Success Story, April 14, 2019

April 14, 2019  |  Jola Glotzer

If you ‘jerk,’ you’ll die…

Four past CBC Awardees from Northwestern contribute to this fascinating Nature Communications publication: Andrew Stephens, John Marko, Guillermo Ameer and Vadim Backman

Northwestern scientists, led by Vadim Beckman, have recently published in Nature Communications a study which describes a real-time observation of changes occurring inside live cells exposed to UV radiation. The authors use a complex microscopy system, including a quantitative imaging technique called Partial Wave Spectroscopy (PWS) previously developed by Backman. They observe a novel biological phenomenon consisting of very rapid (milliseconds), seemingly random movements of chromatin inside the cells that are destined to die. The nature of this unexpected ‘burst of activity’ is currently unknown. Four past CBC Awardees have contributed to the study: Andrew Stephens, John Marko, Guillermo Ameer and Vadim Backman (for more details, please see below). The National Cancer Institute grant U54-CA193419 (CR-PS-OC; or Chicago Region Physical Science-Oncology Center), is acknowledged for providing partial support to the published work. This grant was secured by Backman, Lucy Godley (UChicago) and Jack Kaplan (UIC) in 2015 with the help of a matching CBC Lever Award for the project “Chicago Center for Physical Science-Oncology Innovation and Translation.” Congratulations to all authors involved in the current study and good luck with deciphering the mechanism behind the UV induced cellular paroxysm!

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New Imaging Technique Reveals ‘Burst’ of Activity Before Cell Death

Novel dual-PWS platform reveals connections between macromolecular structure and dynamic movement in the chromatin within eukaryotic cells

Northwestern Engineering News  |  by ALEX GERAGE  |  April 11, 2019

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This time-lapse video compares the structural and dynamics (fractional moving mass) response in control cells in the left column to cells irradiated with UV in the right column. Cellular paroxysm can be seen in the top right quadrant, after about 11 minutes of UV irradiation.

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Studying the movement of tiny cells is no small task. For chromatin, the group of DNA, RNA, and protein macromolecules packed within our genome, motion is an integral part of its active role as a regulator of how our genes get expressed or repressed.

“Understanding macromolecular motion is critical, but scientists know very little about it,” said Vadim Backman, Walter Dill Scott Professor of Biomedical Engineering at Northwestern Engineering. “Part of the reason is because we lack instrumental techniques to observe those processes.”

Now, a research team at the McCormick School of Engineering led by Backman has developed a new optical technique to study the movement of cells without using labels or dyes to track them. The innovative method has also revealed an undiscovered phenomenon that may play a role in the earliest stages of cell death.

The team’s insights were published on April 10 in the journal Nature Communications. The paper is titled “Multimodal interference-based imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm.”

While scientists can currently track the movement of cells using molecular dyes or labels, the practice comes with limitations. Dyes are toxic and alter the behavior of cells before, eventually, killing them. Labels are attached to cells, can be toxic or result in photobleaching, and may alter the motion of the very molecules they label.

The new technique, called dual-PWS, is label-free and can image and measure macromolecular motion without using dyes. Building off of a quantitative imaging technique previously created by Backman called Partial Wave Spectroscopy (PWS), the platform uses the interference and pattern changes from backscattered light to monitor both the macromolecular structure of cells along with their dynamic movement.

“Critical processes like the transcription of a gene or the repair of damaged proteins requires the movement of many molecules simultaneously within a highly packed, complex environment,” said Scott Gladstein, a PhD student in Backman’s lab and the study’s first author. “As an imaging platform with the capability to measure both intracellular structure and macromolecular dynamics in living cells with a sensitivity to structures as small as 20 nm with millisecond temporal resolution, the dual-PWS is uniquely suited to allow us to study these processes.”

The researchers applied dual-PWS to studying the nanoscale structural and dynamic changes of chromatin in eukaryotic cells in vitro. Using ultraviolet light to induce cellular death, the team measured how the movement of the cells’ chromatin was changed.

“It makes sense that as cells are about to die, their dynamics lessen,” Backman said. “The facilitative motion that exists in live cells to help express genes and change their expression in response to stimuli disappear. We expected that.”

What the researchers didn’t expect was to witness a biological phenomenon for the first time. A cell reaches a “point of no return” during decay, where even if the source of the cellular damage is stopped, the cell would be unable to repair itself to a functioning state, Backman said. Using dual-PWS, the researchers observed that just prior to this turning point, the cells’ genomes burst with fast, instantaneous motion, with different parts of the cell moving seemingly at random.

“Every cell we tested that was destined to die experienced this paroxysmal jerk. None of them could return to a viable state after it took place,” said Backman, who leads Northwestern’s new Center for Physical Genomics and Engineering.

The team is unclear why or how the phenomenon, called cellular paroxysm, occurs. Backman originally wondered if the movement could be due to ions entering the cell, but such a process would have taken too long. The uncoordinated motions of the cellular structures occurred over milliseconds.

“There’s simply nothing in biology that moves that fast,” Backman said. He added that members of his lab were so surprised by the results, they joked that the phenomenon could be explained as “Midichlorians” leaving the cell, a reference to the chemical embodiment of “the Force” in the Star Wars films.

While cellular paroxysms remain a mystery for now, Backman believes the team’s findings highlight the importance of studying the macromolecular behavior of live cells. The more insights researchers can gain about chromatin, the more likely they can one day be able to regulate gene expression, which could change how people are treated for diseases like cancer and Alzheimer’s.

“Every single biological process you can imagine involves some sort of macromolecular rearrangement,” Backman said. “As we expand our research, I can’t help but wonder, ‘What will we find next?’”

Northwestern Engineering’s Guillermo Ameer, Daniel Williams Hale Professor of Biomedical Engineering, and Igal Szleifer, Christina Enroth-Cugell Professor of Biomedical Engineering, also contributed to the research.

Other co-authors from the Northwester University include John F. Marko and Andrew D. Stephens.

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Publication linked to CBC funding*:
Gladstein S, Almassalha LM, Cherkezyan L, Chandler JE, Eshein A, Eid A, Zhang D, Wu W, Bauer GM, Stephens AD, Morochnik S, Subramanian H, Marko JF, Ameer GA, Szleifer I, Backman V. Multimodal interference-based imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm. Nat Commun. 2019 Apr 10;10(1):1652. (PubMed)

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Source:
Adapted (with modifications) from the Northwestern Engineering News, by Alex Gerage, published on April 11, 2019.

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Featured CBC Community member(s):

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Articles published in the past about the featured CBC community members:

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Backman

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September 5, 2018
▸ Improving early cancer detection
A simple and inexpensive procedure – taking a swab – can boost early malignancy detection in seven types of cancer – CBC awardee Vadim Backman, NU, explains

March 16, 2018
▸ The promise of increased sensitivity for early cancer detection and management being realized by Vadim Backman and Tom O’Halloran, NU, with the help of instrumentation and a core facility supported by a CBC Lever Award

November 7, 2017
▸ Highlighting progress in cancer research supported in part through a CBC Lever Award. Spotlight on Vadim Backman, Tom O’Halloran and Andrew Mazar.

September 21, 2016
▸ Researchers Discover that DNA Naturally Fluoresces

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Ameer

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September 17, 2018
▸ A liquid bandage?
Developing new bandage with healing properties — Fox 32 Chicago News interview with CBC awardee, Guillermo Ameer, NU

June 18, 2018
▸ A wound-healing bandage

June 13, 2018
▸ NU bioengineer, entrepreneur and past CBC awardee, Guillermo Ameer, to lead the new Center for Advanced Regenerative Engineering (CARE)

December 1, 2017
▸ Guillermo Ameer, NU bioengineer and CBC awardee, discusses the future of regenerative engineering

November 6, 2017
▸ Guillermo Ameer, NU bioengineer and CBC awardee, elected fellow of AIChE

April 7, 2017
▸ The CBC Accelerator Network (CBCAN) off to a great start!