In microfluidic units like this, Bumsoo Han’s workforce observes how most cancers cells behave in a simulated organic setting. Credit score: Purdue College picture/Jared Pike
Most cancers cells migrate by the physique for a number of causes; some are merely following the move of a fluid, whereas others are actively following particular chemical trails. So how do you establish which cells are transferring and why? Purdue College researchers have reverse-engineered a mobile sign processing system and used it like a logic gate – a easy pc – to higher perceive what causes particular cells emigrate.
For a few years, professor of mechanical engineering Bumsoo Han and his analysis group have been learning most cancers cells. He builds microfluidic buildings to simulate their organic setting; he has even used these buildings to construct a “time machine” to reverse the expansion of pancreatic most cancers cells.
“In our experiments, we’ve been observing and learning how these most cancers cells migrate, as a result of it’s an necessary side of most cancers metastasis,” mentioned Hye-ran Moon, postdoctoral researcher on Han’s workforce. “However that is completely different. We are attempting to deal with the basic mechanisms behind these behaviors. And it’s very difficult as a result of cells are very advanced programs of molecules, and they’re uncovered to a number of cues that trigger them to maneuver.”
A kind of cues entails chemical trails, which many cells are inherently drawn to (very like ants following a scent path). One other is fluid move; if fluids are flowing round cells in a sure route, many cells will simply go alongside for the trip. So if a cell is transferring, how are you going to inform if it’s motivated by chemical compounds, fluid motions, or each?
The workforce adopted a ternary logic gate mannequin to research these cues, and predict how cells would transfer beneath completely different environments. Their analysis has been printed in Lab on a Chip, a journal by the Royal Society of Chemistry.
Their experiments befell in a microfluidic platform with a middle chamber for the cells, and two aspect platforms. Utilizing this system, they might replicate fluidic flows in a single route, in the wrong way, or no move in any respect. They may additionally introduce a chemical recognized to trigger the cells emigrate. Once more, that they had the choice of chemotaxis in a single route, the wrong way, or none in any respect. Would these two cues multiply, or cancel one another out?
“With two cues and three selections every, we had sufficient observable knowledge to construct a ternary logic gate mannequin,” mentioned Moon.
Logic gates are a assemble from computing, the place transistors take a 1 or 0 enter and return a 1 or 0 output. Binary logic gates take a mixture of two 1s and 0s, and output completely different outcomes based mostly on what sort of gate it’s. Ternary logic gates do the identical factor, besides with three potential inputs and outputs: 1, 0, and -1.
Moon assigned values to which route the cells moved beneath the 2 completely different stimuli. “If the cells moved within the route of the move, that’s 1,” mentioned Moon. “In the event that they don’t have any directionality, that’s 0. In the event that they transfer in the wrong way to the move, that’s -1.”
When cells encountered both chemical compounds or fluid move individually, they moved within the constructive route (the “1”). When each had been current in the identical route, the impact was additive (nonetheless “1”). Nevertheless, when the 2 flowed in reverse instructions, the cells moved within the route of the chemical compounds (the “-1”), reasonably than the fluid move.
Primarily based on these observations, Moon extrapolated a 3×3 grid to simplify the outcomes. The cues of those most cancers cells may now be diagrammed very like {an electrical} engineer would diagram a circuit.
After all, the actual world isn’t that easy. “In reality, the chemical stimulus is a gradient, not an on-off change,” mentioned Moon. “The cells will solely transfer as soon as a sure threshold of move has been launched; and if you happen to introduce an excessive amount of, the cell short-circuits and doesn’t transfer in any respect. The accuracy with which we can predict that movement is a non-linear relationship.”
Moon also stressed that this particular experiment is very simple: two stimuli, in strictly opposite directions, in a single dimension. The next step would be to build a similar experiment, but in a 2-dimensional plane; and then another in a 3-dimensional volume. And that’s just for starters; once you add multiple stimuli, and factor in time as the 4th dimension, the calculations become incredibly complex. “Now you understand why biologists need to use supercomputers!” said Moon.
“This is a perfect example of how microfluidic devices can be used in cancer research,” said Moon. “Doing this experiment in a biological environment would be extremely difficult. But with these devices, we can go right down to individual cells and study their behavior in a controlled environment.”
“This model can apply to far more than just physical cancer cells,” Moon continued. “Any cells can be impacted by different cues, and this provides a framework for researchers to study those influences and determine why they happen. Genetic engineers also have embraced the logic gate model, treating genes as processors that give different results when you give them certain instructions. There are many branches we can go with this concept.”
Reference: “Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues” by Hye-ran Moon, Soutick Saha, Andrew Mugler and Bumsoo Han, 16 December 2022, Lab on a Chip.
DOI: 10.1039/D2LC00807F
This study was in collaboration with the Purdue Institute for Cancer Research; the Weldon School of Biomedical Engineering; the Purdue Department of Physics and Astronomy; and Andrew Mugler and Soutick Saha of the University of Pittsburgh Department of Physics and Astronomy.
Funding: NIH/National Institutes of Health, National Science Foundation
