Lorne special: Sleuthing oncogenes

Tom Gonda

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

The origin and nature of oncogenes was an enduring mystery of 20th century biology. It was known that some viruses contained oncogenes, and these viruses could cause mutations in cellular proto-oncogenes, leading to the development of cancerous growths.

However, it was a great surprise when Harold Varmus and Michael Bishop showed in 1975 that viral oncogenes were not actually true virus genes. Instead, they were cellular genes that the virus had ‘acquired’ during replication. These proto-oncogenes are pervasive in the animal kingdom and play a crucial role in normal cell growth and division as well as cancer.

Varmus and Bishop were awarded the Nobel Prize in Physiology or Medicine in 1989 for their discovery, which has since transformed cancer research, and set off a search for other oncogenes that continues apace today.

At the Diamantina Institute for Cancer, Immunology and Metabolic Medicine in Brisbane, Professor Tom Gonda is leading an ambitious project to screen the 23,000-odd protein-coding genes in the human genome for these Jekyll-and-Hyde genes.

Gonda, who heads the institute’s Molecular Oncogenesis Laboratory, is a veteran of the hunt for oncogenes. His key collaborator in this endeavour is Associate Professor Brian Gabrielli, also of the Diamantina Institute, who heads the Cell Cycle laboratory.

Proto-oncogenes are a diverse class of genes that normally keep a tight rein on growth and division in healthy cells. But when proto-oncogenes transform into their malignant alter-egos through mutation or dysregulation, the unshackled cells can lapse into uncontrolled growth and division.

Gonda’s team has been running pilot experiments with its new, custom-designed, high-throughput facility, which is designed to screen genes for their potential to induce abnormal cell growth when overexpressed.

Gonda is an invited speaker at this year’s Lorne Genome Conference, where he will describe the screening methodology, how it was developed, how the data are analysed, and will also present some results from the pilot screening program.

Gene hunting

When the facility is fully operational, the Diamantina Institute will offer a service to gene hunters throughout Australasia on a collaborative, cost-recovery basis. “What we’ve developed is a high-throughput, functional genomics platform that involves over-expressing candidate genes in human or other mammalian cell lines,” says Gonda.

“Other research groups are using short interfering RNAs (siRNAs) in lentiviruses to look for new oncogenes. We’re taking a very different approach. We are making a library containing every available human gene, by cloning all the corresponding cDNAs into lentiviruses. We have about 2000 genes cloned into viruses already, and we’ve got about 15,000 genes to do. It’s a long, slow process,” he says.

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