Scientists are still working to understand how morphogens’ signals are broadcast over just the right distances and how cells are calibrated to respond to the proper concentration at the appropriate time. But these questions are difficult to investigate because natural morphogens interact with their environment in many complexes, hard to define ways.
Instead of deconstructing morphogens one interaction at a time, Lim’s synthetic biology team at UCSF and a pair of research groups at the Francis Crick Institute in London – led by Guillaume Salbreux, PhD, and Jean-Paul Vincent, PhD (himself once a post-doc with UCSF’s Patrick O’Farrell, PhD) – independently took the innovative approach of engineering a synthetic morphogen from the ground up. Their goals, as reported in two papers published in Science, were to study what makes morphogens work, and perhaps one day to create synthetic signals that could help control tissue regeneration or guide cellular therapies to heal wounds or fight cancers.
Lim’s team, led by postdoctoral fellow Satoshi Toda, PhD, now an assistant professor at Kanazawa University’s Nano Life Science Institute in Japan, started with an inert molecule called GFP, to which cells are normally completely deaf. To give cells the ability to respond to this new signal, the researchers used special types of antibodies to create GFP-responsive receptors. They genetically inserted these receptors into cells in laboratory dishes and linked them up to a cellular control system called SynNotch, which the lab had previously developed.
When the researchers instructed a subset of organizer cells at one end of the dish to produce GFP, the clouds of the fluorescent protein diffusing away from these anointed organizers activated the engineered receptors and imparted patterned gene activity in surrounding cells.
“I think it’s pretty striking that a crude morphogen is not very hard to make,” said Lim, who is director of the UCSF Cell Design Institute. “It gives us a sense of how simpler signalling molecules might have evolved to become morphogens in the early days of multicellular evolution.”
At UCSF, the researchers showed that these engineered morphogens could direct the formation of novel, user-defined striped patterns. At the Crick Institute, scientists used a similar approach in living flies – showing that engineered morphogens could take the place of natural signals in successfully organizing the intricate patterns of the fly wing.
Because all the interactions in these systems are engineered, their characteristics are known and therefore amenable to mathematical modelling, the researchers say. These studies open the way to a testable theory of pattern formation by morphogens, and one day could help scientists program cells like robots to follow molecular trails to find and regenerate injured or diseased tissues.