Computational biology unlocks rules of tissue self-organization

Every day, your body replaces billions of cells-and yet, your tissues stay perfectly organized. How is that possible?

A team of researchers at ChristianaCare's Helen F. Graham Cancer Center & Research Institute and the University of Delaware believe they've found an answer. In a new study published today in the scientific journal Biology of the Cell, they show that just five basic rules may explain how the body maintains the complex structure of tissues like those in the colon, for example, even as its cells are constantly dying and being replaced.

This research is the product of more than 15 years of collaboration between mathematicians and cancer biologists to unlock the rules that govern tissue structure and cellular behavior.

"This may be the biological version of a blueprint," said Bruce Boman, M.D., Ph.D., senior research scientist at ChristianaCare's Cawley Center for Translational Cancer Research and faculty member in the departments of Biological Sciences and Mathematical Sciences at the University of Delaware.

Just like we have a genetic code that explains how our genes work, we may also have a 'tissue code' that explains how our bodies stay so precisely organized over time."

Bruce Boman, Cawley Center for Translational Cancer Research, ChristianaCare 

Math meets medicine

The researchers used mathematical modeling-essentially, creating a computer simulation of how cells behave-to see if a small number of rules could account for the highly organized structure of the lining of the colon. That's an ideal place to study: cells in the colon renew every few days, but the overall shape and structure stays remarkably stable.

After running many simulations and refining their models, the team identified five core biological rules that appear to govern the structure and behavior of cells:

1. Timing of cell division.
2. The order in which cells divide.
3. The direction cells divide and move.
4. How many times cells divide.
5. How long a cell lives before it dies.

"These rules work together like choreography," said Gilberto Schleiniger, Ph.D., professor in the University of Delaware's Department of Mathematical Sciences. "They control where cells go, when they divide and how long they stick around-and that's what keeps tissues looking and working the way they should."

Decoding human tissue

The researchers believe these rules may apply not just to the colon, but to many different tissues throughout the body-skin, liver, brain and beyond. If true, this "tissue code" could help scientists better understand how tissues heal after injury, how birth defects happen and how diseases like cancer develop when that code gets disrupted.

Boman explained it this way: "Your tissues don't just grow and shrink randomly. They know what they're supposed to look like, and they know how to get back to that state, even after damage. That level of precision needs a set of instructions. What we've found is a strong candidate for those instructions."

This work also has important implications for the Human Cell Atlas, a global scientific collaboration working to map every cell type in the human body. While the Atlas aims to catalog what each cell is and what it's doing at a given moment, this new research offers a dynamic framework for understanding how those cells stay organized over time. By identifying simple, universal rules that govern cell behavior and tissue structure, the findings could help guide future efforts to not only describe cells, but predict how they behave in health and disease.

Implications for disease and discovery

One reason the team turned to mathematical models, rather than traditional biology experiments, is that it's extremely difficult to observe how every single cell in a tissue behaves in real time. But with computer models, researchers can run simulations that reveal patterns and dynamics hidden from view.

This kind of collaboration between biology and math reflects a broader shift in how scientists approach complex problems. It also aligns with national priorities: the National Science Foundation's "Rules of Life" initiative challenges researchers to uncover the fundamental principles that govern living systems. This study is a strong step in that direction.

Next steps for the team include testing the model's predictions experimentally, refining it with additional data and exploring its relevance to cancer biology-especially how disruptions to the tissue code may lead to tumor growth or metastasis.

"This is just the beginning," said Schleiniger. "Once you can identify the rules, you can begin to ask entirely new questions, and maybe even learn how to fix what's gone wrong."