Innovators 2012 part two – Russell Foster
23 April 2012
In a series of three articles, BBSRC Innovator of the Year 2012 winners reveal the secrets behind their innovations.
In this, the second, Professor Russell Foster explains how discovering an entirely new class of photoreceptor in the eye transformed our understanding of how body clocks regulate healthy ageing. In the first, Professor George Lomonossoff of the John Innes Centre explains how a safe and accessible way to make proteins in plants could revolutionise vaccine screening and yield novel metabolites. In the third, Professor Jim Murray of the University of Cardiff describes how new DNA detection technology using light could improve on-the-spot medical and food diagnostics.
In 2009 BBSRC established the annual Innovator of the Year competition to celebrate scientists who delivered science with high economic and social impact. See 'The money of all invention' for details on how innovation powers the technological treadmill that can solve both local and global problems, drive economic growth, and make our lives longer, easier and happier.
How does it feel to win?
I was absolutely thrilled. I thought there was no way I could win so I stayed back from the main stage when the announcement was made. I was told later that I looked amazed.
Why did you think you won?
My research is a perfect example of what BBSRC does – it funds underpinning basic science. It funded a huge chunk of the work that led to the discovery of a new class of photoreceptor first in the fish, then mice and ultimately in humans.
BBSRC is constantly funding the basic stuff but never gets the credit when this science becomes applied. When people say "you're changing the lives of blind people" they never think of BBSRC – they think of the subsequent funding that's taken up the basic science and run with it.
Describe your innovative discovery?
The long-recognised role of the eye is to generate an image of the world using rod and cone photoreceptors. Research from my laboratory led to the discovery that the eye contains another class of photoreceptor based upon a small number of photosensitive retinal ganglion cells (pRGCs). These specialised neurons detect environmental brightness and regulate a wide range of physiology and behaviour including the regulation of 24-hour body clocks, sleep, alertness, mood and even pupil size.
What are the clinical impacts of your work?
The appreciation that vision loss need not mean total loss of eye function has had real impact in ophthalmology on two levels.
If you have lost your visual system as a result of damage to the rods and cones, then we need to check if the pRGCs are still working. If they are, the individual needs to be advised to seek sufficient light to maintain normal alignment of the body clock. In the absence of vision it's difficult to look after your eyes and they can get infected. In the past there has been a tendency to remove eyes without checking whether the pRGCs are still working.
And the other important part is that if you've lost the inner retina where those pRGCs reside, like in glaucoma, then you've lost all light detection. These individuals need counselling and clinical intervention to stabilise their sleep-wake cycle.
Any other areas?
A third area is cataract surgery. The scattering and yellow filtering of a cataractous lens in the aging eye alters both the quantity and quality of light reaching the retina, with a notable reduction of blue light. Our emerging data show a high incidence of sleep disturbance in pre-operative patients and a statistically significant improvement in sleep quality following surgery with clear lens implants.
Beyond eye disease, we are interested in how much light we encounter. Interior office lighting is in the order of 200-400 lux and rich in long wavelength light. Even on a cloudy day outside we are exposed to 10,000 lux. For maximal alertness and circadian regulation light should be in the order of 1000-2000 lux and blue [wavelength] enriched. We are now collaborating with the architects and lighting engineers on a number of projects to enhance artificial light and increase exposure to natural light to optimise human performance at home and in the workplace.
Do you work with patients yourself?
No I don't. We have a team here who work with patients. All our patient work is in close collaboration with Susan Downes, a Consultant Ophthalmologist at the Oxford Eye Hospital, and who's been truly remarkable in spending a great deal of time working with us. I am so impressed that she works with us and then, in addition, copes with a huge clinical load.
How do you filter your impacts to the clinical field?
We do it through our consultants and clinical fellows who are being trained in this new area of eye biology. We're training the next generation at the Oxford Eye Hospital who in turn are connected to other ophthalmology centres across the UK and the world.
How many people might benefit from your work?
The numbers are really frightening. The WHO suggests that at any one time worldwide 49M people will have vision loss; over 270M severe sight problems. There are about 250M people with visual impairment; it is very likely that many of these people could benefit from an understanding of how visual blindness might be affecting their pRGC system.
When did you first get an inkling there may be another class of receptor in the eye?
I was trained as a zoologist, and loved the topic of sensory ecology. And so when I got to think about this problem it made no sense to me how the visual system – which builds, and discards, a picture of the world very quickly – could also measure the total amount of light in the environment over long periods of time. The clock needs information about dawn and dusk not rapid light changes in the environment. Also as an undergraduate and for my PhD I worked on wired light detecting systems in frogs and birds, so the idea that there might be another photoreceptor in the eye was not so crazy.
And how did you discover it?
Our discovery of the VA-opsin gene family in fish led to the demonstration in 1998 that a sub-set of retinal horizontal and ganglion cells are directly photoreceptive. This was the first unambiguous evidence for a non-rod, non-cone photoreceptor in any vertebrate.
We then studied human eye diseases in mutant mice and, to our complete astonishment, visually blind mice that had lost their rods and cones could regulate their body clocks normally. We found these early papers difficult to publish – there was huge opposition.
So we did more experiments. In the end we engineered mice with no rods or cones at all, and this final approach resulted in two papers back to back in Science in 1999 that were BBSRC funded. We had showed that in the absence of all rods and cones the body clock and other responses to light were being regulated by another photoreceptor in the eye.
The Science papers convinced a lot of people – but not everybody. Our later work, and the work of my colleague Mark Hankins, showed that pRGCs use a new pigment called melanopsin, with a maximum spectral response at 480nm in the blue part of the light spectrum.
Did you encounter resistance to your new ideas?
We encountered massive resistance to begin with. The reactions were really ferocious. Grants and papers were simply rejected, I think largely based upon the argument that "we've been studying the eye for 150 years – and are you seriously telling us we've missed a whole receptor system?" That spurred us on to do better experiments and over a decade we just overwhelmed the community with data.
What is exciting to me is that there are now so many vision scientists working on this receptor system – people are making their careers studying something that was until recently unthinkable! I have also been given some remarkably prestigious prizes – but the Innovator prize has been the first one with money attached!
Has this work led onto pharmalogical targets?
This is something we are working on at the moment, and the work is attracting support from one major drug company. I think by understanding how this new photopigment actually signals light – understanding the different signalling molecules – we have a chance of developing ways to manipulate the transduction pathway which may be hugely useful to those who have lost their eyes or who have damaged pRGCs.
What's next for the applications of your research?
It is still in body clocks and sleep but in a different direction. Small changes in brain function can have a big impact on sleep, and disrupted sleep leads to health problems ranging across increased stress hormones, heart disease, weight abnormalities, reduced immunity, increased risk of cancer, and emotional and cognitive problems.
Many mental illnesses are commonly associated with highly disturbed sleep, but the importance of this disruption is frequently overlooked. Significantly, many of the health problems that arise from disturbed sleep are also found in mental illness, but these problems are rarely linked back to sleep abnormalities.
Our very new data suggests that overlapping brain pathways might be affected in mental illness and sleep disturbance. We are working with psychiatrists to understand these common connections. Our aim is to use this basic understanding of the neuroscience to develop new approaches to correct abnormal sleep and so improve the broader health problems and quality of life for patients with mental illness.
You're a regular on the science festival circuit. Is it important for scientists to engage with the public?
I think it's incredibly important. I chair the Cheltenham Science Festival and the reason I decided to commit a considerable amount of time is that at Cheltenham there are fantastic opportunities for scientists to engage with the people who pay our wages!
I think it's critical to engage with non-scientists. Three things can happen: one, hopefully you can help non-scientists make more informed decisions about matters that involve science; two, I think it's really important that scientists learn directly from non-scientists about their views and concerns. These discussions also make scientists think in a different way and this can lead to real insight. And third, collaborating with non-scientists can lead to the uptake and translation of the science for health and business. I really feel that science will help us get out of this current economic mess!
And it helps in other ways – I'm much more interactive now in undergraduate lectures than I was before public engagement.
When did you first become interested in science?
I have always been fascinated by life and biology. My earliest memories as a three-year old child – I can see it now in my mind – are watching lizards basking on the rocks in the garden in Camberley. I was fascinated by these extraordinary creatures. I also remember being given a tiny microscope as a child – perhaps I was eight – and being frustrated that my eyelashes got in the way when I looked down the eye-piece. So I cut my eyelashes off. My mother was horrified!
I went to university thinking I'd become a marine biologist because I loved swimming and was fascinated with the sea, but then discovered physiology in my second year and that you could record a light response from the eye of a locust – that was just fantastic for me. In a sense I have been very lucky, I have always known broadly what I wanted to do. I suppose in that sense I've been profoundly boring!
The UK has perhaps the richest history of scientific innovation of any country in the world, and the Royal Society report The Scientific Century: securing our future prosperity shows that innovation and commercialisation are flourishing in Britain.
For example, from 2006-10 university spinout companies have floated on the stock market or been taken over for a combined total of £3.5Bn and employ 14,000 people in the UK. Furthermore, between 2000 and 2008, patents granted to UK universities increased by 136% and university spin outs had a turnover of £1.1Bn in 2007/08 (ref 1).
The perception that the UK is not successful when it comes to commercialising science, or as some have put it: "Britain invents; the world profits" is therefore clearly outdated, and that strategies to harness and increase innovation are working.
In addition to the benefits it brings, it is argued that present £7.5Bn science budget pays for itself many times over as technology is developed and then taxed as it is sold. The Medical Research Council estimates every pound it spends brings a 39p return each year (ref 2). Moreover, independent studies have shown that for maximum market sector productivity and impact, government innovation policy should focus on direct spending on research councils (ref 3).
Finally, the UK produces more publications and citations for the money it spends on research than any other G8 nation. Specifically, the UK produces 7.9% of the world's publications, receives 11.8% of citations, and 14.4% of citations with the highest impact, even though the UK consists of only 1% of the world's population (ref 1).
- The Scientific Century: securing our future prosperity
- Medical Research: What''s it worth?
- Public support for innovation, intangible investment and productivity growth in the UK market sector
- Nature: Novel retinal photoreceptors
- Characterisation of an ocular photopigment capable of driving pupillary constriction in mice
- Current Biology: Short-wavelength light sensitivity of circadian, pupillary and rudimentary visual awareness in blind humans lacking a functional outer retina
- Current Biology: Disrupted circadian rhythms in a mouse model of schizophrenia