Colorized phage formations photographed under electron microscope compared to flowers
A group of McMaster researchers who routinely work with bacteriophages – viruses that eat bacteria – had a pleasant and potentially very important surprise while preparing slides to view under a powerful microscope.
After treating samples of what are informally called phages so they could be viewed alive under an electron microscope, the researchers were surprised to see they had joined together into three-dimensional shapes that look like sunflowers, but only two-tenths of a millimetre across.
With a little prompting, nature had served up the very kind of structure experts in their field have been trying for decades to construct artificially – one that turns out to be 100 times more efficient than unlinked phages at finding elusive bacterial targets.
Being able to create such structures opens possibilities for the detection and treatment of many forms of disease, all using natural materials and processes, the researchers say.
Their work is explained in a newly published article in the journal Advanced Functional Materials.
The initial discovery was a happy accident flowing from everyday laboratory work.
Rather than expose the sample phages to typical preparation processes, which involve temperatures or solvents that kill viruses, lead author Lei Tian and his colleagues had elected to treat them with high-pressure carbon dioxide instead. Tian, now a principal investigator at Southeast University in China, led the research while he was a PhD student and later a post-doctoral research fellow at McMaster.
While the researchers are used to seeing the microscopic viruses do amazing things, after the treatment they were stunned to see the phages had grouped together in such complex, natural and very useful forms.
“We were trying to protect the structure of this beneficial virus,” Tian says. “That was the technical challenge we were trying to overcome. What we got was this amazing structure, which was made by nature itself.”
The researchers captured images of the formations using the facilities of the Canadian Centre for Electron Microscopy, located at McMaster, and spent the last two years unlocking the process and showing how the new structures can serve very useful purposes in science and medicine.
“It was an accidental discovery,” says the paper’s corresponding author Tohid Didar, a mechanical engineer who holds the Canada Research Chair in Nano-biomaterials. “When we took them out of the high-pressure chamber and saw these beautiful flowers, it completely blew our minds. It took us two years to discover how and why this happened and opened the door to being able to create similar structures with other protein-based materials.”
In. recent years, researchers in the lab of senior author Zeinab Hosseinidoust, a chemical and biomedical engineer who holds the Canada Research Chair in Bacteriophage Bioengineering, have made significant inroads in phage research by making it possible able to prompt the beneficial viruses to connect together like a living, microscopic fabric, and even to form a gel that is visible to the naked eye, opening new vistas for their application – particularly in detecting and fighting infection.
Before the more recent discovery, though, it had not been possible to give the material shape and depth, which it now has through the wrinkles, peaks and crevices of the flower-like structures.
“This is really about building with nature,” says Hosseinidoust. “This kind of beautiful, wrinkled structure is ubiquitous in nature. The mechanical, optical and biological properties of this kind of structure have inspired engineers over decades to build these kinds of structures artificially, in the hope of getting the same kind of properties out of them.”
Now that they have triggered such a transformation and successfully duplicated the process, the researchers are marvelling at the collective efficiency the phages achieve by joining together and taking such forms, and they are exploring ways to use the same properties.
The porous, flower-like phage structures are 100 times better than their unlinked counterparts at finding scattered, diffuse targets even in complex environments, a fact the authors were able to prove by blending them with DNAzymes created by their colleagues in infectious disease research and using the blossom-like formations to find low concentrations of Legionella bacteria in water from commercial cooling towers.
Bacteriophages are re-emerging as treatments for many forms of infection, because they can be programmed to target specific bacteria while leaving others alone.
Work in the field had dropped off after the introduction of penicillin in the middle of the last century, but as antimicrobial resistance continues to erode the effectiveness of existing antibiotics, engineers and scientists, including the McMaster researchers, are returning their attention to phages.
The discovery of the process that causes them to link into flower shapes can boost their already impressive properties, both for finding and killing targeted bacteria, but also for serving as scaffolding for other beneficial microorganisms and materials.
“Nature is so powerful and so intelligent. As engineers, it’s our job to learn how it works, so we can harness processes like this and put them to use,” says Hosseinidoust.
“The possibilities are endless, because now we can make structures using biological building blocks.”
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