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The FLAG Epitope Tag

Molecular biologists and genetic engineers throughout the world rely on a technique originated by Tom: the epitope tagging procedure. When Tom and his colleagues at Immunex Corporation set out in 1983 to create what would become one of the most widely applied biotechnology techniques, no one had ever heard of the concept. Today, many labs use Tom's method in virtually every field of science and medicine, without knowing who originated it. The method has even been used to study the coronavirus COVID-19, searching for a treatment.

Epitope tags are short segments of amino acid sequence attached to proteins via genetic engineering. The code for the flag is written: DYKDDDDK, representing the eight amino acids Tom chose for the synthetic marker sequence. This short tag serves as a molecular handle, allowing the protein to which it is attached to be grabbed by another type of protein, the antibody molecule. Antibodies have been used for decades to pull molecules out of solutions and purify them. Using monoclonal antibodies that grab the FLAG sequence of amino acids, Tom developed the world's first and most successful epitope tagging technique. Article pdf or a short Abstract pdf

The FLAG epitope tag was also the first to incorporate an internal subsegment that can be used to detach the molecular handle from the protein of interest once the tag has been used for detection and purification purposes. The enzyme, enterokinase, neatly clips the FLAG segment away from the protein, yielding a pure, non-tagged product. Tom and coworkers studied the details of this process as well as a unique metal-binding antibody that can form complexes with the FLAG epitope. Article pdf

Many similar systems have been developed subsequently, but the FLAG remains the first, best and most efficient of the molecular handles. The FLAG and several of its "knock-off" immitators (for instance, the c-myc and HA epitopes), have been commercialized along with the antibodies used to grab the tagged proteins, but the FLAG remains among the most widely used. Given that every procedure using the FLAG occurs on the sub-nanometer size scale, the Flag molecular handle also represents the world's first commercially successful nanotechnology device.

Tom's latest concept with FLAG technology is a way to revolutionize protein crystallography using FLAG antibody complexes to determine the 3-D structures of pathogen proteins and therapeutic drug target molecules. Here's a scientific poster he recently presented. However, this concept seems too futuristic for corporations or federal grant agencies. One day, Tom will find a way to scratch together the million dollars or so it will take to re-enter the lab and make this breakthrough as well. Interested parties can learn more by downloading this pdf file of Tom's published article on the subject. Article pdf