Inhaling surprises could shape the future of health and agriculture

Imagine if we could inhale scents that delay the onset of cancer, inflammation, or neurodegenerative disease. Researchers at the University of California, Riverside, are preparing to bring this future technology closer to reality.

In laboratory experiments, a team led by Anandasankar Ray, professor of molecular, cell and systems biology, detected the fruit fly (Black-bellied fruit fly) to diacetyl, a volatile microbial compound secreted by yeast, and found changes in gene expression in the fly's antennae within a few days. In separate experiments, the team found similar changes in gene expression in mice and human cells.

“That exposure to an odor can directly alter gene expression, even in tissues that do not have odor receptors, came as a complete surprise,” Ray said. “These molecules are able to reach the cell nucleus through the cell membrane.”

Diacetyl is widely used to flavor foods and beverages. It is found naturally in a variety of dairy products and is a natural byproduct of fermentation and fermentation. While diacetyl is found in beer, wine, Greek yogurt, and many ripe fruits, it is considered unsafe to inhale in high concentrations.

“Our initial discovery was made using diacetyl, as a proof of concept, and this compound may not be the ideal candidate for treatment,” Ray said. “We are already working to identify other volatiles that lead to changes in gene expression. Our important finding is that some volatile compounds released by microbes and food can alter epigenetic states in neurons and other eukaryotic cells. Our report is the first report on “Common volatile materials that behave this way. It opens a whole field of investigation. The possibilities are limitless.”

Research published in eLifeIt shows that changes in gene expression and chromatin—the mixture of DNA and proteins that make up chromosomes—are possible in an organism even without the organism actively consuming the source of the volatile compound. The source can be at some distance from the organism.

“We have shown for the first time that some of the odor molecules we are exposed to that are absorbed into cells of the skin, nose and lungs, and possibly into the brain via the bloodstream, fundamentally alter gene expression,” Ray said. He said. “Is this something to worry about? How does this affect our susceptibility to certain diseases? How exactly does it affect the genes that we express? These questions remain unanswered.”

Ray's team found that diacetyl can act as an inhibitor of histone deacetylase, or HDAC, enzymes, and they discovered several related volatiles with similar potential. HDAC inhibitors are used as anti-cancer drugs and may also find use in the treatment of inflammatory diseases as well as neurodegeneration. When HDACs, which are conserved in plants and animals, are inhibited, DNA becomes less compact in cells, leading to more gene expression.

“This opens the possibility of odor-based HDAC inhibitors to delay neurodegeneration or memory deficits in diseases,” Ray said.

In fruit flies, Ray's team found that exposure to the volatile diacetyl substance significantly slowed the deterioration of photoreceptor cells associated with Huntington's disease. In genetically modified mice, the team found that exposure to diacetyl showed changes in gene expression in the lungs and brains. Levels of genes that are upregulated in cancers such as neuroblastoma showed a significant reduction in mice exposed to diacetyl.

In human cell lines, the team found that diacetyl changed acetyl levels, with higher levels of acetylation leading to higher levels of gene expression. In further tests on human cancer cell lines, the team found that exposure to diacetyl prevented the spread of neuroblastoma.

Aside from human diseases, the research has huge implications for agriculture. Because HDACs are highly conserved, they also affect plants.

“Plants seem to have a very strong response to some of these volatiles,” Ray said. “In plants, any process that requires changes in gene expression can now be affected by exposure to this special class of odorants.”

Ray explained that volatiles are like mini-medicines that can alter gene expression levels and exploit a plant's genetic potential to improve root, leaf and flower growth and even responses to abiotic stress such as freezing and drought.

“Volatile chemicals can deliver a therapeutic dose to plants and animals, without the need for pills or injections,” he said. “They can simply be inhaled, giving a new meaning to aroma-based therapy.”

With the help of UCLA's Office of Technology Partnerships, Ray filed patents for volatiles that could slow neurodegeneration and cancer and alter plant growth and responses to stress.

Last year, Ray launched a startup, called Remote Epigenetics, which has the exclusive license to use these volatiles that alter gene expression. The company's headquarters are located in the multi-purpose research building on the UCLA campus. The new agritech startup will focus on developing new tools for farming using low-cost volatile materials to address several important problems.

Joining Ray in the research were Sachiko Haga-Yamanaka, Rogelio Nunez-Flores, Christy Ann Scott, Sarah Berry, Stephanie Turner Chen, Crystal Pontrello, and Mira Goh Nair from UCLA.

Ray is also the founder of another startup, Sensorygen, which works on the computational neurobiology of smell and taste.

The research was funded in part by the National Institutes of Health and the UCLA Agricultural Experiment Station.

reference: Haga-Yamanaka S, Nunez-Flores R, Scott CA, et al. Plasticity of gene expression in the nervous system by exposure to environmental odors that inhibit HDACs. eLife. 2024;12:RP86823. doi: 10.7554/eLife.86823.3

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