environment can generally be added to BioBIKE on request with little diﬃculty, and thus be made accessible to BioBIKE users through the standard graphical pro- gramming interface. LEARNING BioBIKE AND STYLES OF BioBIKE USAGE Online tours of BiobIKE are accessible through the BioBIKE portal (biobike.csbc.vcu.edu), and a tour of the resources of the interface and the basic conventions of the language is available through the HELP button. A tour that describes how BioBIKE can be used in motif discovery is included in the Supplementary Material. BioBIKE expressions are often intelligible when read, but new users do not ﬁnd them easy to write. Those new to BioBIKE often begin by using it as a simple query language, asking, for example: ‘What is the sequence of my favorite gene?’ From there, one might construct a pro- gressive series of queries, each one utilizing on the result of the previous, for example: ‘What are the orthologs of the sequence of my favorite gene?’ ‘What are the upstream sequences of those orthologs?’ ‘What common sequence motifs are found in those upstream sequences?’ This progression of questions might have led to Figure 1. This progressive evaluation style is critical for pro- gramming novices (9), and one may continue indeﬁnitely within this style, obtaining useful results. However, it is also possible to create more complex structures from simple elements, facilitated by drag- and-drop and copy-paste operations. Figure 3 provides an example of iteration mixed in with sequential evaluation. Since each simple element may be executed independently by double-clicking on it, users may still examine the intermediate results, even within complex expressions. Complex expressions or sub-expressions can also be collapsed visually into single boxes, making it easier to grasp the larger picture. Moreover, as mentioned above, BioBIKE itself is extensible: if a user should devise a com- plex expression that might be of continued utility, the expression can be packaged, given a unique name, and made accessible via a menu, no diﬀerently from any other BioBIKE function. In this way, complicated opera- tions can be broken up into logical chunks and subse- quently oﬀered as distinct functions. CONCLUSION BioBIKE represents a novel paradigm regarding the interaction of biologists with information of interest to them. Its goal is to put the analysis of large amounts of information directly into the hands of biologists them- selves—to enable them to manipulate biological knowl- edge and data in an interactive computational environment. This oﬀers extraordinary power to biologists with little computational background. BioBIKE has already made possible a deep analysis of proteomic data (10), a cross-genomic analysis of repeated sequences (11), Nucleic Acids Research, 2009, Vol. 37, Web Server issue W31 and the introduction of many dozens undergraduates and high school students to biological analysis on the com- puter (Elhai, unpublished results). Some excellent web-based resources, such as Entrez (12), provide convenient access to sequences and other information. BioBIKE does the same, but the information is returned in a form that may be used immediately for further analysis. Still other resources, such as IMG (13) and the NCBI implementation of Blast (14) provide a good interface for the analysis of sequences with a ﬁxed set of tools. Some, e.g. Taverna (15) and Galaxy (galaxy. psu.edu), go a step further and facilitate the creation of a work ﬂow using a ﬁxed set of tools (ﬁxed to those unfamiliar with computer programming). BioBIKE does these things as well, but does not conﬁne the user to follow predetermined channels. The user new to pro- gramming may use existing tools or combine basic functions to create ways to answer questions for which tools do not exist. Such ﬂexibility has previously required one to employ conventional programming languages, sometimes supplemented with bioinformatic add-ons, such as BioRuby (bioruby.org) or BioPerl (16). BioBIKE is equally powerful but does not require the user to learn the underlying language. BioBIKE is aimed at biologists who do not wish to expend the eﬀort required to learn a conventional programming language but who wish to have the same hands-on relationship with informational objects of study as they do with objects in the laboratory. BioBIKE is a ﬁrst step in a new direction, and although even in its present state it is a powerful tool, it must be stressed that the goal of intuitive use remains unmet. Users should not expect to ﬁgure out BioBIKE as they would a simple web-based tool that oﬀers a small number of func- tions. A greater set of tours and help pages may increase the ability of na ı¨ve users to exploit the resource indepen- dently. However, our current direction is more ambitious. We plan to extend BioDeducta (17), which combines BioBIKE with an automated reasoning system, to enable users to present BioBIKE with a natural language ques- tion (e.g. ‘Is there a common sequence motif found upstream of orthologs of glnA?’), and through a series of natural language interactions, arrive at a BioBIKE expression that answers the question. SOFTWARE AVAILABILITY AND COMPATIBILITY At the time of writing, there are ﬁve BioBIKE instances freely available through the web (Table 1). BioBIKE is written in Common Lisp, operating within the KnowOS paradigm (18), and is distributed under the MIT Open Source license. Although it is freely available for anyone to download and install (see www.BioBIKE.org for instructions), we encourage users to use already-existing servers. The authors are happy to discuss collaboration with communities of biologists who would like to create BioBIKE instances particular to sets of model organisms. At present, the graphical interface is only operational within Firefox 1.5 and above.