Bioimaging informatics tracking provides meaningful insight for multicellular behavior and eerily beautiful images
Science and art intersect…
The Royal Society has been around since 1660. Historically, it has published some of the top scientific papers in the world and continues to do so. Based in the United Kingdom, the society published Isaac Newton’s “Principia Mathematica” and the findings of Benjamin Franklin’s kite experiment. It counts among its fellows the likes of Richard Dawkins, Stephen Hawking and Tim Berners-Lee.
Earning a publication credit in one of the Royal Society’s journals would be a mark of distinction on any researcher’s resume. And now, two members of the MU College of Engineering’s Computer Science Department can claim that honor.
Associate Professor Kannappan Palaniappan and Assistant Research Professor Filiz Bunyak co-authored a research paper with three Princeton University researchers in Professor Joshua Shaevitz’s lab in the Department of Physics and the Lewis-Sigler Institute for Integrative Genomics called “Directional reversals enable Myxococcus xanthus cells to produce collective one-dimensional streams during fruiting body formation.” The paper was published in the August edition of the journal Interface, the Royal Society’s publication for “cross-disciplinary research at the interface between the physical and life sciences.” The research group garnered that issue’s cover image.
“The Royal Society has been publishing discoveries of members and scientists for 350 years,” Palaniappan said. “It’s a very prestigious journal, and to make the cover of the journal is very rare.”
The project at the center of the paper deals with how cells form multicellular patterns using the life cycle of the common bacterium M. xanthus, which can be found in most types of top soil around the world. This bacterium feeds on E. coli and other bacteria hunting in groups and swarms. Once its food source is exhausted, M. xanthus cells organize themselves into a three-dimensional fruiting body numbering upwards of 100,000 or more individual cells, differentiating into spores and becoming dormant until the environment becomes favorable. At that time, the cells shed their spore coats and return to their normal form to feed again. The mechanisms by which prokaryotic cells like M. xanthus form large multicellular structures remains unsolved.
The paper focused on the social motility swarming behavior during the initial stages of fruiting-body formation — namely, how freely motile cells communicate and alert one another and form the multi-cellular biofilm en route to forming the full fruiting body. Following the gliding motion of hundreds to thousands of cells precisely over nearly 10,000 frames is a challenging big data problem in bioimage informatics for which Bunyak and Palaniappan developed novel multicell tracking algorithms that can handle deforming rod-shaped cells. This allowed their collaborators at Princeton — Mingzhai Sun, Shashi Thutupalli and Joshua W. Shaevitz — to mine the quantitative image parameters for analyzing the complex behavior of these cells and develop the phase transition model.
Sun is an MU alumnus who earned his doctorate in physics from MU in 2008.
“The goal is to be able to track a large enough number of bacteria to generate accurate statistics,” Bunyak said. “You can’t just track 10 cells and derive meaningful insight about multicellular behavior from it.”
What the research found was that the cells aggregate and oscillate back and forth in a given local space under nutrient starvation conditions, eventually connecting with other M. xanthus cells to form the streams which eventually make up the biofilm. In other words, starvation conditions trigger a reaction in certain individual cells that makes them stop roaming larger areas and switch to reversal behavior in a localized region.
“The cell glides forward, and then it goes back,” Palaniappan said while showing a video of the phenomenon. “This periodic motion is called directional reversal. The reversal events are critical for triggering complex fluid-like behavior, so that’s one of the signaling mechanisms to shift the cell behavior from adventurous or A-motility into social or S-motility swarming and rippling modes.”
Tracking enough cells to have a statistically significant sample is an exquisite experimental process. The Shaevitz lab at Princeton had to precisely align the microscope stage and high-powered camera needed to track the bacteria organisms with nanometer positioning accuracy over the course of many hours collecting the imagery to use with Palaniappan and Bunyak’s algorithms.
“The scale of data collected and automatically analyzed was a gamechanger,” Palaniappan said. “Our high-throughput quantitative image analysis algorithms tracked more than 4 million cells in all — one of the largest biomedical cell tracking studies.”
“Previous imaging studies were limited in scale or number of cells and didn’t have enough statistics,” Bunyak said. “You could see a few individuals at high resolution or the whole group in low magnification. You could track the motion of the bacteria aggregate but couldn’t image and track all individual cells inside a group. By tracking individual cells, now we can answer questions about behavior like reversal frequency and group dynamics because we have the right data.”
The paper addresses both engineering and science — computational quantitative image analytics combined with modeling the remarkable transition from single cell to multicellular behavior. M. xanthus frequently is used as a model organism for the study of cell to cell interactions thanks to its life cycle. Understanding how the cells communicate could eventually lead to applied breakthroughs, particularly in the medical world.
“The way that we frame it in the paper is it’s a way of characterizing emergent self-organization behaviors. Maybe by developing a model that captures population scale cell behavior, we will be able to relate the emerging behavior to molecular, genomic, proteomic networks and cell-to-cell signaling mechanisms, connecting the two scales together,” Palaniappan said.
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