Programming Complex Cell Behaviors is Becoming Possible


Programming populations of living cells would enable complex tasks to be performed in numerous health domains: diagnostics, therapy and even tissue and material engineering. In Montpellier, researchers from the Center for Structural Biochemistry (CBS) have recently developed a new type of genetic circuit in which complex operations can be programmed on the scale of a group of bacteria.

Controlling the activity of cells for diagnostic or therapeutic purposes is already a reality. For example, scientists can modify a patient’s T cells so that they "oppose" his or her tumor. But this is highly specific work, applicable to one cell type and for a specific indication. A team from Inserm is currently proposing to take synthetic biology much further, thanks to a new system of externally-controllable genetic circuits with which complex functions can be generated. It should then be possible to use this automated system for all types of applications. A bit like an IT tool which performs various tasks according to the requirements of the users.

In concrete terms, the Synthetic Biology laboratory, codirected by Jérôme Bonnet at the Center for Structural Biochemistry in Montpellier*, incorporates synthetic DNA into bacteria in order to reprogram their behavior. This DNA carries independent sequences that are sensitive to various external signals and control the expression of enzymes which themselves can activate or on the contrary inhibit certain genes. These sequences are organized logically in order to obtain responses that differ depending on the combination of external signals used. "We took inspiration from electronic systems which, thanks to a combination of binary signals - 0 and 1 – fulfil various functions, explains Bonnet. Furthermore, in order to increase the possibilities, we do not ask just one cell to perform a complex program: we divide the work among several bacterial strains, each performing part of the program. Like this we harness the power of the bacteria to work collectively in a natural environment".

14 bacterial populations and 65,000 possible programs

To prove that this approach works, the laboratory constructed 14 different bacteria, each capable of executing a specific "subprogram", which can be monitored using control genes that produce fluorescent proteins. By combining these strains in different ways, more than 65,000 possibilities for gene activation or inhibition can be obtained depending on the external signals applied (at this stage, the signals used are the administration of antibiotics and sugars).

Another important characteristic of this research is that it authorizes the automation of this system to obtain the required function. It is based on an algorithm that generates the DNA sequences of the genetic circuit according to the wishes of the researcher. "Until now, most of the biological circuits were tailormade, rendering their preparation slow and reserved for a small number of experts. However, our multicellular genetic circuits can be generated in an automated way, depending on user needs, using CALIN – an online tool. Our aim is to really make bioprogramming more accessible", explains Sarah Guiziou, principal author of this paper. "We created a logical system guaranteeing a predictable response. The researchers can now use it for specific applications".

The laboratory in Montpellier intends to use this system to develop bacteria for therapeutic use. "The microbiota plays an essential role in health, adds Guiziou. We could modify the bacteria of the intestinal flora so that they can detect markers and activate therapeutic processes in order to fight metabolic diseases, for example. Another example is that bacteria lodge in immunosuppressed tumors where they are sheltered from the immune system. It would be useful to program them in order to destroy the cancerous cells".

Source : S Guiziou et al, Hierarchical composition of reliable recombinase logic devices. Nature Communication, on line edition of January 28, 2019.