Why should cell biologists care about single-cell genomics? scRNA-seq, scATAC-seq, SCI-seq, scGESTALT, scCRAZE—is it all a fad? Or is there something interesting to be discovered with these techniques? Here are five things you can do with single-cell genomics that show why it is becoming an essential tool for cell biologists:
First, you can discover the universe of cell types and cell states. Multicellular organisms often consist of hundreds of cell types, and, like single-cell organisms, those cells can be in many different physiological states. Single-cell genomics helps capture and define cell types and states in unprecedented molecular detail. For example, dozens of previously unrecognized cell types have been identified in vertebrate brains. This approach also creates new opportunities to define the diversity and similarities of cell types in different organisms and to reconstruct the evolutionary history of cell type diversification.
Single-cell genomics helps capture and define cell types and states in unprecedented molecular detail.
You can also determine the molecular trajectories of cell differentiation. During development and tissue homeostasis cells become specialized and acquire specific structures and functions. Single-cell genomics time courses reconstruct the molecular changes cells undergo during differentiation. For example, recent studies revealed the cascades of transcriptional changes that underlie vertebrate embryogenesis. Similar approaches are now being used to describe the molecular trajectories underlying regeneration and disease progression.
Third, you can deduce the lineage relationship between cells. Each cell has a mother, a grandmother, a grand-grandmother, and so on, and is thus related to other cells through lineage. Single-cell genomics combined with endogenous or introduced mutations can define the ancestral relationships between cells. For example, complex lineage trees have been reconstructed for cells in the zebrafish brain. These proof-of-principle studies lay the foundation for the future creation of full lineage trees of animal development.
Single-cell genomics time courses reconstruct the molecular changes cells undergo during differentiation.
With single-cell genomics you can detect the emergence of abnormal states. Mutations, toxins, aging, disease, and other disruptions change cellular states. Single-cell genomics is a sensitive tool to identify these changes and their heterogeneity. For example, abnormal cell states or compositions have been identified in several cancers and psychiatric disorders. Exciting current opportunities include the discovery of cellular vulnerabilities and their exploitation or correction.
Exciting current opportunities include the discovery of cellular vulnerabilities and their exploitation or correction.
Finally, you can use single-cell genomics to define entry points to mark and manipulate cells. The analysis of cellular processes relies on the specific accessibility of defined cells. Single-cell genomics is identifying combinations of markers that allow the manipulation of specific cell types and states. For example, highly specific marker genes enable the recording and inhibition of neural circuits. It is conceivable that these approaches will enable the specific targeting of any cell type or state. Many technological, analytical and conceptual challenges remain in this field, but it is now quite clear that single-cell genomics is opening new horizons in cell biology.
About the Author:
Alexander F. Schier is professor in the Department of Molecular and Cellular Biology at Harvard University. A Site Director of the Allen Discovery Center for Cell Lineage Tracing, and Director of the Biozentrum at the University of Basel, Switzerland. He and Andrea Brand will speak at the Symposium “Decisions, Decisions: How cells choose their fates” at the 2019 ASCB|EMBO Meeting.