LEGO blocks can be manually attached to each other in certain prescribed ways to create complex structures. What if we could design living LEGO-like structures that can self-replicate and move, and that can be programmed to grow and self-assemble into any desired target shape?
An interdisciplinary research team, led by an MIT professor Jörn Dunkel and Ingmar Riedel-Kruse of the University of Arizona, has developed an experimental theory platform that comes one step closer to this goal. Using genetically engineered bacteria and mathematical modeling, they were able to program bacterial systems to grow into arbitrary two-dimensional target structures.
The Riedel-Kruse lab has created a bioengineering toolkit that allows them to control the cell-to-cell adhesion properties of motile bacterial cells. Genetically modified bacteria grow certain molecules on their cell walls that act as docking stations for appropriate partner cells. Only cells that have matching molecules can stick to each other, while those with unmatched ones slide past each other. After seeding a small number of bacteria at different positions on a 2D nutrient surface, the cells will grow, divide and move. When two cell populations with matching adhesion molecules collide, they form a visible solid interface whose position and shape are determined by initial seeding positions and cell concentrations.
Using their versatile bioengineering toolbox, the researchers wanted to create models of complex targets. To achieve this goal, the team needed to understand: how many different cell types are needed to realize arbitrary interface models? How should rules for mutual interaction be designed? What are the right seeding conditions to achieve the desired 2D structures?
To answer these questions, Dunkel and his doctoral student Dominic Skinner, now an NSF-Simons postdoctoral fellow at Northwestern University, sought to formulate a mathematical model that would allow them to simulate the growth and dynamics of bacterial swarms and predict the formation of the interface models.
“Doing trial-and-error experiments is very expensive and time-consuming,” says Dunkel. “So Dominic developed and implemented a model that could predict the expected outcome within minutes.”
Skinner compares programmed bacteria to living LEGOs. “Ingmar’s lab creates the biological building blocks, and we generate the manual with our models,” he says. “His lab puts bacteria in the right places – they swarm, divide and collectively build the desired target shape.”
Dunkel adds: “These unique experimental systems allow a number of fundamental biological questions to be explored: how many cell types are needed to develop certain models? How much information must be encoded in DNA to achieve a certain level of structural complexity? What controls emergent forms? The good agreement between the predictions of the experiment and the model allows us to investigate these questions using computer simulations at very little cost.
Beyond this, the research suggests various direct practical applications in the design of biomaterials.
Their research paper “4-Bit Adhesion Logic Enables Universal Multi-Cell Interface Patterning” is featured on the cover of Nature.
“In our paper, we provide proof-of-concept realizations of self-developed elastic sheets and channel structures that can transport liquid droplets to desired locations,” says Dunkel. “Another application is in biosensors – basically, bacteria write a human-readable message when they detect a molecule in their environment.”
As a next step, the team plans to develop three-dimensional structures and add additional functionality to the bacteria, such as the ability to produce certain chemicals at desired locations.
The first author of this book is Honesty Kim; other co-authors are David Glass, Alexander Hamby and Bradey Stuart. All are or were at the Riedel-Kruse lab.
The work was supported by the Alfred P. Sloan Foundation and the National Science Foundation.