Tag Archives: Donald E. 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.

SLIPS (Slippery Liquid-Infused Porous Surfaces) technology repels blood and bacteria from medical devices

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed a coating for medical devices that helps to address some of these devices’ most  troublesome aspects. From an Oct. 12, 2014 news item on ScienceDaily,

From joint replacements to cardiac implants and dialysis machines, medical devices enhance or save lives on a daily basis. However, any device implanted in the body or in contact with flowing blood faces two critical challenges that can threaten the life of the patient the device is meant to help: blood clotting and bacterial infection.

A team of Harvard scientists and engineers may have a solution. They developed a new surface coating for medical devices using materials already approved by the Food and Drug Administration (FDA). The coating repelled blood from more than 20 medically relevant substrates the team tested — made of plastic to glass and metal — and also suppressed biofilm formation in a study reported in Nature Biotechnology. But that’s not all.

The team implanted medical-grade tubing and catheters coated with the material in large blood vessels in pigs, and it prevented blood from clotting for at least eight hours without the use of blood thinners such as heparin. Heparin is notorious for causing potentially lethal side-effects like excessive bleeding but is often a necessary evil in medical treatments where clotting is a risk.

“Devising a way to prevent blood clotting without using anticoagulants is one of the holy grails in medicine,” said Don Ingber, M.D., Ph.D., Founding Director of Harvard’s Wyss Institute for Biologically Inspired Engineering and senior author of the study. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, as well as professor of bioengineering at Harvard School of Engineering and Applied Sciences (SEAS).

An Oct. 12, 2014 Wyss Institute news release (also on EurekAlert), which originated the news item, describes the inspiration for this work,

The idea for the coating evolved from SLIPS, a pioneering surface technology developed by coauthor Joanna Aizenberg, Ph.D., who is a Wyss Institute Core Faculty member and the Amy Smith Berylson Professor of Materials Science at Harvard SEAS. SLIPS stands for Slippery Liquid-Infused Porous Surfaces. Inspired by the slippery surface of the carnivorous pitcher plant, which enables the plant to capture insects, SLIPS repels nearly any material it contacts. The liquid layer on the surface provides a barrier to everything from ice to crude oil and blood.

“Traditional SLIPS uses porous, textured surface substrates to immobilize the liquid layer whereas medical surfaces are mostly flat and smooth – so we further adapted our approach by capitalizing on the natural roughness of chemically modified surfaces of medical devices,” said Aizenberg, who leads the Wyss Institute’s Adaptive Materials platform. “This is yet another incarnation of the highly customizable SLIPS platform that can be designed to create slippery, non-adhesive surfaces on any material.”

The Wyss team developed a super-repellent coating that can be adhered to existing, approved medical devices. In a two-step surface-coating process, they chemically attached a monolayer of perfluorocarbon, which is similar to Teflon. Then they added a layer of liquid perfluorocarbon, which is widely used in medicine for applications such as liquid ventilation for infants with breathing challenges, blood substitution, eye surgery, and more. The team calls the tethered perfluorocarbon plus the liquid layer a Tethered-Liquid Perfluorocarbon surface, or TLP for short.

In addition to working seamlessly when coated on more than 20 different medical surfaces and lasting for more than eight hours to prevent clots in a pig under relatively high blood flow rates without the use of heparin, the TLP coating achieved the following results:

  • TLP-treated medical tubing was stored for more than a year under normal temperature and humidity conditions and still prevented clot formation
  • The TLP surface remained stable under the full range of clinically relevant physiological shear stresses, or rates of blood flow seen in catheters and central lines, all the way up to dialysis machines
  • It repelled the components of blood that cause clotting (fibrin and platelets)
  • When bacteria called Pseudomonas aeruginosa were grown in TLP-coated medical tubing for more than six weeks, less than one in a billion bacteria were able to adhere. Central lines coated with TLP significantly reduce sepsis from Central-Line Mediated Bloodstream Infections (CLABSI). (Sepsis is a life-threatening blood infection caused by bacteria, and a significant risk for patients with implanted medical devices.)

Out of sheer curiosity, the researchers even tested a TLP-coated surface with a gecko – the superstar of sticking whose footpads contain many thousands of hairlike structures with tremendous adhesive strength. The gecko was unable to hold on.

“We were wonderfully surprised by how well the TLP coating worked, particularly in vivo without heparin,” said one of the co-lead authors, Anna Waterhouse, Ph.D., a Wyss Institute Postdoctoral Fellow. “Usually the blood will start to clot within an hour in the extracorporeal circuit, so our experiments really demonstrate the clinical relevance of this new coating.”

While most of the team’s demonstrations were performed on medical devices such as catheters and perfusion tubing using relatively simple setups, they say there is a lot more on the horizon.

“We feel this is just the beginning of how we might test this for use in the clinic,” said co-lead author Daniel Leslie, Ph.D., a Wyss Institute Staff Scientist, who aims to test it on more complex systems such as dialysis machines and ECMO, a machine used in the intensive care unit to help critically ill patients breathe.

I first featured SLIPS technology in a Jan. 15, 2014 post about its possible use for stain-free, self-cleaning clothing. This Wyss Institute video about the latest work featuring the use of  SLIPS technology in medical devices also describes its possible use in pipelines and airplanes,

You can find research paper with this link,

A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling by Daniel C Leslie, Anna Waterhouse, Julia B Berthet, Thomas M Valentin, Alexander L Watters, Abhishek Jain, Philseok Kim, Benjamin D Hatton, Arthur Nedder, Kathryn Donovan, Elana H Super, Caitlin Howell, Christopher P Johnson, Thy L Vu, Dana E Bolgen, Sami Rifai, Anne R Hansen, Michael Aizenberg, Michael Super, Joanna Aizenberg, & Donald E Ingber. Nature Biotechnology (2014) doi:10.1038/nbt.3020 Published online 12 October 2014

This paper is behind a paywall but there is a free preview available via ReadCube Access.

Mesenchymal condensation (a process embryos use to begin forming a variety of organs, including teeth, cartilage, bone, muscle, tendon, and kidney) for complex 3D tissue engineering

It seems that there are three strategies for creating complex 3D tissues and until now scientists have used only two of the three. From a March 5, 2014 news item on ScienceDaily,

A bit of pressure from a new shrinking, sponge-like gel is all it takes to turn transplanted unspecialized cells into cells that lay down minerals and begin to form teeth.

The bioinspired gel material could one day help repair or replace damaged organs, such as teeth and bone, and possibly other organs as well, scientists from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard School of Engineering and Applied Sciences (SEAS), and Boston Children’s Hospital report recently in Advanced Materials.

“Tissue engineers have long raised the idea of using synthetic materials to mimic the inductive power of the embryo,” said Don Ingber, M.D., Ph.D., Founding Director of the Wyss Institute, …, Professor of Bioengineering at SEAS, and senior author of the study. “We’re excited about this work because it shows that it really is possible.”

The March 5, 2014 Wyss Institute news release, which originated the news item, delves into the nature of the research,

Embryonic tissues have the power to drive cells and tissues to specialize and form organs. To do that, they employ biomolecules called growth factors to stimulate growth; gene-activating chemicals that cause the cells to specialize, and mechanical forces that modulate cell responses to these other factors.

But so far tissue engineers who want to build organs in the laboratory have employed only two of the three strategies — growth factors and gene-activating chemicals. Perhaps as a result, they have not yet succeeded in producing complex three-dimensional tissues.

A few years ago, Ingber and Tadanori Mammoto, M.D., Ph.D., Instructor in Surgery at Boston Children’s Hospital and Harvard Medical School, investigated a process called mesenchymal condensation that embryos use to begin forming a variety of organs, including teeth, cartilage, bone, muscle, tendon, and kidney.

In mesenchymal condensation, two adjacent tissue layers — loosely packed connective-tissue cells called mesenchyme and sheet-like tissue called an epithelium that covers it — exchange biochemical signals. This exchange causes the mesenchymal cells to squeeze themselves tightly into a small knot directly below where the new organ will form.

Here’s a video from the Wyss Institute illustrating the squeezing process,

When the temperature rises to just below body temperature, this biocompatible gel shrinks dramatically within minutes, bringing tooth-precursor cells (green) closer together. Credit: Basma Hashmi

Getting back to the research (from the news release),

By examining tissues isolated from the jaws of embryonic mice, Mammoto and Ingber showed that when the compressed mesenchymal cells turn on genes that stimulate them to generate whole teeth composed of mineralized tissues, including dentin and enamel.

Inspired by this embryonic induction mechanism, Ingber and Basma Hashmi, a Ph.D. candidate at SEAS who is the lead author of the current paper, set out to develop a way to engineer artificial teeth by creating a tissue-friendly material that accomplishes the same goal. Specifically, they wanted a porous sponge-like gel that could be impregnated with mesenchymal cells, then, when implanted into the body, induced to shrink in 3D to physically compact the cells inside it.

To develop such a material, Ingber and Hashmi teamed up with researchers led by Joanna Aizenberg, Ph.D., a Wyss Institute Core Faculty member who leads the Institute’s Adaptive Materials Technologies platform. Aizenberg is the Amy Smith Berylson Professor of Materials Science at SEAS and Professor of Chemistry and Chemical Biology at Harvard University.

They chemically modified a special gel-forming polymer called PNIPAAm that scientists have used to deliver drugs to the body’s tissues. PNIPAAm gels have an unusual property: they contract abruptly when they warm.

But they do this at a lukewarm temperature, whereas the researchers wanted them to shrink specifically at 37°C — body temperature — so that they’d squeeze their contents as soon as they were injected into the body. Hashmi worked with Lauren Zarzar, Ph.D., a former SEAS graduate student who’s now a postdoctoral associate at Massachusetts Institute of Technology, for more than a year, modifying PNIPAAm and testing the resulting materials. Ultimately, they developed a polymer that forms a tissue-friendly gel with two key properties: cells stick to it, and it compresses abruptly when warmed to body temperature.

As an initial test, Hashmi implanted mesenchymal cells in the gel and warmed it in the lab. Sure enough, when the temperature reached 37°C, the gel shrank within 15 minutes, causing the cells inside the gel to round up, shrink, and pack tightly together.

“The reason that’s cool is that the cells are alive,” Hashmi said. “Usually when this happens, cells are dead or dying.”

Not only were they alive — they activated three genes that drive tooth formation.

To see if the shrinking gel also worked its magic in the body, Hashmi worked with Mammoto to load mesenchymal cells into the gel, then implant the gel beneath the mouse kidney capsule — a tissue that is well supplied with blood and often used for transplantation experiments.

The implanted cells not only expressed tooth-development genes — they laid down calcium and minerals, just as mesenchymal cells do in the body as they begin to form teeth.

“They were in full-throttle tooth-development mode,” Hashmi said.

The researchers have future plans (from the news release),

In the embryo, mesenchymal cells can’t build teeth alone — they need to be combined with cells that form the epithelium. In the future, the scientists plan to test whether the shrinking gel can stimulate both tissues to generate an entire functional tooth.

Here’s a link to and a citation for the paper about the successful attempt to stimulate mesenchymal cells into the beginnings of tooth formation,

Developmentally-Inspired Shrink-Wrap Polymers for Mechanical Induction of Tissue Differentiation by Basma Hashmi, Lauren D. Zarzar, Tadanori Mammoto, Akiko Mammoto, Amanda Jiang, Joanna Aizenberg, and Donald E. Ingber. Advanced Materials Article first published online: 18 FEB 2014 DOI: 10.1002/adma.201304995

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Thermal control of windows with artificial vasculature

Ben Hatton, a professor of Engineering at the University of Toronto, and his colleagues at Harvard University are proposing a ‘bio-inspired’ alternative to commonly proposed techniques for gaining  thermal control over windows. From an Aug. 2, 2013 news item on ScienceDaily (Note: A link has been removed),

In a recent article in Solar Energy Materials & Solar Cells, Hatton and colleagues at Harvard University describe a novel process to cut down on heat loss during the winter and keep buildings cool during the summer. Their “bio-inspired approach to thermal control for cooling (or heating) building window surfaces” calls for attaching optically clear, flexible elastomer sheets, bonded to regular glass window panes.

The elastomer sheets, made from polydimethylsiloxane (PDMS) have channels running through them through which room temperature water flows. The technique has resulted in 7 to 9 degrees of cooling in laboratory experiments and is effective both at small and large scales, Hatton and his colleagues said.

“Our results show that an artificial vascular network within a transparent layer, composed of channels on the micrometer to millimeter scale, and extending over the surface of a window, offers an additional and novel cooling mechanism for building windows and a new thermal control tool for building design,” he said.

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

An artificial vasculature for adaptive thermal control of windows by Benjamin D. Hatton, Ian Wheeldon, Matthew J. Hancock, Mathias Kolle, Joanna Aizenberg, and Donald E. Ingber. Solar Energy Materials and Solar Cells, 2013; 117: 429 DOI: 10.1016/j.solmat.2013.06.027; Volume 117, October 2013, Pages 429–436.

I have written about thermal control of windows before as per this Sept. 4, 2012 posting which features an excerpt of an article discussing thermochromic, electrochromic, and gasochromic windows.