From Manual to Automated: The Evolution of High-Throughput Sequencing Technologies

Complex organisms are composed of a diverse array of cells. In recent years, single-cell sequencing technology has become increasingly popular for studying cellular heterogeneity. Researchers are now advancing beyond single-level data, adopting multi-omics strategies to integrate genomic, transcriptomic, proteomic, and spatial gene expression data. This comprehensive approach addresses the limitations of analyzing isolated data from separate experiments, revealing essential molecular features within individual cells.

Since the advent of single-cell omics technology in 2014, numerous methodologies have emerged, continually improving sequencing throughput, depth, and coverage. Simultaneous analysis of chromatin accessibility and transcriptome within a single cell provides a deeper insight into the relationship between chromatin states and transcript levels in specific genomic regions. Given that transcription factor binding is transient while epigenetic changes persist longer, techniques that enable concurrent detection of chromatin accessibility and gene expression are crucial for understanding cell states over different time scales. Today, various methods for simultaneous chromatin and transcriptome analysis have been developed.

Initially, high-throughput sequencing relied on manual pipetting by lab technicians, adding reagents to 96-well or 384-well plates. This manual approach is slow and prone to limitations, as reagents added to the 100th reaction might cause delays in the first reaction, challenging the parallelism of these reactions. As a result, high-throughput technologies are advancing towards mechanization and automation, with a range of liquid handling robots and spot samplers available to enhance efficiency.

High-throughput single-cell sequencing is versatile and widely applicable. Many experiments, particularly in the life sciences that involve repetitive liquid handling operations, should transition to high-throughput methods. This shift would free researchers from tedious manual tasks, allowing them to concentrate on critical thinking and scientific exploration. For example, high-throughput screening (HTS) in drug development shows significant promise.

HTS technology accelerates drug screening processes. The journey from drug discovery to clinical application is lengthy, involving molecular characterization and extensive cell and animal testing. These experiments are essential for verifying drug efficacy and optimizing administration conditions but are labor-intensive and costly. HTS technology streamlines the screening process, increasing efficiency. For instance, when screening effective drugs from a library of 300 molecules, high-throughput technology can perform 900 parallel reactions (three reactions per molecule) in a single round.

While single-cell transcriptomics and related studies may currently seem less "practical," they represent a significant shift towards understanding cellular heterogeneity at the individual cell level rather than in populations. This approach offers a more nuanced and precise view of biological complexities, making it a meaningful direction for advancing scientific knowledge.