This report presents recommendations for what the connections in the infrastructure should comprise and how they should be structured in order to best serve the above purpose. It defines interfaces at ISBE nodes that enable R&D activities to integrate seamlessly. Connections include computer‐only, computer-­assisted and human­‐human interactions. This document also defines ways in which large systems biology tasks can be optimally partitioned over activities that can best be accomplished at ISBE nodes, whilst enabling optimal continuous integration through the connections. Through ISBE, large systems biology-­‐driven community efforts become feasible by connecting the expertise and resources of multiple different projects in past and present. This builds ISBE as a platform from which to launch large-­‐scale integrative visionary projects with great scientific and societal impact.