Biological navigation – how to build a human 

During the earliest stages of human development, just three weeks after fertilisation, a crucial rod-like structure appears along an embryo’s length: the notochord. 

Present in all vertebrate animals, this biological scaffold extends from head to tail and acts as the site manager. The signals it releases are essential for instructing cells how to develop, as the embryo’s spine and nervous system take shape.

Background: section of a mouse trunk stained for the notochord marker gene in green and cell membranes in white. Foreground left: section of a human trunk-organoid showing the notochord marker in green, the neuron marker in blue, and cell nuclei in white. Credit: Tiago Rito.

However, despite its critical role, exactly how the notochord forms in the first place has been an embryological mystery that researchers, including the Crick’s James Briscoe, have been trying to crack.

“Until now, it’s been difficult to grow notochord tissue in the lab, making it hard to understand the complex processes that shape our bodies,” says James. “It’s also meant we don’t fully understand medical conditions that arise from developmental disorders.”  

Pieces of trunk organoids are fixed in tape. These samples will subsequently be coated with a thin layer of platinum and then imaged using electron microscopy. Credit: Tiago Rito.

A puzzle of timing and sequence

James and his team have been working out how to grow the notochord from human stem cells. As a first step, they studied development in a range of different vertebrate species, including chickens, to meticulously decipher the sequence of molecular signals that constitute the biological ‘instruction manual’ for the notochord.

Next, they introduced these signals to human stem cells, in the right order, and watched as the cells developed into a tiny notochord scaffold, just over a millimetre in length. Importantly, they found that this structure contained developing neural tissues and bone stem cells in the correct locations for embryonic growth.  

Observations on site

It’s work that provides solid foundations. Thanks to James’s team, researchers are now equipped with a model of the biological building site for the first time, allowing them to observe these early stages of human development unfold in the lab. This represents a profound shift in the way scientists are able to study and understand developmental conditions, including birth defects such as scoliosis or spina bifida. The new model might even present clues to help develop treatments for back pain, most commonly caused by degeneration of disks in the spine.

 Microscopy image of the surface of a trunk organoid (right) and a computer-generated image (left) with notochord in green, surrounded by outer neural tissue (skeletonised in purple). Credit: Tiago Rito.

“The notochord defines human architecture, orchestrating the delicate and precise cell changes required to create a body,” says James. “We hope our discovery is a vital piece of the puzzle in modern developmental biology.”