Profile: Steve Brown
Professor Steve Brown heads up the MRC Mammalian Genetics Unit (MGU) at MRC Harwell, which focuses on using the mouse as a model for human disease. Katherine Nightingale spoke to Steve about the international nature of mouse genetics and his own research that looks at the genes behind deafness.
Professor Steve Brown has an open door policy. “I think it’s absolutely critical for a director to be approachable. I also like to go round talking to people in the lab, finding out how the scientists are getting on,” he says.
Since becoming director in 1996, Steve has been putting his open door policy to good use, increasingly steering the unit towards international collaboration, a vital part of modern mammalian genetics.
“Many of the challenges we have in genetics right now can’t be addressed by just one institute, we need to work in large collaborative enterprises, often internationally,” says Steve.
An international outlook
Almost all mouse genes have a human equivalent, so researchers use ‘knockout’ mice — which lack a functioning version of a particular gene — to determine the role that each gene plays in biology and disease. The International Knockout Mouse Consortium (IKMC), a huge international effort launched in 2006, has taken on the mammoth task of creating a knockout library of all 21,000 mouse genes.
Now an offshoot of the collaboration, the International Mouse Phenotyping Consortium (IMPC), of which Steve chairs the steering committee, is turning its attention to documenting how lacking a gene affects a mouse’s physical characteristics, or ‘phenotype’. The mouse genome will be divided among research centres around the world, and a handful of mice lacking each gene will be given a health check, looking at everything from the health of their coat to their blood glucose levels, their body fat to their behaviour.
“This will create an encyclopaedia of mammalian gene function, a comprehensive insight into what each gene is doing,” says Steve. “That will be tremendously valuable in terms of better understanding the way genes are involved in genetic disease.”
The first phase of IMPC work — to assess 5,000 mice in the next five years — will cost around $200 million. The second phase will complete a further 15,000 phenotypes before 2021.
The MRC contributed £10 million to the first phase in 2011 as part of the investment provided to MRC Harwell, a consortium hub. The MRC has also created the MRC Mouse Network, through which UK researchers can engage with the IMPC.
Researchers anywhere in the world will be able to freely access both the phenotype information and frozen sperm of the knockout mice so they can make and breed the mice, giving them a head start on pursuing their own lines of research. In the UK, the database of phenotype information is being developed by a UK consortium including the bioinformatics team at MGU, the Sanger Institute, and European Bioinformatics Institute. The MRC Mary Lyon Centre — which makes up MRC Harwell along with the MGU — will generate, phenotype and archive the mice.
“I like to think we have the perfect campus here, one with great facilities and core support for good scientists who have the bright ideas,” says Steve.
Heading for translation
This kind of work is beginning to bear fruit in Steve’s own research. His team looks at the genetic basis of deafness and has characterised the role of around 30 mouse genes — and therefore their human counterparts — in the past 15 years.
To do so they combine the modern genetic engineering of knockout mice with a simple tool called a ‘click box’ which emits a high-decibel, high-frequency sound, to test whether a mouse can hear.
If the mouse doesn’t jump in response to the box — the same startle reflex that a person would have to a loud noise — it is most likely deaf, and the gene it lacks is implicated.
The two most exciting areas that Steve’s team is working on bookend the human lifespan: deafness in older age and chronic ear inflammation in young children.
But it’s Steve’s research into deafness in childhood that is closer to changing treatment. Most children will get at least one episode of middle ear infection but some get recurrent infections that can lead to a condition called ‘glue ear’ where the middle ear is continually inflamed and filled with a thick fluid. This damages hearing and can delay a child’s development if it doesn’t clear up. The only treatment is surgery to insert ‘grommets’ or tubes into the eardrum to drain the fluid.
“We’ve found mouse models that have [glue ear] and we’ve found the underlying genes, so we now know about the molecular mechanisms that are involved,” says Steve.
“We’ve been able to treat the mice with particular drugs that target the molecular pathway and have seen stabilised hearing in those mice. We’re very excited because it gives us a potential avenue for treating children which wouldn’t involve this relative crude surgery, and so is less stressful for the child.”
Steve hopes that drugs, which are already on the market, could be delivered directly into the middle ear, perhaps via a patch on the eardrum that could be fitted in the doctor’s surgery.
“We wouldn’t have been able to do this without the mouse model,” he concludes.
See below for a tour of the Mary Lyon Centre, part of MRC Harwell and a national facility that generates mouse models of human disease.