Scientists discover a new gene essential for hearing

Scientists have associated a new gene – Clrn2 – with hearing in mammals. Led by Amraoui and Bowl, the study was a collaborative effort of 32 researchers from institutes in the UK, France, and the USA. The findings were recently published in the journal EMBO Molecular Medicine.


Cilia bundle in the inner ear. Picture adopted from EMBO Molecular Medicine

The sense of hearing results from a combination of events of physical and biological sciences. Mechanical energy from sound waves falling on the inner ear must be converted to neuronal signals for a person to hear. The process is taken care of by the specialized hair cells in the inner ear. On the tip of each hair cell is a bundle of cilia, some tall and some short, arranged in a specific manner and tethered to a complex. The movement of the inner ear fluid, caused by sound, deflects these hair cell bundles towards the tallest cilia. The tension created in the tip open the channels in the complex attached to it. The complex releases neuronal signals, completing the conversion of mechanical energy to neuronal signals.

Hearing loss can be caused by environmental factors, genetic factors or a combination of both. Although scientists have managed to understand early-onset hearing loss and hereditary hearing loss to an extent, very little is known about the genetics behind age-related hearing loss. The research conducted by this team has implicated the involvement of Clrn2 in age-related or progressive hearing loss.

The team mutated the Clrn2 gene in mouse and investigated its effect only to discover a progressive hearing loss. To check if the finding applied to humans as well, the group analysed the CLRN2 gene sequences of 5 lakh people from the UK biobank participants data. Data was segregated as hearing loss cases (163, 333) and controls with normal hearing ability (102,832). The cases and controls selected were above 50 years of age. The classification was made based on the participants’ response two questions recorded in the published paper – (i) Do you have any difficulty with your hearing? (ii) Do you find it difficult to follow a conversation if there is background noise (such as TV, radio, children playing)?  Those who answered ‘No’ to both were controls and other were cases. On analysing their CLRN2 gene sequence, the group found that those who had difficulty in hearing harboured mutations in their CLRN2 genes.

With further experiments on mice, the team discovered that while Clrn2 was necessary for the maintenance of the bundle of cilia in the hair cells of the inner ear after they had been formed. Mutations in this gene would, therefore, lead to poor maintenance of the bundle leading to progressive hearing loss.

From this study, scientists and clinicians now have a reference point to test for hearing loss because of ageing. We may be looking at days when the auditory tests, which are subjective, are replaced by the objective genetic tests for deafness.

Cancer drugs may not be working the way we think they work

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered that many anti-cancer drugs do not work the way we think they work. The study, led by Jason M. Sheltzer, evaluated 10 anti-cancer drugs in the pre-clinical or clinical trials. Findings of this research may help in establishing more stringent tests for drugs before trying them on humans.

cancer colorful word in the wooden background

Sheltzer’s earlier investigations of a protein, MELK, paved way to this study. Several reports had suggested that MELK was essential for the survival of cancer cells. But Sheltzer found otherwise – cancer cells survived even in the absence of MELK. They also found that an anti-cancer drug (OTS167), which the clinicians claimed would target MELK, killed cancer cells that were depleted of MELK. Clearly, OTS167 did not target MELK to kill the cancer cells.

Sheltzer adopted this strategy to study more anti-cancer drugs. The team shortlisted 10 anti-cancer drugs that were in pre-clinical or clinical testing. They selected drugs that clinicians claimed would stop the proliferation of cancer cells by targeting a single protein. The researchers then deleted the gene that coded for the claimed target protein using the CRISPR-Cas9 technology and checked if the cancer cells survived. But cancer cells were killed. This suggested that the drugs were not targeting these proteins.

The researchers particularly studied a drug (OTS964) targeting the protein PBK in greater detail. They gave enough time for cancer cells to accumulate mutations and develop resistance to OTS964 to find what protein the drug targeted. Cancer cells are genetically unstable and accumulate mutations over time. These mutations, resulting in changes in the protein they code for, restrain the drug from binding to the target protein. Knowing the genes that are mutated help us understand the actual target proteins. On analysis, they found that the gene coding for CDK11 had several mutations in it. This indicated that CDK11 was the actual target of this drug.

This may be one reason why 97 per cent of cancer drugs tested in clinical trials do not go on to receive US FDA approval. Understanding the accurate ‘mode of action’ of a drug increases the chances of its success. It is possible that the earlier experimental methods of inhibiting a gene or protein – RNAi and small molecule inhibitors – could be blocking some other protein in the cell. This may well the reason why drugs work differently than how we thought they would.

With advanced technologies like CRISPR-Cas9 technology, we can be more accurate. As the current study showed, this can be used as a method to test the claimed “mode of action” of the drug before they are tested on humans. This study also gives us a method to understand what proteins or genes are essential for the survival of cancer cells.

Pic Courtesy: China Daily