Genetic tool a hot tip to schizophrenia
The study of tiny snippets of genetic material called micro RNAs is one of the hottest areas of medical research, writes Leigh Dayton
MURRAY Cairns never planned to be a schizophrenia researcher. But when the little bio-tech firm for which he worked three years ago collapsed, the molecular biologist was open to all options.
‘‘ I was looking around and saw an advertisement for the Schizophrenia Research Institute,’’ he recalls from his office at the University of Newcastle in NSW. ‘‘ They thought I had useful experience as a molecular biologist, but they didn’t have any idea that I’d come up with this branch of research,’’ he laughs.
It’s hardly surprising that the SRI — a ‘‘ virtual’’ collaboration of Australian biomedical researchers with headquarters at the Garvan Institute in Sydney — had no inkling of what Cairns would get up to down in the lab. After all, nobody in Australia was doing anything like it. What’s more, the genetic tools of Cairns’ trade, so-called micro ribonucleic acids (miRNAs), were only discovered in people in 2000.
Now, Cairns has just published remarkable findings about the inner workings of schizophrenia. And miRNAs, tiny bits of genetic material, are hotter than hot in laboratories around the world. Like Cairns, researchers are excited about the power of the genetic snippets to help them understand the mechanisms of diseases, from schizophrenia to cancer, and to assist in the development of a brand new class of diagnostic tools and therapies for them.
Realistically, the potential of the emerging field of miRNA genetics is huge, claims molecular biologist and geneticist Greg Arndt: ‘‘ It’s enormous. There’s an absolutely enormous potential.’’
Arndt works for the Sydney research arm of the pharmaceutical giant Johnson and Johnson, and ‘‘ Big Pharma’’ is not known for throwing money around frivolously. The fact that Arndt and his J&J colleagues overseas are exploring the role of miRNAs in colorectal cancer is telling.
‘‘ Colorectal cancer is one of the most prominent forms of cancer in the world,’’ Arndt says. ‘‘ One thing that would be very useful for colorectal cancer would be new techniques for detecting the stages of the development of the disease. So we undertook to look at miRNAs at various stages in patient tissue. We saw there was altered activity in the miRNAs,’’ he explains.
Cairns and Arndt’s work reflects the realisation that miRNAs are very busy entities. That’s despite the fact that they’re small — only 20-22 bits, or ‘‘ bases’, long — and make nothing. Larger RNA molecules produce ‘‘ can-do’’ molecules such as proteins or enzymes. What miRNAs do is regulate the activity, or ‘‘ expression’’, of thousands of genes throughout the body.
Arndt’s findings about colorectal cancer are a perfect example. There, the miRNAs promote or suppress the development and spread of cancer cells.
Cairns notes another intriguing fact about miRNAs: ‘‘ They’re promiscuous.’’ One miRNA can affect the expression of many different genes, and can mix-and-match with other miRNAs to regulate more genes which together are involved in a host of biochemical pathways in the body. Some of those pathways are known to play important roles in human development, stress responses and viral infections.
That’s why, like Arndt, molecular biologist Greg Goodall, with the Institute of Medical and Veterinary Science and the University of Adelaide sees ‘‘ tremendous scope’’ for using miRNAs to unravel and control pathways that drive diseases. ‘‘ This is such a new unexplored area that offers so many opportunities for experiencing the joy of discovery,’’ says Goodall.
Currently, he’s focusing on breast cancer. Goodall remains mum, but the word from observers such as Geoff Lindeman, a breast cancer expert at the Walter and Eliza Hall Institute in Melbourne, is that Goodall’s group has publications in the pipeline that will add to an important discovery revealed last month in the journal Nature .
As reported in The Australian (14/1), US researchers identified three miRNAs that halt the spread of breast cancer to the lungs and bones of women with the most dangerous forms of the disease. The team leader Joan Massague, head of the cancer biology and genetics program at the Memorial SloanKettering Cancer Center in New York, said: ‘‘ The tiny RNAs prevent the spread of cancer by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate (to other parts of the body)’’.
According to Massague, that makes miRNAs ‘‘ tiny targets’’ for drug development: control the miRNAs and control the disease. Arndt agrees, pointing to two approaches. The first would be to give a patient a drug containing miRNAS to boost levels of critical miRNAS. That follows the findings from Massague’s team. When the three miRNAs they identified were low or absent, the cancer spread. But when they put them into cancer cells implanted in mice, the deadly cells could not spread.
Arndt says the second strategy is to directly target the miRNAs in a person’s body. Like more conventional therapies, drugs would boost or suppress miRNAs which themselves boost or suppress the activity of genes involved in a disease or condition.
But as Arndt’s work with colorectal cancer suggests, miRNAs also hold huge promise as diagnostic tools, helping doctors to detect diseases early on and to monitor the effectiveness of treatment. Astonishingly, while the entire field of human miRNA only got rolling in 2000, the Israeli firm Rosettta Genomics predicts it will have miRNA-based diagnostic and predictive tests for brain cancers on the market by the end of the year. Treatments for cancers and viruses are bound to follow in the next few years.
All this from a left-field discovery of an RNA ‘‘ gene’’ in a nematode worm, first reported in the journal Cell in 1993. At the time conventional wisdom was that genes were found in deoxyribonucleic acid, the famous double-helix of DNA. Genes told single-stranded RNA what to do and the RNA got onto it, synthesising proteins. But to universal surprise that’s what the weird RNA worm ‘‘ gene’’ appeared to do.
Further investigation uncovered the truth. The ‘‘ gene’’ was a miRNA, says Goodall: ‘‘ It was an unsuspected type of genetic regulator that is really just a small piece of RNA.’’ In other words, a totally new system of controlling what goes on in the human body had been discovered in a worm. The race is on to find out what regulates the newfound regulators.
That’s why Murray Cairns suspected that miRNAs had a role in the onset of the disordered thinking and hallucinations that are the hallmark of schizophrenia. ‘‘ I thought it could have something to do with how the genes are regulated, rather than a series of genetic mutations,’’ he recalls.
To find out Cairns looked at a ‘‘ thinking’’ brain region, the temporal cortex. He discovered that two-thirds of genes were more active, and one-third less active, in people who died from schizophrenia compared to people without the disorder. Significantly, the Cairns and SRI colleagues have just showed the differences correspond to levels of miRNAs in the brain, and have strong evidence that the miRNAs ‘‘ disregulate’’ gene activity in the brains of people with schizophrenia.
Given the complexity of schizophrenia, it’s early days yet. But Cairns has big plans for the tiny regulators.
Groundbreaker: Murray Cairns is fascinated by the role of genetic snippets in disease — his specialty is schizophrenia