Juggling Neurons

Christine 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 mixture of arts and science subjects for ‘A’ levels.

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 tectum. The theory was resisted for several years but is now generally accepted. In addition, Christine discovered that this RNAbased mechanism helps to keep axons alive over the life-time of an organism.

If this were just a matter of solving one of life’s minuscule mysteries, it might please the scientists involved, while only meriting a few lines in microbiological textbooks – but it may have much greater significance, in providing a vital key to understanding how neuro-degenerative diseases work – and ultimately curing them.

Christine’s scientific journey took her around the world in search of the most innovative colleagues in her field. From Oxford, she applied to Bill Harris, an earlycareer Assistant Professor at the University of California in San Diego, who offered her a one-year postdoctoral position. She must have made a good impression. The two young scientists became romantically involved and, the moment Christine got back to her parents’ house, Bill phoned with another offer, asking her to marry him. She said yes, but completed her next postdoctoral year at Oxford before returning full-time to the US.

‘Back in San Diego, I was “the wife” in a part-time teaching position – and started having children – which made doing research even more difficult!’ Julia and Jake were born in 1985 and 1987 and, unsurprisingly, both are now scientists. As Christine only had a ‘soft-money’ position without a lab, she was, at least, free to accompany Bill on his sabbatical to Germany. She got a modest grant from the US National Institutes of Health, sufficient to fund one technician and no students, and tried to make discoveries and publish them. She’s quite sure: ‘it would have been much easier for a guy!’

The Chair of her Department had advised her to keep some professional distance between Bill’s research and her own and to publish scientific papers in her own name, to ensure she got fair credit for her original work. This paid off in the form of two prestigious awards, a Pew Scholar’s Award and a McKnight Award, which gave her ‘a stamp of credibility’.

At last, in 1992, she was offered a “hard money” Assistant Professor’s position at the University of California San Diego, with her own lab space, enabling her to take on graduate students and postdocs – but, two years later, Bill came to Cambridge on another sabbatical and was invited to be Head of the Anatomy Department. Slightly reluctantly, Christine also accepted a position as a Lecturer.

It was ‘a massive drop’ in salary and facilities, because she had tenure in the US. She had to teach neuroanatomy and neurodevelopment to undergraduates in Medicine and Natural Sciences. It was ‘a balancing act’, as she juggled the priorities of school-aged children, a sick mother (her father had died ten years earlier), teaching and trying to keep an international profile with her research.

When Professor Joe Herbert (1976) heard that Christine and Bill were coming to Cambridge, he invited them to dinner in College and she was offered a Fellowship.

Becoming a Caian has been ‘a massively positive experience. People at Caius really care about each other: it’s a wonderful scholarly community. You work away in your lab and come in for lunch and have fascinating conversations with people in all sorts of different areas – at San Diego, there was no opportunity to meet people in other disciplines.’

Even so, the balancing act was hard to maintain. In 2000, severely stressed, she wrote a letter of resignation to the Master, Neil McKendrick – ‘and he refused to accept it! I really appreciated that.’ Soon afterwards, she was promoted to Reader, then Professor and became a Fellow of the Royal Society, so student supervisions became a thing of the past. The pressure was still on, but in a different way:

‘Running a lab is like running a business. You have millions of pounds coming through the door and you have to keep people employed on the grants and you have to produce papers and get them published in high quality journals, if you want to get repeat funding.’

Her current work includes serving on the Scientific Advisory Boards of two of the new Dementia Research Institutes (Cambridge and King’s, London).

It hasn’t been an easy ride, but Christine takes a quiet pleasure and pride in what she has achieved, in the potential of her work to lead to hugely significant results that may save or change many people’s lives – and in the fact that she may have helped to smooth the rocky pathway for the next generation of women scientists.