Day job

Music certainly seems to run in Harvey's genes - his cousin is the Scottish-born, Australian-based singer-songwriter Eric Bogle - but it is neuroscience that he is most well known for.

It wasn't music he was interested in studying when he started his scientific career, but vision. He studied physiology as an undergraduate at Cambridge University, where he had the great good fortune to have lecturers such as Colin Blakemore, Horace Barlow and Fergus Campbell, all big names in the vision field.

He came to Australia to study with the group led by Peter Bishop at the John Curtin School of Medical Research at ANU, worked as a postdoc in the US for three years and spent some time at Flinders University, eventually ending up at UWA, where he has been resident for more than two decades.

At UWA, Harvey is part of the Neurotrauma Research Program and works in several areas: a gene therapy project using viral vectors to insert genes for growth factors to repair retinal ganglion cells in the eye; looking at glial cells and their biology; and another looking at pharmacological agents that interfere with growth inhibitory factors in the central nervous system. He is also a project leader in the WA Centre of Excellence for Alzheimer's Disease Research and Care, directed by Professor Ralph Martins.

Harvey works closely with Dr Giles Plant at UWA on an olfactory ensheathing glia project, an area that is of great interest around the world due to the potential of using these cells in the regeneration and remyelination of the spinal cord.

"There are clinical trials going on at the moment, but there is a lot of controversy over whether these cells can myelinate axons or not," Harvey says. "In the models that Giles has developed, we really can't get them to myelinate in vitro, in conditions where Schwann cells can. This is really Giles' work.

"They do make myelin-related proteins, and in vivo there is some evidence that they can myelinate. It is still controversial because it all comes down to having to be absolutely certain about identifying the cells that you have and whether the myelin that is associated with these cells truly comes from them. If they do myelinate, it is very odd that they don't myelinate in their normal environment, the olfactory nerve."

In the gene therapy project, he and Plant have been collaborating with Professor Joost Verhaagen of the Netherlands Institute for Neuroscience, and one of Verhaagen's former graduate students, Dr Marc Ruitenberg, who is now at UWA. Plant's group is predominantly looking at the spinal cord, while Harvey is looking at the visual system.

"We've published work on brain derived neurotrophic factor (BDNF); neurotrophin-3; ciliary derived neurotrophic factor (CNTF) and glial cell-line derived neurotrophic factor. We've engineered retinal ganglion cells with the adeno-associated virus (AAV).

"One of the AAV serotypes is quite efficient at transducing retinal ganglion cells and we've shown that CNTF enhances survival and regeneration of injured retinal ganglion cells quite significantly. BDNF enhances survival but it doesn't enhance regeneration."

Harvey and his team have found that CTNF is the most effective gene for regenerating injured cells but that it does have its drawbacks, such as causing changes to the photoreceptors. The NRP has begun a large project, led by Dr Jenny Rodger, to fill transduced ganglion cells with dyes to study their dendritic architecture. While transduced neurons may show regenerative axon growth, their morphology also seems to change over time, which is not a good idea in a functional sense.

There is also work on gene silencing, predominantly by another colleague, Dr Cui Qi (now in Hong Kong), who is using RNAi techniques. This is another area where there are downsides, Harvey says.

"There are lots of imponderables with RNAi - how much do you need to inhibit to get a functional readout? And it might depend on the protein, it might depend on the cell, it might depend on whether the cell compensates, as there must be feedback from the cytoplasm to the nucleus to say we need more RNA - so if you actually knock it down, can the cell then respond by upregulating gene expression over a period of time?

"I don't think we know much of that. Unfortunately, you don't get money for investigating downsides, but somebody has to do it, especially when clinical trials are in the offing."