If immunotherapy has the cancer community riveted on the treatment side, liquid biopsies are equally exciting on the diagnostics end. And IBM is bringing its research heft to bear on the world of liquid biopsy with an intent to build a lab-on-a-chip technology that can separate particles at the nanoscale.
The ability to do that can help physicians to detect cancer much earlier before symptoms manifest.
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In a paper published Aug. 1 in Nature Nanotechnology, researchers from Big Blue highlighted dramatic improvements in a technology called nanoscale deterministic lateral displacement. The end result is a biochip that can sift 20 nanometer (a billionth of a meter) samples of DNA, RNA, exosomes and possibly viruses away from larger structures.
“We’ve created a structure in silicon that contains nanoposts — pillars that are about 100 to 200 nanometers,” said Gustavo Stolovitzky, program director of Translational Systems Biology and Nanobiotechnology, IBM Research and the paper’s co-author. “When biological structures are put into solution in the chip, they zig-zag through the pillars. Smaller particles go straight, while the larger pieces veer off, following the natural angle of the chip’s pillar structure. It’s kind of like a Pachinko machine, where the larger particles are bumping off the pillars and going in their natural direction while the smaller particles are not bumping and go straight.”
The chip is the first step towards developing a liquid biopsy, and exosomes may be the greatest prize. These vesicles — small structures within a cell made of fluid and enclosed by two layers of lipid — have been linked to cell signaling, garbage disposal and other functions. They run between 30 and 100 nanometer in size and carry DNA, RNA, surface proteins and other molecules that might deliver a snapshot of cellular health.
“Traditionally, exosomes were viewed as garbage cans that excrete anything that’s not wanted,” said Stolovitzky. “But now we are realizing they exchange information between cells. Exosomes contain mutations that are known to be present in particular types of cancer.”
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While nanoscale deterministic lateral displacement is more than a decade old, this is the first time researchers have been able to use it to sort such tiny structures.
“You have to get into the nanometer range to find interesting stuff,” said researcher Josh Smith, who also contributed to the paper. “The chip could be used instead of ultracentrifugation or size-exclusion chromatography, which are much more expensive and require lab technicians.”
For IBM, this is a high profile entry into the race for a fast and accurate liquid biopsy. These diagnostics could detect cancer early, track a therapy’s effectiveness in real time and accelerate drug development. Liquid biopsy represents a multi-billion dollar market and dozens of companies have entered the ring, including sequencing giant Illumina.
The study is a first step for IBM, proving they can sort by size. The next phase will improve the system’s efficiency, collecting enough exosomes to determine if they come from cancer cells. Eventually, disease information won’t be limited to cancer. Exosomes could provide important clues about neurodegenerative, metabolic and other conditions. The chip could also separate viruses – at least in principle – though that has yet to be tested systematically.
While some have expressed surprise that IBM has entered the liquid biopsy space, Stolovitzky and Smith believe it’s a natural extension of their existing skills.
“IBM is the perfect place to do what we’re doing because of the deep expertise in microelectronics and nanotechnology,” Stolovitzky said.
The group was given a mandate to separate, detect and manipulate single molecules on a chip. Now that they’ve achieved the separation piece, the team wants to create a modular platform that can perform multiple jobs.
“We have taken down what can be done on a chip significantly,” said Smith, “Now we have to build a standardized platform, where we can interchange building blocks. It would be like Lego bricks, where we can arrange them in different ways to perform a variety of diagnostic applications.”
The first target will be prostate cancer. Exosomes should contain a potential marker called prostate specific membrane antigen, which could advance early detection.
“The goal is to do a non-invasive analysis from urine to detect exosomes that indicate the presence of prostate cancer,” says Stolovitzky. “This study is the first proof-of-concept.”
Here’s a video of the technology:
Photo: Flickr user Rosmarie Voegtli
