Back to basic research

"Being unable to hear can be socially isolating for many millions of people."

Jenny Hilton, Ear Nose and Throat doctor, describes her motivations as she pursues her PhD training at the Sanger Institute.

"To see a child provided with a cochlear implant that allows him or her to hear for the first time is truly exciting. I want to find new, alternative ways to improve the provision of therapies, treatments and ultimately the quality of life for many children and adults who are unable to hear."


Jennifer Hilton. Clinician scientist at the Wellcome Trust Sanger Institute.

Jennifer Hilton. Clinician scientist at the Wellcome Trust Sanger Institute.


Mozart and Beethoven-both were classical geniuses of their time; their music is still admired by many. Sadly, for millions of deaf people, they are just names, whose compositions they cannot appreciate. But there is another Mozart and another Beethoven, who - together with many others - have been key in the effort to change that outlook. Not composers - not even human - they are among the mouse models, whose development has laid the foundation for improved understanding and treatment of human deafness. Jenny Hilton, clinician scientist at the Wellcome Trust Sanger Institute, is working with more mice, trying to help to alleviate the burden carried by individuals suffering hearing loss.

From a background as a trainee Ear Nose and Throat surgeon, Jenny joined the Sanger Institute's PhD programme in September 2008. Since then, she has made her first forays into the world of genetic research in otology - the study of the ear and its functions. This unique opportunity allows Jenny to compound her surgical training with genetic understanding of deafness, in the pursuit of improved patient prognoses.

Deafness is the most common form of sensory loss experienced by humans. Approaching 280 million people worldwide have moderate to profound deafness. People of all ages are affected; people in every corner of the globe suffer. Hearing impairment affects one in 800 births and - by the teenage years - that fraction has doubled. 60 per cent of people are affected in old age and the susceptibility rises even more in people who have endured excessive exposure to noise.

"Hearing impairment is a group of many diseases and the array of causes is equally diverse," says Jenny. "Infections and injuries are among the causes of hearing impairment; some ototoxic drugs, including aspirin and certain antibiotics, can also damage the inner ear if taken in excess or by people who are susceptible to the drugs' side effects.

"But it would seem that the single largest cause of human deafness is genetic."

For a timeline of landmark discoveries in deafness, please visit the 'Discovery' tab

For a detailed description of how hearing works, please visit the 'Hearing' tab

The genetics of deafness

In 1995, a team - including Karen Steel, now the leader of the Sanger Institute's Genetics of deafness research programme - discovered the Myo7a gene. It was the first gene to be implicated in deafness. Since then research teams around the world have exposed mutations contributing to hearing loss in hundreds of human and mouse genes. It is thought that these - combined with the many that still remain to be discovered - might be responsible for up to half of all cases of deafness in humans. It is no surprise, then, that it is in this area that Jenny seeks new scientific knowledge and, in turn, new benefits and treatments for human deafness.

"Progress comes when we take science from the bench to the clinic," says Jenny. "Research programmes, including Karen Steel's prolific team here at the Sanger Institute, are integral to the overarching aim to translate scientific results into medical benefits. If we can begin to understand something of the genetic causes of deafness, we will be on the road to new treatments and ultimately we can hope to improve the quality of life of those affected."

But before treatments for deafness can be developed, the genetic causes must first be identified and understood.

Since the first surgical treatments for human deafness began to appear in the middle of the 20th century, several significant discoveries around human deafness have been made. Now, in 2009, new genetic tools to study deafness are firmly in place.

Human deafness can be divided into two categories-conductive hearing loss - whereby the transfer of sound through the middle ear is impaired, and sensorineuronal hearing loss - caused by damage to the sensory structures or neurons of the inner ear. Although it is possible to access the inner ear for surgery, such as placing cochlear implants, this involves drilling into the skull. Access to the human ear for research purposes is therefore extremely limited. More challenging still, the sensory hair cells within the ear - which detect the sound from the ear canal and trigger neural activity in the sensory neurons - are extremely delicate and deteriorate rapidly. As such post-mortem investigation is also not a viable option for researchers seeking to understand the workings of deafness of the inner ear.

" If we can begin to understand something of the genetic causes of deafness, we will be on the road to new treatments and ultimately we can hope to improve the quality of life of those affected. "

Jenny Hilton

"In practical terms, it is near impossible to look at the biology of the inner ear in humans as closely as we would like to," explains Jenny. "That is why the mouse provides an invaluable model for research into human deafness. It allows us physical access to the biology of an otherwise largely inaccessible disease. In pursuing genetic research into deafness, we have been able to use mutagenised mice as an alternative window into human deafness."

Using mice, the Genetics of deafness team are able to perform developmental studies, detailed electrophysiological measurements of cochlear function, genetic manipulation and high-quality ultrastructural studies, which would be unthinkable in humans.


Deafness: a timeline of discovery

The first single-channel cochlear devices are created and implanted in human volunteers
Adam Kissah, a NASA engineer, designs a cochlear implant that is widely used today
Martin Evans' laboratory discovers how to culture embryonic stem cells, a crucial step in the work towards the development of the knockout mouse, now widely used as a model in the study of human deafness
Cochlear implants are approved by the US Food and Drug Administration as suitable to be implanted into adults in the US
A collaboration, including Karen Steel, head of the Genetics of deafness team at the Sanger Institute, uncovers the first gene - called Myo7a - to be implicated in deafness in mice
The connexin 26 gene, believed to be a major contributor to early childhood deafness, is identified by a team from the UK
Researchers assemble the mouse genome and release the draft sequence into the public domain
The human genome sequence is completed, marking the beginning of a new, post-genomic era of discovery in the genetics of disease
A US-Japanese study achieves successful regrowth of cochlear cells in guinea pigs, offering hope that gene therapy might one day be used in 'curing' deafness
A study shows that gene therapy targeting the Atoh1 gene in mice can cause hair cell growth and improve neuronal processes in embryonic mice
A collaboration led by Karen Steel's team at the Sanger Institute finds miR-96, the first microRNA known to result in deafness in mice and in humans when mutated


Into the inner ear: how hearing works

A mouse cochlea dissected open to reveal the surface of the sensory region.

A mouse cochlea dissected open to reveal the surface of the sensory region. [Graham Froggatt, Genome Research Limited]


Hearing is one of the most intricate processes to take place in our bodies. Sound waves are harvested in the ear and, through a series of complex steps, are relayed to the auditory cortex of the brain for interpretation. It is this process that has played a vital role in protecting our species from evolutionary threats, including predators; and it is this process that - should any of the crucial steps fail - can lead to hearing loss.

The folds of cartilage of the outer ear reflect sounds and help our brain to determine where the sound is coming from. As sounds enter and pass through the narrow auditory canal - a tube leading to the ear drum - they are amplified.

Separating the external and middle ear is the tympanic membrane - commonly referred to as the ear drum and the principal piece of machinery in the ear for gathering sounds. At the ear drum, the vibrational energy is passed to the three tiniest bones of the human body: first the malleus, which is attached to the ear drum; then the incus; and finally the stapes, which is attached to the 'oval window' - the opening to the inner ear.

Estimates suggest that the design of the ear amplifies the sound as much as 900-fold before it enters through the oval window into the inner ear.

The inner ear comprises two parts: the cochlea, which is responsible for hearing, and the vestibular system, which serves an important function in motion and balance. Inside the cochlea is the organ of Corti - the sensory organ of hearing, which houses thousands of sensory hair cells that can detect the smallest vibrations in the cochlear fluid. These sensory hair cells are extremely delicate and, if destroyed, are never replaced.

When the hair cells move in reaction to the waves in the cochlear fluid, that motion is converted into electrical signals. The signals are communicated to many thousands of auditory neurons, where they are converted into impulses and sent to the auditory brainstem for processing. They are then transferred to the auditory cortex of the brain, which sits among regions of the brain that are fundamental to memory, attention, perceptual awareness, thought, language, and consciousness. Here, finally, a conscious awareness of the sound takes place.


Using mice to study deafness




A high level of homology between the human and the mouse genome mean that genetic discoveries in the mouse have immediate implications for the research community's understanding of human deafness.

The Institute's Genetics of deafness team has worked with many mice and Jenny is concentrating on two models in particular: dearisch and diminuendo. The team's aims are, in the simplest terms, to identify genes responsible for the deafness and to understand how they can exert their effect. To do this, the team need to look at mouse mutants that exhibit the symptoms of deafness.

The mice Jenny works with at the Sanger Institute were generated using ENU-induced mutagenesis. ENU - or n-ethyl-n-nitrosourea - is a chemical mutagen that can induce frequent mutations in gametes.

Using ENU, research teams can mutagenise the mouse genome at random on a large scale. Mice born from fathers treated with the chemical are subject to behavioural, physiological and dysmorphology assessments. If a deafness phenotype is identified, those mice become the subject of genetic otology research.

Since its discovery as a mutagen in the middle of the 20th century, ENU has led to the discovery of many novel genes for a number of pathologies, cementing the importance of the phenotype-driven method in exploring disease genetics using mouse models.

Jenny and the Sanger Institute team receive deaf mice from a large-scale production of ENU mice which is made as part of the German Human Genome Project. The team generate low resolution genome maps followed by higher resolutions until a candidate gene is identified and confirmed using sequencing or other techniques.

"The diminuendo mouse model is a great example of the processes we have used to study deafness," explains Jenny. "The team examined a mouse that exhibited the characteristics of deafness and were able to breed more mice with identical symptoms. Next they hunted down the specific gene that was causing the deafness, and we are now engaged in trying to understand how the gene exerts its effect to cause the deafness."

The team started studying the diminuendo mouse several years ago, before Jenny had arrived at the Institute. Eventually, in 2008, Morag Lewis, a postdoc in the team, found the gene - a novel microRNA - responsible for the hearing loss. After further investigation, they found that the mutation in the microRNA downregulates the activity of five other genes thought to be associated with hearing loss. Jenny is keen to repeat this success in looking at the next mouse model - called dearisch.

"We hope that it won't be long now before the gene that causes the hearing loss in the dearisch model will also be revealed, as we continue to map the genome of this particular mouse," explains Jenny. "I am looking forward to seeing the results of genetic research 'up close' for the first time. We always hope that the gene we find will be novel and provide the research community with new insights that will help to diminish the problem of deafness in the future."

Already, initial experiments carried out by Jenny and the team seem to suggest that the dearisch model is exhibiting the symptoms of otitis media or inflammation of the middle ear. Acute cases of otitis media can result in conductive hearing loss - one of the most common forms of hearing loss in children.

Once the team identify a mutation, they can explore the consequences of the mutation for gene activity across the whole hearing organ. With the help of the Institute's Microarray facility, they carry out gene expression profiling to provide a global picture of the activity of thousands of genes. To achieve this, they study mouse models at different ages. Jenny and the team look at how a mutation exerts its influence over the activity of other genes downstream in the chain of genetic events. In so doing they hope to reveal a more complete picture of the complex interaction of genes contributing to a deafness phenotype.

"We are now looking at the five genes of interest that are downregulated by the mutation in the diminuendo model," says Jenny. "But we want to delve deeper into the relationship between the genetics and the biology of the ear. We want to know what other genes are affected, but also, we want to know which cells are affected. We are striving for the fullest biological picture we can get."

The future

Mouse embryonic stem cells.

Mouse embryonic stem cells.


Like all genetic research, deafness research seeks to develop a comprehensive understanding of genetic causes. To complement the ENU mutagenised mice, currently used by Jenny's team, the Sanger Institute's Mouse Genetics Programme has ambitious aims to make the organism available to study a whole variety of phenotypes and diseases in more detail. As part of an international collaboration, the Sanger Institute plans to develop a complete resource of mouse models with mutations in each of the 20,000 or so mouse genes. Using mutants derived through individual gene knock-outs will provide an alternative, genotype-driven approach to finding mutations contributing to deafness. Because ENU-induced mutagenesis is random, its efficacy in generating mutations in novel genes is set to decrease. A complete resource of gene knock-outs in the mouse will be of enormous value not only to the Genetics of deafness team, but throughout disease genetics.

Jenny has a strong conviction that turning scientific results into clinical benefits will be the key to progress for her patients, but she is also very aware of the long road that leads to improvements in healthcare.

"Genetic research into deafness will lead to improved treatments for hearing loss, I am sure," says Jenny. "It is more a case of 'when' this will happen than 'if'. Over recent years and indeed months, we have seen important developments, both at the Sanger Institute and elsewhere. These results convince me that, although it may take years or even decades, stem cell and genetic treatments are on the horizon.

"At the same time, some of the most valuable lessons I have learnt since I came to the Sanger Institute are in perceiving the limitations of what can and can't be achieved through research at this time."

As for Jenny's future, there is still a lot of research and discovery ahead on the PhD programme.

"Jenny's enthusiasm and motivations are founded in a desire to improve the prognosis of people affected by hearing impairment," says Professor Karen Steel, leader of the Sanger Institute's Genetics of deafness team. "This is precisely at the foundation of the clinical PhD programme at the Sanger Institute: the program is about linking basic science with medicine.

"That relationship has never been more important than it is now."

In the meanwhile part of Jenny's challenge will be to keep up with developments in clinical practice. Once a fortnight, Jenny works with Dr Patrick Axon, consultant Ear Nose and Throat surgeon at Addenbrooke's hospital, helping him in a clinic that specialises in skullbase inner ear surgery.

Ultimately, Jenny's ambition is to marry her scientific and medical training to boost her clinical career. After her PhD, she plans to embark on more specialist training, hoping to become a Ear Nose and Throat surgeon. However, Jenny's time at the Sanger Institute has also whetted an appetite for research and she hopes to combine her medical career with research in the future.

"The ethos at Addenbrooke's was absolutely instrumental in my decision to come to the Sanger Institute," she says. "It is an ethos that encourages you to be the absolute best you can be and to do the absolute best you can do for the patients in your area. I am very grateful that Karen and her team here at the Sanger Institute have afforded me the opportunity to try to fulfil some of these aspirations here."

  • Minireview: MicroRNAs sound off.
    Weston M D and Soukup G A. (2009)
    Genome Medicine.
    Available online at: 10.1186/gm59
  • An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice.
    Lewis M et al. (2009)
    Nature Genetics.
    Available online at: 10.1038/ng.369
  • A genetic approach to understanding auditory function.
    Steel K P and Kros C J. (2001)
    Nature Genetics.
    Available online at: 10.1038/84758
  • Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses.
    Zheng Q Y, Johnson K R, Erway L C. (1999)
    Hearing Research.
    Available online at: 10.1016/S0378-5955(99)00003-9
  • Genome-wide, large-scale production of mutant mice by ENU mutagenesis.
    Hrabé de Angelis M et al. (2000)
    Nature Genetics.
    Available online at: 10.1038/78146

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