Applications

In terms of production applications of the miRNA technology, the ideal outcome would be some sort of switch or control. "If a particular miRNA is expressed in a specific pattern, we want to be able to increase or decrease it, or even switch it off or on," Tizard says. "Basically we are looking for common or key regulatory pathways to target in the production environment."

In a broader application, Tizard's team also collaborates with Professor Andrew Sinclair and Dr Craig Smith at the Murdoch Childrens Research Institute in Melbourne to study sex determination. Together they are trying to establish how miRNAs might be involved in the process.

"This is a really major cellular reprogramming event that changes an embryo's fate with major anatomical and physiological differences in eventual phenotype," Tizard says. "From a production viewpoint, it becomes fairly obvious that female chickens are necessary for egg production, and males are better for meat production.

"So, a switch to control germ cell fate would be potentially beneficial. Obviously, Andrew's group is interested in how gender is determined during development and what goes wrong with it, especially in human, then how miRNAs might be involved. Our work is generating a suite of tools to address those questions."

Another interesting aspect that has emerged from the miRNA project, according to Tizard, is how it is feeding back into the parent project on RNAi.

"It has become clear to us that while you can bring about RNA interference by dumping dsRNA on cells and letting them deal with it, it is perhaps more efficient and biologically relevant to express the sequence that you want in the cell and use the cell's machinery to process those transcripts - that's the concept of hairpin RNA expression, or ddRNAi - and that's the method that Tim's group is using.

"That process essentially mimics what miRNAs are doing. Therefore understanding how miRNAs are made, their biogenesis, how they are pushed out into the cytoplasm, which ones are processed most efficiently, etc you begin to get a handle on the kinds of structures and sequences involved in promoting that, and you then open up the possibility of tailoring better constructs for RNA interference, be it for antivirals or trait modification or whatever."

In the short term, Tizard is looking to build on the current findings in their miRNA work, and to identify a clear application for CSIRO's external stakeholders. They have some candidate miRNAs in the pipeline with the potential to alter lymphocyte differentiation, and future results in the sex determination work will clearly have the potential attract external research support.

"We are also interested in the viral infection area and how the changes in gene expression relate to levels of miRNA expression during infection with avian influenza, in particular."

Coming from a basic research background before joining CSIRO a decade ago, Tizard is occasionally torn between the pull of pure discovery and the focus on outcomes for external stakeholders.

However, he admits to being in a good situation. "We are lucky in that the research management here at CSIRO has always promoted the idea that if you keep your eye on doing the fundamental science and addressing an important problem, it will reveal an important application. It is all about the question and how you go about addressing it."

(Tizard's group includes two postdoctoral fellows, Pauline Cottee and Evgeny Glazov and a PhD student, Stephanie Bannister. He works closely with other senior scientists, Rob Moore, Brian Dalrymple and Tim Doran at Livestock Industries together with Chris Helliwell and Frank Gubler at Plant Industry.)