Single Cell Sequencing: Unwinding Embryonic Development One Cell at a Time

January 4, 2019

At one point, we were all just one single cell: a fertilized zygote formed when a sperm and egg fused together. That one cell gave rise to all of the roughly 37 trillion specialized cells that make up each of our bodies today. All the cells from our heads to our toes, every single one of them, can be traced back to one single cell.

The mystery of how embryonic development choreographs the formation of specialized tissues and organs from one original cell has captivated, and baffled, developmental biologists for centuries. How does one cell divide and specialize into different cell types? How do cells know when, where, and what kind of cell to become (e.g. a brain cell versus a blood cell)? Recently named the 2018 Science MagazineBreakthrough of the Year,” single cell sequencing allows scientists to retrace the steps that cells took during development, one cell at a time.

A family tree of cells

Every cell is related to all of the others within a living organism. Imagine drawing a family tree where an initial fertilized cell is at the apex and every subsequent cell division leads to successive branching. That single cell would become two, then four, then eight, and so on. After many, many cell divisions the family tree would result in 37 trillion progeny, all with one common ancestor cell at the very top. Now that’s a family tree!

By developing a detailed family tree outlining the steps that cells undertake during development, scientists hope to piece together a blueprint of how different cell types are made in organisms and how some diseases progress. It could also help them mimic the process with stem cells in the lab to make replacement tissues and organs for those damaged by injury or disease.

Going back in time

The combination of three cutting-edge technologies, single cell sequencing, CRISPR gene editing, and powerful computer algorithms, has enabled scientists to retrace the cells of entire organisms back to their early embryonic stages, in order to understand how they form. The work is not yet being done in humans, but several pioneering studies have been carried out in smaller organisms.

Scientists are able to track cells when they are at the embryonic stage by branding them with different DNA barcodes that can be read (sequenced) at later times. After an organism develops, the DNA or RNA in individual single cells can be sequenced, thus the term ‘single cell sequencing.’ The barcodes identify which cells in the early embryo gave rise to which cells in the adult, retracing the history of individual cells. 

Tracing cellular development

Scientists have made great progress in retracing cell lineages in small, simple organisms. In zebrafish, as many as 92,000 cells from one fish were retraced back to their progenitors in the early embryo. After retracing the development of fish, worms, frogs, and salamanders, in August, 2018, scientists reported using single cell sequencing to study the development of a whole mouse. Together, studies over the last year have revealed:

  • some organ systems appeared to be established from small numbers of founder cells very early in development (e.g. the blood system);
  • seemingly similar cell types can have different developmental histories;
  • the front-back axis of the brain may develop before the left-right axis;
  • ·novel roles for genes in the development of different cell types.

In addition to unraveling fascinating mysteries of embryonic development, this technology may provide key insights into how diseases develop, and how cells might be regenerated for repair.

Applying this technology to help people

Single cell sequencing is fundamentally revolutionizing how researchers study and understand embryonic development. By tracking organs cell by cell over time, scientists may better understand how diseases such as Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), diabetes, or even cancers originate and develop. These insights may lead researchers to find ways to repair tissues or organs, replicate processes in the lab to make cell types to help patients, or find new strategies to prevent or fight devastating diseases. We are just learning about the many ways this technology can be applied to research to advance human health.