Inspiration

The ability to hear is one of most essential ways for us to interact with the world. Without this ability, a lot of joy could have been taken away from one's life. However, there are 360 million hearing-impaired people around the world, accounting for 5% of the world’s total population.^[1] In China, approximately one in six people has some hearing impairment, where more than 20% of them are completely incapable of hearing.

Suddenly, the audible world comes to an end. Demonic buzzing replaced the ambient sound I have been hearing for years.

Despite this serious situation, hearing loss is still categorized as "incurable" for most of the patients.^[3]

The neurological and physical causes of hearing loss are complicated. Human hearing system is a complex pipeline with both mechanical and neural components. While the mechanical part can be repaired by surgical processes, cure for sensorineural hearing loss remains highly experimental and ineffective.^[4]

One ingenious invention, namely the cochlear implant, greatly changed the situation for the people with hearing impairment. This little device converts sound directly into electronic pulses recognizable by the cochlear nerve endings, the structure that passes audio information to the brain. However, such devices significantly increases the probability of bacterial meningitis.^[5] We cannot hesitate to wonder, "What if the bulky electronics can be replaced by a tiny layer of cells?".

After putting extensive effort into researching previous literature, we gradually realized that there is a winding road awaiting our exploration. Compared to what has been done for optogenetics and chemogenetics, work done on regulating gene expression by sound, namely "audiogenetics", is like starlight to moonshine. How could we help people hear without a way to sense sound?

We decided to use synthetic biology methods to explore how cells sense mechanical stress, such as sound wave. Traditional gene expression regulation techniques, for example, optogenetics and chemical genetics, are commonly used in biological science but with certain limitations. Here we design a new way, audiogenetics, by which we can not only regulate gene expression in cells precisely and nontoxically, but also have an in-depth and comprehensive understanding of our feelings.

Research

Here we designed a new way called audiogenetics, to precisely and nontoxically regulate the gene expression in cells. It used a membrane mechanosensitive channel, transient receptor potential channel 5 (TRPC5), and mammalian mechanosensitive Piezo1 channel, to transform the audio wave energy as the extracellular input signal into intracellular downstream signal. Also, we quantitatively examine the sensibility of TRPC5 and Piezo to mechanical stress by using microfluidics and hypoosmolarity.

To make TRPC5 more sensitive to mechanical stress, we use protein engineering by evolution to get a mutated sTRPC5 (super TRPC5) with a high sensitivity to mechanical stress. The downstream signal is calcium ion, which is a second messenger in cells and we use calcium indicator (R-GECO) to quantify the intracellular calcium using live cell image. Cytosolic calcium regulates a series of phosphorylation and we know that it can induce specific promoters (PNFAT) transgene expression. Finally, we use GFP as the output signal to quantitatively analyze the regulatory ability of audiogenetics.

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Formula of Feeling Sound

References

1. ↑ Oishi, N.; Schacht, J. (June 2011). "Emerging treatments for noise-induced hearing loss". Expert opinion on emerging drugs. 16 (2): 235–45. PMID 21247358.
2. ↑ Our team member Fan Jiang has a history of hearing loss in his childhood at age 5, which took the audible world away from him for half a year.
3. ↑ Nakagawa, Takayuki (2014). "Strategies for developing novel therapeutics for sensorineural hearing loss". Frontiers in Pharmacology. 5. doi:10.3389/fphar.2014.00206
4. ↑ Sun H, Huang A, Cao S. 2011. Current status and prospects of gene therapy for the inner ear. Human gene therapy 22: 1311-22
5. ↑ Reefhuis, J., ... & Costa, P. (2003). Risk of bacterial meningitis in children with cochlear implants. New England Journal of Medicine, 349(5), 435-445.