Tracking the life cycle of a single cell

Microchip-like technology allows single cell analysis

Lloyd Dunlap
DURHAM, N.C.—A U.S. and Korean research team has developed a chip-like device that could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes. The system is similar to a random access memory chip, but it moves cells rather than electrons.
 
Researchers at Duke University and Daegu Gyeongbuk Institute of Science and Technology (DGIST) in the Republic of Korea hope the cell-sorting system will revolutionize research by allowing the fast, efficient control and separation of individual cells that could then be studied in vast numbers.
 
“Most experiments grind up a bunch of cells and analyze genetic activity by averaging the population of an entire tissue rather than looking at the differences between single cells within that population,” explains Benjamin Yellen, an associate professor of mechanical engineering and materials science at Duke’s Pratt School of Engineering. “That’s like taking the eye color of everyone in a room and finding that the average color is grey, when not a single person in the room has grey eyes. You need to be able to study individual cells to understand and appreciate small but significant differences in a similar population.”
 
“The goal is to track the life cycle of a single cell from inception to lysis,” Yellen adds. What happens to the cell when a drug is added, dosages are changed or drug combinations are tested? “We would want to include reporter genes,” Yellen notes, “to find out when they come out of latency.”
 
A journal article about the study, “Magnetophoretic circuits for digital control of single particles and cells,” that was written up by the Duke-Korean team appeared online May 14 in Nature Communications. In it, they point out that rare biological responses “are overlooked by the ensemble averaging approaches of traditional biology. Improved understanding of these rare cellular responses can profoundly impact the development of vaccines and pharmaceuticals for curing infectious diseases and cancer . . . In particular, there is an urgent need for tools to organize large arrays of single cells and single-cell pairs, evaluate [their] temporal responses over long durations and retrieve specific cells from the array for follow-on analyses. The desired capabilities of single-cell arrays bear strong resemblance to random access memory (RAM) computer chips, including the ability to introduce and retrieve single cells from precise location of the chip (writing data) and query the biological state of specified cells at future time points (reading data).”
 
Yellen and his collaborator, Cheol Gi Kim of DGIST, printed thin electromagnetic components like those found on microchips onto a slide. These patterns create magnetic tracks and elements like switches, transistors and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin liquid film.
 
Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much like electrons are controlled on computer chips.
 
In the study, the engineers demonstrate a 3-by-3 grid of compartments that allow magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied and retrieved.
 
In a RAM chip, similar logic circuits manipulate electrons on a nanometer scale, controlling billions of compartments in a square inch. But cells are much larger than electrons, which would limit the new devices to hundreds of thousands of storage spaces per square inch.
 
But Yellen and Kim say that’s still plenty small for their purposes.
 
“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” says Yellen. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”
 
As an example, Yellen points to cells afflicted by HIV or cancer. In both diseases, most afflicted cells are active and can be targeted by therapeutics. A few rare cells, however, remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission. With the new technology, the researchers hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them and analyze their genetic activity.
 
Yellen admits that they are far away from that goal right now, but as they move forward, “Maybe then we could find a way to target the dormant cells,” said Yellen.
 

Lloyd Dunlap

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