Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and post-market surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, while post-market surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work.

Synthetic lethality is a genetic interaction wherein two otherwise nonessential genes cause cellular inviability when knocked out simultaneously. Drugs can mimic genetic knock-out effects; therefore, our understanding of promiscuous drugs, polypharmacology-related adverse drug reactions, and multi-drug therapies, especially cancer combination therapy, may be informed by a deeper understanding of synthetic lethality. However, the colossal experimental burden in humans necessitates in silico methods to guide the identification of synthetic lethal pairs. Here, we present SINaTRA (Species-INdependent TRAnslation), a network-based methodology that discovers genome-wide synthetic lethality in translation between species. SINaTRA uses connectivity homology, defined as biological connectivity patterns that persist across species, to identify synthetic lethal pairs. Importantly, our approach does not rely on genetic homology or structural and functional similarity, and it significantly outperforms models utilizing these data. We validate SINaTRA by predicting synthetic lethality in S. pombe using S. cerevisiae data, then identify over one million putative human synthetic lethal pairs to guide experimental approaches. We highlight the translational applications of our algorithm for drug discovery by identifying clusters of genes significantly enriched for single- and multi-drug cancer therapies.

In 2011, >2.5 million people died from only 15 causes in the United States. Ten of these involved complex or infectious diseases for which there is insufficient knowledge or treatment, such as heart disease, influenza, and Alzheimer's disease.(1) Complex diseases have been difficult to understand due to their multifarious genetic and molecular fingerprints, while certain infectious agents have evolved to elude treatment and prophylaxis. Network medicine provides a macroscopic approach to understanding and treating such illnesses. It integrates experimental data on gene, protein, and metabolic interactions with clinical knowledge of disease and pharmacology in order to extend the understanding of diseases and their treatments. The resulting "big picture" allows for the development of computational and mathematical methods to identify novel disease pathways and predict patient drug response, among others. In this review, we discuss recent advances in network medicine.

The current strategy to detect acute injury of kidney tubular cells relies on changes in serum levels of creatinine. Yet serum creatinine (sCr) is a marker of both functional and pathological processes and does not adequately assay tubular injury. In addition, sCr may require days to reach diagnostic thresholds, yet tubular cells respond with programs of damage and repair within minutes or hours. To detect acute responses to clinically relevant stimuli, we created Rosa26-floxed-stop uracil phosphoribosyltransferase (Uprt) expressing mice and inoculated 4-thiouracil (TU) to tag nascent RNA at selected time points. Cre-driven TU-tagged RNA was isolated from intact kidneys and demonstrated that volume depletion and ischemia induced different genetic programs in collecting ducts and intercalated cells. Even lineage related cell types expressed different genes in response to the two stressors. TU-tagging also demonstrated the transient nature of the responses. Because we placed Uprt in the ubiquitously active Rosa-26 locus, nascent RNAs from many cell types can be tagged in vivo and their roles interrogated under various conditions. In short, TU labeling identifies stimulus-specific, cell-specific, and time-dependent acute responses that are otherwise difficult to detect with other technologies and are entirely obscured when sCr is the sole metric of kidney damage.

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