Caltech Researchers Propose a New Origin Story for Multicellular Life

How did life make the leap from single cells to coordinated, multicellular organisms? And how do genetically identical cells still perform a version of that feat every time an embryo begins to take shape?

In a new Perspective paper appearing in the journal Nature Biotechnology, Bren Professor of Biology and Biological Engineering Magdalena Zernicka-Goetz and collaborator Qi Chen of the University of Utah ask one of biology's oldest questions in a new way.

Self-organization is the process by which individual cells spontaneously assemble into complex structures, like organs and tissues. In the new Perspective, Zernicka-Goetz and Chen reframe self-organization not as a mysterious byproduct of biological complexity, but as something closer to a physical inevitability. Once cells grow and begin to crowd together, they start to become limited by how far oxygen and nutrients can travel and which cells are in contact with the external environment. These limitations push tissues toward a small set of recurring architectural solutions: Hollowing out (cavitation), folding, and branching. These simple strategies, repeated and layered over time, can give rise to the elaborate structures of embryos, organs, and living tissues.

Also at the heart of the Perspective is a new idea the authors call the Asymmetric Initiation Hypothesis. Classical theories have suggested that multicellularity began when cells either remained attached after division, or aggregated into cooperative groups. Zernicka-Goetz and Chen propose that an even earlier step may have been an imbalance inside a single cell: An uneven distribution of molecules, organelles, or mechanical tension that created the first spatial bias in function and fate. Such asymmetries, potentially triggered by crowding, compression, or other environmental forces, could have helped set the stage for polarization, adhesion, division of labor, and eventually multicellular organization.

Recent studies show that archaea (a type of single-celled organism) form tissue-like structures under mechanical compression, lending support to the idea that physical forces may have played an important role in early multicellular evolution. In this view, the leap from one cell to many was not only a genetic innovation, but also a response to the pressures and possibilities imposed by physics.

The new Perspective article also surveys how stem cell–based embryo models, a field Zernicka-Goetz's laboratory has helped pioneer, now allow scientists to build these processes from their component parts in the dish, watching self-organization succeed, fail, and reveal its underlying logic. Understanding that logic, the authors argue, opens the door to rationally engineering living tissues, with implications for regenerative medicine, reproductive health, and synthetic biology.

The work echoes a famous line from Richard Feynman's Caltech blackboard: "What I cannot create, I do not understand."

"For developmental biology, the same principle is becoming increasingly literal," says Zernicka-Goetz. "By reconstructing how life assembles itself, we are moving from observing biology to prototyping it."

The paper is titled "Decoding the origins of cellular self-organization for engineered biology." Zernicka-Goetz and Chen are the study's authors. Funding was provided by the National Institutes of Health.