Cells that refuse to die, paradoxically, pose a threat to the lives of their owners. Just one immortalised cell can proliferate and cause a lethal cancer, so it is unsurprising that natural selection has provided multicellular organisms with suicide mechanisms that eliminate most pre-cancerous cells before they can pose a threat.
Cellular suicide, or apoptosis, has become a hot research field in immunology and molecular genetics. Dr Trevor Lithgow, of the Department of Biochemistry says some of the genes involved in apoptosis have been isolated, and while the process of apoptosis is understood in a broad way, little is known about precisely how the genes involved work.
Apoptosis is clearly a complex process involving many genes, and the only way to understand it is to pull it apart, gene by gene. Dr Lithgow's group has been working with Dr Andreas Strasser's group at the Walter and Eliza Hall Medical Research Institute to see what happens when human genes involved in the cell-suicide pathway are transplanted into a simple, single-celled organism - baker's yeast (Saccharomyces cerevisiae)
They are investigating a human gene called BCL-2, which actually prevents cell suicide - "As long as ahuman cell makes enough BCL-2 protein, it won't die," Dr Lithgow said. "It plays an important role in some leukaemias - when BCL-2 turns on at a high level in white blood cells, the cell becomes immortal and eventually multiplies out of control. In AIDS, apoptosis leads to immune deficiency - researchers think the virus probably triggers the mass suicide of the body's defensive white cells."
"We know that BCL-2 CAN help white cells to evade programmed cell death, but we're in the dark about what it does at a molecular level," Dr Lithgow said. "So we decided to take the BCL-2 gene and see what it does in a yeast cell, then work backwards from our findings to determine what it does in human cells."
They obtained an unexpected result: BCL-2 caused the transgenic yeast cells to stop dividing - virtually the opposite of its inferred role in human cells.
"Yeast cells are genetically incapable of undergo programmed cell death. Every gene in yeast has now been identified, and there is no yeast gene equivalent. That means BCL-2 must have arisen in multicellular organisms."
"We suspect yeast cells can't copy with BCL-2 - they can't control it. When we put an active BCL-2 into yeast cells in the on state, they can't switch the gene off."
If it stops yeast cells dividing, what does this imply for its role in human white cells? One possibility, says Dr Lithgow, is that its normal role in human cells is to prevent them dividing before they are good and ready - if they were to divide prematurely, it could induce the apoptosis mechanism and the cells would then die."Dr Strasser's group has gone back to the mouse and human cell lines to test this idea."
Last year Dr Lithgow's group began developing expertise in gene-transformation in yeast cells, with the intention of providing a simple vehicle in which other research groups in Melbourne and elsewhere in Australia could "test-drive" newly cloned genes from higher organisms - particularly humans and the mouse, but also from plants - to gain insights into their normal roles in cells.
Apoptosis genes are only the first of many genes that will go into the La Trobe group's yeast cells in coming years - Dr Lithgow's group is already working with another La Trobe team headed by plant molecular biologist Dr Marilyn Anderson, which is investigating a suite of genes that protect plants against insect attack.
"These genes make proteins, called [G4] protease inhibitors, that are expressed in flowers and other floral organs at times when the plant can't afford to have these tissues damaged by insects," Dr Lithgow said. "Dr Anderson's group has found that when the insect eats these proteins, they inhibit the proteases that the insect needs to digest its food. It feels bloated and stops feeding."
"We want to put these genes into yeast cells and get some idea of where the proteins are synthesised, and how they end up on the surface of the plant's reproductive tissues."
Dr Lithgow says baker's yeast cells are an ideal model for human and plant cells because they have the same organelles, but they have a much more compact genome, consisting of just 6500 genes, arrayed on 16 chromosomes - and the yeast genome project has given researchers a catalogue of every individual gene, its DNA sequence, and its location on a specific chromosome.
"We have the luxury of being able to isolate a small amount of any protein, going to a computer and using the Internet to search the yeast data base to find the complete sequence of the equivalent gene, and in relatively little time, determining its function within the cell."