Changing the Genetic Code to Improve Biomedicine
Proteins are the workhorses of life, and are comprised of strings of amino acids, which in turn are specified by the triplet codons of the genetic code. Currently, only 20 amino acids make up the genetic code in most organisms. In order to expand the functionalities of proteins, genetic engineers have been attempting to expand the genetic code with new amino acids that offer novel chemistries.
There are already some known departures from the genetic code, including the amino acid selenocysteine, in which the sulfur atom of cysteine is replaced by the element immediately below it in the Periodic Table, selenium. Selenocysteine augments the chemistry of proteins in a number of ways, including changing their ability to catalyze reactions, shuttle electrons, and form very stable bonds. For example, while the disulfide bridges (shown below) in antibodies can be readily broken during storage or in the body, similar bonds based on selenium (diselenide bonds) are much more stable.
A researcher at the University of Texas at Austin, Dr. Ross Thyer, is working to enhance the stability of therapeutic proteins, giving them longer shelf lives and better pharmacological properties. Dr. Thyer and his team started with an engineered bacteria from the labs of George Church (Harvard) and Farren Isaacs (Yale) that lacks a single codon (normally used to ‘stop’ protein biosynthesis), and have introduced machinery that incorporates selenocysteine at this now ‘blank’ codon. By replacing the cysteine codons in a gene encoding a therapeutic antibody, an antibody can be produced which contains diselenide rather than disulfide bonds. Dr. Thyer and other researchers have started a company, GRO Biosciences, to further develop this innovation.
As an analogy, Dr. Thyer suggested that having a new amino acid is akin to having a new Lego piece; when you’re building a structure and you have 20 lego pieces to work with, you can only do so much, but adding that 21st piece opens up many new possibilities. Selenocysteine can now be added in different places to make many protein structures beyond stronger, more stable antibodies. Whether bacteria with access to a larger Lego set can build their own new structures is a question for the future.
Shaharyar Lakhani - 6/13/2019