Hunting for ways to stem disease: Huntington's disease

AFTER working with Huntington's disease researchers in California biochemist Daniel Hatters knew he'd found a way to put his skills to use.

AFTER working with Huntington's disease researchers in California, Australian biochemist Daniel Hatters knew he'd finally found a way to put his skills to use in the real world, improving peoples' lives.

"My research has opened my eyes to the challenges faced by the Huntington's affected community," he says. "And working with affected families has been a moving experience."

Huntington's disease, a deadly genetic condition, causes loss of muscle co-ordination and cognitive decline and reduces life expectancy to 20 years from the onset of symptoms.

But the work of researchers such as Hatters, Sydney IVF's Tomas Stojanov and Britain's Jenny Morton raises hope it may be possible to eradicate the disease.

Huntington's occurs when a gene called huntingtin mutates, causing proteins also called huntingtin to become sticky and cluster together.

Until recently scientists believed the brain damage associated with Huntington's was caused by these clusters growing, but now Hatters and his colleagues at the University of Melbourne have demonstrated they don't grow at all.

Instead, they're already present in three different sizes, providing a steady stress rather than a sudden annihilation of brain cells. The cells only die when the stress reaches a certain level.

"Our research shows huntingtin clusters to be more ordered and organised than was previously thought," Hatters explains. "The fact the clusters were quite uniform and ordered was surprising and not what we expected."

Hatters and his team used a process called analytical ultracentrifugation to measure the size of the clusters and the way they change through time. The technique is key to assessing the effectiveness of treatments aimed at reducing or removing clusters.

According to Hatters, this will be central to the development of drugs targeting disease at the molecular level. It could also lead to treatments for Parkinson's and other neurological diseases which, like Huntington's, are thought to result from clusters of abnormally sticky proteins.

Hatters intends to apply the findings and technique to a fruit fly model of Huntington's.

He explains: "Fruit flies are very useful models to study disease processes and we can use them to mimic the onset and progression of Huntington's by inserting the mutated huntingtin gene into them."

Still, experiments on flies can't fully replicate the onset of the disease in people. Human cognitive functions are clearly very different from those of insects. That's why it's important to work with more complex animals. Case in point: sheep.

Morton is a neuroscientist with Britain's Cambridge University. She argues sheep have enormous untapped potential as an animal model for Huntington's as they develop the disease if the mutated human huntingtin gene is inserted into them.

"Because sheep live a long time and develop symptoms of Huntington's slowly, they can be used to test preventive and gene therapies," Morton says.

But to to determine just how valuable they could be for Huntington's research, Morton has teamed up with the South Australian Research and Development Institute to test the motor and social behaviour of sheep. To do so they're using a video analysis system and global positioning system tracking devices to monitor how each animal in a flock of a hundred is behaving at any time in a 24-hour period.

If all goes well, sheep could be used in early stage trials of gene therapies, which carry a big risk for people. That's because the treatment can't be stopped if there are problems.

In the meantime, biotechnologist Stojanov and his Sydney IVF team are working to prevent the disease-causing huntingtin gene from being passed on in the first place. Their approach is based on the knowledge that children have a 50-50 chance of inheriting it from an affected parent. The basic idea is to test children in the womb and IVF embryos before they are implanted to determine if they carry the gene.

As an infertility treatment centre, Sydney IVF has a preimplantation genetic diagnosis program to help couples with a family history of Huntington's to have healthy children.

"Our PGD program is probably one of the world's biggest by scale and scope and Huntington's is one of the [single gene] disorders we are testing for," says Stojanov, Sydney IVF's director of research.

In the PGF process, embryos are cultured for five days until they develop into blastocysts. Embryos that don't carry the mutation from the parent are used for embryo transfers, while affected ones are either discarded or, with the consent of the patient, used for stem cell research.

"We are in the process of developing a stem cell-based platform for drug discovery and drug screening," Stojanov says.

"But the problem with Huntington's is that it's not in the blockbuster disease category for pharmaceutical companies, so they're sometimes hesitant to research and develop drugs."

That's why Stojanov argues it would be a good idea if Australia had a system like that of the US. There companies get a tax rebate from the government if they put research money into diseases that don't normally attract pharmaceutical company interest.

"It's very difficult for a private organisation to go into the field in Australia," he says. "As a result, not many biotechs are looking at those issues."

According to Stojanov, Sydney IVF is working with a medium-size US-based pharmaceutical firm -- whose name he can't disclose -- to advance their stem cell-based model of drug discovery. Meanwhile, Hatters says Australian researchers and biotechs can, and will, play an important role in tackling diseases such as Huntington's, since at the moment all the drugs on the market are directed towards alleviating the secondary effects of Huntington's. "They don't address the underlying cause of the disease," he says.

Why? Because the ways in which the mutated huntingtin gene leads to the disease remain poorly understood. Teasing out the fundamental process is the crucial step towards finding a cure.

"There is intense international effort to redress this shortfall in our understanding," Hatters says, "and our work with the clusters is one of many prongs in the fork towards this goal."