How Stem Cell Embryo Models Won Method of the Year

A collection of ingenious biological tools for studying the genesis of life has been awarded Nature Methods’ coveted Method of the Year award for 2023. Unlike many previous years, where a single, influential technique has taken the prize, 2023’s award has gone to “methods for modeling development”, which encompasses techniques for studying individual cells, locating cells within developing embryos, editing genes and visualizing the early stages of life.

At the start of life, a single cell divides, kickstarting a complex developmental process that continues beyond birth. Analyzing these steps has remained a fraught exercise, but one that remains key to unraveling how life begins.

Challenges – both ethical and technical – have been partially overcome by new methods for studying these early life stages. Perhaps the central foundation of these innovations is the rise in stem cell models that allow these “blank-slate” cells, which can become many of the other tissues in the body, to morph into structures that mimic the growing embryo. A 2023 paper detailed a stem cell model of gastrulation – a critical developmental process where the single-layered blastula becomes the more complex gastrula. This stage sets up a basic structure that the developing embryo maintains through to birth. Such models not only recreate the blastula, but also mimics the signals that direct these powerful changes.

Star techniques from across biology chip in

While stem cell models might be the key substrate of developmental biology, other techniques have shaped these structures and enhanced their accuracy and depth. Single-cell sequencing and spatial transcriptomics – both previous Methods of the Year – have proved essential to helping researchers understand embryonic events at the cellular level. They have helped create developmental cell atlases that act as guidebooks for the field, tracking cell changes over the course of development.

CRISPR gene editing, a versatile technique that has advanced many other fields within molecular biology, has also left its mark on developmental biology. CRISPR, which slices into the genome as it edits, can be used to mark tiny molecular barcodes onto early embryos, allowing cells’ lineages to be traced.

Advances in imaging have given researchers deeper insight into development. Light-sheet microscopy, where thin slices of a sample are illuminated by a sheet of laser light, has been used to image and track cells within developmental mouse organoids over a four-day period. The tech was paired with deep learning to segment individual cells over the imaging period. The field has also advanced its understanding of how cells in a developing embryo move around. Tissue mechanics studies have revealed that cells in developing embryos show properties of both solids and fluids.

Additionally, researchers have gotten more adept at recreating features of the uterine lining – where the developing embryo grows – inside a test tube. A 2022 paper demonstrated a dish environment that used collagen and a polymer called polydimethylsiloxane (PDMS) to support a mouse embryo to the age where a heartbeat starts.

Ethical questions remain for stem cell research

All these advances mean that our understanding of embryonic development is deeper than ever before. But as stem cell models become more faithful representations of actual embryos, more models will enter a moral grey area. When culturing human embryos, an internationally agreed 14-day postfertilization limit applies. Stem cell models allow researchers to partially circumvent such restrictions – with no “fertilization” in these models, where a 14-day limit should apply remains unclear. But the faithfulness of later-stage embryo models cannot be assessed if restrictions still apply on the sperm-egg embryos they would be compared with. An ethical analysis included in the “Method of the Year” issue highlighted the incredible variety in ethical restrictions between countries. Some only class a “human embryo” as a structure created from a human egg, whereas others have broader definitions that would encompass stem cell models.

Roughly half of all human pregnancies fail between fertilization and birth. Stem cell models are a key tool for understanding this critical period of life and improving pregnancy outcomes. Developmental biology is set for huge strides over the next decade, but these leaps will need to be paired with advances in ethical frameworks to guarantee the field’s long-term progress. 

Reference: Method of the Year 2023: methods for modeling development. Nat Methods. 2023;20(12):1831-1832. doi:10.1038/s41592-023-02134-0