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The cells synchronize to release the toxins in unison



Manu Prakash, an associate professor of bioengineering at Stanford University, was squatting in the mud of the Baylands Nature Reserve in Palo Alto. He scanned his Foldscope – an origami microscope of his invention – examining the inhabitants of the marsh's brackish waters. With his eye trained on a large single cell organism, called Spirostomumhe watched her do something that immediately made her her next research topic.

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Kurt Hickman

Cell life in a local swamp led researchers Manu Prakash and Arnold Mathijssen to discover a new type of intercellular communication.

"I still remember for the first time ever seeing this body swimming under the Foldscope," Prakash said. "It's a massive cell, but it shrinks in less than a blink of an eye and accelerates faster than almost any other cell. When we do not wait, it's as if it disappears. I remember being so excited that I had to take the cells back to the lab and take a close look at them.

This observation, made using a simple tool, just five miles (4.8 km) from the Prakash laboratory, led him and his colleagues to discover a new form of communication between cells that they detail in an article published on July 10 in Nature. Without touching and without electrical or chemical signals, individual Spirostomum can coordinate their ultra-fast contractions so tightly that groups of them seem to contract simultaneously – a reaction to predators that causes them to release paralyzing toxins in a synchronous manner.

"There are many ways to communicate in biology, but it's a new kind of cell-to-cell signaling that we're trying to understand," said Arnold Mathijssen, a postdoctoral researcher at Prakash Lab and lead author of the article. "It is possible that it is more universal than what we have described so far and that many types of organisms communicate."

Benches with black holes

The Prakash lab collects wild samples of various tiny organisms in an area they call Peggy's Bench – so named in reference to a nearby memorial bench – and they come here for years, often two or three times a week. A mixture of salt and fresh water, changing tides and migrations of birds make the marsh a hot spot of potential biodiversity. Although Prakash did not know anything about this during his first visit.

"Lake Lagunita was dry and I was looking for a new place to taste," said Prakash, referring to a small seasonal lake on the Stanford campus. "I looked at the GPS map on my phone and saw that blue dot. I did not know anything at first, but it was worth it to try. "

Back in the lab, the group studied wild samples of Spirostomum while developing their own cultures of Spirostomum ambiguum, and began a deep dive into the details of this ultra-fast contraction. Using high-speed imaging, they discovered that this occurred in 5 milliseconds – the human eye took between 100 and 400 milliseconds to flash – and that the cell withstood about 14 times the force of gravity of the process. In narrowing, pockets of toxin detach from the edges of the cell and release their contents into the surrounding liquid.

During a late night in the lab, the researchers also noticed that the cells all seemed to contract at the same time.

"We were wondering," How can cells that are several centimeters apart synchronize to do something simultaneously? Said Said Bhamla, a former postdoctoral fellow at Prakash Lab, who became assistant professor at Georgia Tech.

The researchers solved this mystery by applying the findings of various research conducted by Deepak Krishnamurthy, another graduate student at Prakash Lab, on how an individual cell can detect the movement of water around it. Once they observed the flow fields around Spirostomumit became clear that they communicated via hydrodynamic flows.

"The first cell contracts and generates a flow that triggers the second and triggers the third. So you get that trigger wave that is spreading throughout the colony, "Mathijssen said. "These are large, long-range vortex flows and communication speeds increase to several meters per second, even though each cell is only 1 to 4 millimeters long."

Mathijssen understood what triggers the contraction of the first cell through an experiment that Prakash and Krishnamurthy had already built for Krishnamurthy's research. By sucking the liquid very carefully through a small hole in a pair of slides containing S. ambiguumMathijssen imitated the food action of his predators. The closer the cell was to the hole, the more one end of its body was stretched in relation to the other, as happens when an object approaches a black hole. With this simple and relatively large experiment, the researchers determined that a specific amount of body tension was likely to cause the opening or closing of tension-dependent ion channels. S. ambiguum, by contracting it.

Where the wild things are

Prakash laboratory and Bhamla laboratory continue to work on S. ambiguum to learn more about how, when and why these cells contract. They also want to know if the hydrodynamic communication they have discovered is used by other organisms, because in nature, creating and detecting flow is essential for survival. As part of this research and other work, Prakash Laboratory regularly visited Peggy's Bench.

"Although this place was an accidental discovery for me, we are working on several projects in the lab that have been inspired by what we have collected here," said Prakash, while standing on the edge of the swamp. "This work is only one example of the many hidden gems we can find when we leave the lab – and anyone with simple tools, like Foldscope, can discover and begin to explore."

In the near future, Prakash plans an extensive biodiversity study in the swamp where they collect Spirostomum, which would include creating a live video-based microscope of the aquatic world of their subjects and leading undergraduates to explore this swampy field.

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Additional co-authors are from the Georgia Institute of Technology. Prakash is also a member of Stanford Bio-X and the Institute for Research on Maternal and Child Health (MCHRI), a member of Stanford ChEM-H and an affiliate of the Stanford Woods Institute for the Environment

This research was funded by the Human Frontier Science Program, the Center for Cellular Construction of the National Science Foundation, the US Army Research Laboratory, and the US Army Research Bureau, BioHub Chan Zuckerberg. Howard Hughes Medical Institute.


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