Tag: cell biology

Posted on

Penn Bioengineering Student Wins Gilliam Fellowship

Sam Preza (Image: Courtesy of Penn Medicine News)

Sam Preza, a doctoral student in Bioengineering, was named one of two Penn graduate students and one of 50 graduate students nationwide to receive a 2024 Howard Hughes Medical Institute (HHMI) Gilliam Fellowship.  The HHMI Gilliam Fellowship cohort is awarded annually to graduate students and their advisors for outstanding research and commitment to advancing equity and inclusion in science. The fellowship includes a one-year mentorship skills development course and support to promote healthy and inclusive graduate training environments at their home institution.

Preza is a member of lab of Juan Rene Alvarez Dominguez, Assistant Professor of Cell and Developmental Biology in the Perelman School of Medicine and member of the Bioengineering Graduate Group. He graduated from University of Maryland in 2019 with a degree in Chemical Engineering. After working for t three years at AstraZeneca in Bioprocess Development, he joined the J-RAD Lab where he researches technologies for unmet medical needs:

“[Preza’s] PhD program harnesses the power of stem cells and circadian rhythms to ultimately develop a cure for Type I diabetes, which he researches alongside his advisor, Juan Alvarez, PhD, an assistant professor in the Department of Cell and Developmental Biology. Their studies focus on beta cells, the type of cell found in the pancreas that helps regulate glucose. In the lab, they study how exposing cells to circadian rhythms could lead to functional beta cells that can be transplanted into diabetic patients to restore function. This work will be supported by their HHMI Fellowship grant.  

The fellowship not only supports their scientific research but also helps foster an inclusive research environment, ensuring various backgrounds and ideologies contribute to their research. Preza is starting a DEI ‘potluck’, where bioengineering students can gather to discuss new research or career ideas. The meetups are catered by whichever student is hosting the meeting and can either showcase their nationality’s food or a cuisine they are passionate about, highlighting the celebration of diversity of ideas through food.

‘I believe STEM fields should look more like a mosaic of all our backgrounds rather than a melting pot, to add to the richness that is the art of science,’ Preza said.”

Read “Inclusion meets innovation: Meet Penn’s new Gilliam Fellows” in Penn Medicine News.

Posted on

Understanding the Cellular Mechanisms Driving Solid Tumors’ Robust Defense System

by Nathi Magubane

In a collaborative interdisciplinary study, Michael Mitchell of the School of Engineering and Applied Science, Wei Guo of the School of Arts & Sciences, and Drew Weissman of the Perelman School of Medicine show that solid tumors can block drug-delivery mechanisms with a “forcefield-like” effect but certain genetic elements that can effectively “shut down” the forcefield. Their findings hint at new targets for delivering cancer treatments that use the body’s immune system to fight tumors. (Image: iStock / CIPhotos)

The tumor microenvironment—an ad hoc, messy amalgamation of signaling molecules, immune cells, fibroblasts, blood vessels, and the extracellular matrix—acts like a “powerful security system that protects solid tumors from invaders seeking to destroy them,” says Michael Mitchell, a bioengineer at the University of Pennsylvania working on nanoscale therapeutics aimed at targeting cancers.

“A lot like the Death Star with its surrounding fleet of fighter ships and protective shields, solid tumors can use features like immune cells and vasculature to exert force, acting as a physical barrier to rebel forces (nanoparticles) coming in to deliver the payload that destroys it,” Mitchell says.

Now, researchers in the Mitchell lab have teamed up with Wei Guo’s group in the School of Arts & Sciences at Penn and Drew Weissman of the Perelman School of Medicine to figure out the molecular mechanisms that make tumor microenvironments seemingly impenetrable and found that small extracellular vesicles (sEVs) are secreted by tumor cells and act as a “forcefield,” blocking therapeutics. Their findings are published in Nature Materials.

“This discovery reveals how tumors create a robust defense system, making it challenging for nanoparticle-based therapies to reach and effectively target cancer cells,” Guo says. “By understanding the cellular mechanisms driving these responses, we can potentially develop strategies to disable this defense, allowing therapeutics to penetrate and attack the tumor more efficiently.”

The research builds on a prior collaboration between Guo and Mitchell’s labs, wherein the teams focused on how tumor-associated immune cells, known as macrophages, contribute to the suppression of anti-tumor immunity by secreting extracellular vesicles.

Read the full story in Penn Today.

Michael Mitchell is an associate professor in the Department of Bioengineering in the School of Engineering and Applied Science and director of the Lipid Nanoparticle Synthesis Core at the Penn Institute for RNA Innovation at the University of Pennsylvania.

Wei Guo is the Hirsch Family President’s Distinguished Professor in the Department of Biology in Penn’s School of Arts & Sciences.

Ningqiang Gong, a former postdoctoral researcher in the Mitchell lab at Penn Engineering, is an assistant professor at the University of Science and Technology of China.

Wenqun Zhong is a reseearch associate in the Guo Laboratory in Penn Arts & Sciences.

Other authors include: Alex G Hamilton, Dongyoon Kim, Junchao Xu, and Lulu Xue of Penn Engineering; Junhyong Kim, Zhiyuan Qin, and Fengyuan Xu of Penn Arts & Sciences; Mohamad-Gabriel Alameh and Drew Weissman of the Perelman School of Medicine; Andrew E. Vaughn and Gan Zhao of the Penn School of Veterinary Medicine; Jinghong Li and Xucong Teng of the University of Beijing; and Xing-Jie Liang of the Chinese Academy of Sciences.

This research received support from the U.S. National Institutes of Health (DP2 TR002776, R35 GM141832, and NCI P50 CA261608), Burroughs Wellcome Fund, U.S. National Science Foundation CAREER Award (CBET-2145491), and an American Cancer Society Research Scholar Grant (RGS-22-1122-01-ET.)

Posted on

Carl June on the Boundless Potential of CAR T Cell Therapy

by Meagan Raeke

Carl June, at the flash mob celebration of the FDA approval of the CAR T cell therapy he developed, in August 2017. (Image: Courtesy of Penn Medicine Magazine)

For most of modern medicine, cancer drugs have been developed the same way: by designing molecules to treat diseased cells. With the advent of immunotherapy, that changed. For the first time, scientists engineered patients’ own immune systems to recognize and attack diseased cells.

One of the best examples of this pioneering type of medicine is CAR T cell therapy. Invented in the Perelman School of Medicine by Carl June, the Richard W. Vague Professor in Immunotherapy, CAR T cell therapy works by collecting T cells from a patient, modifying those cells in the lab so that they are designed to destroy cancerous cells, and reinfusing them into the patient. June’s research led to the first FDA approval for this type of therapy, in 2017. Six different CAR T cell therapies are now approved to treat various types of blood cancers. Carl June, at the flash mob celebration of the FDA approval of the CAR T cell therapy he developed, in August 2017. (Image: Courtesy of Penn Medicine Magazine)

CAR T cell therapy holds the potential to help millions more patients—if it can be successfully translated to other conditions. June and colleagues, including Daniel Baker, a fourth-year doctoral student in the Cell and Molecular Biology department, discuss this potential in a perspective published in Nature.

In the piece, June and Baker highlight other diseases that CAR T cell therapy could be effective.

“CAR T cell therapy has been remarkably successful for blood cancers like leukemias and lymphomas. There’s a lot of work happening here at Penn and elsewhere to push it to other blood cancers and to earlier stage disease, so patients don’t have to go through chemo first,” June says. “Another big priority is patients with solid tumors because they make up the vast majority of cancer patients. Beyond cancer, we’re seeing early signs that CAR T cell therapy could work in autoimmune diseases, like lupus.”

As for which diseases to pursue as for possible future treatment, June says, “essentially it boils down to two questions: Can we identify a population of cells that are bad? And can we target them specifically? Whether that’s asthma or chronic diseases or lupus, if you can find a bad population of cells and get rid of them, then CAR T cells could be therapeutic in that context.”

“What’s exciting is it’s not just theoretical at this point. There have been clinical reports in other autoimmune diseases, including myasthenia gravis and inflammatory myopathy,” Baker says. “But we are seeing early evidence that CAR T cell therapy will be successful beyond cancer. And it’s really opening the minds of people in the field to think about how else we could use CAR T. For example, there’s some pioneering work at Penn from the Epstein lab for heart failure. The idea is that you could use CAR T cells to get rid of fibrotic tissue after a cardiac injury, and potentially restore the damage following a heart attack.”

Baker adds, “there’s no question that over the last decade, CAR T cell therapy has revolutionized cancer. I’m hoping to play a role in bringing these next generation therapies to patients and make a real impact over the next decade. I think there’s potential for cell therapy to be a new pillar of medicine at large, and not just a new pillar of oncology.”

Read the full story at Penn Medicine Today.

Posted on

“QR Code for Cancer Cells” – Uncovering Why Some Cells Become Resistant to Anti-Cancer Therapies

by Win Reynolds

QR codeA research team led by engineers at the University of Pennsylvania and Northwestern University scientists has created a new synthetic biology approach, or a “QR code for cancer cells,” to follow tumor cells over time, finding there are meaningful differences in why a cancer cell dies or survives in response to anti-cancer therapies.

Remarkably, what fate cancer cells choose after months of therapy is “entirely predictable” based on seemingly small, yet important, differences that appear even before treatment begins. The researchers also discovered the reason is not genetics, contrary to beliefs held in the field.

The findings were recently published in Nature.

The study outlined the team’s new technology platform that developed a QR code for each of the millions of cells for scientists to find and use later — much like tagging swans in a pond. The QR code directs researchers to a genome-wide molecular makeup of these cells and provides information about how they’ve reacted to cancer treatment.

“We think this work stands to really change how we think about therapy resistance,” said Arjun Raj, co-senior author and Professor in Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania. “Rather than drug-resistant cells coming in just one flavor, we show that even in highly controlled conditions, different ‘flavors’ can emerge, raising the possibility that each of these flavors may need to be treated individually.”

In the study, the lab and collaborators sought to apply synthetic biology tools to answer a key question in cancer research: What makes certain tumors come back a few months or years after therapy? In other words, could the lab understand what causes some rare cells to develop therapeutic resistance to a drug?

“There are many ways cells become different from each other,” said Yogesh Goyal, the co-senior author at Northwestern University. “Our lab asks, how do individual cells make decisions? Understanding this in the context of cancer is all the more exciting because there’s a clinically relevant dichotomy: A cell dies or becomes resistant when faced with therapies.”

Using the interdisciplinary team, the scientists put the before-and-after cloned cells through a whole genome sequencing pipeline to compare the populations and found no systematic underlying genetic mutations to investigate the hypothesis. Raj and Goyal  helped develop the QR code framework, FateMap, that could identify each unique cell that seemed to develop resistance to drug therapy. “Fate” refers to whether a cell dies or survives (and if so, how), and the scientists “map” the cells across their lifespan, prior to and following anti-cancer therapy. FateMap is the result of work from several research institutions, and it applies an amalgamation of concepts spanning several disciplines, including synthetic biology, genome engineering, bioinformatics, machine learning and thermodynamics.

“Some are different by chance — just as not all leaves on a tree look the same — but we wanted to determine if that matters,” Goyal said. “The cell biology field has a hard time defining if differences have meaning.”

Read the full story in Penn Engineering Today.

Posted on

Mustafa Mir Named HHMI Freeman Hrabowski Scholar

Mustafa Mir

Mustafa Mir, Assistant Professor of Cell and Developmental Biology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was selected as one of Howard Hughes Medical Institute’s 31 new Freeman Hrabowski Scholars. The group consists of outstanding early career faculty in science who have potential to become leaders in their research fields and to create diverse and inclusive lab environments in which everyone can thrive. Mir and his lab develop and apply new microscopes to directly visualize the molecular scale events that underlie gene expression within live embryos.

Read a Q&A with Mir in the Children’s Hopsital of Philadelphia (CHOP)’s Cornerstone Blog: “‘New Technologies Lead to New Discoveries’: Q&A With HHMI Scholar Mustafa Mir, PhD.“

This announcement originally appeared in Penn Medicine News.

Posted on

Two from Penn Bioengineering Graduate Group Elected to the National Academy of Sciences

Four faculty from the University of Pennsylvania have been elected to the United States National Academy of Sciences (NAS). They are David Brainard of the School of Arts & Sciences; Duncan Watts of the Annenberg School of Communication, School of Engineering and Applied Science, and Wharton School; and Susan R. Weiss and Kenneth S. Zaret of the Perelman School of Medicine.

They join 120 members and 23 international members elected by their peers this year to NAS. Recognized for “distinguished and continuing achievements in original research,” this new class brings the total number of active members to 2,565 and of international members to 526.

Brainard and Zaret are members of the Penn Bioengineering Graduate Group.

David Brainard is the RRL Professor of Psychology, director of the Vision Research Center, and associate dean for the natural sciences in the School of Arts & Sciences. His research focuses on human vision, using both experiments and computer modeling of visual processing, to understand how the visual system deciphers information about objects from light entering the eye. Specifically, he and his lab are interested in color vision, conducting psychophysical experiments to investigate how the appearance of color is affected by an object’s surface properties and ambient light, and how color perception aids in identifying objects. Brainard is the recipient of many honors, including the Macbeth Award from the Inter-Society Color Council, Stein Innovation Award from Research to Prevent Blindness, and Edgard D. Tillyer Award from Optica. He is an elected member of the Society of Experimental Psychologists, a Silver Fellow of the Association for Research in Vision and Ophthalmology, and a Fellow of the Association for Psychological Science.

Kenneth Zaret

Kenneth S. Zaret is the Joseph Leidy Professor in the Department of Cell and Developmental Biology at the Perelman School of Medicine, director of the Institute for Regenerative Medicine, and a member of the Cell and Molecular Biology Graduate Program. His research focuses on gene regulation, cell differentiation, and chromatin structure, with a goal of elucidating these phenomena in the context of embryonic development and tissue regeneration. Pinpointing these aspects of development at the cellular level can serve as the basis for developing future therapeutics and experimental models that further scientists’ ability to understand and cure disease. Zaret has been the recipient of many honors, including a MERIT Award from the National Institutes of Health, the Stanley N. Cohen Biomedical Research Award, and election as a fellow of the American Association for the Advancement of Science.

Read the full announcement in Penn Today.

Posted on

Understanding the Physics of Kidney Development

Abstract image of tubules repelling each other and shifting around.
The model of tubule packing developed by the Hughes Lab shows the tubules repelling each other and shifting around.

A recent study by Penn Bioengineering researchers sheds new light on the role of physics in kidney development. The kidney uses structures called nephrons and tubules to filter blood and pass urine to the bladder. Nephron number is set at birth and can vary over an order of magnitude (anywhere from 100,000 to over a million nephrons in an individual kidney). While the reasons for this variability remain unclear, low numbers of nephrons predispose patients to hypertension and chronic kidney disease. 

Now, research published in Developmental Cell led by Alex J. Hughes, Assistant Professor in the Department of Bioengineering, demonstrates a new physics-driven approach to better visualize and understand how a healthy kidney develops to avoid organizational defects that would impair its function. While previous efforts have typically approached this problem using molecular genetics and mouse models, the Hughes Lab’s physics-based approach could link particular types of defects to this genetic information and possibly highlight new treatments to prevent or fix congenital defects.

During embryonic development, kidney tubules grow and the tips divide to make a branched tree with clusters of nephron stem cells surrounding each branch tip. In order to build more nephrons, the tree needs to grow more branches. To keep the branches from overlapping, the kidney’s surface grows more crowded as the number of branches increase. “At this point, it’s like adding more people to a crowded elevator,” says Louis Prahl, first author of the paper and Postdoctoral Fellow in the Hughes Lab. “The branches need to keep rearranging to accommodate more until organ growth stops.”

To understand this process, Hughes, Prahl and their team investigated branch organization in mouse kidneys as well as using computer models and a 3D printed model of tubules. Their results show that tubules have to actively restructure – essentially divide at narrower angles – to accommodate more tubules. Computer simulations also identified ‘defective’ packing, in which the simulation parameters caused tubules to either overlap or be forced beneath the kidney surface. The team’s experimentation and analysis of published studies of genetic mouse models of kidney disease confirmed that these defects do occur.

This study represents a unique synthesis of different fields to understand congenital kidney disease. Mathematicians have studied geometric packing problems for decades in other contexts, but the structural features of the kidney present new applications for these models. Previous models of kidney branching have approached these problems from the perspective of individual branches or using purely geometric models that don’t account for tissue mechanics. By contrast, The Hughes Lab’s computer model demonstrates the physics of how tubule families interact with each other, allowing them to identify ‘phases’ of kidney organization that either relate to normal kidney development or organizational defects. Their 3D printed model of tubules shows that these effects can occur even when one sets the biology aside.

Hughes has been widely recognized for his research in the understanding of kidney development. This new publication is the first fruit of his 2021 CAREER Award from the National Science Foundation (NSF) and he was recently named a 2023 Rising Star by the Cellular and Molecular Bioengineering (CMBE) Special Interest Group. In 2020 he became the first Penn Engineering faculty member to receive the Maximizing Investigators’ Research Award (MIRA) from the National Institutes of Health (NIH) for his forward-thinking work in the creation of new tools for tissue engineering.

Pediatric nephrologists have long worked to understand the cause of these childhood kidney defects. These efforts are often confounded by a lack of evidence for a single causative mutation. The Hughes Lab’s approach presents a new and different application of the packing problem and could help answer some of these unsolved questions and open doors to prevention of these diseases. Following this study, Hughes and his lab members will continue to explore the physics of kidney tubule packing, looking for interesting connections between packing organization, mechanical stresses between neighboring tubule tips, and nephron formation while attempting to copy these principles to build stem cell derived tissues to replace damaged or diseased kidney tissue. Mechanical forces play an important role in developmental biology and there is much scope for Hughes, Prahl and their colleagues to learn about these properties in relation to the kidney.

Read “The developing murine kidney actively negotiates geometric packing conflicts to avoid defects” in Developmental Cell.

Other authors include Bioengineering Ph.D. students and Hughes Lab members John Viola and Jiageng Liu.

This work was supported by NSF CAREER 2047271, NIH MIRA R35GM133380, Predoctoral Training Program in Developmental Biology T32HD083185, and NIH F32 fellowship DK126385.

Posted on

New Single Cell Analysis Tool

by Nathi Magubane

Researchers at Penn and colleagues have developed a tool to analyze single cells that assesses both the patterns of gene activation within a cell and which sibling cells shared a common progenitor.

3D illustration of a cell held by a pipet and a needle
Arjun Raj of the School of Engineering and Applied Science and the Perelman School of Medicine, former postdoc Lee Richman, now of Brigham and Women’s Hospital, and colleagues have developed a new analysis tool that combines a cell’s unique gene expression data with information about the cell’s origins. The method can be applied to identify new cell subsets throughout development and better understand drug resistance.

Recent advances in analyzing data at the single-cell level have helped biologists make great strides in uncovering new information about cells and their behaviors. One commonly used approach, known as clustering, allows scientists to group cells based on characteristics such as the unique patterns of active or inactive genes or by the progeny of duplicating cells, known as clones, over several generations.

Although single-cell clustering has led to many significant findings, for example, new cancer cell subsets or the way immature stem cells mature into “specialized” cells, researchers to this point had not been able to marry what they knew about gene-activation patterns with what they knew about clone lineages.

Now, research published in Cell Genomics led by University of Pennsylvania professor of bioengineering Arjun Raj has resulted in the development of ClonoCluster, an open-source tool that combines unique patterns of gene activation with clonal information. This produces hybrid cluster data that can quickly identify new cellular traits; that can then be used to better understand resistance to some cancer therapies.

“Before, these were independent modalities, where you would cluster the cells that express the same genes in one lot and cluster the others that share a common ancestor in another,” says Lee Richman, first paper author and a former postdoc in the Raj lab who is now at Brigham and Women’s Hospital in Boston. “What’s exciting is that this tool allows you to draw new lines around your clusters and explore their properties, which could help us identify new cell types, functions, and molecular pathways.”

Researchers in the Raj Lab use a technique known as barcoding to assign labels to cells they are interested in studying, particularly useful for tracking cells, clustering data based on cells’ offspring, and following lineages over time. Believing they could parse more valuable information out of this data by incorporating the cell’s unique patterns of gene activation, the researchers applied ClonoCluster to six experimental datasets that used barcoding to track dividing cells’ offspring. Specifically, they looked at the development of chemotherapy resistance and of stem cells into specialized tissue types.

Read the full story in Penn Today.

Posted on

Alex Hughes Named CMBE Rising Star

A collage of photos: Alex Hughes presenting, the title slide of his presentation with the title "Interpreting geometric rules of early kidney formation for synthetic morphogenesis," and his acknowledgements slides.
Alex J. Hughes presents at the BMES CMBE conference in January 2023. (Image credit: Riccardo Gottardi, Assistant Professor in Pediatrics and Bioengineering)

Alex J. Hughes, Assistant Professor in the Department of Bioengineering, was one of thirteen recipients of the 2023 Rising Star Award for Junior Faculty by the Cellular and Molecular Bioengineering (CMBE) Special Interest Group. The Rising Star Award recognizes a CMBE member in their early independent career stage that has made an outstanding impact on the field of cellular and molecular bioengineering. CMBE is a special interest group of the Biomedical Engineering Society (BMES), the premier professional organization of bioengineers.

The Hughes Lab in Penn Bioengineering works to “bring developmental processes that operate in vertebrate embryos and regenerating organs under an engineering control framework” in order to “build better tissues.” Hughes’s research interest is in harnessing the developmental principles of organs, allowing him to design medically relevant scaffolds and machines. In 2020 he became the first Penn Engineering faculty member to receive the Maximizing Investigators’ Research Award (MIRA) from the National Institutes of Health (NIH), and he was awarded a prestigious CAREER Award from the National Science Foundation (NSF) in 2021. Most recently, Hughes’s work has focused on understanding the development of cells and tissues in the human kidney via the creation of “organoids”: miniscule organ models that can mimic the biochemical and mechanical properties of the developing kidney. Understanding and engineering how the kidney functions could open doors to more successful regenerative medicine strategies to address highly prevalent congenital and adult diseases.

Hughes and his fellow award recipients were recognized at the annual BMES CBME conference in Indian Wells, CA in January 2023.

Read the full list of 2023 CMBE Award Winners.

Posted on

OCTOPUS, an Optimized Device for Growing Mini-Organs in a Dish

by Devorah Fischler

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.

A recent study published in Nature Methods helmed by Huh introduces OCTOPUS, a device that nurtures organs-in-a-dish to unmatched levels of maturity. The study leaders include Estelle Park, doctoral student in Bioengineering, Tatiana Karakasheva, Associate Director of the Gastrointestinal Epithelium Modeling Program at Children’s Hospital of Philadelphia (CHOP), and Kathryn Hamilton, Assistant Professor of Pediatrics in Penn’s Perelman School of Medicine and Co-Director of the Gastrointestinal Epithelial Modeling Program at CHOP.

Read the full story in Penn Engineering Today.