Proteins are biological molecules that play a role in every aspect of life’s processes. Proteins are masters of versatility achieving essentially unlimited variability in size and shape. The properties of any one protein molecule are determined by the specific DNA sequence (gene) which serves as a ‘blue-print’ for its synthesis. DNA sequences are easily manipulated in the laboratory, providing a way to develop proteins, never before been seen in Nature. Some of these are expected to be effective as pharmaceuticals.
The project group “Directed Evolution” has developed new methods utilizing synthetic genes that can generate billions of small variant proteins. Efficient screening and selection for useful proteins from the vast arrays of variants generated by these so-called “gene libraries” is done by: (a) linking the selected protein to the gene encoding it; (b) binding the favoured DNA-protein product to a particular immobilized target; (c) washing non-binding material away; (d) amplifying the gene of the enriched product material; and (e) sequencing it. The gene sequence automatically reveals the sequence of the enriched protein variant(s) which have bound to the chosen target molecule.
The group is developing novel libraries in which the critical protein-gene connection is ensured by; (i) presenting the protein on the surface of a virus (phage), which is grown in bacteria, or (ii) producing it in the test-tube, where the protein product is coupled enzymatically to a chemically-modified DNA.
These methods are being applied to septic- and toxic-shock in response to bacterial infections or food poisoning. In these diseases specialized blood-cells, called T-helper cells, are over-stimulated. This life-threatening syndrome arises when bacterial super-antigen toxins (SAT) bind to a receptor found on the surface of the T-helper cells. Professor Ray Kaempfer’s group, at the Hebrew University of Jerusalem, has shown that a small protein, competing for the binding of SAT to this receptor, reduces mortality. The aim is to find even better competitors amongst the vast array of protein variants afforded by our dramatically improved gene libraries.
