Cellular Insights: How Researchers Are Using Cell Models To Study the Mechanisms of Disease

Advances in modeling human diseases using cultured cells are revolutionizing biomedical research, paving the way for the development of new diagnostics and therapeutics.Effective disease models are an essential tool for biomedical research – providing scientists with experimental systems to study the cellular and molecular mechanisms underpinning different diseases and develop new ways to prevent and treat them. Traditionally, animal models have been invaluable tools for modeling human disorders – but the considerable developmental, genetic and physiological differences between species can be problematic.“You can study a lot of human biology in animal models because they share mechanisms that are evolutionarily conserved,” says Paola Arlotta, Golub family professor of stem and regenerative cell biology at Harvard University, USA. “But our cells also exhibit many features that are unique to our species – for example, the human brain is very different to the mouse brain.”But thanks to the most recent advances in cellular modeling – including the availability of human pluripotent stem cells (PSCs), genome editing and 3D organoid culture – researchers are generating increasingly complex cell-based systems that can help overcome some of the limitations of animal models.“There are certain things that we just can’t determine the relevance to humans without looking at cells,” says Melanie Alpaugh, assistant professor at the University of Guelph, Canada. “A lot of my work is focused on trying to validate findings from animal models using a system that’s closer to what’s happening in patients.”These next-generation cell models are helping to advance the understanding of disease mechanisms, improve drug discovery and development — and also offer the potential to transform the future of personalized medicine.A brief history of cell cultureAdvertisement Optimizing Organoid Culture Conditions Outlines the importance of reagent consistency in organoid tissue culture. View Application Note The first cell culture techniques were developed more than a century ago, helping to transform biomedical research. The process is defined as the removal of cells from an organism and cultivating them in an artificial environment that supports their growth. These cells may be collected directly from a tissue, or derived from an established cell line. The most commonly used cell lines – such as immortalized cells – essentially allow a limitless supply of material for experimentation.“Cell lines derived from cancer cells have the advantage that they’re easy to work with,” says Alpaugh. “But they’re further away from what you’d see in the healthy body.”Primary cells – which are isolated directly from an organism – are closer at a physiological level to the tissue of interest and provide a good model for studying how cells would function in a more real-life context. However, their disadvantages include their limited lifespan – and they can be more difficult to culture and maintain than immortalized cell lines.“They can get you closer to what’s happening in the body – but they’re aren’t identical and they are more costly and challenging to work with,” says Alpaugh. “And for certain cell types, like neurons, it’s extremely difficult to get ahold of these from humans – and they can’t be continuously grown in culture.”Stem cell technologiesAdvertisement Whole Transcriptome Expression of FFPE Samples Reveal the true biological complexity of FFPE samples. View Poster Recent progress in cell reprogramming has ushered in a new era of disease modeling using human embryonic stem cells (ES cells) or induced PSCs (iPSCs). These cells possess the capability for indefinite self-renewal and the potential to differentiate into virtually any cell type – including human neuronal cells, facilitating the modeling of diseases affecting the central nervous system, such as Huntington’s disease, Alzheimer’s disease and schizophrenia.“I use human iPSCs to produce astrocytes, neurons and endothelial cells – and then we can mix and match these together to understand how they interact,” describes Alpaugh. “You can generate these from healthy adult donors or patients, enabling us to study how these cells differ between healthy and disease states.”The application of genome editing, particularly CRISPR-Cas9 technology, has further extended the potential of iPSCs – by enabling the introduction of specific genetic alterations (such as the insertion, deletion, or replacement of a DNA sequence) associated with a particular disease. This approach also enables the generation of genetically matched (isogenic) pairs that differ only by the disease-causing mutation.“These provide an extremely powerful tool for studying the effects of a disease-associated mutation, ignoring all other genetic variability,” explains Alpaugh.Researchers can also perform CRISPR screening to rapidly analyze the functional impact of thousands of genetic changes in iPSCs in a single experiment.Brain avatarsAdvertisement Fully Automated Image-Based Single-Cell Isolation and Picking Learn how you can select 20 individual CTCs in 10 minutes. View Application Note In recent years, 3D organoids – miniature organ-like models typically derived from human PSCs – have emerged as a powerful system to bridge the gap between animal models and humans. Such models have now been generated for many different organs and vary in their complexity – but are typically composed of several cell types and possess a high degree of self-organization. Because they are thought to closely resemble the structural, physiological and microenvironmental features of human tissues – and to mimic, to a certain extent, organ functionality – organoids are an excellent model for applications spanning from developmental biology to personalized medicine.“The ability to generate human brain organoids has revolutionized how we study human brain development and how it is affected by disease,” says Arlotta.These organoids – or “brain avatars” offer a window into the early stages of human brain development that were previously inaccessible. This has made it possible to study the complex disease processes that underlie neurodevelopmental and neurodegenerative disorders in a human context.“In the early days, every organoid was a snowflake – so we had to make sure we could control their development so it was reproducible,” reflects Arlotta. “We also needed to figure out how to grow them for a very long time – because the speed of the formation of the human brain is very slow.”Numerous variations of these organoid models have now been developed – and it is now possible to recapitulate essentially every part of the human brain. Researchers can use these to study the effects of genetic risk variants associated with a particular disease in a dish – and can even model the disease on a patient-specific genomic background by generating organoids from patient-derived iPSCs.“I’m interested in autism spectrum disorders – and there have been thousands of genetic variants associated with this pathology but nobody knows how these genes work,” explains Arlotta. “We’re using organoid models to find out exactly what cell types are affected – and to define the events that occur during brain development that later cause the disease phenotype.”Recent advances in technology, including single-cell sequencing, are enabling researchers to study the property, function and cellular networks that form inside these tiny brains in unprecedented detail. Arlotta’s team is also developing human brain chimeroids that are made up of cells from several different people, enabling them to investigate inter-individual variation in brain development and disease in a single experiment.“We can imagine a future where the capability of scaling up these systems will offer many exciting new opportunities – such as improved drug screening and personalized medicine,” says Arlotta.A new era in disease modelingAdvertisement Using Immune Cell Metabolism To Build Next-Generation Cell Therapies Introducing a novel tool for the real-time measurement of immune cell bioenergetics. View eBook In recent decades, developing a better understanding of the molecular alterations behind different diseases has led to many breakthroughs in the diagnosis and treatment of a variety of human illnesses – including targeted cancer drugs and precision gene therapies. But to gain new insights into other diseases where progress has been more limited, researchers are now gravitating towards cell-based systems that can better recapitulate human development and pathology more closely than existing models.“I like working with cells because there’s so much you can do with them, there’s so much room to try new things and also to mix and match and expand into different areas,” enthuses Alpaugh.Increasingly complex systems – such as 3D organoids – are becoming invaluable disease models, particularly for studying organs that have previously lacked relevant models.“These cell-based systems are providing us with a door into the human brain that we’ve never had before. They offer the potential to change completely how we develop therapeutics and understand how our brain is made and works,” concludes Arlotta. “I find that very exciting.”

Proteomics & Metabolomics

Proteomics & Metabolomics

Cellular Insights: How Researchers Are Using Cell Models To Study the Mechanisms of Disease