Interplay of two molecules
Khammash and his interdisciplinary team of control theorists, mathematicians and experimental biologists have now succeeded for the first time in engineering such an integral feedback controller in the form of a synthetic genetic regulatory network inside a bacterium. Their feedback mechanism relies on two molecules – A and B – that bind to each other to become inactive. Together, these two molecules have the ability to maintain a constant concentration of a third molecule, C. The system is designed so that molecule B promotes the production of C, while the production rate of A depends on the concentration of C. The feedback loop consists in the fact that when C is abundant, more A will be produced, which will inactivate more B, which in turn will cause production of C to fall.
As a proof of concept, the ETH scientists made use of this principle to control the production of a green fluorescent protein in
bacteria. Thanks to the feedback controller, the bacteria produced a constant amount of the fluorescent protein – even when the scientists, who wanted to test the system, attempted to suppress its production using strong inhibitors. In a second experiment, the researchers managed to produce a bacterial population that grew at a constant rate in spite of the scientists’ attempts to disrupt growth, again in an effort to test the feedback mechanism.
Improving biotech and therapies
Biotechnology could now put this new control mechanism to work in bacteria to produce vitamins, medications, chemicals or biofuels, with the mechanism ensuring that the production rate within the bacteria is held constant at its optimum level.
The ETH scientists are developing an analogous control mechanism for mammalian cells in subsequent research work, which will pave the way for further applications, including designer cells featuring genetic regulatory networks to produce hormones inside a patient’s body. Among those who would stand to benefit from such an approach are people with diabetes or thyroid deficiency. The synthetic feedback controllers could also be used to improve cancer immunotherapy. “In this form of therapy, immune cells need to be active enough to fight the tumour, but not overactive, as they would then attack healthy tissue,” Khammash says. “A mechanism like ours would be able to fine-tune their activity.”