Researchers at UCLA’s Samueli School of Engineering and the University of Rome Tor Vergata in Italy have developed synthetic genes that function like genes in living cells.
Artificial genes can build intracellular structures through a cascade sequence that builds self-assembled structures piece by piece. The approach is similar to building furniture with modular units, much like those found at IKEA. Using the same parts, one can build many different things and it is easy to take the whole thing apart and rebuild the parts for something else. The discovery offers a path toward using a set of simple building blocks that can be programmed to make complex biomolecular materials, such as nanoscale tubes from DNA plates. The same components can also be programmed to split the design into different materials.
The research study was recently published in Nature Communications and led by Elisa Franco, professor of mechanical and aerospace engineering and bioengineering at UCLA Samueli. Daniela Sorrentino, a postdoctoral researcher in Franco’s Dynamic Nucleic Acid Systems laboratory, is the first author of the study.
“Our work suggests a way to increase the complexity of biomolecular materials by taking advantage of the timing of molecular instructions for self-assembly, rather than increasing the number of molecules that carry those instructions,” Franco said. “This points to the interesting possibility of generating different materials that can spontaneously ‘unfold’ from the same finite set of parts simply by reconnecting the elements that control the temporal order of the assembly.”
Complex organisms develop from a single cell through sequential events of division and differentiation. These processes involve numerous biomolecules coordinated by gene cascades that guide the timing and location of gene activation. When a molecular signal is received, a series of genes are activated and assembled in a specific order, leading to a particular biological response. A well-known example in biology is the gene cascade that controls the formation of body segments in fruit flies. In this process, genes are perfectly synchronized to trigger the formation of specific body segments in the correct order.
“We had the idea to recreate in the laboratory similar gene cascades that, depending on the moment of gene activation, could induce the formation or disassembly of synthetic materials,” said co-author Franceso Ricci, professor of chemical science at the University of Rome. Tor Vergata.
In their study, the researchers used DNA mosaic building blocks made up of a few strands of synthetic DNA. They then created a solution containing millions of these tiles, which interacted with each other to form micrometer-scale tubular structures. The structures only form in the presence of a specific RNA molecule that triggers the formation. A different RNA trigger molecule can also induce disassembly of the same structures.
They then programmed different synthetic genes that produce the RNA activators at specific times so that the formation and dissolution of the DNA structures could be precisely timed.
By connecting these genes, they created a synthetic genetic cascade, similar to that of a fruit fly, that can control not only when a certain type of DNA structures form or dissolve, but also their specific compositional properties at any given time. .
“Our approach is not limited to DNA structures, it can be extended to other materials and systems that depend on the timing of biochemical signals,” Sorrentino said. “By coordinating these signals, we can assign different functions to the same components, creating materials that spontaneously evolve from the same parts. This opens up exciting advances in synthetic biology and paves the way for new applications in medicine and biotechnology.”
The research was supported by the US Department of Energy’s Office of Science, the US National Science Foundation, the European Research Council, the Italian Association for Cancer Research, the Italian Ministry of University and Research and Italy’s National Recovery and Resilience Plan, which is funded through the European Union’s NextGenerationEU stimulus package. Sorrentino holds a scholarship funded by the Italian Association for Cancer Research.
Simona Ranallo, a researcher at the University of Rome Tor Vergata, is also an author of the study.