It is high time in 2024, and science grapples with the question that seems to be more simple than profound: what precisely is a cell type? This question cuts to the core of biology and medical research-questions that have grown increasingly complex as technologies like single-cell RNA sequencing have become more capable. The topic is the subject of a spate of recent articles that provide context on how we demarcate the myriad flavors of life at the level of individual cells.
Below is a summary of key findings, challenges, and implications from this work across a broad range of scientific disciplines.
Defining a Cell Type: More than RNA Profiles
The traditional view of a cell type focuses on function and structure, classifying cells according to their specialized roles within an organism: neurons, muscle cells, blood cells. But as a feature in Nature pointed out, this is a definition that recent studies have muddled. According to investigators like Hongkui Zeng of the Allen Institute for Brain Science, the approach of simply aggregating cells with shared attributes doesn’t fully capture the subtlety.
It is apparent from single-cell RNA sequencing that identically profiled cells of RNA can exhibit a wide range of different behaviors dependent upon environment, structural organization, and developmental time. On one side, systems biologists like Itai Yanai believe genes hold the key in cell classification. That if it were known which genes were turned on, according to Yanai’s camp, then one could infer a cell’s type. This gene-centric approach has been supportive, envisioning RNA sequencing as a very important means of cataloging cells based on their genetic activity. Others, however, such as Alfonso Martinez Arias, believe that the focus on RNA alone lacks information about the big picture of a cell’s overall structure and function.
Martinez Arias stresses that while RNA sequencing is valuable, it cannot account for all facets of cell differentiation and development, especially in 3D models of early embryos.
The Core Regulatory Complex Theory Another paradigm that is getting attention in recent years is the core regulatory complex, or CoRC. Helmed by evolutionary biologist Günter Wagner, this hypothesis believes that the cell types are controlled by large complexes of regulatory molecules that control the expression of genes. It acts like a conductor, pulling on strings of DNA to turn some genes on or others off. One view here is that cell type arises not only from RNA profiles but from larger-scale genomic and regulatory interactions.
Though still in its infancy, CoRC theory might offer a more holistic approach toward cell-type classification-one that looks beyond gene expression as such and embraces chromatin structure and transcriptional dynamics.
The Cell State and Identity Problem
The attempts at cell-type definition have a further wrinkle, namely, the issue of cell state . Cells-most notably, immune cells-can change state without changing their type. For example, a quiescent immune cell might activate in response to an infection and change state drastically without changing cell type. Sam Morris, a stem-cell biologist at Washington University, argued that any effort to define cell types must account for cells transient states.
This, in turn, presents yet another problem, as often the line separating cell type and cell state is somewhat blurred.
Evolutionary Perspectives: A Continuum of Cell Types?
Some scientists still think in 2024 that cell type is a continuum rather than a discrete category. The developmental geneticist Jay Shendure favours a tree-like mapping of the cell types whose branches signify the evolutionary and developmental trajectories that yield them. This would have to do with broader questions about how life evolved and how cell types came out of simpler forms.
Supportive of that view, Shendure’s work on single-cell transcriptomes in mice shows how cells transition across different types during an organism’s development.
Applied Directions: Medicine and Drug Development
Such debates are not merely academic. The consequences of these debates ramify into such vital fields as medicine and the development of drugs. For instance, pharmaceutical companies like Genentech make use of cell-atlas data in their drug repurposing to treat new conditions. A drug initially targeted at lung cells proved effective in inflammatory bowel disease upon the observation that both lung and gut cells express the same receptor. Without such minute cellular mapping, these connections would have remained hidden.
Cell Typing: The Future is a Work in Progress.
The new research on cell types brought as many questions, as answers. Technologies like single-cell RNA sequencing revolutionized the knowledge of cell diversity but also demonstrate real limitations of our current definitions. As some researchers at Harvard Medical School, like Allon Klein, note, perhaps the vagueness of a “cell type” definition is not really a problem but is due to the nature of reality.
The same vagueness was found in biological species classification, and understanding cell types will probably evolve as genetic and proteomic data continue to build up.
Conclusion
The attempt at defining the cell type is an ever-evolving task in biology. While one probes into genetic ways, structural manners, and developmental approaches to classifying cells, it arguably becomes clear that no single definition may ever be enough. Instead, the breakthroughs may be in combining several methodologies—RNA sequencing, genomic analysis, and evolutionary biology—to obtain the intricate roadmap of life’s peremptory unit.
The discussions and findings of 2024 brought into view the multifaceted nature of biology but, in so doing, unleashed a potential excitement toward deeper understanding and medical advancement at the same time. The journey has barely just begun as researchers continue to push the edge on what is known about the cell and, by extension, life itself.
