Unnatural selection: The "evolution machine" that drives bacteria to produce new drugs
If there's one thing life is good at, it's adapting to new environments, but that's not always a good thing. Bacteria are fast adapting to antibiotics, rendering drugs less and less effective and threatening to cast us back into the dark ages of medicine. Now a research project backed by the European Union is trying to turn that same process to our advantage, with an "evolution machine" that directs the evolution of bacteria by making changes to their environment, guiding them to produce molecules that could one day lead to new drugs.
The evolution machine, dubbed EVOPROG, was developed as part of the European Union's Future and Emerging Technologies (FET) initiative. The system contains bioreactors full of mixed bacteria species and bacteriophages – viruses that attack bacteria and change their DNA, which in this case makes them produce molecules with certain functions.
According to the researchers, EVOPROG functions like an analog computer: To make specific molecules users feed in certain chemicals, cell lines, or other raw materials, and the machine makes environmental changes to the bioreactor to guide the phages and bacteria to produce those molecules.
"Just like computers are programmed to carry out arithmetic or logical operations based on variables for performing different tasks, the new device can be programmed to carry out logical operations inside living cells using DNA as a variable to generate new molecules," says Alfonso Jaramillo, coordinator of the EVOPROG project.
Phages are some of the fastest-evolving organisms, so to make EVOPROG work the scientists engineered them to function like biological versions of the "IF/THEN" statements that are key to programming. Here they've been designed so that "IF" a certain change is artificially introduced into their environment, "THEN" they attach themselves to a certain type of bacteria (which have also been carefully engineered) to produce molecules. Like natural evolution, the most effective phages are then selected for and allowed to replicate.
"The phages interact with certain types of engineered bacteria, according to the types of molecules wanted, and replicate only if the mutated proteins they produce are compatible with the genes and chemicals present in those bacteria," says Jaramillo. "With our approach we can find new antimicrobial molecules by using evolution to kill bacteria. For example, if a given antibiotic molecule enters the bacterial cell and is immediately pumped out of the cell, thus not killing it, we can induce a selection of the DNA content of phages and drive them to block that bacterial pump so that the antibiotic will remain in the cell and kill it."
According to the team, EVOPROG's directed evolution process takes about two weeks to produce the desired molecules, which would allow scientists to experiment much faster than other development methods. And the system could not only help researchers identify new drug targets, but once a recipe has been nailed down it can be shared with other teams to allow them to produce the drug in their own lab. In that same spirit, the bioreactors themselves are 3D printed, so different designs can also be reproduced accurately and inexpensively.
"EVOPROG is an exciting approach to address the present bottleneck of engineering synthetic biological systems," says Baojun Wang, a biomedical engineer who was not involved with the project. "Not only does it have the potential to significantly expand the library of biological building blocks and shorten development time, but it could also lead to programmable, efficient phage therapeutics that may treat the fast-changing human bacterial pathogens in the future."