Tag Archives: Don Ingber

Art influences science

It’s not often you see research that combines biologically inspired engineering and a molecular biophysicist with a professional animator who worked at Peter Jackson’s (Lord of the Rings film trilogy, etc.) Park Road Post film studio. An Oct. 18, 2017 news item on ScienceDaily describes the project,

Like many other scientists, Don Ingber, M.D., Ph.D., the Founding Director of the Wyss Institute, is concerned that non-scientists have become skeptical and even fearful of his field at a time when technology can offer solutions to many of the world’s greatest problems. “I feel that there’s a huge disconnect between science and the public because it’s depicted as rote memorization in schools, when by definition, if you can memorize it, it’s not science,” says Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at the Harvard Paulson School of Engineering and Applied Sciences (SEAS). “Science is the pursuit of the unknown. We have a responsibility to reach out to the public and convey that excitement of exploration and discovery, and fortunately, the film industry is already great at doing that.”

An October 18, 2017 Wyss Institute at Harvard University news release (also on EurekAlert) by Lindsay Brownell, which originated the news item, details the work,

To see if entertainment could offer a solution to this challenge, Ingber teamed up with Charles Reilly, Ph.D., a molecular biophysicist, professional animator, and Staff Scientist at the Wyss Institute who previously worked at movie director Peter Jackson’s Park Road Post film studio, to create a film that would capture viewers’ imaginations by telling the story of a biological process that was accurate down to the atomic level. “Don and I quickly found that we have a lot of things in common, especially that we’re both systems thinkers,” says Reilly. “Applying an artistic process to science frees you from the typically reductionist approach of analyzing one particular hypothesis and teaches you a different way of observing things. As a result, we not only created an entertaining tool for public outreach, we conducted robust theoretical biology research that led to new scientific insight into molecular-scale processes.” The research is now published in ACS Nano and the film can be found here.

Wyss researchers created a model of an axoneme that displays how different segments of the microtubules bend and flex relative to each other to create movement. Credit: Wyss Institute at Harvard University

Any good movie needs characters and drama, and a “hook” to get the audience invested in watching. The scientists decided to make a parody of a trailer for a Star Wars® movie, but instead of showing starship cruisers hurtling through space towards the Death Star, they chose a biological process with its own built-in narrative: the fertilization of an egg by a sperm, in which millions of sperm race to be the one that succeeds and creates the next generation of life. The patterns and mechanics of sperm swimming have been studied and described in scientific literature, but visually showing the accurate movement of a sperm tail required tackling one of the toughest challenges facing science today: how to create a multi-scale biological model that maintains accuracy at different sizes, from cells all the way down to atoms. That would be like starting with the Empire State Building and then zooming in close enough to see every individual screw, nut and bolt that holds it together, as well as how individual water molecules flow inside its pipes, while maintaining crystal-clear resolution – not an easy task.

“It turns out that creating an accurate biological model and creating a believable computer-generated depiction of life in film are very similar, in that you’re constantly troubleshooting and modifying your virtual object until it fits the way things actually look and move,” says Reilly. “However, for biology, the simulations also have to align with recorded scientific data and theoretical models that have previously been experimentally validated.” The scientists created a design-based animation pipeline that integrates physics-based film animation software with molecular dynamics simulation software to create a model of how a sperm tail moves based on scientific data, with the criterion that the model had to work across all size scales. “This is really a design thinking approach, where you have to be willing to throw out your model if it doesn’t work correctly when you integrate it with data from another scale,” Reilly says. “A lot of scientific investigations use a reductionist approach, focusing on one molecule or one biological system with higher and higher resolution without placing it in context, which makes it difficult to converge on a picture of the larger whole.”

This video shows dynein’s two different shapes as determined from scientific observations, and how the Wyss researchers’ molecular model of dynein’s movement fits those conformations. Credit: Wyss Institute at Harvard University

The core of a sperm’s whip-like tail is the axoneme, a long tube consisting of nine pairs of microtubules arranged in a column around a central pair, all of which extend the entire length of the tail. The axoneme’s rhythmic bending and stretching is the source of the tail’s movement, and the scientists knew they needed to realistically depict that process in order to show the film’s viewers how a sperm moves. Rather than construct a model in a linear fashion by “zooming in” or “zooming out” to add more information to a single starting structure, they built the model at different scales simultaneously, repeatedly checking it against scientific data to ensure it was accurate and modifying it until the pieces fit together.

The axoneme’s movement is accomplished via rows of motor proteins called dyneins that are attached along the microtubules and exert force on them so the microtubules “slide” past each other, which then causes the entire axoneme and sperm tail to bend and move. The dynein protein has a long “arm” portion that grabs onto the neighboring microtubule and, when the protein changes from one shape to another, pulls the microtubule along with it. Dynein switches between these different conformations as a result of the conversion of a molecule of ATP to ADP at a specific binding site on the protein, which releases energy as a chemical bond is broken. To model this molecular motor, the scientists created a molecular dynamics simulation of a dynein protein and applied energy at the ATP binding site to approximate the transfer of energy from ATP. They found that this caused atoms in the entire protein to move in random directions when they performed their simulation of dynein floating in solution, as most conventional scientific simulations do. However, when they then “fixed” a specific hinge region of the dynein molecule that is known to connect dynein to its microtubule, they discovered that the dynein spontaneously moved in its characteristic direction when force was applied at the ATP binding site, matching the way it moves in nature.

This video shows rows of dynein proteins along the microtubules of an axoneme moving in sync to cause the axoneme’s motion, like rowers pulling synchronously in a boat. Credit: Wyss Institute at Harvard University

“Not only is our physics-based simulation and animation system as good as other data-based modeling systems, it led to the new scientific insight that the limited motion of the dynein hinge focuses the energy released by ATP hydrolysis, which causes dynein’s shape change and drives microtubule sliding and axoneme motion,” says Ingber. “Additionally, while previous studies of dynein have revealed the molecule’s two different static conformations, our animation visually depicts one plausible way that the protein can transition between those shapes at atomic resolution, which is something that other simulations can’t do. The animation approach also allows us to visualize how rows of dyneins work in unison, like rowers pulling together in a boat, which is difficult using conventional scientific simulation approaches.”

Using this biologically accurate model of how dynein moves the microtubules within the axoneme, Ingber and Reilly created a short film called “The Beginning,” which draws parallels between sperm swimming toward an egg and spaceships flying toward a planet in space, giving an artistic bent to a scientific topic. The film depicts several sperm attempting to fertilize the egg, “zooms in” on one sperm’s tail to show how the dynein proteins move in sync to cause the tail to bend and flex, and ends with the sperm’s successful journey into the egg and the initiation of cell division that will ultimately create a new organism. The scientists submitted the film along with the paper to several academic journals, and it took a long time before they found an open-minded editor who recognized that the paper and film together were a powerful demonstration of how starting with an artistic goal can end up generating new scientific discoveries along with a tool for public outreach.

*Due to distortion images deleted March 9, 2018.*

“Both science and art are about observation, interpretation, and communication. Our goal is that presenting science to the public in an entertaining, system-based way, rather than bogging them down with a series of scattered facts, will help more people understand it and feel that they can contribute to the scientific conversation. The more people engage with science, the more likely humanity is to solve the world’s big problems,” says Reilly. “I also hope that this paper and video encourage more scientists to take an artistic approach when they start a new project, not necessarily to create a narrative-based story, but to explore their idea the way an artist explores a canvas, because that makes the mind open to a different form of serendipity that can lead to unexpected results.”

“The Wyss Institute is driven by biological design. In this project, we used design tools and approaches borrowed from the art world to solve problems related to motion, form, and complexity to create something entertaining, which ultimately led to new scientific insights and, hopefully, new ways to excite the public about science,” says Ingber. “We’ve demonstrated that art and science can benefit each other in a truly reciprocal way, and we hope that this project spurs future collaborations with the entertainment industry so that both art and science can get even closer to depicting reality in ways that anyone can appreciate and enjoy.”

*Due to distortion images deleted on March 9, 2018.*

The film,

Here’s a link to and a citation for the paper,

Art Advancing Science: Filmmaking Leads to Molecular Insights at the Nanoscale by Charles Reilly and Donald E. Ingber. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b05266 Publication Date (Web): October 18, 2017

Copyright © 2017 American Chemical Society

This paper appears to be open access.

Asthma on a chip

Harvard University’s Wyss Institute for Biologically Inspired Engineering has found a way to mimic the lung’s muscle action when an asthma attack is being experienced according to a Sept. 23, 2014 news item on Nanowerk,

The majority of drugs used to treat asthma today are the same ones that were used 50 years ago. New drugs are urgently needed to treat this chronic respiratory disease, which causes nearly 25 million people in the United States alone to wheeze, cough, and find it difficult at best to take a deep breath.

But finding new treatments is tough: asthma is a patient-specific disease, so what works for one person doesn’t necessarily work for another, and the animal models traditionally used to test new drug candidates often fail to mimic human responses–costing tremendous money and time.

Hope for healthier airways may be on the horizon thanks to a Harvard University team that has developed a human airway muscle-on-a-chip that could be used to test new drugs because it accurately mimics the way smooth muscle contracts in the human airway, under normal circumstances and when exposed to asthma triggers. [emphasis mine]

A Sept. 23, 2014 Wyss Institute news release (also on EurekAlert*), which originated the news item, provides more details about the technology and its advantages,

The chip, a soft polymer well that is mounted on a glass substrate, contains a planar array of microscale, engineered human airway muscles, designed to mimic the laminar structure of the muscular layers of the human airway.

To mimic a typical allergic asthma response, the team first introduced interleukin-13 (IL-13) to the chip. IL-13 is a natural protein often found in the airway of asthmatic patients that mediates the response of smooth muscle to an allergen.

Then they introduced acetylcholine, a neurotransmitter that causes smooth muscle to contract. Sure enough, the airway muscle on the chip hypercontracted – and the soft chip curled up – in response to higher doses of the neurotransmitter.

They achieved the reverse effect as well and triggered the muscle to relax using drugs called β-agonists, which are used in inhalers.

Significantly, they were able to measure the contractile stress of the muscle tissue as it responded to varying doses of the drugs, said lead author Alexander Peyton Nesmith, a Ph.D./M.D. student at Harvard SEAS and the University of Alabama at Birmingham. “Our chip offers a simple, reliable and direct way to measure human responses to an asthma trigger,” he said.

The team then investigated what happened on a cellular level in response to the IL-13 and confirmed, for example, that the smooth muscle cells grew larger in the presence of IL-13 over time – a structural hallmark of the airways in asthma patients as well. They also documented an increased alignment of actin fibers within smooth muscle cells, which is consistent with the muscle in the airway of asthma patients. Actin fibers are super-thin cellular components involved in muscle contraction.

Next they observed how IL-13 changes the expression of contractile proteins called RhoA proteins, which have been implicated in the asthmatic response, although the details of their activation and signaling have remained elusive. To do this they introduced a drug called HA1077, which is not currently used to treat asthmatic patients – but targets the RhoA pathway. It turns out that the drug made the asthmatic tissue on the chip less sensitive to the asthma trigger – and preliminary tests indicated that using a combined therapy of HA1077 plus a currently approved asthma drug worked better than the single drug alone.

“Asthma is one of the top reasons for trips to the emergency room – particularly for children, and a large segment of the asthmatic population doesn’t respond to currently available treatments,” said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. “The airway muscle-on-a-chip provides an important and exciting new tool for discovering new therapeutic agents.”

The scientists have provided an illustration of healthy and asthmatic airways,

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard's Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard’s Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Here’s link to and a citation for the paper,

Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation by Alexander Peyton Nesmith, Ashutosh Agarwal, Megan Laura McCain and Kevin Kit Parker.Lab Chip, 2014,14, 3925-3936 DOI: 10.1039/C4LC00688G First published online 05 Aug 2014

This paper is open access provided you have registered yourself for free at the site.

* EurekAlert link added Sept. 24, 2014.