David M. Bailey

Transforming fragments into candidates: small becomes big in medicinal chemistry

Fragment-based drug discovery (FBDD) represents a logical and efficient approach to lead discovery and optimisation. It can draw on structural, biophysical and biochemical data, incorporating a wide range of inputs, from precise mode-of-binding information on specific fragments to wider ranging pharmacophoric screening surveys using traditional HTS approaches. It is truly an enabling technology for the imaginative medicinal chemist. In this review, we analyse a representative set of 23 published FBDD studies that describe how low molecular weight fragments are being identified and efficiently transformed into higher molecular weight drug candidates. FBDD is now becoming warmly endorsed by industry as well as academia and the focus on small interacting molecules is making a big scientific impact.

Temporal change in deep-sea benthic ecosystems: a review of the evidence from recent time-series studies

Societal concerns over the potential impacts of recent global change have prompted renewed interest in the long-term ecological monitoring of large ecosystems. The deep sea is the largest ecosystem on the planet, the least accessible, and perhaps the least understood. Nevertheless, deep-sea data collected over the last few decades are now being synthesised with a view to both measuring global change and predicting the future impacts of further rises in atmospheric carbon dioxide concentrations. For many years, it was assumed by many that the deep sea is a stable habitat, buffered from short-term changes in the atmosphere or upper ocean. However, recent studies suggest that deep-seafloor ecosystems may respond relatively quickly to seasonal, inter-annual and decadal-scale shifts in upper-ocean variables. In this review, we assess the evidence for these long-term (i.e. inter-annual to decadal-scale) changes both in biologically driven, sedimented, deep-sea ecosystems (e.g. abyssal plains) and in chemosynthetic ecosystems that are partially geologically driven, such as hydrothermal vents and cold seeps. We have identified 11 deep-sea sedimented ecosystems for which published analyses of long-term biological data exist. At three of these, we have found evidence for a progressive trend that could be potentially linked to recent climate change, although the evidence is not conclusive. At the other sites, we have concluded that the changes were either not significant, or were stochastically variable without being clearly linked to climate change or climate variability indices. For chemosynthetic ecosystems, we have identified 14 sites for which there are some published long-term data. Data for temporal changes at chemosynthetic ecosystems are scarce, with few sites being subjected to repeated visits. However, the limited evidence from hydrothermal vents suggests that at fast-spreading centres such as the East Pacific Rise, vent communities are impacted on decadal scales by stochastic events such as volcanic eruptions, with associated fauna showing complex patterns of community succession. For the slow-spreading centres such as the Mid-Atlantic Ridge, vent sites appear to be stable over the time periods measured, with no discernable long-term trend. At cold seeps, inferences based on spatial studies in the Gulf of Mexico, and data on organism longevity, suggest that these sites are stable over many hundreds of years. However, at the Haakon Mosby mud volcano, a large, well-studied seep in the Barents Sea, periodic mud slides associated with gas and fluid venting may disrupt benthic communities, leading to successional sequences over time. For chemosynthetic ecosystems of biogenic origin (e.g. whale-falls), it is likely that the longevity of the habitat depends mainly on the size of the carcass and the ecological setting, with large remains persisting as a distinct seafloor habitat for up to 100 years. Studies of shallow-water analogs of deep-sea ecosystems such as marine caves may also yield insights into temporal processes. Although it is obvious from the geological record that past climate change has impacted deep-sea faunas, the evidence that recent climate change or climate variability has altered deep-sea benthic communities is extremely limited. This mainly reflects the lack of remote sensing of this vast seafloor habitat. Current and future advances in deep-ocean benthic science involve new remote observing technologies that combine a high temporal resolution (e.g. cabled observatories) with spatial capabilities (e.g. autonomous vehicles undertaking image surveys of the seabed).

Trends in body size across an environmental gradient : A differential response in scavenging and non-scavenging demersal deep-sea fish

Body size trends across environmental gradients are widely reported but poorly understood. Here, we investigate contrasting relationships between size (body mass) and depth in the scavenging and predatory demersal ichthyofauna (800–4800 m) of the North-east Atlantic. The mean size of scavenging fish, identified as those regularly attracted to baited cameras, increased significantly with depth, while in non-scavengers there was a significant decline in size. The increase in scavenger size is a consequence of both intra and inter-specific effects. The observation of opposing relationships, in different functional groups, across the same environmental gradient indicates ecological rather than physiological causes. Simple energetic models indicate that the dissimilarity can be explained by different patterns of food distribution. While food availability declines with depth for both groups, the food is likely to be in large, randomly distributed packages for scavengers and as smaller but more evenly distributed items for predators. Larger size in scavengers permits higher swimming speeds, greater endurance as a consequence of larger energy reserves and lower mass specific metabolic rate, factors that are critical to survival on sporadic food items.

Long-term changes in deep-water fish populations in the northeast Atlantic: a deeper reaching effect of fisheries?

A severe scarcity of life history and population data for deep-water fishes is a major impediment to successful fisheries management. Long-term data for non-target species and those living deeper than the fishing grounds are particularly rare. We analysed a unique dataset of scientific trawls made from 1977 to 1989 and from 1997 to 2002, at depths from 800 to 4800 m. Over this time, overall fish abundance fell significantly at all depths from 800 to 2500 m, considerably deeper than the maximum depth of commercial fishing (approx. 1600 m). Changes in abundance were significantly larger in species whose ranges fell at least partly within fished depths and did not appear to be consistent with any natural factors such as changes in fluxes from the surface or the abundance of potential prey. If the observed decreases in abundance are due to fishing, then its effects now extend into the lower bathyal zone, resulting in declines in areas that have been previously thought to be unaffected. A possible mechanism is impacts on the shallow parts of the ranges of fish species, resulting in declines in abundance in the lower parts of their ranges. This unexpected phenomenon has important consequences for fisheries and marine reserve management, as this would indicate that the impacts of fisheries can be transmitted into deep offshore areas that are neither routinely monitored nor considered as part of the managed fishery areas.

The absence of sharks from abyssal regions of the world's oceans

The oceanic abyss (depths greater than 3000 m), one of the largest environments on the planet, is characterized by absence of solar light, high pressures and remoteness from surface food supply necessitating special molecular, physiological, behavioural and ecological adaptations of organisms that live there. Sampling by trawl, baited hooks and cameras we show that the Chondrichthyes (sharks, rays and chimaeras) are absent from, or very rare in this region. Analysis of a global data set shows a trend of rapid disappearance of chondrichthyan species with depth when compared with bony fishes. Sharks, apparently well adapted to life at high pressures are conspicuous on slopes down to 2000 m including scavenging at food falls such as dead whales. We propose that they are excluded from the abyss by high-energy demand, including an oil-rich liver for buoyancy, which cannot be sustained in extreme oligotrophic conditions. Sharks are apparently confined to ca 30% of the total ocean and distribution of many species is fragmented around sea mounts, ocean ridges and ocean margins. All populations are therefore within reach of human fisheries, and there is no hidden reserve of chondrichthyan biomass or biodiversity in the deep sea. Sharks may be more vulnerable to over-exploitation than previously thought.

LONG-TERM CHANGE IN BENTHOPELAGIC FISH ABUNDANCE IN THE ABYSSAL NORTHEAST PACIFIC OCEAN

Food web structure, particularly the relative importance of bottom-up and top-down control of animal abundances, is poorly known for the Earths largest habitats: the abyssal plains. A unique 15-yr time series of climate, productivity, particulate flux, and abundance of primary consumers (primarily echinoderms) and secondary consumers (fish) was examined to elucidate the response of trophic levels to temporal variation in one another. Towed camera sled deployments in the abyssal northeast Pacific (4100 m water depth) showed that annual mean numbers of the dominant fish genus (Coryphaenoides spp.) more than doubled over the period 1989-2004. Coryphaenoides spp. abundance was significantly correlated with total abundance of mobile epibenthic megafauna (echinoderms), with changes in fish abundance lagging behind changes in the echinoderms. Direct correlations between surface climate and fish abundances, and particulate organic carbon (POC) flux and fish abundances, were insignificant, which may be related to the varied response of the potential prey taxa to climate and POC flux. This study provides a rare opportunity to study the long-term dynamics of an unexploited marine fish population and suggests a dominant role for bottom-up control in this system.

High-energy phosphate metabolism during exercise and recovery in temperate and Antarctic scallops: an in vivo 31P-NMR study.

In vivo 31P‐nuclear magnetic resonance (NMR) spectroscopy was used to measure the levels of ATP, phospho‐l‐arginine (PLA), and inorganic phosphate in the adductor muscle of the Antarctic scallop Adamussium colbecki and two temperate species, Aequipecten opercularis and Pecten maximus. Graded exercise regimes from light (one to two contractions) to exhausting (failing to respond to further stimulation) were imposed on animals of each species at its habitat temperature (0° vs. 12°C, respectively). NMR spectroscopy allowed noninvasive measurement of metabolite levels and intracellular pH at high time resolution (30–120‐s intervals) during exercise and throughout the recovery period. Significant differences were shown between the magnitude and form of the metabolic response with increasing levels of exercise in each species. After exhaustion, short‐term (first 15 min) muscle alkalosis was followed by acidosis of up to 0.2 pH units during the recovery process. Aequipecten opercularis had similar resting muscle PLA levels compared with either P. maximus or A. colbecki but used a fivefold greater proportion of this store per contraction and was able to perform only half as many claps (maximum of 24) as the other species before exhaustion. All species regenerated their PLA store at a similar rate despite different environmental temperatures. These findings argue for some cold compensation of muscular performance and recovery capacities in the Antarctic scallop, albeit at levels of performance similar to scallops with low activity lifestyles from temperate latitudes.

High swimming and metabolic activity in the deep-sea eel Synaphobranchus kaupii revealed by integrated in situ and in vitro measurements.

Several complementary studies were undertaken on a single species of deep‐sea fish (the eel Synaphobranchus kaupii) within a small temporal and spatial range. In situ experiments on swimming and foraging behaviour, muscle performance, and metabolic rate were performed in the Porcupine Seabight, northeast Atlantic, alongside measurements of temperature and current regime. Deep‐water trawling was used to collect eels for studies of animal distribution and for anatomical and biochemical analyses, including white muscle citrate synthase (CS), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), and pyruvate kinase (PK) activities. Synaphobranchus kaupii demonstrated whole‐animal swimming speeds similar to those of other active deep‐sea fish such as Antimora rostrata. Metabolic rates were an order of magnitude higher (31.6 mL kg−1 h−1) than those recorded in other deep‐sea scavenging fish. Activities of CS, LDH, MDH, and PK were higher than expected, and all scaled negatively with body mass, indicating a general decrease in muscle energy supply with fish growth. Despite this apparent constraint, observed in situ burst or routine swimming performances scaled in a similar fashion to other studied species. The higher‐than‐expected metabolic rates and activity levels, and the unusual scaling relationships of both aerobic and anaerobic metabolism enzymes in white muscle, probably reflect the changes in habitat and feeding ecology experienced during ontogeny in this bathyal species.

Measurement of in situ oxygen consumption of deep-sea fish using an autonomous lander vehicle

Conventional laboratory studies of deep-sea fish metabolism are not possible as these fish are typically killed during recovery to the surface. As these species are important members of deep-sea communities, the lack of these data represents a significant limitation to our understanding of the functioning of this ecosystem. An autonomous fish respirometer vehicle was developed in order to measure the oxygen consumption of deep-sea fish in situ. This new lander allows measurements to be made without handling or stressing the animals and without the logistical problems and great cost of submersible operations. The design, operation, and measurement methodology are described and preliminary data for Coryphaenoides armatus at 4000 m are presented. These Atlantic data appear to confirm the low metabolic rate measured in this species when compared to other gadid species.

In situ investigation of burst swimming and muscle performance in the deep-sea fish Antimora rostrata (Gunther, 1878)

The few existing measurements of deep-sea fish physiology consistently indicate reduced basal metabolism and metabolic power. A possible explanation for this is the reduction in selective pressure for burst activity capacity due to a reduction in the frequency and duration of predator-prey interactions in the sparsely distributed fish community and continuous darkness. Video recordings of stimulated fast-starts in deep-sea fish were obtained by a lander vehicle and analysed to give the swimming velocities, accelerations, and inertial power requirements of fast-start swimming in Antimora rostrata. With a mean peak velocity of 0.7 m s(-1), and white muscle power output of only 17.0 W kg(-1). A. rostrata is a slow moving fish, but no slower than shallow-water fishes at the same temperature.