Prof Karen Steel - Genes and deafness

Kat - Around one in six people in the UK has some kind of hearing loss, including most people over 70, and the number is rising. Professor Karen Steel, now at King's College London but formerly at the Wellcome Trust Sanger Institute, is an expert in hearing loss in old age, and has played a major role in tracking down some of the genes involved. I spoke to her about how far she and her team have come, and how they're trying to use this knowledge to help people at risk of losing their hearing.

Karen -  We've identified a large number of genes, well over a hundred genes, that are involved in deafness either in humans or in animal models.  We use the mouse mainly as our animal model.  We know a lot of these genes are very different sorts of genes.  They vary from genes called transcription factors which control the activity of other genes, or they could be structural proteins, they could encode structural proteins.  There's a whole variety of them.  When I started working on genetics of deafness, I thought that all genes involved in deafness were going to turn out to be ion channel genes.  But of course, it wasn't - the first one that we identified was a gene called myosin VIIA, which is an unconventional myosin molecule. 

Kat -  That's a kind of "muscley" sort of protein.

Karen -  That's exactly what you'd think.  There's lots of other myosins in the body that perform other functions other than muscular contraction and this was one of them.  This one was very important for both hearing and for vision, as it turned out.  It turned out to be involved in a human disease called Usher syndrome where children are born deaf and with a balance problem.  In the first 10 years or so of life, they start to develop visual problems as well until they lose their vision.  So, it's a very nasty disease for the children to have and identifying several of the genes involved in that has been a very useful start to thinking about how it could be treated.

Kat -  So, we have genes that are involved in hereditary deafness and hearing problems, and then there's presumably genetic variations between us as humans that mean maybe some people will lose their hearing earlier as they get older or struggle with different aspects.  Do we know if it's the same kind of genes involved or different sort of genes involved in different types of hearing problems?

Karen -  That's a good question.  When you talk about hereditary deafness, I think most people are thinking about individual families where some children are born with a hearing impairment and others are born without a hearing impairment.  That is very clearly genetic and usually a single gene that's affected that's causing that pattern of inheritance.  But actually, genes do a lot more.  

As you say, there are lots of genes out there that vary from individual to individual, and some of those genes can make us more or less likely to have damage to our hearing as a result of environmental problems.  Some of them are important for the long term maintenance of the hearing structure in the ear.  And so, as we get older, it may well be that just a single gene can make us more likely to lose our hearing.  So, there's lots of different causes. 

At the moment, we know quite a lot of genes, over a hundred in humans alone that are involved in childhood deafness that we know very, very little about the genetic basis of hearing impairment as we get older.  And that's one of the main things that I moved here to Kings College to study because it's a basic neuroscience question - why is hearing gradually deteriorating as we get older?  Is it a general part of growing old or is it something that's very specific to the auditory system?  I think we'll the evidence is pointing towards it being very specific.

Kat -  Not just because everything is falling apart? 

Karen -  Exactly, yes.  So, there's lots of people who are very old who have perfect hearing and other people who relatively young who have very poor hearing.  So, it's not just a general aspect of growing old.  There are specific factors that make our hearing progressively get worse as we get older at different rates from individual to individual.

Kat -  So, how are you trying to get the answers to this question?

Karen -  I'm a geneticist, basically.  So, I'm always thinking about how we can use genetics as a tool to get an understanding of the molecular basis of hearing and progressive deafness - particularly, progressive deafness.  Because I think with progressive deafness then we have a much greater chance of being able to develop treatments.  So, progressive hearing impairment is the main thing that I'm interested in.  The technique I use is to look for single genes that when they're mutated or changed, will lead to progressive hearing loss.  I use the mouse as my main model system because there are many models now or mouse mutants where they have a particular mutation in a particular gene that we've been able to show have progressing loss of their hearing.  And so, we think, mimic the human progressive hearing loss.

Kat -  How do you tell if a mouse is losing its hearing?

Karen -  We use a physiological measurement called auditory brainstem response measurements or ABR.  This is exactly the same technique that many hospitals use to screen newborn babies for deafness when they're born.  So, it's a non-invasive technique and it's a very powerful technique to carry out at different ages that you could follow that progression of the hearing impairment in a mouse as it gets worse and worse.  We can distinguish lots of different aspects of their response including whether you need to deliver a higher level of sound in order to elicit a response.  And also, whether different frequencies -  high frequencies or low frequencies - are responding at the right sort of threshold.  This is quite important for humans because humans, as they get older, have a tendency to lose their sensitivity to high frequencies first. That's the earliest sign of progressive hearing loss.

And we found a number of different mouse mutants with single gene mutations that did have progressive hearing loss starting at the high frequencies.  So, we think that these particular mouse mutants are going to be very useful to us in providing models for the normal natural history of progressive hearing loss in humans.

Kat -  So, where would you like to see this research going maybe over the next 5 to 10 years, given the pace at which everything is accelerating in science and technology?

Karen -  Well, we have some very good clues now.  We have a number of different genes that we've identified as being involved in progressive hearing loss.  Now, we're in a position where we can start thinking about what molecular pathways those genes are involved in and whether those are pathways that we can manipulate particularly, using small molecules.  So, the traditional drug approach.  This is an approach that really hasn't been very seriously adopted in hearing.  

Most people think of hearing being treated by using hearing aids or perhaps cochlear implants if it's a very severe hearing impairment.  Those are prosthetic devices.  Those aren't treating the hearing because the person still has the hearing impairment.  Whereas, we think that we should be able to develop some drugs or small molecules that will stop the progression of hearing impairment.  But this is a long time off.  

We think in the next few years - next 2 or 3 years, we should have some animal model work that will give some proof of principle of using small molecules to stop the progression of hearing impairment.  Developing that to get into the clinic is going to take a lot longer as I'm sure you hear for many different diseases.  It's always a long process to get the initial concept of using a small molecule to treat a disease from an animal model into the clinic.  So, deafness is no different from that.

Kat - That was Professor Karen Steel from King's College London.