Large-scale small molecule bioactivity data are not routinely integrated in daily biological research to the extent of other ‘omics’ information. Compound data are scattered and diverse, making them inaccessible to most researchers and not suited to standard statistical analyses. IRB have recently developed the Chemical Checker (CC), a resource that provides processed, harmonized and integrated bioactivity data on small molecules (Duran-Frigola et al. 2020 Nat Biotechnol in press, available at bioRxiv). The CC divides data into five levels of increasing complexity, ranging from the chemical properties of compounds to their clinical outcomes. In between, it considers targets, off-targets, perturbed biological networks and several cell-based assays such as gene expression, growth inhibition and morphological profiles. In the CC, bioactivity data are expressed in a vector format, which naturally extends the notion of chemical similarity between compounds to similarities between bioactivity signatures of different kinds. CC signatures have been shown to boost the performance of drug discovery tasks that typically capitalize on chemical descriptors, and we demonstrated and experimentally validated that CC signatures can be used to reverse and mimic biological signatures of disease models and genetic perturbations, options that are otherwise impossible using chemical information alone. The nexr stage is to develop a generalised connectivity mapping, as a form of virtual phenotypic screening, to discover novel chemical or genetic modulators able to revert the specific signatures of disease and ‘cancel out’ the phenotypic traits of complex disorders.
The successful candidate will work in a very collaborative environment, and he/she will be responsible for the experimental validation of the mechanistic hypotheses, generated in the lab, on the molecular routes that need to be active/inactive in a given complex pathological state for its onset and progression. In addition, he/she will also help to design and validate a systems pharmacology approach, based on concerted multi-target perturbations, able to modify the biology of the diseases and stop their advance.
Bachelor in Biosciences. PhD in Pharmacology, Molecular or Cell biology.
Previous experience in working with complex diseases, including molecular and cellular models. Strong publications record according to his/her career stage.
Experience with standard biochemistry, molecular and cell biology techniques.
Experience in CRISPR-Cas9, RNAi, target validation and drug screening.
Knowledge of 'omics technologies and high-throughout approaches.
Positive organizational, problem solving and communication skills.
Previous experience working on Alzheimer's disease.