Returns to R&D on new drug introductions in the 1980s.

This study finds that the mean IRR for 1980-84 U.S. new drug introductions is 11.1%, and the mean NPV is 22 million (1990 dollars). The distribution of returns is highly skewed. The results are robust to plausible changes in the baseline assumptions. Our work is also compared with a 1993 study by the OTA. Despite some important differences in assumptions, both studies imply that returns for the average NCE are within one percentage point of the industry's cost of capital. This is much less than what is typically observed in analyses based on accounting data.

Intergenic and genic sequence lengths have opposite relationships with respect to gene expression.

Eukaryotic genomes are mostly composed of noncoding DNA whose role is still poorly understood. Studies in several organisms have shown correlations between the length of the intergenic and genic sequences of a gene and the expression of its corresponding mRNA transcript. Some studies have found a positive relationship between intergenic sequence length and expression diversity between tissues, and concluded that genes under greater regulatory control require more regulatory information in their intergenic sequences. Other reports found a negative relationship between expression level and gene length and the interpretation was that there is selection pressure for highly expressed genes to remain small. However, a correlation between gene sequence length and expression diversity, opposite to that observed for intergenic sequences, has also been reported, and to date there is no testable explanation for this observation. To shed light on these varied and sometimes conflicting results, we performed a thorough study of the relationships between sequence length and gene expression using cell-type (tissue) specific microarray data in Arabidopsis thaliana. We measured median gene expression across tissues (expression level), expression variability between tissues (expression pattern uniformity), and expression variability between replicates (expression noise). We found that intergenic (upstream and downstream) and genic (coding and noncoding) sequences have generally opposite relationships with respect to expression, whether it is tissue variability, median, or expression noise. To explain these results we propose a model, in which the lengths of the intergenic and genic sequences have opposite effects on the ability of the transcribed region of the gene to be epigenetically regulated for differential expression. These findings could shed light on the role and influence of noncoding sequences on gene expression.

Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.

Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 beta and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

R&D Costs and Returns to New Drug Development: A Review of the Evidence

© 2012 by Oxford University Press. All rights reserved.This article reviews the extensive literature on R&D costs and returns. The first section focuses on R&D costs and the various factors that have affected the trends in real R&D costs over time. The second section considers economic studies on the distribution of returns in pharmaceuticals for different cohorts of new drug introductions. It also reviews the use of these studies to analyze the impact of policy actions on R&D costs and returns. The final section concludes and discusses open questions for further research.

Novel Computational Protein Design Algorithms with Applications to Cystic Fibrosis and HIV

Proteins are essential components of cells and are crucial for catalyzing reactions, signaling, recognition, motility, recycling, and structural stability. This diversity of function suggests that nature is only scratching the surface of protein functional space. Protein function is determined by structure, which in turn is determined predominantly by amino acid sequence. Protein design aims to explore protein sequence and conformational space to design novel proteins with new or improved function. The vast number of possible protein sequences makes exploring the space a challenging problem.

Computational structure-based protein design (CSPD) allows for the rational design of proteins. Because of the large search space, CSPD methods must balance search accuracy and modeling simplifications. We have developed algorithms that allow for the accurate and efficient search of protein conformational space. Specifically, we focus on algorithms that maintain provability, account for protein flexibility, and use ensemble-based rankings. We present several novel algorithms for incorporating improved flexibility into CSPD with continuous rotamers. We applied these algorithms to two biomedically important design problems. We designed peptide inhibitors of the cystic fibrosis agonist CAL that were able to restore function of the vital cystic fibrosis protein CFTR. We also designed improved HIV antibodies and nanobodies to combat HIV infections.

Stochastic switching in infinite dimensions with applications to random parabolic PDE

© 2015 Society for Industrial and Applied Mathematics.We consider parabolic PDEs with randomly switching boundary conditions. In order to analyze these random PDEs, we consider more general stochastic hybrid systems and prove convergence to, and properties of, a stationary distribution. Applying these general results to the heat equation with randomly switching boundary conditions, we find explicit formulae for various statistics of the solution and obtain almost sure results about its regularity and structure. These results are of particular interest for biological applications as well as for their significant departure from behavior seen in PDEs forced by disparate Gaussian noise. Our general results also have applications to other types of stochastic hybrid systems, such as ODEs with randomly switching right-hand sides.