We have advanced the field of Cybergenetics significantly since the beginning of the project. Most notably, we have developed the theory for designing molecular control systems that achieve a special property called “robust perfect adaptation”. This property means that our specially designed molecular controllers are guaranteed to bring cellular variables of interest to a desired value and maintain it there, in spite of the large uncertainty and randomness inside living cells and other disturbances. Our theory also gives us all controllers that will have this property, so we can select a suitable one that can achieve additional desirable objectives. The theory tells us that such controllers must implement the mathematical process of integration using molecular calculations. With this in mind, we have succeeded in the lab in building and testing the first ever such control system in a living cell. Such molecular control systems should have several applications in industrial biotechnology and medical therapy. We have then proceeded to characterize all controllers that achieve these adaptation, properties and developed a new Internal Model Principle for characterizing them. We then went on to develop the necessary methods for designing and building more advanced control systems with desirable dynamic properties and then we demonstrated how these controllers can be genetically engineered using special proteins called inteins. In short, more than any other group in the work, we have significantly advanced the theory and methods for building genetic feedback control systems.
We have also taken a parallel approach for controlling living cells—this time using a digital computer to carry out the controlling. The computer measures the behavior of living cells in real time, and then based on a sophisticated control algorithm commands a light emitting diode to shine light with a carefully chosen intensity on the cells of interest, which have been especially engineered to respond to this light. By continuously measuring the cellular response and correcting it with light, the computer is able to control precisely the dynamic behavior of these cells. We have advanced this type of control in two ways. In the first, we have instrumented bioreactors so we can control cell populations with light and computer feedback in an effort to make bioproduction much more efficient. In the second approach, we have engineered devices that allow us to shine light on single cells. The resulting platform, called Cyberloop, allows single cells to be controlled independently under the microscope. This has many applications in stem cell differentiation, tissue engineering, and basic biology. As we have developed these platforms, we have also developed the necessary theoretical foundations that allow us to understand how to best use them to achieve robust regulation with good performance.
The work carried out in this project has been widely disseminated through journal articles, conference and workshop presentations, and numerous lectures. We have also filed for two patents to protect the IP developed.
