Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine.

Molecular and Functional Neuroscience in Immunity.

The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.

Translating metabolic and cardiovascular research into effective treatments: What's next?

The future of healthcare for cardiovascular diseases holds immense promise, not only based in new discoveries in cardiac metabolism but also in translating them to solutions for critical challenges faced by society. Here, ten scientists share their insights, shedding light on the future that lies ahead for this field.

Translational potential of mouse models of human metabolic disease.

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

The immunobiology of interleukin-27.

Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4(+) and CD8(+) T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8(+) T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target.

Understanding the biological basis of psychiatric disease: What's next?

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

Human hemato-lymphoid system mice: current use and future potential for medicine.

To directly study complex human hemato-lymphoid system physiology and respective system-associated diseases in vivo, human-to-mouse xenotransplantation models for human blood and blood-forming cells and organs have been developed over the past three decades. We here review the fundamental requirements and the remarkable progress made over the past few years in improving these systems, the current major achievements reached by use of these models, and the future challenges to more closely model and study human health and disease and to achieve predictive preclinical testing of both prevention measures and potential new therapies.

A Diagnosis for All Rare Genetic Diseases: The Horizon and the Next Frontiers.

The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances. To provide diagnostic clarity to all of these patients, however, there is a critical need for the field to develop and implement strategies to understand the mechanisms underlying all rare diseases and translate these to clinical care.

Cellular senescence in ageing: from mechanisms to therapeutic opportunities.

Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.

Stem Cells, Genome Editing, and the Path to Translational Medicine.

The derivation of human embryonic stem cells (hESCs) and the stunning discovery that somatic cells can be reprogrammed into human induced pluripotent stem cells (hiPSCs) holds the promise to revolutionize biomedical research and regenerative medicine. In this Review, we focus on disorders of the central nervous system and explore how advances in human pluripotent stem cells (hPSCs) coincide with evolutions in genome engineering and genomic technologies to provide realistic opportunities to tackle some of the most devastating complex disorders.

Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development.

The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.

Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation.

The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.

Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

In Vivo Cellular Reprogramming: The Next Generation.

Cellular reprogramming technology has created new opportunities in understanding human disease, drug discovery, and regenerative medicine. While a combinatorial code was initially found to reprogram somatic cells to pluripotency, a "second generation" of cellular reprogramming involves lineage-restricted transcription factors and microRNAs that directly reprogram one somatic cell to another. This technology was enabled by gene networks active during development, which induce global shifts in the epigenetic landscape driving cell fate decisions. A major utility of direct reprogramming is the potential of harnessing resident support cells within damaged organs to regenerate lost tissue by converting them into the desired cell type in situ. Here, we review the progress in direct cellular reprogramming, with a focus on the paradigm of in vivo reprogramming for regenerative medicine, while pointing to hurdles that must be overcome to translate this technology into future therapeutics.

Hedgehog Pathway Inhibition.

The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC).

SnapShot: Growing Organoids from Stem Cells.

Tissue stem cells require unique niche microenvironments. In the presence of specific combinations of niche factors, mouse and human epithelial tissues from stomach, small intestine, colon, pancreas duct, and liver bile duct efficiently form stereotypic organoids. The platform of epitheloid organoids can also be employed for in vitro generation of digestive tissue from human pluripotent stem cells. Organoids hold great promise for basic and translational research.

Mechanisms and consequences of Jak-STAT signaling in the immune system.

Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.

Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Progeria: a paradigm for translational medicine.

Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.