It was the discovery of insulin's role in diabetes that paved the way for the development of a treatment. Hoping to repeat that success, scientists worldwide have put enormous effort into deciphering the roles of the myriad proteins our bodies produce in the course of daily living. But despite the scientists' best efforts, the function of large numbers of them remain unknown.
A new biological tool developed at the Weizmann Institute may help to change that situation. Prof. Moti Liscovitch and graduate student Oran Erster of the Biological Regulation Department, together with Dr. Miri Eisenstein of Chemical Research Support, have developed a unique protein "switch" that allows scientists to easily observe how the activity of a specific protein affects the cell's functions. This switch can control virtually any protein, raising its activity or reducing it, several-fold.
To create the switch, the scientists used genetic engineering techniques to insert a short chain of amino acids into the sequence making up the protein. This chain is capable of binding strongly and selectively to a particular chemical drug, which then affects the activity level of the engineered protein – increasing or reducing it. When the drug is no longer applied to or removed from the system, the protein's original activity level is restored.
As reported in Nature Methods, the first stage of the method consists of preparing a set of genetically engineered proteins (called a "library" in scientific language) with the amino acid segment inserted in different places. In the second stage, the engineered proteins are screened to identify those that respond to the drug in a desired manner. The researchers have discovered that in some of the engineered proteins the drug increased activity, while in others that activity was reduced. Liscovitch: "We were surprised by the effectiveness of the method – it turns out that only a small set of engineered proteins is needed to find the ones that respond to the drug."
The method developed by the Weizmann Institute scientists is ready for immediate use, both in basic biomedical research and in the pharmaceutical industry's search for new drugs. The method has an important advantage compared with other techniques: It allows total and precise control over the activity of an engineered protein. By giving exact and well-timed doses of the same simple drug, that activity can be raised, lowered or returned to its natural state, at any time and in any place in the body.
Eventually, this method might have many other uses: In gene therapy, it may be possible to replace damaged proteins that cause severe diseases with genetically engineered proteins and to control these proteins' activity levels in a precise manner. In agricultural genetic engineering, the method might make it possible to create genetically engineered plants in which fruit ripening could be perfectly timed. For the numerous proteins used in industrial processes as biological sensors and in other applications, the Weizmann Institute method opens new possibilities for controlling these applications.
Prof. Moti Liscovitch's research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; La Fondation Raphael et Regina Levy; and the estate of Simon Pupko, Mexico. Prof. Liscovitch is the incumbent of the Harold L. Korda Chair of Biology.