How can we address the complexity and cost of applying science to societal challenges? Open science and collaborative R&D may help [1]–[3]. Open science has been described as “a research accelerator” [4]. Open science implies open access [5] but goes beyond it: “Imagine a connected online web of scientific knowledge that integrates and connects data, computer code, chains of scientific reasoning, descriptions of open problems, and beyond …. tightly integrated with a scientific social web that directs scientists' attention where it is most valuable, releasing enormous collaborative potential.” [1]. Open science and collaborative approaches are often described as open source, by analogy with open-source software such as the operating system Linux which powers Google and Amazon—collaboratively created software which is free to use and adapt, and popular for Internet infrastructure and scientific research [6], [7]. However, this use of “open source” is unclear. Some people use “open source” when a project's results are free to use, others when a project's process is highly collaborative [4]. It is clearer to classify open source and open science within a broader class of collaborative R&D, which can be defined as scalable collaboration (usually enabled by information technology) across organizational boundaries to solve R&D challenges [8]. Many approaches to open science and collaborative R&D have been tried [1], [9]. The Gene Wiki has created over 10,000 Wikipedia articles, and aims to provide one for every notable human gene [10]. The crowdsourcing platform InnoCentive has reportedly facilitated solutions to roughly half of the thousands of technical problems posed on the site, including many in life sciences such as the $1 million ALS Biomarker Prize [11]. Other examples include prizes (X-Prize [12]), scientific games (FoldIt [13]), and licensing schemes inspired by open-source software (BIOS [14]). Collaborative R&D approaches vary in openness [15]. In some approaches, the R&D process and outputs are open to all—for example, open-science projects like the Gene Wiki described above. In other approaches which demonstrate what might be called controlled collaboration, there are strong controls on who contributes and benefits—for example, computational platforms like Collaborative Drug Discovery or InnoCentive that support both commercial and nonprofit research [9], [11]. Collaborative approaches can unleash innovation from unforeseen sources, as with crowdsourcing health technologies [11]–[13], [16]. They may help in global challenges like drug development [17], as with India's OSDD (Open Source Drug Discovery) project that recruited over 7,000 volunteers [16] and an open-source drug synthesis project that improved an existing drug without increasing its cost [18]. If you want to apply open science and collaborative R&D, what principles are useful? We suggest Ten Simple Rules for Cultivating Open Science and Collaborative R&D. We also offer eight conversational interviews exploring life experiences that led to these rules (Box 1). Box 1. Conversations on Open Science and Collaborative R&D Many commentators have considered challenges in translating open science and collaborative methods to biomedical research [2]–[4], [9], [17], [20], [24], [26], [28], [29]. How can protecting intellectual property be balanced with freeing researchers to build on previous knowledge? If R&D results are collaboratively created and freely available, who will take responsibility for costly clinical trials and quality control? What will be the Linux of open-source R&D? To explore such challenges and convey life experiences in biomedical open science and collaborative R&D, we offer eight conversational interviews by the first author of this article as supplementary material. The conversations were done on behalf of the Results for Development Institute and are with: Alph Bingham, cofounder of InnoCentive (Text S1) Barry Bunin, CEO of Collaborative Drug Discovery (Text S2) Leslie Chan, open access pioneer and director of Bioline International (Text S3) Aled Edwards, director of the Structural Genomics Consortium (Text S4) Benjamin Good, coleader of the Gene Wiki initiative (Text S5) Bernard Munos, pharmaceutical innovation thought leader (Text S6) Zakir Thomas, director of India's Open Source Drug Discovery (OSDD) project (Text S7) Matt Todd, open science and drug development pioneer (Text S8)

BACKGROUND: Gene expression profiling has the potential to unravel molecular mechanisms behind gene regulation and identify gene targets for therapeutic interventions. As microarray technology matures, the number of microarray studies has increased, resulting in many different datasets available for any given disease. The increase in sensitivity and reliability of measurements of gene expression changes can be improved through a systematic integration of different microarray datasets that address the same or similar biological questions. RESULTS: Traditional effect size models can not be used to integrate array data that directly compare treatment to control samples expressed as log ratios of gene expressions. Here we extend the traditional effect size model to integrate as many array datasets as possible. The extended effect size model (MAID) can integrate any array datatype generated with either single or two channel arrays using either direct or indirect designs across different laboratories and platforms. The model uses two standardized indices, the standard effect size score for experiments with two groups of data, and a new standardized index that measures the difference in gene expression between treatment and control groups for one sample data with replicate arrays. The statistical significance of treatment effect across studies for each gene is determined by appropriate permutation methods depending on the type of data integrated. We apply our method to three different expression datasets from two different laboratories generated using three different array platforms and two different experimental designs. Our results indicate that the proposed integration model produces an increase in statistical power for identifying differentially expressed genes when integrating data across experiments and when compared to other integration models. We also show that genes found to be significant using our data integration method are of direct biological relevance to the three experiments integrated. CONCLUSION: High-throughput genomics data provide a rich and complex source of information that could play a key role in deciphering intricate molecular networks behind disease. Here we propose an extension of the traditional effect size model to allow the integration of as many array experiments as possible with the aim of increasing the statistical power for identifying differentially expressed genes.

MOTIVATION: In the present work we combine computational analysis and experimental data to explore the extent to which binding site similarities between members of the human cytosolic sulfotransferase family correlate with small-molecule binding profiles. Conversely, from a small-molecule point of view, we explore the extent to which structural similarities between small molecules correlate to protein binding profiles. RESULTS: The comparison of binding site structural similarities and small-molecule binding profiles shows that proteins with similar small-molecule binding profiles tend to have a higher degree of binding site similarity but the latter is not sufficient to predict small-molecule binding patterns, highlighting the difficulty of predicting small-molecule binding patterns from sequence or structure. Likewise, from a small-molecule perspective, small molecules with similar protein binding profiles tend to be topologically similar but topological similarity is not sufficient to predict their protein binding patterns. These observations have important consequences for function prediction and drug design.

MOTIVATION: Target selection strategies for structural genomic projects must be able to prioritize gene regions on the basis of significant sequence similarity with proteins that have already been structurally determined. With the rapid development of protein comparison software a robust prioritization scheme should be independent of the choice of algorithm and be able to incorporate different sequence similarity thresholds. RESULTS: A robust target selection strategy has been developed that can assign a priority level to all genes in any genome. Structural assignments to genome sequences are calculated at two thresholds and six levels (1-6) describe the prioritization of all whole genes and partial gene regions. This simple two-threshold approach can be implemented with any fold recognition or homology detection algorithms. The results for 10 genomes are presented using the SSEARCH and PSI-BLAST programs. AVAILABILITY: Programs are available on request from the authors.