Translating biomedical research to the bedside: a national crisis and a call to action.
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Biomedical Research↗
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US biomedical research: basic, translational, and clinical sciences.
The National Institutes of Health (NIH) is the world's largest biomedical research agency, with a 75-year record of responding to the nation's key medical challenges. Today, medical science is entering a revolutionary period marked by a shift in focus from acute to chronic diseases, rapidly escalating health care costs, a torrent of biological data generated by the sequencing of the human genome, and the development of advanced high-throughput technologies that allow for the study of vast molecular networks in health and disease. This unique period offers the unprecedented opportunity to identify individuals at risk of disease based on precise molecular knowledge, and the chance to intervene to preempt disease before it strikes. Conceptually, this represents the core scientific challenge of the coming century. The NIH is committed to the discoveries that will change the practice of medicine as we know it in order to meet this challenge. The NIH Roadmap constitutes an important vehicle for generating change-a most critical element of this plan is the reengineering of the national clinical research enterprise. This reinvention will call for the transformation of translational clinical science and for novel interdisciplinary approaches that will advance science and enhance the health of the nation.
Awards and Prizes↗
What's next in translational medicine?
Translational medicine is the integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve disease understanding, confidence in human drug targets and increase confidence in drug candidates, understand the therapeutic index in humans, enhance cost-effective decision making in exploratory development and increase phase II success. Translational research is one of the most important activities of translational medicine as it supports predictions about probable drug activities across species and is especially important when compounds with unprecedented drug targets are brought to humans for the first time. Translational research has the potential to deliver many practical benefits for patients and justify the extensive investments placed by the private and public sector in biomedical research. Translational research encompasses a complexity of scientific, financial, ethical, regulatory, legislative and practical hurdles that need to be addressed at several levels to make the process efficient. Several have resisted the idea of supporting translational research because of its high costs and the fear that it may re-direct funds from other biomedical disciplines. Resistance also comes from those more familiar with traditional clinical research methods. In this review, we argue that translational research should be seen as enabled by ongoing efforts in basic and clinical research and not competing with them. Translational research provides the knowledge necessary to draw important conclusions from clinical testing regarding disease and the viability of novel drug mechanisms. Advancing translational research requires education and new sources of funding. This could be achieved through public and congressional education by a joint coalition of patients' advocacy groups, academia, drug regulatory agencies and industry.
Animals↗
Pharmacogenomics in inflammatory bowel disease.
Inherited variations in the nucleotide sequence of genes influence how individual patients respond to drugs. Most commonly, clinically significant genetic variations consist of single nucleotide polymorphisms (SNPs) within genes that affect drug disposition or drug targets. Up to now, relatively few clinically important examples of inherited traits that affect drug responses have been studied in detail. However, one of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. Individuals with 2 normal alleles of the gene encoding thiopurine methyltransferase metabolize and clear thiopurines such as azathioprine and 6-mercaptopurine rapidly. Individuals with 1 normal and 1 variant allele are intermediate, whereas those with 2 variant alleles clear thiopurines very slowly. Intermediate and slow metabolizers are predisposed to have high active thiopurine drug levels and develop bone marrow suppression. Genomic era technology permits determination of large numbers of SNPs in large numbers of individuals. This capability is allowing the field of pharmacogenomics to become one of the most productive interfaces in translational biomedical research at present. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, pharmacogenomic research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention. If this promise can be realized, pharmacogenomics will deliver the opportunity for personalized medicine.
Anti-Inflammatory Agents↗
Interfering with hemostatic system components: possible new approaches to antiangiogenic therapy.
Inhibition of angiogenesis has progressed from a theoretical and esoteric discipline scrutinized in but a few laboratories far removed from the clinic, to mainstream experimental clinical cancer therapeutics. Dramatic progress in this field represents a triumph of the concept of translational biomedical research. Growth of knowledge in this discipline has brought to light a bewildering yet tantalizing array of interacting enzymatic algorithms that participate in the highly orchestrated process of new blood vessel formation critical for tumor growth and dissemination. It is clear that pathways of blood coagulation (in broad context) and angiogenesis are inextricably linked. The facts that much is already known about many components of these pathways and that stalling of tumor growth has already been demonstrated for several interventions aimed at participants in these reactions send a clear signal that more effective and less toxic cancer therapy may be at hand in the near future. There is no lack of candidate targets for intervention brought to light by preclinical scientists. Numerous well-characterized investigational agents are on hand for testing. The challenge is clearly in the hands of the clinical investigators to proceed with human intervention studies while armed with knowledge of opportunities and pitfalls that should guide insightful clinical trial design. A particularly compelling feature of this treatment paradigm is that it is not aimed directly at destruction of tumor through inhibition of the DNA replication machinery of the cell. Rather it is aimed at restoring the normal state by modulating the dysregulated interaction of tumor cells with their environment that is characteristic of cancer.
Angiogenesis Inhibitors↗
An XML-based system for synthesis of data from disparate databases.
Diverse data sets have become key building blocks of translational biomedical research. Data types captured and referenced by sophisticated research studies include high throughput genomic and proteomic data, laboratory data, data from imagery, and outcome data. In this paper, the authors present the application of an XML-based data management system to support integration of data from disparate data sources and large data sets. This system facilitates management of XML schemas and on-demand creation and management of XML databases that conform to these schemas. They illustrate the use of this system in an application for genotype-phenotype correlation analyses. This application implements a method of phenotype-genotype correlation based on phylogenetic optimization of large data sets of mouse SNPs and phenotypic data. The application workflow requires the management and integration of genomic information and phenotypic data from external data repositories and from the results of phenotype-genotype correlation analyses. Our implementation supports the process of carrying out a complex workflow that includes large-scale phylogenetic tree optimizations and application of Maddison's concentrated changes test to large phylogenetic tree data sets. The data management system also allows collaborators to share data in a uniform way and supports complex queries that target data sets.
Animals↗
The North Shore-Long Island Jewish Research Institute.
The North Shore-Long Island Jewish Research Institute is directed by Nicholas Chiorazzi, MD. It provides investigators from a variety of scientific fields and backgrounds with the opportunity to focus on disease-oriented medical research. The goal of the institute is to understand the underlying biological processes of disease and ultimately to develop new and more effective therapies for patients. The affiliation with the North Shore-Long Island Jewish Health System and its patients provides a unique opportunity for focused biomedical and translational research.
Biology↗
Breaking the translational barriers: the value of integrating biomedical informatics and translational research.
The conduct of translational health research has become a vital national enterprise. However, multiple barriers prevent the effective translation of basic science discoveries into clinical and community practice. New information technology (IT) applications could help address these barriers. Unfortunately, owing to a combination of organizational, technical, and social factors, neither physician-investigators and research staff nor their clinical and community counterparts have harnessed such applications. Recently, at the request of the Institute of Medicine's Clinical Research Roundtable, a qualitative study of these factors was conducted at several leading academic medical centers. We explore the current status of IT in the translational research domain, describe the qualitative results, and conclude with a proposed set of initiatives to further increase the integration of IT into translational research.
Biomedical Research↗
Lost in clinical translation.
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Biomedical Research↗
The Subtle Crisis: Public Domain Genomes and the Ethics of Translational Infrastructure.
Public domain human genomic resources are infrastructure: tools researchers use to ask basic biological questions whose answers are then translated into products and care. Translational science now asks them to support an expanding set of tasks, including clinical variant interpretation for diverse populations, pharmacogenomic prescribing, polygenic risk prediction, and the training of clinical artificial intelligence. The corpus of public domain genomes, due in large part to upstream recruitment choices, is not fit for these purposes, and the gap between discovery and translation is widening. This essay argues that closing the gap requires treating public domain genomic infrastructure as a particular object of translational bioethics rather than a technical precondition for it. The limited number of genomes in the public domain relative to the broader genomic record, and the typology-friendliness of how that record represents human variation, are two faces of the same set of upstream choices. Reversing them is not a matter of more sampling under existing terms; it is a matter of building infrastructure of a particular kind; infrastructure made from people. That category, common in genomics but absent from the rest of science, demands an ethical apparatus the field has not yet built. Here we consider the commitments such an apparatus requires, and argue that where, how, and with whom we build genomic infrastructure is itself an ethics question the field has largely declined to ask.
Humans↗
Large cell neuroendocrine carcinoma of the lung: Current standards, emerging targets, and translational foundations.
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is one of the most complex and heterogenous clinical entities in thoracic oncology, sharing features with both non-small cell lung cancer (NSLC) and neuroendocrine lung cancers. LCNEC diagnosis and classification relies on evolving histopathological and molecular criteria that define its diagnostic boundaries. Recent advances have confirmed the dual nature of LCNEC, with distinct small cell-like and non-small cell-like molecular characteristics, which guide treatment decisions. In this review, we synthesize current evidence on the diagnosis, molecular characterization, and multimodality management of LCNEC to provide a comprehensive framework for clinical and translational decision-making. A comprehensive literature search was conducted using the PubMed database with no date restrictions, last updated on 12th of April 2026. Articles were selected based on relevance to the diagnosis, molecular characterization, and management of pulmonary LCNEC. Emphasis was placed on studies providing clinical, pathological, and molecular insights into the field. In this review, we summarize contemporary diagnostic approaches, including the expanding role of immunohistochemistry, next‑generation sequencing, and integrated morpho‑molecular assessment. This review represents a consolidated update on LCNEC genomic and transcriptional landscapes, and actionable molecular alterations that are anticipated to impact treatment decisions. Additionally, it provides a state-of-the-art overview of multimodality management, covering surgical approaches, radiotherapy, perioperative therapy, systemic treatment, and the emerging role of immunotherapy. Despite incremental progress, LCNEC remains constrained by limited prospective data and lack of consensus on optimal treatment pathways. By conducting literature review, we identified persistent gaps in LCNEC published data and hereby highlight key priorities for future research.
Humans↗
Organoids in translation: a bench-to-bedside framework for pancreatic cancer precision medicine.
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a 5-year survival rate of < 13%. Standard treatments such as FOLFIRINOX or gemcitabine/nab-paclitaxel yield modest response rates, underscoring the urgent need for precision oncology approaches. Patient-derived organoids (PDOs) preserve the genomic, phenotypic, and histopathological features of the source tumor and offer a promising platform for drug screening, biomarker development, and personalized therapy. However, a systematic evaluation of their translational capacities is lacking. METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines (PROSPERO registration pending) using PubMed, EMBASE, and Cochrane CENTRAL (December 10, 2024) to identify English-language PDAC PDO studies that incorporated therapeutic testing. Ninety-five studies met the inclusion criteria. Data extraction captured >75 variables per study, including spanning culture methodology, therapeutic profiling, biomarker integration, and clinical correlation. A 13-domain weighted Translatability Scoring Framework adapted from Wehling et al. assessed predictive validity, biomarker strength, pharmacogenetics, and clinical trial alignment. Scores ranged from 0 to 5 and were categorized as good (>4.0), moderate (3.0-4.0), or low (<3.0) translational potential. RESULTS: Of the 95 studies, 70.5% have been published since 2021, reflecting the rapid growth in this field. The mean PDO generation success rate was 89.7%, with the primary tumor tissue being the predominant source (48.4%). Only 24.8% were directly linked to clinical trials and 5.3% incorporated multi-omic profiling. The median translatability score was 3.13 (range, 1.72-4.59): 45.3% of the studies had low translatability, 50.5% moderate, and only 4.2% had good translational potential. High-scoring studies consistently combine multi-omic biomarker platforms, in vivo validation, clinical outcome correlation, and prospective trial integration. Conversely, the weakest domains were pharmacogenetics, endpoint strategies, and biomarker validation, limiting their overall clinical relevance. CONCLUSIONS: PDOs have demonstrated strong feasibility and in vitro clinical correlation in PDAC; however, their clinical translation remains constrained by limited multi-omic integration, absence of pharmacogenomic modeling, and sparse clinical trial embedding. Standardization of protocols, adoption of harmonized and clinically relevant endpoints, and systematic incorporation of biomarker-driven co-clinical trial frameworks are urgently needed to transition PDOs from promising experimental surrogates to validating precision oncology tools capable of informing therapeutic decision-making in PDAC.
Humans↗
Temporal mismatch in allogeneic iPSC therapies: biological risks and implications for clinical translation.
INTRODUCTION: The clinical translation of pluripotent stem cell-derived therapies has entered a new phase following conditional approval of first-in-class allogeneic induced pluripotent stem cell (iPSC)-derived products in Japan. These approvals highlight both the therapeutic promise of iPSC technologies and regulatory challenges associated with evaluating complex cell-based interventions. AREAS COVERED: This report examines the evidentiary basis supporting recent approvals and reviews key biological characteristics of allogeneic iPSC-derived therapies, including pluripotency-associated instability, immunological constraints, and manufacturing-related genomic variability. Drawing on recent clinical studies and relevant experimental literature, we analyze how these multilayered risks evolve over extended time horizons and assess their implications for the interpretation of early-phase clinical data and current regulatory frameworks. EXPERT OPINION: We argue that the central challenge extends beyond limited clinical evidence to a fundamental mismatch between the temporal dynamics of biological risk and the duration of conventional clinical evaluation. As a result, early clinical observations may systematically underestimate long-term risks. Conditional approval pathways should therefore incorporate safeguards aligned with this temporal uncertainty, including long-term follow-up, rigorous post-approval evaluation, and enhanced transparency in biological and manufacturing data. Aligning regulatory design with intrinsic properties of pluripotent stem cell-derived therapies will be essential for ensuring safe and responsible clinical translation.
Humans↗
Advocacy groups as research organizations: the PXE International example.
Advocacy organizations for genetic diseases are increasingly becoming involved in biomedical research, particularly translational research, in order to meet the needs of the individuals that they serve. PXE International, an advocacy organization for the disease pseudoxanthoma elasticum, provides an example of how research can be accelerated by these groups. It has adopted methods that were pioneered by other advocacy organizations, and has integrated these along with new approaches into franchizable elements. The model has been followed for other conditions and has led to the establishment of a common infrastructure to enable advocacy groups to initiate, conduct and accelerate research.
Biomedical Research↗
[Updates form Diabetology. Between fundamental research and patient care. The 34th Annual Meeting of the German Diabetes Society. Amy 12-15, 1999, Frankfurt am Main, Germany].
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Diabetes Mellitus↗
CRISPR-Cas and Infectious Diseases: A Decade of Translational Advances in Molecular Biotechnology.
CRISPR-Cas systems have emerged as a versatile tool for diagnosing, treating, and preventing infectious diseases. This review highlights translational advancements in CRISPR-Cas-based applications, concentrating on the past decades in diagnostics, therapeutic genome editing, and vaccine development. The article highlights key platforms like DETECTR and SHERLOCK, which enable rapid, sensitive pathogen detection, and explores CRISPR-Cas9 systems in therapeutic strategies for directly targeting viral genomes and combating antimicrobial resistance. It also examines the role of CRISPR-Cas9 in engineering live-attenuated and personalized neoantigen vaccines. Principal findings demonstrate a clear progression from experimental proof-of-concept to preclinical applications primarily in CRISPR-based diagnostics and the engineering of live-attenuated vaccine candidates, whereas translation in CRISPR-based therapeutics and personalized neoantigen vaccines for infectious diseases remains at earlier, more exploratory stages. CRISPR-based diagnostics have progressed further toward clinical evaluation than therapeutics due to delivery and safety constraints, while personalized neoantigen vaccines are included mainly as an emerging, comparative concept for infectious diseases rather than a mature application. This review uniquely integrates CRISPR-based diagnostics, therapeutics, and vaccine development within a single infectious disease framework, critically assesses their current maturity, and systematically highlights technical, regulatory, and ethical barriers alongside realistic future priorities. The review concludes that while CRISPR-Cas holds transformative potential for infectious disease management, significant challenges in delivery efficiency, off-target effects, and ethical regulation must be addressed to ensure safe and equitable clinical translation.
Humans↗
Overcoming Immunological Barriers in MSC-Derived Insulin-Producing Cells through CRISPR-Based Hypoimmunogenic Engineering and Translational Perspectives for Type 1 Diabetes.
Mesenchymal stromal cell (MSC)-derived insulin-producing cells (IPCs) represent an emerging strategy for β-cell replacement in type 1 diabetes mellitus (T1DM) owing to their differentiation potential, intrinsic immunomodulatory properties, and lower tumorigenic risk compared with pluripotent stem cell-derived platforms. However, accumulating evidence indicates that differentiation-associated immunogenicity, context-dependent immune recognition, and recurrent autoimmune responses may substantially limit long-term graft survival and therapeutic durability following transplantation. This review critically examines the immunological barriers associated with MSC-derived IPCs, including altered MHC expression, susceptibility to alloimmune and autoimmune-mediated rejection, and potential reactivation of autoreactive immune memory. We discuss the application of CRISPR-based hypoimmunogenic engineering strategies targeting antigen presentation pathways, NK-cell activation, and immune checkpoint modulation to generate more immune-evasive MSC-derived IPCs while preserving β-cell functionality. By integrating insights from T1DM immunopathogenesis, MSC biology, genome editing, and translational immunology, we propose a framework linking immune engineering with controlled differentiation, functional maturation, and long-term safety evaluation. In parallel, we comparatively position MSC-derived IPCs alongside clinically advancing iPSC-derived β-cell platforms to highlight their distinct translational niche, including potential advantages related to safety, immunomodulatory capacity, manufacturing accessibility, and scalability, while acknowledging the superior functional maturity and clinical progression currently demonstrated by iPSC-derived systems. Finally, we discuss key translational challenges, including genomic stability, immune-evasion durability, GMP-compliant manufacturing, and the need for rigorous functional and immunological benchmarking prior to clinical application of hypoimmunogenic MSC-derived IPC therapies in T1DM.
Humans↗
The opioid receptor-ligand network in human cancers: pan-cancer multi-omics profiling and translational implications.
BACKGROUND: Opioid receptor-ligand signalling has been implicated in tumour biology and perioperative outcomes; however, its pan-cancer molecular landscape and clinical relevance remain incompletely defined. METHODS: We performed a pan-cancer multi-omics analysis of eight predefined opioid receptor-ligand genes across 33 tumour types from The Cancer Genome Atlas. Analyses included gene expression analysis using the linear models for microarray data (limma) package, genomic alterations, DNA methylation, regulatory network inference, pathway activity estimation using gene set variation analysis, and survival modelling. Multivariable Cox regression models were adjusted for age, sex, and tumour stage. RESULTS: Opioid receptor-ligand genes exhibited heterogeneous and generally low-to-moderate expression across tumour types. Genomic and epigenetic alterations were tumour-specific and variably associated with gene expression. Selected genes showed associations with overall survival in a tumour-dependent manner; however, these associations were attenuated after adjustment for clinical covariates and were accompanied by wide confidence intervals in some cohorts. Pathway analyses suggested associations with broader biological programmes, including epithelial-mesenchymal transition and immune-related pathways. Regulatory analyses identified candidate transcription factors and miRNAs, although these findings are exploratory. CONCLUSIONS: This pan-cancer analysis provides a systematic overview of opioid receptor-ligand gene features across human cancers. The observed associations are context-dependent and should be interpreted as hypothesis-generating. Further mechanistic and prospective studies are required to determine the clinical relevance of opioid signalling in cancer and perioperative settings.
Humans↗