Cell fate reprogramming by control of intracellular network dynamics

Identifying control strategies for biological networks is paramount for practical applications that involve reprogramming a cell's fate, such as disease therapeutics and stem cell reprogramming. Here we develop a novel network control framework that integrates the structural and functional information available for intracellular networks to predict control targets. Formulated in a logical dynamic scheme, our approach drives any initial state to the target state with 100% effectiveness and needs to be applied only transiently for the network to reach and stay in the desired state. We illustrate our method's potential to find intervention targets for cancer treatment and cell differentiation by applying it to a leukemia signaling network and to the network controlling the differentiation of helper T cells. We find that the predicted control targets are effective in a broad dynamic framework. Moreover, several of the predicted interventions are supported by experiments.Comment: 61 pages (main text, 15 pages; supporting information, 46 pages) and 12 figures (main text, 6 figures; supporting information, 6 figures). In revie

A Natural Law of Succession

Consider the problem of multinomial estimation. You are given an alphabet of k distinct symbols and are told that the i-th symbol occurred exactly n_i times in the past. On the basis of this information alone, you must now estimate the conditional probability that the next symbol will be i. In this report, we present a new solution to this fundamental problem in statistics and demonstrate that our solution outperforms standard approaches, both in theory and in practice.Comment: 23 page