This morning, I noted the huge amount of combinations that could possibly occur for a 100 nucleotide RNA sequence. Peter Seeberger of ETH Hönggerberg, where Synthetic Biology 3.0 is being held, kicked the complexity up a notch by talking about carbohydrates. The trouble with carbohydrates is synthesis. Proteins and nucleotides are generally quite easy to synthesize through either chemical or biologic means. Carbohydrates present a formidable challenge however.
Here comes the math again. So, for a 6 nucleotide sequence there are 4ˆ6 or 4096 possible combinations. For a protein sequence there are 64 million. A carbohydrate chain six units long has 192,780,943,360 potential combinations according to Seeberger, give or take. In order to synthesize carbohydrates without simply going crazy, his group had to define a standard set of building blocks that could essentially mimic most of the necessary carbohydrate componentry. They landed on five including N-glycans, O-glycans, and glycosphingolipids. That makes the space for creativity significantly smaller, although his team has been able to engineer additional changes, bonds, linkages to proteins, and more to mirror nature in sugar production.
One of the projects he has been working on is a carbohydrate based malaria vaccine. The method by which a malaria parasite enters an erythrocyte appears to be controlled by Glycosylphosphatidylinositols (GPIs). By synthesizing a similar protein-carbohydrate molecule and setting up ways to produce high volumes of it, they might be in clinical trials in humans by 2008. Moreover, the work on GPIs indicate to some extent why Malaria might be so deadly. Free malaria GPIs bound to uninfected cells may be triggering immune response and inflammation. People were buzzing about it. I’ll be interested in seeing where this work goes.