Hacking the cell's machinery - Dr Jason Chin
Jason:: We've been interested in making a new version of the translational machinery that allows you to put together, assemble new proteins composed of new amino acids. And the way we thought about doing this is really to think about building. If we think about the translational machinery that normally makes proteins as being like a factory that essentially assembles a series of beads onto a string, with the beads being amino acids and you want to put them onto the string of the necklace in a defined sequence.
What we've been able to do is to really think about building in the cell a new factory that allows us to build entirely new types of necklaces with new types of beads. And so, at the molecular level, that involves creating a new version of the ribosome itself and new aminoacyl-tRNA synthetases, and tRNAs that can recognise new amino acids and put those new amino acids onto tRNAs.
Kat:: This seems like quite a challenging thing to do. Some of the molecules you're talking about are quite small, but ribosomes are enormous. How do you go about rebuilding a ribosome?
Jason:: To give you an idea of the scale, I mean, these are macromolecules in the cell, so these are molecules that are on the nanometre scale so it's true that a ribosome is large relative to an atom or relative to a small molecule, but it's still small relative to a person or relative to a cell. And so, what you have to do to engineer these components of the cell is to really use the ability to engineer the genes that the cell uses to make those molecules. So in the case of creating a new version of the ribosome, what we've been able to do is to create versions of the genes that the host cell machinery then uses to assemble ribosomes, but to put in new versions of these genes, and then to use the cell itself to assemble new versions of the ribosome that we would like the cell to be able to build.
Kat:: So what could be some of the applications of these new proteins that you could make?
Jason:: So there's a variety of things that we're actively pursuing in terms of making new proteins on these new versions of the translation machinery. One broad class of problem we're interested in is being able to put new designer amino acids into proteins that don't naturally exist in biology but have different properties that allow us to report actually on what the protein that contains these amino acids is actually doing in the cell.
So for example, we've been able to make amino acids that we can put into proteins in the cell that when you shine light on them, they then actually form an irreversible chemical bond between the protein and any protein that that proteins in the neighbourhood of and that allows you to find out at the level of basic biology who they actually socialise with and talk to in the cell.
And that's important for understanding at a very basic level what proteins are doing in the cells and what their functions might actually be and how they'd change shape, and who they talk to as a function of the state of the cell.