Last updated January 24, 2018 at 4:50 pm
Californian researchers have cleared the way for ultrasound to become a tool to interact within the body at the micro-scale.
Bacteria containing gas-filled protein nanostructures known as gas vesicles. The nanostructures can scatter sound waves to produce ultrasound contrast. This allows the bacterial cells to be tracked non-invasively inside animal hosts. Credit: Barth van Rossum/Caltech
By combining ultrasound imaging with genetic engineering of bacterial microbes, scientists have been able to track bacteria dispatched to deliver therapies deep inside the body.
The potential, they say, is for doctors to use this approach to keep tabs on the effectiveness of treatments for everything from inflammatory disease to cancer.
“Ultrasound has been around for 100 years; it has been used in diagnostic imaging for 50 years and for therapies in the clinic for 10 years or so,” said Dr Randy King from the National Institute of Biomedical Imaging and Bioengineering, which funded the work by a team from California Institute of Technology (Caltech) .
Bioengineering bacteria
“This is the next step, where we will see ultrasound become a tool to interact within the body at the micro-scale.”
The key to the breakthrough was discovering a way to bioengineer bacteria with ultrasound scattering particles to create a good image. When injected into mice and scanned with ultrasound, the genetically altered bacteria can be tracked.
The new technique offers greater precision than popular light-based methods such as fluorescence and bioluminescence for biological detection when used for imaging of living organisms.
Fluorescence uses a dye molecule or genetically coded fluorescent protein that can be detected under a light source. Bioluminescence, like the light of a firefly, glows on its own.
The work build on previous research by team leader Dr Mikhail G. Shapiro, an assistant professor of chemical engineering at Caltech, who discovered that cylindrical gas-filled protein nanostructures called gas vesicles, which exist in various types of aquatic microbes, could be imaged with ultrasound.
The gas vesicles give the microbes buoyancy in their natural environment and their gas contents yield a distinct signal on an ultrasound scan.
Modified bacteria visible to ultrasound
By isolating the genetic sequence for the gas vesicles from aquatic microbes, then inserting that sequence into the genome of bacteria, the researchers produced modified bacteria visible to ultrasound.
They then adapted the genetic sequence for gas vesicles from two types of microbes to make optimally detectable bacteria.
Luminescent bacteria are detected, left, but optical imaging lacks detail of surrounding deep anatomy. Ultrasound imaging, right, depicts modified bacteria in the colon and nearby the bladder. Credit: Shapiro Lab, Caltech
“The challenge was to take this fairly complex genetic machinery to form these structures and move it into this new cellular environment, and have it work properly,” Dr Shapiro said.
To enhance the ultrasound contrast, the researchers used high-pressure pulses to collapse the gas vesicles during imaging.
They wanted to produce slightly different gas vesicles that collapse at different pressure thresholds to demarcate two separate microbes in a biological environment.
They also demonstrated that collapsing gas vesicles did not damage or affect cells’ reproductive potential.
Genetically engineered cell therapies
Dr Shapiro believes genetically engineered cell therapies offer some advantages over working with small molecules that today are the focus of many of pharmacological discoveries.
“Molecules as a therapeutic solution are fairly limited, going somewhere in the body to bind to a receptor or block a particular enzyme,” he said.
“Cells that you’ve engineered genetically can be more versatile; they can migrate to sites of disease, detect signals in their surroundings and perform functions based on those signals that allow them to decide whether to either kill cells, release molecules, self-destruct, or multiply.”
The researchers are depositing the gene sequences for gas vesicle modification of bacteria to AddGene, a not-for-profit repository that facilitates free data sharing among scientists around the world.
The paper was recently published by Nature.
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