|Articles taken from the MARCH 2005 Huntington's News. The Quarterly Newsletter of the Huntington's Disease Associations of New Zealand|
What if the injured brain could repair itself? JOANNA WANE meets a young scientist whose research aims to stimulate stern cells to go on fix-it missions.In the universe of the human body, the brain is largely uncharted space which has only in recent years begun to surrender its deepest secrets to scientific inquiry.A highly complex command centre controlling memory, movement and even our moods, it was always believed to have one fatal flaw: that it lacked the capacity for self repair.
This theory was finally debunked in 1999. Researchers in California analysing brain tissue from cancer patients who had been rejected with a dye that labels dividing cells, stumbled across something unexpected: not only did the adult brains contain stem cells, those cellular building blocks thought to exist only in the brains of newborn babies; they were able to divide and create new brain cells.
Then University of Auckland pharmacologist Dr Bronwen Connor dropped a bombshell of her own. In research funded by the New Zealand Neurological Foundation, she discovered that, in adults with brain disease, stem cells responded to a distress call from the area under attack by sending out reinforcements on a rescue mission to replace brain cells that had died.
That, says Connor, was a revolutionary concept. The whole regenerative side of the brain was thought to be non-existent. But this opened up a whole new set of ideas about the potential treatment of brain disease and injury.
In brain tissue bequeathed by patients suffering from the degenerative neurological disorder Huntingtons disease, a team led by Connor and Professor Richard Faull (of the Universitys Anatomy Department) found more stem cells than normal in the brains of Huntingtons patients. New brain cells had started to form.
Next, she tracked the development of stem cells in brain tissue from rats with Huntingtons lesions. Again, the cells began to replicate. Then they went on the move, spreading like an invading army into the damage zone. The brain it seemed, was trying fight back.
Connor, who spent three years in Chicago doing her post-doctoral fellowship, says it was particularly satisfying to share such a significant breakthrough with colleagues in the United States. It absolutely polarized views, she says. Some thought it was incredibly exciting; others were a bit skeptical and said, Show us more. When people react like that, you know youre onto something.
Connor, 31, a senior lecturer in the Faculty of Medical and Health Sciences, is widely respected as one of the Universitys most talented young scientists. A keen athlete who represented New Zealand in rowing, she initially planned to do sports physiology before being drawn into pharmacology, then deciding to specialise in neurological research.
The brain is a fascinating organ that does so many different things, she says. We keep finding that it has more and more potential. And because its associated with our individuality and our personality, its always thought of as something special. The only other organ that comes close is the heart.
The project that Connor is heading will focus on Huntingtons disease, an inherited disorder that affects about one in 15,000 New Zealanders. Currently untreatable, it short-circuits the part of the brain that controls movement, causing a slow, insidious deterioration of motor function over a period of 10 to 15 years.
The reason for focusing on Huntingtons is that the part of the brain destroyed by the disease sits right alongside the strip where stem cells cluster, so new migrating brain cells dont have to travel far to do their work
Connor believes the brain already goes into fix-it mode when damaged by trauma or disease but its too little, too late. The focus of the research is to enhance that natural process, by stimulating the formation of new brain cells and luring them to where they are needed to replace the functions being lost.
Two experiments, both using gene transfer techniques, will run in parallel during the three-year project. In the first, stem cells in a cultured brain tissue from rats with Huntingtons lesions will be tagged with a viral vector. The virus itself is harmless its disease-causing elements are carefully removed before insertion but it infects dividing cells and makes them glow under a fluorescent light.
What happens next tests the belief that specific proteins in the brain play a role in stimulating stem cell renewal. A dot of these proteins will be dropped on to the diseased tissue and also onto a sample of healthy tissue. Both will then be videotaped, using time-lapse imaging, every three hours to track the migration of the labeled cells in response to both the delivered protein and to cell loss in the diseased tissue.
In the second experiment, a gene carrying the proteins DNA will be injected directly into the striatum of rats with Huntingtons.
The striatum is the part of the brain that controls movement and is affected by the disease. This time, instead of infecting only dividing cells, the virus on the gene will distribute proteins indiscriminately, in an attempt to encourage the creation of new brain cells and attract them to the key site of cell destruction
Equally important is finding out whether this fresh supply is of brain cells is the right type to start taking over brain functions that have been impaired. One way of testing this will be to analyse the rats motor skills, to see if there is any reversal or slowing in the degenerative effects of the disease.
The migrating brain cells make relatively speedy progress, says Connor. In rats, theyve been tracked from the middle of the brain to the olfactory bulb in the nose in less than seven days. Inching along like microscopic caterpillars on their heroic journey, they stretch out feathery-looking feelers, constantly searching for a new connection.
Connors own career pathway has been all about making the right connections, too. Her research team co-leader, Professor Richard Faull, was one of her PhD supervisors and is the director of the New Zealand Neurological Foundation Brain Bank which stores tissue bequeathed for medical use an invaluable resource that Connor has drawn on for her ground-breaking research.
In Chicago, Connor spent three years at Northwestern University at a time when the controversial field of gene therapy first erupted on the scene becoming trained in techniques which are at the heart of her brain-repair project today.
From there, she returned home in 2000 to set up her own laboratory where she now leads a team of 10.
Still in its infancy, research on brain repair is a fast-moving field internationally and the potential for limiting or reversing critical damage is enormous.
Although not directly involved in clinical trials, Connor says that she never loses sight of the human cost of neurological disorders. Her grandmother suffered from Alzheimers and she has regular contact with families affected by Huntingtons disease.
They remind you exactly what youre doing and why, she says.
Acknowledgement: This article was written by Joanna Wane and appeared in
Ingenio Magazine of the University of Auckland Spring 2004