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The mission of translational science is to bring predictivity and efficiency to the development and dissemination of interventions that improve human health. Ten years ago this year, the National Center for Advancing Translational Sciences was founded to embody, conduct, and support this new discipline. The Center’s first decade has brought substantial progress across a broad range of translational areas, from diagnostic and drug development to clinical trials to implementation science to education. The origins of the translational science and advances to this point are reviewed here and allow the establishment of an ambitious future research agenda for the field.

The term ‘translation’ has emerged as a dominant concept in biomedical science over the last decade, but confusion around what the term means, and how it differs from translational research and translational science, is common. This article aims to help address this issue by clarifying the distinctions.

Organs-on-chips (OoCs), also known as microphysiological systems or ‘tissue chips’ (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term. In the past decade, the OoC field has seen dramatic advances in the sophistication of biology and engineering, in the demonstration of physiological relevance and in the range of applications. These advances have also revealed new challenges and opportunities, and expertise from multiple biomedical and engineering fields will be needed to fully realize the promise of OoCs for fundamental and translational applications. This Review provides a snapshot of this fast-evolving technology, discusses current applications and caveats for their implementation, and offers suggestions for directions in the next decade.Organs-on-chips (OoCs) could be useful at various stages of drug discovery and development, providing insight regarding human organ physiology in both normal and disease contexts, as well as accurately predicting developmental drug safety and efficacy. This Review discusses the advances that have enabled OoCs to demonstrate physiological relevance, and the challenges and opportunities that need to be tackled to tap the full potential of OoC utility for translational research.

Human pluripotent stem cells (hPSCs) are capable of extensive self-renewal yet remain highly sensitive to environmental perturbations in vitro, posing challenges to their therapeutic use. There is an urgent need to advance strategies that ensure safe and robust long-term growth and functional differentiation of these cells. Here, we deployed high-throughput screening strategies to identify a small-molecule cocktail that improves viability of hPSCs and their differentiated progeny. The combination of chroman 1, emricasan, polyamines, and trans-ISRIB (CEPT) enhanced cell survival of genetically stable hPSCs by simultaneously blocking several stress mechanisms that otherwise compromise cell structure and function. CEPT provided strong improvements for several key applications in stem-cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body (EB) and organoid formation, single-cell cloning, and genome editing. Thus, CEPT represents a unique poly-pharmacological strategy for comprehensive cytoprotection, providing a rationale for efficient and safe utilization of hPSCs.The CEPT cocktail comprising four small molecules enhances pluripotent stem cell survival, biobanking, organoid formation, and single-cell cloning efficiency by reducing cellular stress.

Misconceptions about translation — defined as the process of turning observations in the laboratory, clinic and community into interventions that improve the health of individuals — hinder efforts to close gaps and address challenges related to the translational process. This article highlights some misconceptions with the aim of improving understanding and advancing solutions.Misconceptions about translation — defined as the process of turning observations in the laboratory, clinic and community into interventions that improve the health of individuals — hinder efforts to close gaps and address challenges related to the translational process. This article highlights some misconceptions with the aim of improving understanding and advancing solutions.

In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency's National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on \"high throughput screening, toxicity pathway profiling, and biological interpretation of findings.\" In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.Most rare diseases still lack approved treatments. This article analyses the main therapeutic modalities available to researchers interested in translating advances in the scientific understanding of rare diseases into therapies, highlights progress so far and discusses overarching issues in drug development for rare diseases.

Chemical genomics aims to comprehensively define, and ultimately predict, the effects of small molecule compounds on biological systems. Chemical activity profiling approaches must consider chemical effects on all pathways operative in mammalian cells. To enable a strategic and maximally efficient chemical profiling of pathway space, we have created the NCATS BioPlanet, a comprehensive integrated pathway resource that incorporates the universe of 1,658 human pathways sourced from publicly available, manually curated sources, which have been subjected to thorough redundancy and consistency cross-evaluation. BioPlanet supports interactive browsing, retrieval, and analysis of pathways, exploration of pathway connections, and pathway search by gene targets, category, and availability of corresponding bioactivity assay, as well as visualization of pathways on a 3-dimensional globe, in which the distance between any two pathways is proportional to their degree of gene component overlap. Using this resource, we propose a strategy to identify a minimal set of 362 biological assays that can interrogate the universe of human pathways. The NCATS BioPlanet is a public resource, which will be continually expanded and updated, for systems biology, toxicology, and chemical genomics, available at http://tripod.nih.gov/bioplanet/.

Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. Here we report the first comprehensive analysis of the Tox21 effort, a large-scale in vitro toxicity screening of chemicals. We test ∼10,000 chemicals in triplicates at 15 concentrations against a panel of nuclear receptor and stress response pathway assays, producing more than 50 million data points. Compound clustering by structure similarity and activity profile similarity across the assays reveals structure–activity relationships that are useful for the generation of mechanistic hypotheses. We apply structural information and activity data to build predictive models for 72 in vivo toxicity end points using a cluster-based approach. Models based on in vitro assay data perform better in predicting human toxicity end points than animal toxicity, while a combination of structural and activity data results in better models than using structure or activity data alone. Our results suggest that in vitro activity profiles can be applied as signatures of compound mechanism of toxicity and used in prioritization for more in-depth toxicological testing. Large-scale in vitro assays may reduce the number of toxicological tests carried out in animals. Here, Huang et al . report a large dataset containing results of in vitro tests of approximately 10,000 chemicals, and use these data to create models that can potentially predict toxicity in humans.

We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics. This article reviews initiatives of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR) that are aimed at catalyzing rare diseases research. These initiatives fall into two groups: Promoting information sharing; and building multi-disciplinary multi-stakeholder collaborations. Among ORDR’s information sharing initiatives are GARD (The Genetics and Rare Diseases Information Center), RaDaR (The Rare Diseases Registries Program) and the NCATS Toolkit for Patient-Focused Therapy Development (Toolkit). Among the collaboration initiatives are the RDCRN (Rare Diseases Clinical Research Network), and the NCATS ORDR support for conferences and workshops. Despite the success of these programs, there remains substantial work to be done to build enhanced collaborations, clinical harmonization and interoperability, and stakeholder engagement so that the recent scientific advances can benefit all patients on the long list of rare diseases waiting for help.