Human Models
Michele Firmasyah
The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.
Migraine is a complex disorder characterized by recurrent episodes of headache, and is one of the most prevalent and disabling neurological disorders. A key feature of migraine is that various factors can trigger an attack, and this phenomenon provides a unique opportunity to investigate disease mechanisms by experimentally inducing migraine attacks. In this Review, we summarize the existing experimental models of migraine in humans, including those that exploit nitric oxide, histamine, neuropeptide and prostaglandin signalling. We describe the development and use of these models in the discovery of molecular pathways that are responsible for initiation of migraine attacks. Combining experimental human models with advanced imaging techniques might help to identify biomarkers of migraine, and in the ongoing search for new and better migraine treatments, human models will have a key role in the discovery of future targets for more-specific and more-effective mechanism-based antimigraine drugs.
Significant progress has been made in understanding the neurobiological mechanisms through which exercise protects and restores the brain. In this feature review, we integrate animal and human research, examining physical activity effects across multiple levels of description (neurons up to inter-regional pathways). We evaluate the influence of exercise on hippocampal structure and function, addressing common themes such as spatial memory and pattern separation, brain structure and plasticity, neurotrophic factors, and vasculature. Areas of research focused more within species, such as hippocampal neurogenesis in rodents, also provide crucial insight into the protective role of physical activity. Overall, converging evidence suggests exercise benefits brain function and cognition across the mammalian lifespan, which may translate into reduced risk for Alzheimer's disease (AD) in humans.
Background: The aging phenotype in humans is very heterogeneous and can be described as a complex mosaic resulting from the interaction of a variety of environmental, stochastic and genetic-epigenetic variables. Therefore, each old person must be considered as a singleton, and consequently the definition of 'aging phenotype' is very difficult.
Objective: We discuss the phenotype of centenarians, the best example of successful aging, as well as other models exploited to study human aging and longevity, such as families enriched in long-living subjects, twins and cohorts of unrelated subjects.
Conclusions: No single model can be considered the gold standard for the study of aging and longevity, instead the combination of results obtained from different models must be considered in order to better understand these complex phenomena. We propose that a systems biology concept such as that of 'bow-tie' architecture, useful for managing information flow, could help in this demanding task.
Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
Biomedical research is undergoing a paradigm shift towards approaches centred on human disease models owing to the notoriously high failure rates of the current drug development process. Major drivers for this transition are the limitations of animal models, which, despite remaining the gold standard in basic and preclinical research, suffer from interspecies differences and poor prediction of human physiological and pathological conditions. To bridge this translational gap, bioengineered human disease models with high clinical mimicry are being developed. In this Review, we discuss preclinical and clinical studies that benefited from these models, focusing on organoids, bioengineered tissue models and organs-on-chips. Furthermore, we provide a high-level design framework to facilitate clinical translation and accelerate drug development using bioengineered human disease models.
Biomedical research is currently undergoing a paradigm shift towards approaches centred on human disease models1. This shift has been driven by the notoriously high failure rates of the current drug development process. Although investments increased at unprecedented rates over the past decade (US$133 billion research and development expenditures of the 15 biggest pharma companies in 2021, a 44% increase since 2016)2, the drug attrition rate hit an all-time high of 95% in 2021 (ref. 3). Most drugs fail in clinical stages (Fig. 1) despite proven efficacy and safety in animal models4,5. Different reasons account for this translational gap, one of them being that the decision on entry of a drug candidate into clinical trials relies almost exclusively on animal-derived data.
Current development pipeline of new drugs with proven preclinical safety and efficacy in animal models. The average duration of the different (pre-)clinical stages, the percentage of drugs (averaged over the past 5 years) that move to the next phase and the median costs of the different stages per drug are illustrated3,180.
Animal models, however, often fail to filter out harmful or ineffective drugs6. Moreover, potentially effective drug candidates never enter clinical trials owing to negative preclinical tests given that most animal models poorly resemble human conditions and thus have low predictive values. The discrepancies derive from different anatomical layouts and biological barriers, divergent receptor expression and immune responses, host specificities of microorganisms, and distinct pathomechanisms. In addition, animals are inbred and kept under standardized conditions and thus do not account for the genetic and ethnic diversity of humans. Therefore, drug safety or efficacy issues that only affect certain subpopulations go unnoticed.
Furthermore, fast-paced advances in genome editing and antibody therapies have direct implications for the drug development process. Currently, 40% of the drugs undergoing clinical trials are antibodies3. However, their high target specificity requires the identification of cross-reactive species during preclinical testing. Non-human primates are often the only pharmacologically relevant species, whose use has ethical and economic implications7. Species-specificity is also a concern for gene therapies because genetic sequences and therapeutic efficacy differ between animals. For example, base editors yield 61% in vivo gene editing efficacy in the liver of mice compared to 26% in primates8.
Two-dimensional (2D) cultivated patient-derived cells are an invaluable tool to study disease phenotypes and pathomechanisms, especially during the early phases of drug development (Fig. 2). Primary cells are the preferred option owing to their higher genetic heterogeneity compared to cell lines, but their limited availability or in vitro proliferation capacity restricts their use. Multipotent adult stem cells (ASCs) and induced pluripotent stem (iPS) cells can help overcome this shortage, as they can readily and indefinitely propagate and convert into any somatic cell10. Engineered cells, such as reporter cell lines, are also commonly used as they are amenable to high-throughput manufacturing and have high reproducibility and lower costs relative to stem cell-based methods.
From left to right, bioengineered models are ordered from the least to the most complex, including their advantages, limitations and stage of application during the drug development process. iPS cell, induced pluripotent stem cell.
Nonetheless, 2D cell cultures have limitations. For example, the epithelial differentiation stages of stratified epithelia, such as the skin, cannot be mimicked in 2D. Moreover, cell responses and gene and/or protein expression patterns greatly differ between 2D and three-dimensional (3D) models11. For example, 3D cultures of lung fibroblasts resemble in vivo tumour necrosis factor (TNF) receptor expression and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation patterns more closely than 2D cultures12. Similarly, the biomimicry of tissue-specific transporters and cell junctions is often higher in 3D models13.
Protocols for the generation of iPS cell-derived organoids are available for a variety of human organs, including the gut27, stomach28, liver29, pancreas30, lung31, thyroid32, kidney33, retinal and optic cup34, and brain35. However, iPS cell-derived organoids fail to mature beyond the fetal phenotype unless they are grafted into living organisms36,37. To overcome this limitation, the use of tissue-resident ASCs derived from postnatal or adult tissues has gained increasing attention, resulting in organoids of endoderm-derived tissues such as lung38, gut39, pancreas40, stomach41, liver organoids42, endometrium43, prostate44, fallopian tube45 and mammary gland46. Although the application of ASCs has been hampered by their limited availability in the past, some commercial suppliers now provide ASC-derived organoids. Nonetheless, ASC-derived organoids lack cells from the ectodermal and mesenchymal germ layer and are usually smaller than iPS cell-derived counterparts. Furthermore, the cell type composition of organoids of the same organ can vary depending on the protocol47, ultimately hindering reproducibility.
4a15465005