A team led by Assoc Prof John Reynolds has spent seven years searching for a ground-breaking treatment for the debilitating Parkinson's. The signs are promising, but there is still a way to go. Bruce Munro asks how you go about curing the incurable.
''If this was easy, it would have already been done,'' Assoc Prof John Reynolds says.
The 50-year-old neuroscientist is sitting in a modest office on the third floor of a nondescript building between Dunedin's main street and the city hospital. A white-board spanning one wall is drowning in red and blue scrawls, boxes and arrows; the indecipherable outpouring of a long-past planning meeting.
Prof Reynolds is half an hour into an animated account of his passionate, obsessive hunt for a new treatment for Parkinson's - a degenerative and incurable central nervous system disorder that afflicts more than 10,000 people in New Zealand and six million worldwide.
He leans back in his chair and checks his watch. This conversation has been allotted the only gap in the week's schedule, wedged between a departmental gathering and a lunchtime research meeting.
He rocks forward again. Elbows land on the table, friendly face looms, eyes flashing, intense.
''This is the most difficult work, by far, I have ever been involved in,'' he says.
''It is really very painstaking. You make very small increments.
''It's been slow and hard-won, but it's building up.
''It's a really exciting time.''
Parkinson's results from a dearth of dopamine in the brain, Prof Reynolds explains. Dopamine is a vital chemical that drives our ability to move. It also interacts with the part of the brain involved in personality, planning and motivation.
The cells that produce dopamine are probably progressively dying off in all of us, he says. Typically, however, people diagnosed with Parkinson's have already lost 70% or more of those cells. The cause is not clear, but some sort of interplay between genetic and environmental factors is suspected. What is better understood, despite it still being ''a very mysterious system'', is the role dopamine plays in the brain.
During the past decade, University of Otago researchers including Prof Reynolds and his collaborators have been pivotal in uncovering what activates dopamine cells and how the dopamine then interacts with other cells.
Dopamine is released when something good happens; whether it be seeing someone you like, successfully tying shoelaces, being congratulated for a job well done, or walking across the room in order to go outside.
''It's a way of reinforcing the things that are useful to you,'' he says.
But depleted dopamine leads to those stored movements being depressed or even extinguished.
''When you've lost dopamine, it is like having no fuel in the tank.
''People lose the ability to cue certain movements and to make sure they are doing only the movements required to achieve a certain goal.''
To treat those symptoms, people with Parkinson's are normally given synthetic L-dopa, the amino acid which is used to make dopamine. It floods the brain, ''supercharging'' the remaining cells, and eliminating most of the physical symptoms of Parkinson's.
But there are two significant complications, Prof Reynolds says. The cells continue to die off, in time rendering the L-dopa ineffective. And the medication has side effects. After being taken for a few years it can trigger its own involuntary body movements, called dyskinesia.
''We would like to work on something that will give them recovery of function without dyskinesia ... That's really what our vision is,'' Prof Reynolds says.
''This is a big, broad claim. But I think people need to know the vision that drives what we are doing every day.''
Prof Reynolds' first significant contact with Parkinson's was after graduating as a medical doctor. He had grown up in Hawkes Bay wanting to be an engineer. But some bad careers advice saw him spending eight years as an electronics technician in the health industry.
He did, however, acquire a passion for health that led him as a 25-year-old to enrol at Otago to study medicine.
As a junior doctor working with Parkinson's, stroke and head-injury patients in a rehabilitation unit in Whangarei, he became frustrated by medicine's inability to do more to aid recovery.
''I used to think, why can't we do better with the brain? And one of the main issues is we can't get drugs into the brain in the way we would like.''
He decided to research the topic, and was encouraged by his former medical school teacher, Prof Brian Hyland, to do a PhD. That was 1997.
''I haven't looked back since, because it has been such an amazing journey.''
At times, it has been almost all-consuming. He can list no regular hobbies or leisure-time pursuits.
''I have work and I have family. The balance [between the two] has been wrong for many years, and now I am really actively trying to sway it the other way,'' he admits.
It is all very well to have a vision as grand as his is for Parkinson's, but then you have to pursue it. So how has Prof Reynolds gone about trying to tackle the incurable?''You start off with an idea. Then you try a few things,'' he says.
''Then you have to get some money. You can't do this stuff without money, because we need people and they cost money.''
The idea was to attempt to create a way to release dopamine in the brain in normal quantities and only when it was needed. To do that, the scientists are working on developing a two-component system, a biological package and a medical device. The biological package would contain dopamine-like cells which would float undetected in the brain until the medical device releases the chemical in the right amount at the right time.
If they can perfect it, it will mean the death of dopamine-producing cells in the brain will no longer prevent the treatment of the physical symptoms of Parkinson's. IT would not be a cure. But it would be the next best thing.
Following on from their breakthrough discoveries of dopamine processes, the next major step came in 2009.
''In discussion with our chemist Dr Eng Tan ... he had an idea of a particular way of driving the release from these packages. We tried a few experiments and it looked like it had legs, and we've run with it from there.''
Funding the research has been a continual, sometimes seemingly insurmountable, burden. Translational research - turning scientific discoveries in the laboratory into useful products - is the hardest research to get funding for in New Zealand, Prof Reynolds says.
''I'm constantly stressing myself out thinking how can we stretch these dollars as far as possible.''
A three-year, $350,000 a year, government grant in 2008 got them started. But despite meeting their objectives, a change in funding priorities saw further grant applications turned down.
''We kind of fell between the cracks,'' he says.
''It does make me sad ... To be honest, that would have made us significantly further ahead now.
''So we've done it on the sniff of an oily rag; lots of begging, stealing and borrowing. It's been hard.''
In 2011, Prof Reynolds was given a five-year Rutherford Discovery Fellowship; money to ensure up-and-coming scientists stay in New Zealand and focus on transformative research. The funding has enabled him to keep the Parkinson's research ticking along through tough patches.
The support of the University of Otago and its commercialisation wing Otago Innovation Ltd has also been ''absolutely amazing, phenomenal''.
In recent months, the prospect of the project being scrapped has loomed large again. The saving grace was a Health Research Council grant announced last month.
''I have to think very smart about what can we do with the $150,000 to keep this programme going,'' Prof Reynolds says, as much to himself as anyone listening.
''It will give us 18 months. That will be very helpful in getting us to the next stage.''
Critical to the success of what is being attempted is the team, he says.
Physiologists, neuroscientists, chemists, pharmacists, Prof Reynolds' former teachers turned collaborators, specialists in other fields, high-level thinkers, those at the laboratory bench ... about 10 in all. Plus several more who have come and gone, seconded for short periods when money permitted.
''If you took one person out; for example, if we got rid of one of the chemistry people who is thinking about and designing and making these packages - it's got to be safe and to last in the conditions and for long enough at the right temperature - if you took that person out, you wouldn't have the packages to put in to do our research to say, yes it's worthwhile. And if we didn't have my person here doing the physiology on the brain, then they [chemists] wouldn't have anything. So, each is absolutely crucial.''
A determination to keep going, no matter what, has paid dividends.
''This has been a lot of sweat. We try, and many, many times we fail. Because we've got to alter something, the package, or the way we are applying our control.
''It's getting better and better, but there's been a lot of surprises along the way, things that haven't quite worked out that we thought would. And some things that have worked really well that we didn't expect.''
The team is now at the point of seeing whether the biological packages and the device work together as hoped in a living Parkinson's model.
Success there will enable them to apply for larger funding to take it further.
Clinical trials could be five to 10 years away, Prof Reynolds estimates. In the meantime, the costs, monetary and otherwise, continue to mount up.
For academics, publishing the results of research is ''our lifeblood, our currency'', Prof Reynolds says.
But these researchers have been unable to do that.
Taking their treatment to clinical trial will cost hundreds of millions of dollars. It will be impossible without the deep pockets of a large international pharmaceutical company. But no drug company will take on that burden unless there is a better than even chance of turning a profit.
So, the team have taken a provisional patent on their potential Parkinson's treatment.
''[It] is not because we want to go off and live in the Bahamas. We want somebody, when it's required, to pour the money in to get it to clinical trial.
''So we have protected our intellectual property. And part of that is that we don't tell lots of details about it, we don't talk about it in public meetings, and we don't publish it at the moment.
''So we are sitting on some pretty powerful publication.
''You take a lot of people on a lot of trust. You say, trust me, we will get there, but we won't be able to publish until we get to this level. I've asked some people to wait seven years so far. That's hard.
''We've managed to keep this going because we've had a lot of people who have been driven by the idea of trying to make this treatment a reality.''