ScienceWeek

SCIENCEWEEK

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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