6 Once a Caian...
Juggling Neurons by Mick Le Moignan (2004) Juggling priorities is a core skill for wife, mother, Fellow and Professor of Developmental Neuroscience, Christine Holt (1997)
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hristine makes the point that it is still harder for women than men to build a successful career in scientific research, but several prestigious awards, including the €1 million Champalimaud Vision Award in 2016 and the Ferrier Medal of the Royal Society in 2017, are helping to make her own juggling act a little easier. There is considerable public interest in Christine’s ground-breaking discoveries about how nerve cells grow and develop, because they may ultimately lead to a better understanding of neurodegenerative conditions, such as Parkinson’s, Huntington’s and Alzheimer’s Diseases. Success in such a complex field requires many years of patient work. Christine pays warm tribute to her husband, Professor Bill Harris, who retired last year as Head of Cambridge University’s Department of Physiology Development and Neuroscience, for loyally supporting her research. For many years, they have worked in adjoining labs, investigating similar areas, and collaborated closely. ‘It’s great’ she says, ‘to have a working partner who understands what you’re doing.’ Christine grew up in rural Northumberland, the youngest of three children of a wartime naval officer and a Wren, attending a tiny village school with only two classes for pupils aged 4 -13, where the comedian, Rowan Atkinson, was a contemporary. She went on to board at Harrogate College and then St Clare’s Sixth Form College in Oxford, where she studied a
The growth cone of a retinal ganglion cell axon, exhibiting polarised synthesis of a protein (beta-actin) on the right side, near a Netrin-1 gradient (not shown). 'Hot' red represents high concentration of protein. ‘Cool’ green/blue represents lower concentration. The entire growth cone is only 5-10 µm (microns) across, finer than the finest human hair
mixture of arts and science subjects for ‘A’ levels. ‘In those days,’ she says, ‘girls weren’t really encouraged to go on to university, but in Oxford, my eyes were opened to the possibilities of university.’ She chose Sussex because of its strength in Biology and because she could continue an arts subject, but in her final year she homed in on Neurobiology and the development of embryos. This led to a PhD studentship at King’s College, London, to work on the development of the eye and its central connections, and then the first year of a postdoctoral MRC fellowship at Oxford with Sir Colin Blakemore. Essentially, that work on the wiring of the brain continues to this day: she says she is ‘still trying to figure out how nerves get connected properly’. It goes back to the earliest moments of life: ‘We all start as a single cell. It divides and divides and divides. How does the single cell develop into, for example, a brain cell or a liver cell?’ In particular, Christine wants to work out how neurons form connections between the eye and the brain. Our optic nerve is not a single strand, but contains about a million axons from cells in the retina, called retinal ganglion cells, each carrying information from the eye to the brain to be translated into pictures. In a human foetus, these axons begin growing about six weeks after conception. They start in the retina and take several weeks to extend and navigate their way to their target in the optic tectum in the midbrain. It is obviously impractical to study
this process in humans in vivo, so Christine uses the axons from Xenopus frogs, which develop in about 20 hours, and behave in a petri dish in the lab much as they would in the growing brain of a tadpole or frog. The axons travel vast distances, in relation to their size, comparable, on a human scale, to walking from London to Birmingham. How can the originating cell ‘control’ this process from so far away? A key part of the answer, of course, lies in its DNA. At the tip of each growing axon is a specialised ‘growth cone’, which reaches out tendrils to find its correct pathway, carrying messenger RNA (mRNA) from the original cell body. The growing brain already has a ‘roadmap’ of molecules to guide the growth cone on its way. When it encounters Netrin, for example, it is attracted towards it, and so the axon grows in that direction. When it meets with EphrinB, it is repelled and turns away. These chemicals are ‘signposts’ that show the way to go, but how does the axon keep growing on its long journey? In her Ferrier Lecture at the Royal Society, Christine compared this phenomenon to ‘an amoeba on a leash’. When the leash is deliberately broken in the lab, cutting off an axon from its originating cell body in the retina, the growth cone continues to function perfectly well for about three hours. This apparent autonomy is a clue to how it works. In 2001, Christine and her team discovered that the mRNA in the growth cone can generate its own proteins on demand, locally, swiftly and whenever required. This is how the axons complete their long journey to the optic
