With OCTOPUS, Dan Huh’s team has significantly advanced the frontiers of organoid research, providing a platform superior to conventional gel droplets. OCTOPUS splits the soft hydrogel culture material into a tentacled geometry. The thin, radial culture chambers sit on a circular disk the size of a U.S. quarter, allowing organoids to advance to an unprecedented degree of maturity.
When it comes to human bodies, there is no such thing as typical. Variation is the rule. In recent years, the biological sciences have increased their focus on exploring the poignant lack of norms between individuals, and medical and pharmaceutical researchers are asking questions about translating insights concerning biological variation into more precise and compassionate care.
What if therapies could be tailored to each patient? What would happen if we could predict an individual body’s response to a drug before trial-and-error treatment? Is it possible to understand the way a person’s disease begins and develops so we can know exactly how to cure it?
Dan Huh, Associate Professor in the Department of Bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science, seeks answers to these questions by replicating biological systems outside of the body. These external copies of internal systems promise to boost drug efficacy while providing new levels of knowledge about patient health.
An innovator of organ-on-a-chip technology, or miniature copies of bodily systems stored in plastic devices no larger than a thumb drive, Huh has broadened his attention to engineering mini-organs in a dish using a patient’s own cells.
Penn Medicine researchers laud the early results for CAR T therapy in lupus patients, which point to broader horizons for the use of personalized cellular therapies.
Penn Medicine’s Carl June and Daniel Baker.
Engineered immune cells, known as CAR T cells, have shown the world what personalized immunotherapies can do to fight blood cancers. Now, investigators have reported highly promising early results for CAR T therapy in a small set of patients with the autoimmune disease lupus. Penn Medicine CAR T pioneer Carl June and Daniel Baker, a doctoral student in cell and molecular biology in the Perelman School of Medicine, discuss this development in a commentary published in Cell.
“We’ve always known that in principle, CAR T therapies could have broad applications, and it’s very encouraging to see early evidence that this promise is now being realized,” says June, who is the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at Penn Medicine and director of the Center for Cellular Immunotherapies at the Abramson Cancer Center.
T cells are among the immune system’s most powerful weapons. They can bind to, and kill, other cells they recognize as valid targets, including virus-infected cells. CAR T cells are T cells that have been redirected, through genetic engineering, to efficiently kill specifically defined cell types.
CAR T therapies are created out of each patient’s own cells—collected from the patient’s blood, and then engineered and multiplied in the lab before being reinfused into the patient as a “living drug.” The first CAR T therapy, Kymriah, was developed by June and his team at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States, for six different cancers.
From the start of CAR T research, experts believed that T cells could be engineered to fight many conditions other than B cell cancers. Dozens of research teams around the world, including teams at Penn Medicine and biotech spinoffs who are working to develop effective treatments from Penn-developed personalized cellular therapy constructs, are examining these potential new applications. Researchers say lupus is an obvious choice for CAR T therapy because it too is driven by B cells, and thus experimental CAR T therapies against it can employ existing anti-B-cell designs. B cells are the immune system’s antibody-producing cells, and, in lupus, B cells arise that attack the patient’s own organs and tissues.
Eight researchers from the Perelman School of Medicine have received research grants designed to invest in high-risk, high-reward projects.
Bushra Raj, Assistant Professor of Cell and Developmental Biology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was one of three Penn winners of the NIH Director’s New Innovator Award for independent projects developed by early-career investigators. More additional Penn scientists who received NIH Director’s Transformative Research Award for a project focusing on cancer research.
Raj’s project focuses on “testing a novel technology that uses CRISPR/Cas gene-editing tools to genomically record inputs from two signaling pathways in the developing zebrafish brain.”
Established in 2009, the Transformative Research Award promotes cross-cutting, interdisciplinary science and is open to individuals and teams of investigators who propose research that could potentially create or challenge existing paradigms.
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.”
A Philadelphia life sciences company spun out of Penn is emerging from stealth mode with nearly $10 million from a seed funding round. Vittoria Biotherapeutics’ mission is to overcome limitations of CAR T cell therapy by using unique cell engineering and gene editing technologies to create new therapies that address unmet clinical needs. The technology the company is attempting to commercialize was developed by Marco Ruella, M.D., Assistant Professor of Medicine in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, who is the company’s scientific founder.
Qazi obtained his Ph.D. at the Technical University of Berlin and the Charité Hospital in Berlin, Germany working on translational approaches for musculoskeletal tissue repair using biomaterials and stem cells under the co-advisement of Georg Duda, Director of the Berlin Institute of Health and David Mooney, Mercator Fellow at Charité – Universitätsmedizin Berlin. After arriving at Penn in 2019, Qazi performed research on microscale granular hydrogels in the Polymeric Biomaterials Laboratory of Jason Burdick, Adjunct Professor in Bioengineering at Penn and Bowman Endowed Professor in Chemical and Biological Engineering at the University of Colorado, Boulder. While conducting postdoctoral research, Qazi also collaborated with the groups of David Issadore, Associate Professor in Bioengineering and in Electrical and Systems Engineering, and Daeyeon Lee, Professor and Evan C. Thompson Term Chair for Excellence in Teaching in Chemical and Biomolecular Engineering and member of the Penn Bioengineering Graduate Group. Qazi’s postdoctoral research was supported through a fellowship from the German Research Foundation, and resulted in several publications in high-profile journals, including Advanced Materials, Cell Stem Cell, Small, and ACS Biomaterials Science and Engineering.
“Taimoor has done really fantastic research as a postdoctoral fellow in the group,” says Burdick. “Purdue has a long history of excellence in biomaterials research and will be a great place for him to build a strong research program.”
Qazi’s future research program will engineer biomaterials to make fundamental and translational advances in musculoskeletal tissue engineering, including the study of how rare tissue-resident cells respond to spatiotemporal signals and participate in tissue repair, and developing modular hydrogels that permit minimally invasive delivery for tissue regeneration. The ultimate goal is to create scalable, translational, and biologically inspired healthcare solutions that benefit a patient population that is expected to grow manifold in the coming years.
Qazi is looking to build a strong and inclusive team of scientists and engineers with diverse backgrounds interested in tackling problems at the interface of translational medicine, materials science, bioengineering, and cell biology, and will be recruiting graduate students immediately. Interested students can contact him directly at thqazi@seas.upenn.edu.
“I am excited to launch my independent research career at a prestigious institution like Purdue,” says Qazi. “Being at Penn and particularly in the Department of Bioengineering greatly helped me prepare for the journey ahead. I am grateful for Jason’s mentorship over the years and the access to resources provided by Jason, Dave Issadore, Ravi, Dave Meany and other faculty which support the training and professional development of postdoctoral fellows in Penn Bioengineering.”
Congratulations to Dr. Qazi from everyone at Penn Bioengineering!
The Solomon R. Pollack Award for Excellence in Graduate Bioengineering Research is given annually to the most deserving Bioengineering graduate students who have successfully completed research that is original and recognized as being at the forefront of their field. This year Penn Bioengineering recognizes the outstanding work of two graduate students in Bioengineering: Erin Berlew and Rhea Chitalia.
Erin Berlew, Ph.D. candidate in Bioengineering
Erin Berlew is a Ph.D. candidate in the lab of Brian Chow, Associate Professor in Bioengineering. She successfully defended her thesis, titled “Single-component optogenetic tools for cytoskeletal rearrangements,” in December 2021. In her research, she used the BcLOV4 optogenetic platform discovered/developed in the Chow lab to control RhoGTPase signaling. Erin earned a B.S. in Chemistry from Haverford College in 2015 and was an Americorps member with City Year Philadelphia from 2015-2016. “Erin is a world-class bioengineering with an uncommon record of productivity gained through her complementary expertise in molecular, cellular, and computational biology,” says Chow. “She embodies everything wonderful, both academically and culturally, about our graduate program and its distinguished history.” Erin’s hobbies outside the lab include spending time with family, reading mystery novels, enjoying Philadelphia, and crossword puzzles. In the future, she hopes to continue to teach for the BE department (she has already taught ENGR 105 and served as a TA for undergraduate and graduate courses) and to conduct further research at Penn.
Rhea Chitalia, Ph.D. candidate in Bioengineering
Rhea Chitalia is a Ph.D. candidate in Bioengineering and a member of the Computational Biomarker Imaging Group (CBIG), advised by Despina Kontos, Matthew J. Wilson Associate Professor of Research Radiology II in the Perelman School of Medicine. Rhea completed her B.S.E. in Biomedical Engineering at Duke University in 2015. Her doctoral research concerns leveraging machine learning, bioinformatics, and computer vision to develop computational imaging biomarkers for improved precision cancer care. In December 2021 she successfully defended her thesis titled “Computational imaging biomarkers for precision medicine: characterizing intratumor heterogeneity in breast cancer.” “It has been such a privilege to mentor Rhea on her dissertation research,” says Kontos. “Rhea has been a star graduate student. Her work has made fundamental contributions in developing computational methods that will allow us to gain important insight into tumor heterogeneity by utilizing a multi-modality imaging approach.” David Mankoff, Matthew J. Wilson Professor of Research Radiology in the Perelman School of Medicine, served as Rhea’s second thesis advisor. “It was a true pleasure for me to work with Rhea and to Chair her BE Thesis Committee,” Mankoff adds. “Rhea’s Ph.D. thesis and thesis presentation was one of the best I have had the chance to be involved with in my graduate mentoring career.” After graduation, Rhea hopes to further precision medicine initiatives through the use of real world, multi-omic data in translational industry settings. She will be joining Invicro as an Imaging Scientist. In her spare time, Rhea enjoys trying new restaurants, reading, and spending time with friends and family.
Jennifer E. Phillips-Cremins, Associate Professor and Dean’s Faculty Fellow in Bioengineering and Genetics, has been awarded the 2022 Dr. Susan Lim Award for Outstanding Young Investigator by the International Society for Stem Cell Research (ISSCR), the preeminent, global organization dedicated to stem cells research.
This award recognizes the exceptional achievements of an investigator in the early part of his or her independent career in stem cell research. Cremins works in the field of epigenetics, and is a pioneer in understanding how chromatin, the substance within a chromosome, works:
“Dr. Phillips-Cremins is a gifted researcher with diverse skills across cell, molecular, and computational biology. She is a shining star in the stem cell field who has already made landmark contributions in bringing long-range chromatin folding mechanisms to stem cell research. In addition to her skills as an outstanding researcher,” ISSCR President Melissa Little, Ph.D., said. “She has flourished as an independent investigator, providing the stem cell field with unique and creative approaches that have facilitated conceptual leaps in our understanding of long-range spatial regulation of stem cell fate. Congratulations, Jennifer, on this prestigious honor.”
Cremins was awarded a NIH Director’s Pioneer Award in 2021 and a Chan Zuckerberg Initiative (CZI) grant as part of the CZI Collaborative Pairs Pilot Project in 2020. The long-term goal of her lab is to understand the mechanisms by which chromatin architecture governs genome function. The ISSCR will recognize Cremins and her research in a plenary session during the ISSCR annual meeting on June 15.
The brighter edges of the cells in the middle and upper right panels show the optogenetic proteins collecting at the membrane after light exposure. At higher temperatures, however, the proteins become rapidly inactivated and thus do not stay at the membrane, resulting in the duller edges seen in the bottom right panel.
Most organisms have proteins that react to light. Even creatures that don’t have eyes or other visual organs use these proteins to regulate many cellular processes, such as transcription, translation, cell growth and cell survival.
The field of optogenetics relies on such proteins to better understand and manipulate these processes. Using lasers and genetically engineered versions of these naturally occurring proteins, known as probes, researchers can precisely activate and deactivate a variety of cellular pathways, just like flipping a switch.
Now, Penn Engineering researchers have described a new type of optogenetic protein that can be controlled not only by light, but also by temperature, allowing for a higher degree of control in the manipulation of cellular pathways. The research will open new horizons for both basic science and translational research.
Lukasz Bugaj, Bomyi Lim, and Brian Chow
Lukasz Bugaj, Assistant Professor in Bioengineering (BE), Bomyi Lim, Assistant Professor in Chemical and Biomolecular Engineering, Brian Chow, Associate Professor in BE, and graduate students William Benman in Bugaj’s lab, Hao Deng in Lim’s lab, and Erin Berlew and Ivan Kuznetsov in Chow’s lab, published their study in Nature Chemical Biology. Arndt Siekmann, Associate Professor of Cell and Developmental Biology at the Perelman School of Medicine, and Caitlyn Parker, a research technician in his lab, also contributed to this research.
The team’s original aim was to develop a single-component probe that would be able to manipulate specific cellular pathways more efficiently. The model for their probe was a protein called BcLOV4, and through further investigation of this protein’s function, they made a fortuitous discovery: that the protein is controlled by both light and temperature.
Yogesh Goyal, Ph.D., a postdoctoral researcher in Genetics and Bioengineering, has been selected as a 2021 STAT Wunderkind, which honors the “next generation of scientific superstars.” Goyal’s research is centered around developing novel mathematical and experimental frameworks to study how a rare subpopulation of cancer cells are able to survive drug therapy and develop resistance, resulting in relapse in patients. In particular, his work provides a view of different paths that single cancer cells take when becoming resistant, at unprecedented resolution and scale. This research aims to help devise novel therapeutic strategies to combat the challenge of drug resistance in cancer.
Goyal is a Jane Coffin Childs Postdoctoral Fellow in the systems biology lab of Arjun Raj, Professor in Bioengineering and Genetics at Penn. He will begin an appointment as Assistant Professor in the Department of Cell and Developmental Biology (CDB) in the Feinberg School of Medicine at Northwestern University in spring 2022.
