Multi-scale cellular engineering: From molecules to organ-on-a-chip.

Recent technological advances in cellular and molecular engineering have provided new insights into biology and enabled the design, manufacturing, and manipulation of complex living systems. Here, we summarize the state of advances at the molecular, cellular, and multi-cellular levels using experimental and computational tools. The areas of focus include intrinsically disordered proteins, synthetic proteins, spatiotemporally dynamic extracellular matrices, organ-on-a-chip approaches, and computational modeling, which all have tremendous potential for advancing fundamental and translational science. Perspectives on the current limitations and future directions are also described, with the goal of stimulating interest to overcome these hurdles using multi-disciplinary approaches

The Research Space: using the career paths of scholars to predict the evolution of the research output of individuals, institutions, and nations

In recent years scholars have built maps of science by connecting the academic fields that cite each other, are cited together, or that cite a similar literature. But since scholars cannot always publish in the fields they cite, or that cite them, these science maps are only rough proxies for the potential of a scholar, organization, or country, to enter a new academic field. Here we use a large dataset of scholarly publications disambiguated at the individual level to create a map of science-or research space-where links connect pairs of fields based on the probability that an individual has published in both of them. We find that the research space is a significantly more accurate predictor of the fields that individuals and organizations will enter in the future than citation based science maps. At the country level, however, the research space and citations based science maps are equally accurate. These findings show that data on career trajectories-the set of fields that individuals have previously published in-provide more accurate predictors of future research output for more focalized units-such as individuals or organizations-than citation based science maps

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

A multiscale model for collagen alignment in wound healing

It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring

Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes

An important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages

Numerical model for material parameter identification of cells

Bacteria have a complex external layer that render them with an increased stiffness and more resistant to external invasion. The works aims to model the squeezing of a bacteria between two walls, and deduce the composition of bacterial external layer from the observed deformations. A FE based model will be developed for inferring the stiffness of baceria, solving an inverse problem from the applied loading and measured displacements. The results will be applied to laboraotry experiments carried out at Institu of Bioengineering of Catalunya (IBEC)