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CEMB Researchers Find that Disease Can Change the Physical Structure of Cells

by Ebonee Johnson

In these super-resolution images of tendon cell nuclei, the color coding represents chromatin density map, from low density in blue to high density in red. Comparing a healthy human tendon cell nucleus (left) to one diagnosed with tendinosis (right) shows that disease alters the spatial localization and compaction of chromatin.

Researchers from Penn’s Center for Engineering Mechanobiology (CEMB) have discovered that cells change the physical structure of their genome when they’re affected by disease.

In a recent study published in Nature Biomedical Engineering, the team detailed what they found when they closely observed the nucleus of cells inside connective tissues deteriorating as a result of tendinosis, which is the chronic condition that results from a tendon repeatedly suffering small injuries that don’t heal correctly. Using the latest super-resolution imaging techniques, they found that the tendon cells involved in maintaining the tissue’s structure in a diseased microenvironment improperly reorder their chromatin — the DNA-containing material that chromosomes are composed of — when attempting to repair.

This and other findings highlighted in the report point to the possibility of new treatments, such as small-molecule therapies, that could restore order to the affected cells.

“Interestingly, we were able to explain the role of mechanical forces on the 3-D organization of chromatin by developing a theory that integrates fundamental thermodynamic principles (physics) with the kinetics of epigenetic regulation (biology),” said study co-author and CEMB Director Vivek Shenoy in a news release from Penn Medicine News.

The CEMB, one of 18 active interdisciplinary research centers funded by the National Science Foundation’s Science and Technology Center (STC) program, brings together dozens of researchers from Penn Engineering and the Perelman School of Medicine, as well as others spread across campus and at partner institutions around the world.

With its funding recently renewed for another five years, the CEMB has entered  into a new phase of its mission, centered on the nascent concept of “mechanointelligence,” which is exemplified by studies like this one. While mechanobiology is the study of the physical forces that govern the behavior of cells and their communication with their neighbors, mechanointelligence adds another layer of complexity: attempting to understand the forces that allow cells to sense, remember and adapt to their environments.

Ultimately, harnessing these forces would allow researchers to help multicellular organisms — plants, animals and humans — better adapt to their environments as well.

Read “Aberrant chromatin reorganization in cells from diseased fibrous connective tissue in response to altered chemomechanical cues” at Nature Biomedical Engineering.

Read “The Locked Library: Disease Causes Cells to Reorder Their DNA Incorrectly” at Penn Medicine News.

This story originally appeared in Penn Engineering Today.

Vivek Shenoy is Eduardo D. Glandt President’s Distinguished Professor in Materials Science and Engineering, Bioengineering, and in Mechanical Engineering and Applied Mechanics.

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‘Curious Minds: The Power of Connection’

Twin siblings and scholars Dani S. Bassett of Penn and Perry Zurn of American University collaborated over half a dozen years to write “Curious Minds: The Power of Connection.” (Image: Tony and Tracy Wood Photography)

With appointments in the Departments of Bioengineering and Electrical and Systems Engineering, as well as the Department of Physics and Astronomy in Penn Arts & Science, and the Departments of Neuroscience and Psychiatry in Penn Perelman’s School of Medicine, Dani S. Bassett is no stranger to following the thread of an idea, no matter where it might lead.

Curious Minds book cover

Those wide-ranging fields and disciplines orbit around an appropriate central question: how does the tangle of neurons in our brains wire itself up to learn new things? Bassett, J. Peter Skirkanich Professor and director of the Complex Systems Lab, studies the relationship between the shape of those networks of neurons and the brain’s abilities, especially the way the shape of the network grows and changes with the addition of new knowledge.

 

To get at the fundamentals of the question of curiosity, Bassett needed to draw on even more disciplines. Fortunately, they didn’t have to look far; Bassett’s identical twin is Perry Zurn, a professor of philosophy at American University, and the two have investigated the many different ways a person can exhibit curiosity.

Bassett and Zurn have now published a new book on the subject. In Curious Minds: The Power of Connection, the twins draw on their previous research, as well as an expansive network of ideas from philosophy, history, education and art.

In an interview with The Guardian, Bassett explains how these threads wove together:

“It wasn’t clear at the beginning of our careers that we would even ever have a chance to write a book together because our areas were so wildly different,” Bassett says – but then, as postgraduates, Zurn was studying the philosophy of curiosity while Bassett was working on the neuroscience of learning. “And so that’s when we started talking. That talking led to seven years of doing research together,” Bassett says. “This book is a culmination of that.”

How exactly do philosophy and neuroscience complement each other? It all starts with the book’s first, and most deceptively simple question: what is curiosity? “Several investigators in science have underscored that perhaps the field isn’t even ready to define curiosity and how it’s different from other cognitive processes,” says Bassett. The ambiguity in the neuroscience literature motivated Bassett to turn to philosophy, “where there are really rich historical definitions and styles and subtypes that we can then put back into neuroscience and ask: ‘Can we see these in the brain?’”

Curious Minds: The Power of Connection is available now. Read Amelia Tait’s review “Are you a busybody, a hunter or a dancer? A new book about curiosity reveals all,” in The Guardian. 

This story originally appeared in Penn Engineering Today.

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2022 Career Award Recipient: Michael Mitchell

by Melissa Pappas

Michael Mitchell (Illustration by Melissa Pappas)

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is one of this year’s recipients of the National Science Foundation’s CAREER Award. The award is given to early-career faculty researchers who demonstrate the potential to be role models in their field and invest in the outreach and education of their work.

Mitchell’s award will fund research on techniques for “immunoengineering” macrophages. By providing new instructions to these cells via nanoparticles laden with mRNA and DNA sequences, the immune system could be trained to target and eliminate solid tumors. The award will also support graduate students and postdoctoral fellows in his lab over the next five years.

The project aligns with Mitchell’s larger research goals and the current explosion of interest in therapies that use mRNA, thanks to the technological breakthroughs that enabled the development of COVID-19 vaccines.

“The development of the COVID vaccine using mRNA has opened doors for other cell therapies,” says Mitchell. “The high-priority area of research that we are focusing on is oncological therapies, and there are multiple applications for mRNA engineering in the fight against cancer.”

A new wave of remarkably effective cancer treatments incorporates chimeric antigen receptor T-cell (CAR-T) therapy. There, a patient’s T-cells, a type of white blood cell that fights infections, are genetically engineered to identify, target and kill individual cancer cells that accumulate in the circulatory system.

However, despite CART-T therapy’s success in treating certain blood cancers, the approach is not effective against cancers that form solid tumors. Because T-cells are not able to penetrate tumors’ fibrous barriers, Mitchell and his colleagues have turned to another part of the immune system for help.

Read the full story in Penn Engineering Today.

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Penn Medicine CAR T Therapy Expert Carl June Receives 2022 Keio Medical Science Prize

by Brandon Lausch

The award from Japan’s oldest private university honors outstanding contributions to medicine and life sciences.

Richard W. Vague Professor in Immunotherapy Carl June.

Carl June, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center, has been named a 2022 Keio Medical Science Prize Laureate. He is recognized for his pioneering role in the development of CAR T cell therapy for cancer, which uses modified versions of patients’ own immune cells to attack their cancer.

The Keio Medical Science Prize is an annual award endowed by Keio University, Japan’s oldest private university, which recognizes researchers who have made an outstanding contribution to the fields of medicine or the life sciences. It is the only prize of its kind awarded by a Japanese university, and eight laureates of this prize have later won the Nobel Prize. Now in its 27th year, the prize encourages the expansion of researcher networks throughout the world and contributes to the well-being of humankind.

“Dr. June exemplifies the spirit of curiosity and fortitude that make Penn home to so many ‘firsts’ in science and medicine,” said Penn President Liz Magill. “His work provides hope to cancer patients and their families across the world, and inspiration to our global community of physicians and scientists who are working to develop the next generation of treatments and cures for diseases of all kinds.”

Read the full story in Penn Today.

June is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June’s research here.

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Training the Next Generation of Scientists on Soft Materials, Machine Learning and Science Policy

by Melissa Pappas

Developing new soft materials requires new data-driven research techniques, such as autonomous experimentation. Data regarding nanometer-scale material structure, taken by X-ray measurements at a synchrotron, can be fed into an algorithm that identifies the most relevant features, represented here as red dots. The algorithm then determines the optimum conditions for the next set of measurements and directs their execution without human intervention. Brookhaven National Laboratory’s Kevin Yager, who helped develop this technique, will co-teach a course on it as part of a new Penn project on Data Driven Soft Materials Research.

The National Science Foundation’s Research Traineeship Program aims to support graduate students, educate the STEM leaders of tomorrow and strengthen the national research infrastructure. The program’s latest series of grants are going toward university programs focused on artificial intelligence and quantum information science and engineering – two areas of high priority in academia, industry and government.

Chinedum Osuji, Eduardo D. Glandt Presidential Professor and Chair of the Department of Chemical and Biomolecular Engineering (CBE), has received one of these grants to apply data science and machine learning to the field of soft materials. The grant will provide five years of support and a total of $3 million for a new Penn project on Data Driven Soft Materials Research.

Osuji will work with co-PIs Russell Composto, Professor and Howell Family Faculty Fellow in Materials Science and Engineering, Bioengineering, and in CBE, Zahra Fakhraai, Associate Professor of Chemistry in Penn’s School of Arts & Sciences (SAS) with a secondary appointment in CBE, Paris Perdikaris, Assistant Professor in Mechanical Engineering and Applied Mechanics, and Andrea Liu, Hepburn Professor of Physics and Astronomy in SAS, all of whom will help run the program and provide the connections between the multiple fields of study where its students will train.

These and other affiliated faculty members will work closely with co-PI Kristin Field, who will serve as Program Coordinator and Director of Education.

Read the full story in Penn Engineering Today.

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The Penn Center for Precision Engineering for Health Announces First Round of Seed Funding

by Melissa Pappas

CPE4H is one of the focal points of Penn Engineering signature initiative on Engineering Health.

The Penn Center for Precision Engineering for Health (CPE4H) was established late last year to accelerate engineering solutions to significant problems in healthcare. The center is one of the signature initiatives for Penn’s School of Engineering and Applied Science and is supported by a $100 million commitment to hire faculty and support new research on innovative approaches to those problems.

Acting on that commitment, CPE4H solicited proposals during the spring of 2022 for seed grants of $80K per year for two years for research projects that address healthcare challenges in several key areas of strategic importance to Penn: synthetic biology and tissue engineering, diagnosis and drug delivery, and the development of innovative devices. While the primary investigators (PIs) for the proposed projects were required to have a primary faculty appointment within Penn Engineering, teams involving co-PIs and collaborators from other schools were eligible for support. The seed program is expected to continue for the next four years.

“It was a delight to read so many novel and creative proposals,” says Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and the Inaugural Director of CPE4H. “It was very hard to make the final selection from a pool of such promising projects.”

Judged on technical innovation, potential to attract future resources, and ability to address a significant medical problem, the following research projects were selected to receive funding.

Evolving and Engineering Thermal Control of Mammalian Cells

Led by Lukasz Bugaj, Assistant Professor in Bioengineering, this project will engineer molecular switches that can be toggled on and off inside mammalian cells at near-physiological temperatures. Successful development of these switches will provide new ways to communicate with cells, an advance that could be used to make safer and more effective cellular therapies.  The project will use directed evolution to generate and find candidate molecular tools with the desired properties. Separately, the research will also develop new technology for manipulating cellular temperature in a rapid and programmable way. Such devices will enhance the speed and sophistication of studies of biological temperature regulation.

A Quantum Sensing Platform for Rapid and Accurate Point-of-Care Detection of Respiratory Viral Infections

Combining microfluidics and quantum photonics, PI Liang Feng, Professor in Materials Science and Engineering and Electrical and Systems Engineering, Ritesh Agarwal, Professor in Materials Science Engineering, and Shu Yang, Joseph Bordogna Professor in Materials Science and Engineering and Chemical and Biomolecular Engineering, are teaming up with Ping Wang, Professor of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine, to design, build and test an ultrasensitive point-of-care detector for respiratory pathogens. In light of the COVID-19 pandemic, a generalizable platform for rapid and accurate detection of viral pathogenesis would be extremely important and timely.

Versatile Coacervating Peptides as Carriers and Synthetic Organelles for Cell Engineering

PI Amish Patel, Associate Professor in Chemical and Biomolecular Engineering, and Matthew C. Good, Associate Professor of Cell and Developmental Biology in the Perelman School of Medicine and in Bioengineering, will design and create small proteins that self-assemble into droplet-like structures known as coacervates, which can then pass through the membranes of biological cells. Upon cellular entry, these protein coacervates can disassemble to deliver cargo that modulates cell behavior or be maintained as synthetic membraneless organelles. The team will design new chemistries that will facilitate passage across cell membranes, and molecular switches to sequester and release protein therapeutics. If successful, this approach could be used to deliver a wide range of macromolecule drugs to cells.

Towards an Artificial Muscle Replacement for Facial Reanimation

Cynthia Sung, Gabel Family Term Assistant Professor in Mechanical Engineering and Applied Mechanics and Computer Information Science, will lead a research team including Flavia Vitale, Assistant Professor of Neurology and Bioengineering, and Niv Milbar, Assistant Instructor in Surgery in the Perelman School of Medicine. The team will develop and validate an electrically driven actuator to restore basic muscle responses in patients with partial facial paralysis, which can occur after a stroke or injury. The research will combine elements of robotics and biology, and aims to produce a device that can be clinically tested.

“These novel ideas are a great way to kick off the activities of the center,” says Hammer. “We look forward to soliciting other exciting seed proposals over the next several years.”

This article originally appeared in Penn Engineering Today.

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Konrad Kording’s CENTER is Part of a New NIH Education Initiative on Scientific Rigor

by Melissa Pappas

Konrad Kording (Photo by Eric Sucar)

In 2005, John Ioannidis published a bombshell paper titled “Why Most Published Research Findings Are False.” In it, Ioannidis argued that a lack of scientific rigor in biomedical research — such as poor study design, small sample sizes and improper assessment of the significance of data— meant that a large percentage of experiments would not return the same results if they were conducted again.

Since then, researchers’ awareness of this “replication crisis” has grown, especially in fields that directly impact the health and wellbeing of people, where lapses in rigor can have life-or-death consequences. Despite this attention and motivation, however, little progress has been made in addressing the roots of the problem. Formal training in rigorous research practices remains rare; while mentors advise their students on how to properly construct and conduct experiments to produce the most reliable evidence, few educational resources exist to support them.

To address this discrepancy, the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), has launched the Initiative to Improve Education in the Principles of Rigorous Research.

Konrad Kording, a Penn Integrates Knowledge Professor with appointments in the Departments of Bioengineering and Computer and Information Science in Penn Engineering and the Department of Neuroscience in Penn’s Perelman School of Medicine, has been awarded one of the initiative’s first five grants.

“The replication crisis is real,” says Kording. “I’ve tried to replicate the research of others and failed. I’ve reanalyzed my own data and found major mistakes that needed to be corrected. I was never properly taught how to do rigorous science, and I want to improve that for the next generation.”

Read the full story in Penn Engineering Today.

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2022 CAREER Award Recipient: Lukasz Bugaj

by Melissa Pappas

Lukasz Bugaj (illustration by Melissa Pappas)

Therapies that use engineered cells to treat diseases, infections and chronic illnesses are opening doors to solutions for longstanding medical challenges. Lukasz Bugaj, Assistant Professor in Bioengineering, has been awarded a National Science Foundation CAREER Award for research that may be key to opening some of those doors.

Such cellular therapies take advantage of the complex molecular mechanisms that cells naturally use to interact with one another, enabling them to be more precise and less toxic than traditional pharmaceutical drugs, which are based on simpler small molecules. Cellular therapies that use engineered immune system cells, for example, have recently been shown to be highly successful in treating certain cancers and protecting against viral infections.

However, there is still a need to further fine-tune the behavior of cells in these targeted therapies. Bugaj and colleagues are addressing that need by developing new ways to communicate with engineered cells once they are in the body, such as turning molecular events on and off at specific times.

The research team recently discovered that both temperature and light can act as triggers of a specific fungal protein, dynamically controlling its location within a mammalian cell. By using light or temperature to instruct that protein to migrate toward or away from the cell’s membrane, Bugaj and his colleagues showed how it could serve as a key component in controlling the behavior of human cells.

Read the full story in Penn Engineering Today.

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Applying Microrobotics in Endodontic Treatment and Diagnostics

by Beth Adams

Controlled and actuated by magnetic fields, these mircrorobots are capable of precisely targeting the apical region — the opening where blood vessels and nerve enter the tooth — in a root canal.

With its irregularities and anatomical complexities, the root canal system is one of the most clinically challenging spaces in the oral cavity. As a result, biofilm not fully cleared from the nooks and crannies of the canals remains a leading cause of treatment failure and persistent endodontic infections, and there are limited means to diagnose or assess the efficacy of disinfection. One day, clinicians may have a new tool to overcome these challenges in the form of microrobots.

In a proof-of-concept study, researchers from Penn Dental Medicine and its Center for Innovation & Precision Dentistry (CiPD), have shown that microrobots can access the difficult to reach surfaces of the root canal with controlled precision, treating and disrupting biofilms and even retrieving samples for diagnostics, enabling a more personalized treatment plan. The Penn team shared their findings on the use of two different microrobotic platforms for endodontic therapy in the August issue of the Journal of Dental Research; the work was selected for the issue’s cover.

“The technology could enable multimodal functionalities to achieve controlled, precision targeting of biofilms in hard-to-reach spaces, obtain microbiological samples, and perform targeted drug delivery, ” says Dr. Alaa Babeer, lead author of the study and a Penn Dental Medicine Doctor of Science in Dentistry (DScD) and endodontics graduate, who is now within the lab of Dr. Michel Koo, co-director of the CiPD .

In both platforms, the building blocks for the microrobots are iron oxide nanoparticles (NPs) that have both catalytic and magnetic activity and have been FDA approved for other uses. In the first platform, a magnetic field is used to concentrate the NPs in aggregated microswarms and magnetically control them to the apical area of the tooth to disrupt and retrieve biofilms through a catalytic reaction. The second platform uses 3D printing to create miniaturized helix-shaped robots embedded with iron oxide NPs. These helicoids are guided by magnetic fields to move within the root canal, transporting bioactives or drugs that can be released on site.

“This technology offers the potential to advance clinical care on a variety of levels,” says Dr. Koo, co-corresponding author of the study with Dr. Edward Steager, a senior research investigator in Penn’s School of Engineering and Applied Science. “One important aspect is the ability to have diagnostic as well as therapeutic applications. In the microswarm platform, we can not only remove the biofilm, but also retrieve it, enabling us identify what microorganisms caused the infection. In addition, the ability to conform to the narrow and difficult-to-reach spaces within the root canal allows for a more effective disinfection in comparison to the files and instrumentation techniques presently used.”

Continue reading at Penn Dental Medicine News

Michel Koo is a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in Penn Dental Medicine and co-director of the Center for Innovation & Precision Dentistry. He is a member of the Penn Bioengineering Graduate Group.

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Konrad Kording on the Future of Brain-Computer Interfaces

Konrad Kording (Photo by Eric Sucar)

Though the technology for brain-computer interfaces (or BCI’s) has existed for decades, recent strides have been made to create BCI devices which are safer, smaller, and more effective. Konrad Kording, Nathan Francis Mossell University Professor in Bioengineering, Neuroscience, and Computer and Information Science, helps to elucidate the potential future of this technology in a recent feature in Wired. In the article, he discusses the “invasive” aspects of previous BCI technology, in contrast to recent innovations, such as a new device by Synchron, which do not require surgery and are consequently much less risky:

“The device, called a Stentrode, has a mesh-like design and is about the length of a AAA battery. It is implanted endovascularly, meaning it’s placed into a blood vessel in the brain, in the region known as the motor cortex, which controls movement. Insertion involves cutting into the jugular vein in the neck, snaking a catheter in, and feeding the device through it all the way up into the brain, where, when the catheter is removed, it opens up like a flower and nestles itself into the blood vessel’s wall. Most neurosurgeons are already up to speed on the basic approach required to put it in, which reduces a high-risk surgery to a procedure that could send the patient home the very same day. ‘And that is the big innovation,” Kording says.

Read “The Age of Brain-Computer Interfaces Is on the Horizon” in Wired.