In a remarkable development for medicine, scientists have engineered new artificial protein called LOCKR that behaves like a computer circuit, opening the possibility of creating "smart" cells whose biological processes can be directly controlled.

LOCKR, an Entirely New Form of Artificial Protein

In medicine, when to apply a specific therapy and to what degree it must be applied is of critical importance. Too much or too little of a drug, or if the drug is given too late or too early, can render the therapy ineffective, even dangerous. Finding the precise amount and moment to administer a therapy is one of the greatest challenges in medicine, and until now there hasn't been an effective way to make these determinations.

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Now, bioengineers from the University of California at San Francisco (UCSF) and the University of Washington (UW) have come together to develop a remarkable new solution to this problem; an entirely artificial protein that can operate like a circuit that can turn cells into 'smart cells' that may be able to determine when they have been damaged or infected and respond by delivering the necessary dose exactly when it is needed.

Designed through computer simulations and synthesized in a laboratory, this new protein--which the bioengineers call the Latching Orthogonal Cage-Key pRotein, or LOCKR, is detailed in twopapers published this week in the journal Nature--is unlike any protein found in nature itself.

“While many tools in the biotech arsenal employ naturally occurring molecules that were repurposed for use in the lab, LOCKR has no counterpart in nature,” said Hana El-Samad, UCSF Kuo Family Professor of Biochemistry and Biophysics and co-senior author of the new studies.

“LOCKR is a biotechnology that was conceived of and built by humans from start to finish. This provides an unprecedented level of control over the way the protein interacts with other components of the cell, and will allow us to begin tackling unsolved – and previously unsolvable – problems in biology, with important implications for medicine and industry.”

One of the published papers described the structure of the new protein, which can be thought of as a trunk or locker--hence the name. Inside the locker, there is a molecular 'arm' that can be designed to manipulate the movement of chemical molecules through the cell, break down specific molecules or proteins, and even tell the cell that it needs to self-destruct.

The key, literally, to the whole process is that the arm is locked away inside the protein unless another chemical key is introduced that perfectly fits the lock on the LOCKR. Without the chemical key, the LOCKR remains inactive, exactly the way a computer circuit is inactive in the absence of an electric signal. The circuit analogy isn't a fluke either, it was built into the very design of the protein.

“In the same way that integrated circuits enabled the explosion of the computer chip industry, these versatile and dynamic biological switches could soon unlock precise control over the behavior of living cells and, ultimately, our health,” said El-Samad.

Making Programmable Smart Cells

Circuits build off each other to develop highly complex behaviors that enable modern electronics and computing, so the potential for developing something similar for biological processes cannot be understated. The second paper published by the bioengineers demonstrated the potential for this kind of circuit building behavior in the cell.

Using a modified version of LOCKR called degronLOCKR, the scientists programmed the tool to degrade a specific protein. The circuit-building capacity of the protein allowed the team to create a regulating mechanism inside the cell that would dynamically control cellular activity in response to internal and external conditions.

Whenever the degronLOCKR tool detected the disruption of certain cellular activities, it was able to break down the protein that was triggering the disruption until the disruption stopped, after which is would deactivate. If the disruption occurred again, the degronLOCKR tool would reactivate and continue to break down the protein until cell function returned to normal.

“LOCKR, and more specifically, degronLOCKR, opens a whole new realm of possibility for programming cells to treat a wide range of debilitating conditions for which safe and effective treatments are not yet available,” said Andrew Ng, PhD, co-first author of the two papers who completed his doctoral studies in El-Samad's lab. “With these technologies, we are constrained only by our imagination.”