Paradigm shift in proteomics

It was genomics vs proteomics, toe-to-toe, a contest for a rare prize: the mystery gene responsible for Hutchison-Gilford progeria syndrome. Francis Collins' team at the National Human Genome Research Institute, in the US, took the honours for identifying the Lamin A gene as the locus of the rare, sporadic mutations that cause the accelerated-aging disorder.

But a research collaboration between the University of Sydney and Sydney-based proteomics technology developer and research company Proteome Systems has claimed the spoils from the discovery.

At the time the NHGRI team published its discovery in Science in March, 2003, the Sydney team had not only identified Lamin A as the prime culprit in progeria, it had identified more than a dozen other genes downstream that go awry when Lamin A is mutant.

When not jammed in fast-forward mode, the genes that rely on Lamin A's phosphorylation services are likely to be key players in the normal process of aging. Sydney University and Proteome Systems are sitting on a portfolio of protein targets for anti-aging drugs.

Proteome Systems' CEO Dr Keith Williams says humans and chimps share 35,000-odd genes, but most of the differences between them are probably minor. The real evolutionary tale will emerge from a comparison of their million-molecule proteomes.

Australia developed the concept of proteomics, and Williams was a technology pioneer.

He says Australian research institutions and biotech companies have embraced proteomics, while Human Genome Project players like the UK, Japan and the US have invested heavily in genomics infrastructure, and remain intellectually bound to expressing genes in model organisms. Proteins at work in their native cells are where the real action -- and insights into processes such as intron shuffling, phosphorylation and glycosylation -- are to be found.

Having developed its own instrumentation, and secured licensing deals with companies like Japan's Shimadzu, Proteome Systems has assembled an integrated, highly automated proteomics platform, and tied it together with an informatics package that comprehensively stores and integrates images and data. No more lab notebooks or lost CD-ROMs. It is designed to provide companies and research institutions with a plug-and-play proteomics system, free of the teething problems of mix-and-match systems with non-matching bioinformatics packages, and capable of being used by tyros and experts alike.

Meanwhile, many of Australia's research agencies and biotech companies -- even those with in-house proteomics capacity -- are contracting out their proteomics to the Australian Proteomics Analysis Facility (APAF) in Sydney.

Established under the Australian Government's Major National Research Facilities Program in 1995, APAF was the world's first dedicated proteomics centre.

It offers state-of-the-art facilities, expert advisers, and a complete analysis service to its clients. For an access fee, clients may also locate their own research staff within one of APAF's four service centres, at the University of Sydney, the University of NSW, Macquarie University and TGR Biosciences.

APAF's Business Development Manager, Lindsay Woods, says APAF works with a range with private and publicly funded research agencies, including Australia's Cooperative Research Centres (CRCs), small pharma and biotech companies, and rural industry bodies that fund research. It has a major program discovering biomarkers for what Woods calls "directed evolution" -- the application of sophisticated, non-transgenic breeding techniques to grain and horticultural crops, and livestock species, to improve traits such as protein quality, productivity and disease resistance.

"The example is the caterpillar and the butterfly -- same genome, totally different proteomes," he says. "It's the same with the plant and the seed."

One of APAF's grain projects is exploring the wheat proteins that give bread dough its extraordinary extensibility, and identifying biomarkers associated with resistance to fungus diseases. APAF is also working with a South Korean company to explore the rice proteome.

Woods says personalised medicine is APAF's other major research focus -- it is identifying biomarkers associated with metabolic disorders and disease states such as cancer, as potential targets for diagnostics and therapeutic drugs. One project, for example, is looking for protein markers associated with heart attack and stroke.

"With proteomics we can compare normal with diseased cells, to work out which proteins are upregulated or downregulated," he says.

While APAF's work involves proteins that are typically present at around 1000 to 2000 copies in cells, clients are increasingly interested in functional proteomics: protein-protein and protein-substrate interactions, or the bioactivity of low-abundance proteins that switch genes on and off. Cells may contain as few as 10 to 100 copies of these proteins.

Woods says APAF is seeking to use its influence, and industry-leading expertise, to help coordinate the activities of proteomics facilities across Australia. "We need to pool our expertise, so there's a little less competition, less duplication, and more working together," he says.