The Future of Drug Development: The Economics of Pharmacogenomics

This paper models how the evolving field of pharmacogenomics (PG), which is the science of using genomic markers to predict drug response, may impact drug development times, attrition rates, costs, and the future returns to research and development (R&D). While there still remains an abundance of uncertainty around how PG will impact the future landscape of pharmaceutical and biological R&D, we identify several likely outcomes. We conclude PG has the potential to significantly reduce both expected drug development costs (via higher probabilities of technical success, shorter clinical development times, and smaller clinical trials) and returns. The impact PG has on expected returns is partially mitigated by higher equilibrium prices, expedited product launches, and longer effective patent lives. Our conclusions are, of course, accompanied by numerous caveats.

Precipitation as the main driver of Neoglacial fluctuations of Gualas glacier, Northern Patagonian Icefield

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Climate of the Past 8 (2012): 519-534, doi:10.5194/cp-8-519-2012.Glaciers are frequently used as indicators of climate change. However, the link between past glacier fluctuations and climate variability is still highly debated. Here, we investigate the mid- to late-Holocene fluctuations of Gualas Glacier, one of the northernmost outlet glaciers of the Northern Patagonian Icefield, using a multi-proxy sedimentological and geochemical analysis of a 15 m long fjord sediment core from Golfo Elefantes, Chile, and historical documents from early Spanish explorers. Our results show that the core can be sub-divided into three main lithological units that were deposited under very different hydrodynamic conditions. Between 5400 and 4180 cal yr BP and after 750 cal yr BP, sedimentation in Golfo Elefantes was characterized by the rapid deposition of fine silt, most likely transported by fluvio-glacial processes. By contrast, the sediment deposited between 4130 and 850 cal yr BP is composed of poorly sorted sand that is free of shells. This interval is particularly marked by high magnetic susceptibility values and Zr concentrations, and likely reflects a major advance of Gualas glacier towards Golfo Elefantes during the Neoglaciation. Several thin silt layers observed in the upper part of the core are interpreted as secondary fluctuations of Gualas glacier during the Little Ice Age, in agreement with historical and dendrochronological data. Our interpretation of the Golfo Elefantes glaciomarine sediment record in terms of fluctuations of Gualas glacier is in excellent agreement with the glacier chronology proposed for the Southern Patagonian Icefield, which is based on terrestrial (moraine) deposits. By comparing our results with independent proxy records of precipitation and sea surface temperature, we suggest that the fluctuations of Gualas glacier during the last 5400 yr were mainly driven by changes in precipitation in the North Patagonian Andes.This research was supported by an EU FP6 Marie Curie Outgoing Fellowship to S.B. Cruise NBP0505 was funded by the US National Science Foundation, Office of Polar Programs grant number NSF/OPP 03-38137 to J. Anderson (Rice University) and J. Smith Wellner (University of Houston). The Cimar-7 Program was supported by the Chilean National Oceanographic Committee (CONA, Grant C7F 01-10 to S. Pantoja)

Purinergic receptors activating rapid intracellular Ca 2+ increases in microglia

We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y6, P2Y12 and P2Y13 receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y6, P2Y12, P2Y13 and P2X4 receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord

Last deglaciation in the Okinawa Trough : subtropical northwest Pacific link to Northern Hemisphere and tropical climate

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 20 (2005): PA4005, doi:10.1029/2004PA001061.Detailed deglacial and Holocene records of planktonic δ18O and Mg/Ca–based sea surface temperature (SST) from the Okinawa Trough suggest that at ∼18 to 17 thousand years before present (kyr B.P.), late spring/early summer SSTs were approximately 3°C cooler than today, while surface waters were up to 1 practical salinity unit saltier. These conditions are consistent with a weaker influence of the summer East Asian Monsoon (EAM) than today. The timing of suborbital SST oscillations suggests a close link with abrupt changes in the EAM and North Atlantic climate. A tropical influence, however, may have resulted in subtle decoupling between the North Atlantic and the Okinawa Trough/EAM during the deglaciation. Okinawa Trough surface water trends in the Holocene are consistent with model simulations of an inland shift of intense EAM precipitation during the middle Holocene. Millennial-scale alternations between relatively warm, salty conditions and relatively cold, fresh conditions suggest varying influence of the Kuroshio during the Holocene.Funding for this research was provided by NSFC (grants 40106006 and 40206007), SKLLQG (grant LLQG0204), and the NSF (OCE-020776 to DWO). Y.S.'s visit to WHOI was supported via a NSF START Fellowship

CO\u3csub\u3e2\u3c/sub\u3e and fire influence tropical ecosystem stability in response to climate change

Interactions between climate, fire and CO2 are believed to play a crucial role in controlling the distributions of tropical woodlands and savannas, but our understanding of these processes is limited by the paucity of data from undisturbed tropical ecosystems. Here we use a 28,000-year integrated record of vegetation, climate and fire from West Africa to examine the role of these interactions on tropical ecosystem stability. We find that increased aridity between 28–15 kyr B.P. led to the widespread expansion of tropical grasslands, but that frequent fires and low CO2 played a crucial role in stabilizing these ecosystems, even as humidity changed. This resulted in an unstable ecosystem state, which transitioned abruptly from grassland to woodlands as gradual changes in CO2 and fire shifted the balance in favor of woody plants. Since then, high atmospheric CO2 has stabilized tropical forests by promoting woody plant growth, despite increased aridity. Our results indicate that the interactions between climate, CO2 and fire can make tropical ecosystems more resilient to change, but that these systems are dynamically unstable and potentially susceptible to abrupt shifts between woodland and grassland dominated states in the future

Evidence from the Florida Straits for Younger Dryas ocean circulation changes

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 26 (2011): PA1205, doi:10.1029/2010PA002032.The waters passing through the Florida Straits today reflect both the western portion of the wind-driven subtropical gyre and the northward flow of the upper waters which cross the equator, compensating North Atlantic Deep Water export as part of the large-scale Atlantic meridional overturning circulation. It has been postulated from various lines of evidence that the overturning circulation was weaker during the Younger Dryas cold event of the last deglaciation. We show here that the contrast in the oxygen isotopic composition of benthic foraminiferal tests across the Florida Current is reduced during the Younger Dryas. This most likely reflects a decrease in the density gradient across the channel and a decrease in the vertical shear of the Florida Current. This reduced shear is consistent with the postulated reduction in the Atlantic meridional overturning circulation. We find that the onset of this change in density structure and flow at the start of the Younger Dryas is very abrupt, occurring in less than 70 years.We thank the National Science Foundation (grants OCE‐0648258 and OCE‐0096472) and the Comer Science and Education Foundation for supporting this research. MWS was supported by a NOAA Global Change Postdoctoral Fellowship

IntCal09 and Marine09 radiocarbon age calibration curves, 0-50,000yeats cal BP

The IntCal04 and Marine04 radiocarbon calibration curves have been updated from 12 cal kBP (cal kBP is here defined as thousands of calibrated years before AD 1950), and extended to 50 cal kBP, utilizing newly available data sets that meet the IntCal Working Group criteria for pristine corals and other carbonates and for quantification of uncertainty in both the 14C and calendar timescales as established in 2002. No change was made to the curves from 0–12 cal kBP. The curves were constructed using a Markov chain Monte Carlo (MCMC) implementation of the random walk model used for IntCal04 and Marine04. The new curves were ratified at the 20th International Radiocarbon Conference in June 2009 and are available in the Supplemental Material at www.radiocarbon.org

2008: Sea surface temperature and salinity variability at Bermuda during the end of the Little Ice Age

[1] We use geochemical and isotope measurements on a 225-year old brain coral (Diploria labyrinthiformis) from the south shore of Bermuda (64°W, 32°N) to construct a record of decadal-to-centennial-scale climate variability. The coral was collected alive, and annual density bands visible in X radiographs delineate cold and warm seasons allowing for precise dating. Coral skeletons incorporate strontium (Sr) and calcium (Ca) in relative proportions inversely to the sea surface temperature (SST) in which the skeleton is secreted. Previous studies on this and other coral colonies from this region document the ability to reconstruct mean annual and wintertime SST using Sr/Ca measurements 18 O of seawater (dO w ), where dO w is proportional to sea surface salinity (SSS). We show in this study that mean annual and wintertime d 18 O of the carbonate (dO c ) are correlated to both SST and SSS, but a robust, quantitative measure of SSS is not found with present calibration data. In combination, however, the Sr/Ca and dO c qualitatively reconstruct lower salinities at the end of the Little Ice Age relative to modern day. Temperature changes agree with other records from the Bermuda region. Radiative and atmospheric forcing may explain some of the SST variability, but the scales of implied changes in SST and SSS indicate large-scale ocean circulation impacts as well

Obliquity-driven expansion of North Atlantic sea ice during the last glacial

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 42 (2015): 10,382–10,390, doi:10.1002/2015GL066344.North Atlantic late Pleistocene climate (60,000 to 11,650 years ago) was characterized by abrupt and extreme millennial duration oscillations known as Dansgaard-Oeschger (D-O) events. However, during the Last Glacial Maximum (LGM) 23,000 to 19,000 cal years ago (23 to 19 ka), no D-O events are observed in the Greenland ice cores. Our new analysis of the Greenland δ18O record reveals a switch in the stability of the climate system around 30 ka, suggesting that a critical threshold was passed. Climate system modeling suggests that low axial obliquity at this time caused vastly expanded sea ice in the Labrador Sea, shifting Northern Hemisphere westerly winds south and reducing the strength of meridional overturning circulation. The results suggest that these feedbacks tipped the climate system into full glacial conditions, leading to maximum continental ice growth during the LGM.Australian Research Council2016-06-1