Month: October 2020

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Through Brain Imaging Analysis in Rats, Penn Researchers Show Potential to Predict Whether Pain Will be Acute or Persistent

Beth Winkelstein, Megan Sperry, and Eric Granquist

Pain may be a universal experience, but what actually causes that experience within our brains is still poorly understood. Pain often continues long after the relevant receptors in the body have stopped being stimulated and can persist even after those receptors cease to exist, as is the case with “phantom limb” pain.

The exact experience an individual will have after a painful incident comes down to the complex, variable connections formed between several different parts of the brain. The inability to predict how those connections will form and evolve can make pain management a tricky, frustrating endeavor for both healthcare providers and patients.

Now, a team of Penn researchers has shown a way to make such predictions from the pattern of neural connections that begin to take shape soon after the first onset of pain. Though their study was conducted in rats, it suggests that similar brain imaging techniques could be used to guide treatment decisions in humans, such as which individuals are most likely to benefit from different drugs or therapies.

The study, published in the journal Pain, was led by Beth Winkelstein, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Bioengineering and Deputy Provost of the University of Pennsylvania, along with Megan Sperry, then a graduate student in her lab. Eric Granquist, Director of the Center for Temporomandibular Joint Disease at the Hospital of the University of Pennsylvania in the Department of Oral & Maxillofacial Surgery, and assistant professor of Oral & Maxillofacial Surgery in Penn’s School of Dental Medicine, also contributed to the research.

“Our findings provide the first evidence that brain networks differ between acute and persistent pain states, even before those different groups of rats actually show different pain symptoms,” says Winkelstein.

Read the full story at Penn Engineering Today. Media contact Evan Lerner.

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Ravi Radhakrishnan Adapts Multiscale Modeling Course

 

Ravi Radhakrishnan, PhD

Ravi Radhakrishnan, Professor and Chair of the Department of Bioengineering and Professor in Chemical and Biomolecular Engineering, is among the many faculty who quickly adapted their courses to an online format in the wake of the COVID-19 pandemic. Now, a recent publication in the American Institute of Chemical Engineers (AIChE) Journal reflects one of these revamped courses. The course BE 559: “Multiscale Modeling of Chemical and Biological Systems” provides theoretical, conceptual, and hands-on modeling experience on three different length and time scales: (1) electronic structure (A, ps); (2) molecular mechanics (100A, ns); and (3) deterministic and stochastic approaches for microscale systems (um, sec). During the course, students gained hands-on experience in running codes on real applications together with the following theoretical formalisms: molecular dynamics, Monte Carlo, free energy methods, deterministic and stochastic modeling. The transition to the online format was greatly facilitated by a grant from the Extreme Science and Engineering Discovery Environment (XSEDE) which provided cloud and supercomputing resources to the students facilitating the computational laboratory experience. Radhakrishnan’s article, “A survey of multiscale modeling: Foundations, historical milestones, current status, and future prospects,” reviews the foundations, historical developments, and current paradigms in multiscale modeling (MSM).

Radhakrishnan aspires to modernize computational science, integrating Multiscale Modeling and Data Science for Biological and Biomedical Science & Engineering. His team does so by integrating multiphysics modeling, computing, data science to tackle applications. The integrative approach is pictorially depicted here in terms of modeling different length and timescales using techniques such as molecular dynamics of atomistic systems, Brownian dynamics of coarse-grained systems, and field equations governing continuum scales of macroscopic systems.

Read the full article in the AIChE Journal: https://doi.org/10.1002/aic.17026

Funding source: National Institutes of Health, Grant/Award Number: CA227550

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Brianne Connizzo Appointed Assistant Professor at Boston University

by Mahelet Asrat

Brianne Connizzo, PhD

The Department of Bioengineering is proud to congratulate alumna Brianne Connizzo, PhD on her appointment as a tenure-track Assistant Professor in the Department of Biomedical Engineering in the College of Engineering at Boston University. Connizzo’s appointment will begin in January 2021, after completing her work as a postdoctoral researcher in Biological Engineering at MIT under the supervision of Alan J. Grodzinsky, ScD, Professor of Biological, Electrical, and Mechanical Engineering.

Connizzo got her BS in Engineering Science from Smith College (the first all women’s engineering program in the country) where she graduated in 2010 with highest honors. During her time there, she worked in the laboratory of Borjana Mikic, Rosemary Bradford Hewlett 1940 Professor of Engineering. While working in the lab, she explored the role of myostatin deficiency on Achilles tendon biomechanics and built mechanical testing fixtures for submerged testing of biological tissues. Connizzo continued along this path during her graduate studies in Bioengineering at Penn while working with Louis J. Soslowsky, Fairhill Professor in Orthopaedic Surgery and Professor in Bioengineering, at the McKay Orthopaedic Research Laboratory. Her thesis work focused on the dynamic re-organizations of collagen during tendon loading in the rotator cuff, developing a novel AFM-based method for measuring collagen fibril sliding along the way. During her time at Penn, Connizzo also served as the Social Chair for the Graduate Association of Bioengineers (GABE) and the Graduate Student Engineering Group (GSEG), both of which play a vital role in representing graduate students across the School of Engineering and Applied Sciences. She completed her PhD in Bioengineering in 2015 and then pursued her postdoctoral studies at MIT, focusing on fluid flow during compressive loading and developing novel explant culture models to explore real-time extracellular matrix turnover. For her work she was awarded both an NIH F32 postdoctoral fellowship and the NIH K99/R00 Pathway Independence Award, which are just a few of her long list of impressive accomplishments.

Although Connizzo’s interests in soft tissue mechanobiology span development, injury, and disease, her more recent work has targeted how aging influences tendon function and biology. With a fast-growing active and aging population, she believes that identifying the cause and contributors of age-related changes is critical to finding treatments and therapies that could prevent tendon disease, and thus improve overall population healthspan and quality of life. The primary objectives of the Connizzo Lab at Boston University will be to harness novel in vitro and in vivo models to study cell-controlled extracellular matrix remodeling and tissue biomechanics and to better understand normal tendon maintenance and the initiation of tendon damage in the context of aging.

“I am so grateful to have had the guidance of my mentors and peers at Penn during my doctoral studies, and even more thankful that many of those relationships remain a significant part of my support system to this day,” Connizzo says. “I’m really looking forward to this next chapter — to all the successes and failures in pursuing the science, to building a community at BU and in my own laboratory, and to supporting the next generation of brilliant young scientists.”

Congratulations Dr. Connizzo from everyone at Penn Bioengineering!

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Engineering Bacteria-Killing Molecules from Wasp Venom

César de la Fuente, PhD

César de la Fuente a Presidential Assistant Professor in the Perelman School of Medicine’s departments of Psychiatry and Microbiology and Engineering’s department of Bioengineering, has racked up accolades for his innovative, computational approach to discovering new antibiotics.

Now, in his most recent study, de la Fuente has shown how these vital drugs might be derived from wasp venom.

The study, published in The Proceedings of the National Academy of Sciences, involved altering a highly toxic small protein from a common Asian wasp species, Vespula lewisii, the Korean yellow-jacket wasp. The alterations enhanced the molecule’s ability to kill bacterial cells while greatly reducing its ability to harm human cells. In animal models, de la Fuente and his colleagues showed that this family of new antimicrobial molecules made with these alterations could protect mice from otherwise lethal bacterial infections.

There is an urgent need for new drug treatments for bacterial infections, as many circulating bacterial species have developed a resistance to older drugs. The U.S. Centers for Disease Control & Prevention has estimated that each year nearly three million Americans are infected with antibiotic-resistant microbes and more than 35,000 die of them. Globally the problem is even worse: Sepsis, an often-fatal inflammatory syndrome triggered by extensive bacterial infection, is thought to have accounted for about one in five deaths around the world as recently as 2017.

“New antibiotics are urgently needed to treat the ever-increasing number of drug-resistant infections, and venoms are an untapped source of novel potential drugs. We think that venom-derived molecules such as the ones we engineered in this study are going to be a valuable source of new antibiotics,” says de la Fuente.

De la Fuente and his team started with a small protein, or “peptide,” called mastoparan-L, a key ingredient in the venom of Vespula lewisii wasps. Mastoparan-L-containing venom is usually not dangerous to humans in the small doses delivered by wasp stings, but it is quite toxic. It destroys red blood cells, and triggers a type of allergic/inflammatory reaction that in susceptible individuals can lead to a fatal syndrome called anaphylaxis—in which blood pressure drops and breathing becomes difficult or impossible.

Mastoparan-L (mast-L) also is known for its moderate toxicity to bacterial species, making it a potential starting point for engineering new antibiotics. But there are still some unknowns, including how to enhance its anti-bacterial properties, and how to make it safe for humans.

Continue reading at Penn Medicine News.

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Brian Litt Receives NIH Pioneer Award to Develop Implantable Neurodevices

Brian Litt, MD

Brian Litt, professor in Engineering’s Department of Bioengineering and the Perelman School of Medicine’s departments of Neurology and Neurosurgery, has received a five-year, $5.6 million Pioneer Award from the National Institutes of Health, which will support his research on implantable devices for monitoring, recording and responding to neural activity.

The Pioneer Award is part of the agency’s High-Risk, High-Reward Research Program honoring exceptionally creative scientists. It challenges investigators to pursue new research directions and develop groundbreaking, high-impact approaches to a broad area of biomedical or behavioral science. Litt’s neurodevice research represents a new frontier in addressing a wide variety of neurological conditions.

In epilepsy, for example, these devices would predict and prevent seizures; in Parkinson’s patients, implants will measure and communicate with patients to improve mobility, reduce tremor and enhance responsiveness. Other implants might improve hearing or psychiatric symptoms by querying patient perceptions, feelings, and altering stimulation patterns algorithmically to improve them

Continue reading about Litt’s Pioneer Award at Penn Medicine News.

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New Research from Penn Engineering and MIT Shows How Nanoparticles Can Turn Off Genes in Bone Marrow

Michael Mitchell
Michael Mitchell, PhD

by Evan Lerner

Using specialized nanoparticles, researchers from Penn Engineering and the Massachusetts Institute of Technology (MIT) have developed a way to turn off specific genes in cells of bone marrow, which play an important role in producing blood cells. These particles could be tailored to help treat heart disease or to boost the yield of stem cells in patients who need stem cell transplants.

This type of genetic therapy, known as RNA interference, is usually difficult to target to organs other than the liver, where nanoparticles would tend to accumulate. The researchers were able to modify their particles in such a way that they would accumulate in the cells found in the bone marrow.

In a recent Nature Biomedical Engineering study, conducted in mice, the researchers showed that they could use this approach to improve recovery after a heart attack by inhibiting the release of bone marrow blood cells that promote inflammation and contribute to heart disease.

“If we can get these particles to hit other organs of interest, there could be a broader range of disease applications to explore, and one that we were really interested in in this paper was the bone marrow. The bone marrow is a site for hematopoiesis of blood cells, and these give rise to a whole lineage of cells that contribute to various types of diseases,” says Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, one of the lead authors of the study.

Marvin Krohn-Grimberghe, a cardiologist at the Freiburg University Heart Center in Germany, and Maximilian Schloss, a research fellow at Massachusetts General Hospital (MGH), are also lead authors on the paper, which appears today in Nature Biomedical Engineering. The paper’s senior authors are Daniel Anderson, a professor of Chemical Engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and Matthias Nahrendorf, a professor of Radiology at MGH.

Mitchell’s expertise is in the design of nanoparticles and other drug delivery vehicles, engineering them to cross biological barriers that normally block foreign agents. In 2018, he received the NIH Director’s New Innovator Award to support research on delivering therapeutics to bone marrow, a key component of this new study.

The researchers have shown they can deliver nanoparticles to the bone marrow, influencing their function with RNA silencing. At top right, the bone marrow is not yet treated with particles that turn off a gene called SDF1. At bottom right, the number of neutrophils (blue) decreases, indicating that they have been released from bone marrow after treatment. At left, treatment with a control nanoparticle does not affect the number of neutrophils before and after treatment.

Read the full story at Penn Engineering Today.

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BE Seminar: “High-throughput Screening of a Combinatorial CAR Co-stimulatory Domain Library” (Kyle Daniels)

Kyle Daniels, PhD

Speaker: Kyle Daniels, Ph.D.
Postdoctoral Scholar, Cellular Molecular Pharmacology
University of California, San Francisco

Date: Thursday, October 22, 2020
Time: 3:00-4:00 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “High-throughput Screening of a Combinatorial CAR Co-stimulatory Domain Library”

Abstract:

CAR T cells—T cells engineered to express a chimeric antigen receptor that redirects their function to a specific antigen—have proven to be an effective therapy for certain B cell cancers, but many issues remain in order to apply CAR T cells to a broader range of cancers. The activity of CAR T cells can be modulated by varying their co-stimulatory domains. Most CARs use co-stimulatory domains from natural proteins such as 41BB or CD28, each of which contains motifs that recruit unique signaling molecules and elicit a corresponding T cell response. One strategy to achieve increased control over T cell function is to engineer synthetic co-stimulatory domains composed of novel combinations of motifs from natural co-stimulatory proteins. We constructed libraries of CARs containing synthetic co-stimulatory domains and screened these library in primary human T cells for the ability to promote proliferation, degranulation, and memory formation. The results of the screens give insights into how signaling motifs dictate cell function and offer clues on how to engineer co-stimulatory domains that promote desired CAR T cell functions.

Bio:

Kyle completed his BS in Biochemistry at University of Maryland-College Park, and did undergraduate research in the lab of Dorothy Beckett where he studied ligand binding to biotin protein ligases. He did his graduate work at Duke University with Terry Oas working to understand the mechanism of coupled binding and folding in the protein subunit of B. subtilis RNase P. He is currently a postdoctoral fellow in Wendell Lim’s lab at UCSF studying how combinations of linear motifs in receptors dictate cell function. He was an HHMI undergraduate researcher, an NSF graduate research fellow, and a Damon Runyon Cancer Research Foundation postdoctoral fellow. His research interests include synthetic biology, how cells process information and make decisions, and cellular therapy. Outside of lab, he enjoys swimming, videogames, and quality time with friends.

See the full list of upcoming Penn Bioengineering fall seminars here.

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In Memoriam: David Geselowitz, 1930-2020

David Geselowitz

Penn Engineering mourns the death of our former colleague Dr. David Geselowitz, who died on August 22, 2020. The Penn Engineering and Penn State communities have lost a brilliant scientist and researcher, and an extraordinary teacher, mentor and friend.

Dr. Geselowitz was born in Philadelphia in 1930, and graduated from the University of Pennsylvania, where he received his bachelor’s, master’s and doctoral degrees in Electrical Engineering in 1951, 1954 and 1958, respectively. As the top student in his undergraduate class, he received the Atwater Kent Award.

After receiving his Ph.D., he joined the faculty of the University of Pennsylvania and subsequently founded Penn’s doctoral program in biomedical engineering. In 1971, he moved to Penn State University to implement a graduate program in bioengineering.

Dr. Geselowitz was known for his contributions to the theory of the electrocardiogram (EKG) and the development of the artificial heart. As noted by the late Dr. Herman Schwan, “David was the best man I had met in electrocardiography work. The National Academy of Engineering recognized him for that work. He became a leader in the country in the field.”

For more on the life of Dr. Geselowitz, please see the tribute from his longtime colleagues at Penn State: https://news.engr.psu.edu/2020/geselowitz-david-obituary.aspx

This story originally appeared in Penn Engineering News.

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A potential cause of CAR T side effects, and a path forward

Single cell sequencing aided researchers in identifying a previously undiscovered molecule in the brain.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of leukemia, lymphoma, and multiple myeloma. But some people who have received this treatment experience neurotoxicity, or damage to the brain or nervous system.

New research from a team led by Avery Posey, an assistant professor of systems pharmacology and translational therapeutics in the Perelman School of Medicine, provides evidence that this side effect may owe to a molecule in the brain that scientists previously didn’t know was there.

The work, published in the journal Cell, revealed that the protein CD19 is present in brain cells that protect the blood-brain barrier. Prior to the finding, scientists believed CD19 was only expressed on B cells, and the protein served as a target for certain forms of CAR-T therapy. The discovery may chart a path forward for new strategies to effectively treat cancer while sparing the brain.

“The next question is,” says Posey, “can we identify a better target for eliminating B cell related malignancies other than CD19, or can we engineer around this brain cell expression of CD19 and build a CAR T cell that makes decisions based on the type of cell it encounters—for instance, CAR T cells that kill the B cells they encounter, but spare the CD19 positive brain cells?”

Read more at Penn Medicine News. Avery Posey is a member of the Department of Bioengineering Graduate Group.