Revealing Cellular Complexity: Integrating Single-Cell Multiomics

Complex organisms consist of diverse and heterogeneous cells. In the last decade, single-cell sequencing technology has gained traction in studying cellular heterogeneity. However, researchers are now moving beyond single-level information, embracing multi-omics strategies to integrate genomic, transcriptomic, proteomic, and spatial gene expression data. This holistic approach overcomes the limitations of analyzing single-modal data from disparate experiments and unveils crucial molecular features within individual cells.

Although the inception of single-cell omics technology dates back to 2014, numerous methodologies have since emerged, continuously enhancing sequencing throughput, depth, and coverage. The concurrent analysis of chromatin accessibility and transcriptome within a single cell facilitates a deeper understanding of the direct relationship between chromatin states and transcript levels in specific genomic regions. Furthermore, as transcription factor binding is transient whereas changes in epigenetic marks persist over longer durations, techniques enabling simultaneous detection of chromatin accessibility and gene expression assist in dissecting cell states across different time scales. Presently, researchers have devised diverse methodologies for simultaneous chromatin and transcriptome analysis.

Initially, achieving high throughput relied on manual pipetting by lab technicians, adding various reagents to 96-well or 384-well plates. However, manual operation is inherently slow and poses significant limitations. There is a risk that by the time reagents are added to the 100th reaction, the first reaction may have already concluded, questioning the parallelism of these reactions. Consequently, high-throughput technologies are evolving towards mechanization and automation, with numerous liquid handling robots and spot samplers available on the market possessing such capabilities.

High-throughput single cell sequencing is versatile and widely applicable. Ideally, many experiments, especially those in the life sciences necessitating numerous repetitive liquid handling operations, should transition towards high throughput. This would liberate researchers from manual tasks, allowing them to focus on critical thinking and genuine scientific inquiry. For instance, consider high-throughput screening (HTS).

HTS technology holds immense promise in drug screening. The journey from drug synthesis to clinical application is lengthy. Before administering drugs to humans, they undergo molecular characterization as well as cell and animal experiments. These experiments not only verify the efficacy of drugs but also involve screening the drugs themselves and selecting optimal administration conditions from a plethora of options. This process is both labor-intensive and costly. HTS technology streamlines screening timelines and enhances efficiency. For instance, in screening effective drugs from a library containing 300 molecules, if high-throughput technology can conduct 900 parallel reactions (three reactions for each molecule), the screening process can be completed in one go.

Presently, single-cell transcriptomics sequencing and other single-cell studies may appear less "practical." However, they signify a growing awareness of cellular heterogeneity, shifting the focus towards individual cells rather than populations. This approach offers a deeper perspective and a more precise understanding of life's intricacies. Merely contemplating this direction suffices to render it meaningful enough.