NATURE OUTLOOK -- Biologists studying extracellular RNA (exRNA) — and the tiny spherical structures known as exosomes that shuttle this genetic information from cell to cell — typically focus on mammals. As long ago as the 1960s, however, scientists found that plant cells also generate vesicles that carry cargo out of the cell membrane. But for decades, these botanical observations were largely forgotten.
Plant biologist Hailing Jin at the University of California, Riverside, is trying to revive the field to work out how plants send cellular messages. She has found evidence that plants do this, in part, to thwart their fungal enemies. She is now designing fungicides that are based on exRNA.
Her team has engineered tomato plants to release exRNA that can silence the genes of the fungus Botrytis cinerea1, which causes the grey mould disease that destroys millions of fruit, vegetable and flower plants every year. “The plants are much healthier” than those that lack this special twist, Jin says. When sprayed with the fungus, the leaves of engineered plants remain green and vibrant, whereas their normal counterparts develop splotchy leaves that are darkened and dying.
In 2013, her group found evidence that exosomes facilitate ‘cross-talk’ between plants and fungi2. The researchers suggested that B. cinerea releases small RNAs that silence immunity genes in the model organism Arabidopsis thaliana. “Her 2013 paper was a real landmark,” says Roger Innes, a biologist at Indiana University in Bloomington. “It opened up whole new directions in plant science.”
Jin’s lab has since shown that Arabidopsis cells release extracellular vesicles that deliver RNA into B. cinerea, and that this RNA silences genes that are important in the fungus’s ability to infect plants3. And in a paper posted on the preprint server bioRxiv4, biologists reported that altering Arabidopsis so that the plants release exRNA offers some protection against a type of pathogenic bacteria. These results, which have not been peer reviewed, are “really shocking”, Innes says. “Bacteria don’t have a classic RNA-interference pathway — so it has to be incorporated into some novel pathway that’s leading to gene silencing in bacteria.”
Jin says that although some scientists are continuing to genetically modify vegetables and fruits to fight destructive fungi and bacteria with exRNA, the lengthy and expensive regulatory process for genetically modified food means her team is pursuing a different approach. It is instead designing antifungal crop sprays that contain the silencing RNA.
Other scientists have taken inspiration from the exRNA communication seen in plants to design human therapies. Huang-Ge Zhang, an immunologist at the University of Louisville School of Medicine in Kentucky, is trying to mimic the RNA-shuttling vesicles found in plants by extracting and repurposing cellular components of fruits and vegetables. He has shown that grapefruit juice contains lipids — molecules that make up much of the membrane of cells and exosomes — that can be assembled into small shells that he calls “exosome-like nanovectors”5. Zhang and his colleagues loaded these nanovectors with anti-cancer drugs and gave them to mice with tumours. They found that mice that received this form of therapy lived for an average of 42.5 days, whereas mice treated with either empty nanovectors or with the chemotherapy agent on its own lived for 20–30 days. Zhang says that one of the advantages of encapsulating drugs in this way is that the foods from which they are derived are non-toxic and cheap.
Zhang has received more than US$1 million from the US National Institutes of Health for his work. He is currently collaborating with researchers at Louisville’s James Graham Brown Cancer Center on a clinical trial to test the use of plant-derived vectors to deliver curcumin — a component of the spice turmeric — to treat colorectal cancer. Zhang is also exploring whether ginger-derived vectors can be loaded with RNA-based therapeutics. His projects have attracted some commercial interest. Other groups are also exploring whether plant-derived nanovesicles can be used to deliver cancer therapeutics.
Some scientists say, however, that Zhang’s drug-shuttling structures can’t be called exosome-like. They point out that even though the structures are roughly the same size as exosomes, and are built with lipid molecules, that doesn’t mean the structures behave in the same way. It’s not just their size that makes exosomes special, says Clotilde Théry, who studies exosome biology at the Curie Institute in Paris. “Many extracellular vesicles or particles other than exosomes can display the same range of size,” Théry explains, but they don’t necessarily behave like exosomes. It is unclear, for example, whether the nanovectors can transmit payloads to cells in the same way as some exosomes do. And the human immune system might thwart plant-derived nanovectors, rendering them useless.
Innes, for his part, is looking for more evidence that exosomes are indeed involved in RNA signalling. Circular cross-sections can be seen near plant cells under a microscope, but Innes wants to confirm that these shapes are exosome spheres, and not just cylindrical tubes. To do this, his group is creating ultra-thin slices of plant cells and capturing an image of each slice with an electron microscope. It can then digitally recreate the 3D shape of the tiny structures assumed to be exosomes. He’s sure that plants do send out RNA signals, but he wants to definitively show the form of the structures that shuttle this genetic information. “We know it works,” Innes says. “The big question right now is how.”
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