi:10.1038/448757a;
Published online 15 August 2007
Biochemistry: Designer Enzymes
Michael P. Robertson & William G. Scott
Evolution has crafted thousands of enzymes that are efficient
catalysts for a plethora of reactions. Human attempts at enzyme
design trail far behind, but may benefit from exploiting
evolutionary tactics.
Chemical reactions in living organisms are catalysed by enzymes,
the vast majority of which are proteins. These finely tuned
catalysts are the result of billions of years of evolution, and
far surpass anything yet created by humans. Indeed, our ability
to design enzymes, on the basis of our knowledge of protein
structure and reaction mechanisms, can most charitably be
described as primitive. The structure and catalytic properties of
an enzyme are dictated by its amino-acid sequence in ways that
are not understood well enough to reproduce. On page 828 of this
issue, Seelig and Szostak1 describe how they bypass this
intractable difficulty by simulating evolution. They use an in
vitro artificial selection process to isolate new protein enzymes
that join the ends of two RNA molecules together.
The ability to make enzymes for specific purposes is of great
practical interest - designer enzymes could be made for many
potential applications. They could, for example, be used to
prepare drugs efficiently. In fact, some methods for preparing
new enzymes already exist. One approach is the randomization and
in vivo selection of variants of existing enzymes. This strategy
has been reasonably successful, but it is limited by the
relatively small number of possible variants (typically from 106
to 108; for comparison, a system that generates more than 1012
would be desirable).
Another approach is to use an organism's immune system in a form
of natural selection to create catalytic antibodies2, 3. Enzymes
work by binding and stabilizing the transition state of a
reaction - the highest-energy configuration of atoms in the
reaction pathway. So if an antibody can bind to molecules that
have the same geometry as a reaction's transition state, then it
can also catalyse that reaction. Generating catalytic antibodies
thus requires a detailed knowledge of the reaction's mechanism
and the ability to synthesize a transition-state mimic -
conditions that are often not met.
Catalytic antibodies can be thought of as rationally designed
enzymes, because knowledge of the reaction pathway is required to
make them. But the creation of particular antibodies in this way
is purely the product of in vivo genetic rearrangements that
generate a vast number of antibody variants, and of the immune
selection process itself. Catalytic antibodies typically provide
a 104-fold to 106-fold rate enhancement of reactions, but usually
fall short of the catalytic prowess exhibited by their natural
enzyme counterparts. This is probably because transition-state
stabilization is only one of several strategies used by natural
enzymes to accelerate reactions.
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10.
Nature 448, 753 (16 August 2007) | doi:10.1038/448753a; Published
online 15 August 2007
Science In Culture: Left To Digest
Paolo Mazzarello & Maurizio Harari
In ancient art, banqueters always recline on their left side -
perhaps to aid digestion.
The élite of most advanced ancient Mediterranean societies
partook of banquets lying down. We know this from iconographic
records dating back to the seventh century BC. Some scholars
assume that the custom was widespread in the originally nomadic
tribes that finally settled in Syria or Iran, befitting their
modest tent furnishings. But the social prestige that soon became
associated with reclining at a banquet might owe more to the
preciousness of the beds of the rich, as suggested by the
outpouring of the biblical prophet Amos (around 750 BC), against
those used by the Samarians: "Lying upon beds of ivory, stretched
comfortably on their couches, they eat lambs taken from the
flock." (Bible, Amos 6:4-7).
So it's not surprising that one of the oldest images of a
reclining banquet is a royal one: the famous bas-relief of King
Assurbanipal of Assyria lying on his left side while his wife
sits on the throne (pictured). This form of aristocratic banquet
was widespread in the seventh century BC in Greece - the poet
Archilochus wrote, "leaning on my lance I drink (wine)" - and
among the Etruscans, who traded with the Greeks. It came to span
the entire Mediterranean Greek and Roman civilizations.
Art historians have often noted that banqueters almost always
appear to be reclining on their left sides. The usual explanation
is that lying on the left leaves the right hand free to hold the
dining vessels. But in funereal art there is good documentation
of presumptive left-handed banqueters also reclining to the left.
Jean-Marie Dentzer in his book Le motif due banquet couché dans
le Proche-Orient et le monde Grec du VIIe au IVe siècle avant J.-
C. (Ecole Francais, Rome, 1982) has compiled an extensive
inventory of the banquet couché between the seventh and fourth
centuries BC. Of the more than 700 illustrations, including at
least a dozen banqueters holding pots in their left hand, not one
is lying on their right side.
One explanation could lie in the anatomy of the stomach and in
the digestive mechanism. The stomach has an irregular shape that
curves upon itself. Its rounded base is turned to the left. There
are two openings: one at the top where food enters from the
oesophagus and one at the base, the pyloric orifice, from which
part-digested food exits.
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11.
Nature 448, 732-733 (16 August 2007) | doi:10.1038/448732a;
Published online 15 August 2007
Microbiology: Labs Not So Secure After All
Daniel Cressey
How safe are our microbiology labs? Not so secure after all.
In the movie 28 Days Later a deadly virus escapes from a British
research lab and wreaks havoc across the country. That was
fiction, but concerns about lab safety are not.
It is now nearly certain that the foot-and-mouth virus discovered
on 3 August in cattle near Guildford, UK, originated at the
nearby animal-research facility in Pirbright. The incident seems
to have been due to an accidental leak of the virus from either
the government-run Institute for Animal Health (IAH) or
commercial vaccine manufacturer Merial Animal Health, which share
the Pirbright facility. Merial said last week that it "has
complete confidence in its safety and environmental protection".
The IAH also says it does not know of any security breaches and
is cooperating with the inspectors.
This latest incident highlights the problems that can occur with
the security of so-called 'dual-use' research - work that could
be of use to terrorists as well as to legitimate researchers.
Investigations into the foot-and-mouth outbreak are ongoing, but
engineering or personnel failure must have been to blame if the
virus escaped from a secure lab, in the opinion of Keith Plumb, a
bioprocess engineer at the Institution of Chemical Engineers in
London. It could have emerged only through the ventilation
system, in waste, or on people, he says. Waste should be
sterilized before disposal in the sewers, either by steam or
chemicals. Damage to filters in the negative-pressure air system,
for example, could have given the virus a possible exit route,
says Plumb.
Lab workers are fully covered by a gown, with only their eyes
exposed, and must enter the lab via air-locks. After leaving the
lab and removing the gown, researchers must shower to get rid of
any contamination that might have occurred. Not taking enough
time to shower is another possible exit route for the virus,
Plumb says.
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