A team of researchers led by the School of Arts & Science’s Wei Guo offers new insights into a mechanism that promotes tumor growth. “This information could be used to help clinicians diagnose cancers earlier in the future,” says Guo.
In many instances, the physical manifestation of cancers and the ways they are subsequently diagnosed is via a tumor, tissue masses of mutated cells and structures that grow excessively. One of the major mysteries in understanding what goes awry in cancers relates to the environments within which these structures grow, commonly known as the tumor microenvironment.
These microenvironments play a role in facilitating tumor survival, growth, and spread. Tumors can help generate their own infrastructure in the form of vasculature, immune cells, signaling molecules, and extracellular matrices (ECMs), three-dimensional networks of collagen-rich support scaffolding for a cell. ECMs also help regulate cellular communications, and in the tumor microenvironment ECMs can be a key promoter of tumor growth by providing structural support for cancerous cells and in modulating signaling pathways that promote growth.
Now, new research led by the School of Arts & Science’sWei Guo and published in the journal Nature Cell Biology has bridged the complex structural interactions within the tumor microenvironment to the signals that trigger tumor growth. The researchers studied cancerous liver cells grown on ECMs of varying stiffness and discovered that the stiffening associated with tumor growth can initiate a cascade that increases the production of small lipid-encapsulated vesicles known as exosomes.
“Think of these exosomes as packages that each cell couriers out, and, depending on the address, they get directed to other cells,” says Ravi Radhakrishnan, professor of bioengineering in the School of Engineering and Applied Science and a co-author of the paper.
“By recording the number of packages sent, the addresses on these packages, their contents, and most importantly, how they’re regulated and generated, we can better understand the relationship between a patient’s tumor microenvironment and their unique molecular signaling signatures, hinting at more robust personalized cancer therapies,” Radhakrishnan says.
While studying exosomes in relation to tumor growth and metastasis has been well-documented in recent years, researchers have mostly focused on cataloging their characteristics rather than investigating the many processes that govern the creation and shuttling of exosomes between cells. As members of Penn’s Physical Sciences Oncology Center (PSOC), Guo and Radhakrishnan have long collaborated on projects concerning tissue stiffness. For this paper, they sought to elucidate how stiffening promotes exosome trafficking in cancerous intracellular signaling.
“Our lab previously found that high stiffness promotes the secretion of exosomes,” says Di-Ao Liu, co-first author of the paper and a graduate student in the Guo Lab. “Now, we were able to model the stiffening processes through experiments and identify molecular pathways and protein networks that cause this, which better links ECM stiffening to cancerous signaling.”
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.
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.
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.
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.
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.
Each year, the the Department of Bioengineering seeks exceptional candidates to conduct summer research in bioengineering with the support of two scholarships: the Abraham Noordergraaf Student Summer Bioengineering Research Fund and the Blair Undergraduate Research Fund in the Department of Bioengineering. These scholarships provide a living stipend for students to conduct research on campus in a Penn research lab under the mentorship of a faculty member. The Abraham Noordergraaf Student Summer Bioengineering Research Fund provides financial support for undergraduate or graduate summer research opportunities in bioengineering with a preference for study in the area of cardiovascular systems. Dr. Noordergraaf, who died in 2014, was a founding member and first chair of Penn Bioengineering. The Blair Undergraduate Research Fund in the Department of Bioengineering supports three to five undergraduate research scholars each year with the support of Dr. James C. Blair II. After a competitive round of proposals, the following six scholars were chosen for the Summer 2022 semester. Keep reading below for the research abstracts and bios of the awardees.
The Blair Undergraduate Research Fund in the Department of Bioengineering (Blair Scholars)
Ella Atsavapranee
Student: Ella Atsavapranee (BE Class of 2023)
PI: Michael J. Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation, Bioengineering
“Lipid nanoparticle-mediated delivery of RAS protease to inhibit cancer cell growth”
Mutations in RAS, a family of proteins found in all human cells, drive a third of cancers, including many pancreatic, colorectal, and lung cancers. However, there are still no therapies that can effectively prevent RAS from causing tumor growth. Recently, a protease was engineered to specifically degrade active RAS, offering a promising new tool for treating these cancers. However, many protein-based therapies still cannot be effectively delivered to patients. Lipid nanoparticles (LNPs), which were used in the Pfizer-BioNTech and Moderna COVID-19 vaccines, have emerged as a promising platform for safe and effective delivery of both nucleic acids and proteins. We formulated a library of LNPs using different cationic lipids. We characterized the LNPs by size, charge, and pKa, and tested their ability to deliver fluorescently labeled protease. The LNPs were able to encapsulate and deliver a RAS protease, successfully reducing proliferation of colon cancer cells.
Ella is a senior from Maryland studying bioengineering and chemistry. She works in Dr. Michael Mitchell’s lab, developing lipid nanoparticles to deliver proteins that reduce cancer cell proliferation. She has also conducted research on early-stage cancer detection and therapy monitoring (at Stanford University) and drug delivery across the blood-brain barrier for neurodegenerative diseases (at University of Maryland). She is passionate about translational research, science communication, and promoting diversity in STEM.
Chiadika Eleh
Student: Chiadika Eleh (BE and CIS Class of 2024)
PI: Eric J. Brown, Associate Professor of Cancer Biology, Perelman School of Medicine
“Investigating Viability in ATR and WEE1 Inhibitor Treated Ovarian Cancer Cells”
High-grade serous ovarian cancers (HGSOCs) are an aggressive subtype of ovarian cancer, accounting for up to 80% of all ovarian cancer-related deaths. More than half of HGSOCs are homologous recombination deficient; thus, they lack a favorable response when treated with common chemotherapeutic trials. Therefore, new treatment strategies must be developed to increase the life expectancy and quality of life of HGSOC patients. To address the lack of effective treatment options, the Brown Lab is interested in combining ATR and WEE1 inhibition (ATRi/WEE1i) to target HGSOC cells. It has previously been shown that low-dose ATRi/WEE1i is an effective treatment strategy for CCNE1-amplified ovarian cancer-derived PDX tumors (Xu et al., 2021, Cell Reports Medicine). Therefore, the next step is to characterize the HGSOC-specific response to ATRi/WEE1i treatment. This project aims to characterize the viability phenotype of ovarian cancer (OVCAR3) cells in the presence of ATRi/WEE1i in both single and combination treatments. With further research, Eleh hopes to prove the hypothesis low-dose combination ATRi/WEE1i treatment will result in the synergistic loss of viability in OVCAR3 cells. This goal will be achieved through the treatment of OVCAR3 cells with ranging doses of ATRi and Wee1i over 24 and 48 hour time intervals. We hope that this data will help set a treatment baseline that can be used for all OVCAR30-based viability experiments in the future.
Chiadika Eleh is a Bioengineering and Computer Science junior and a member of Penn Engineering’s Rachleff Scholar program. As a Blair Scholar, she worked in Dr. Eric Brown’s cancer biology lab, where she studied cell cycle checkpoint inhibitors as a form of cancer treatment.
“Tbc1d2b regulates vascular formation during development and tissue repair after ischemia”
The mechanisms behind endothelial cells forming blood vessels remains unknown. We have identified Tbc1d2b as a protein that is integral to the regulation of vascular formation. In order to investigate the role of Tbc1d2b in tubule formation, fibrin gel bead assays will be conducted to evaluate how the presence of Tbc1d2b is required for angiogenesis. Fibrin gel bead assays simulate the extracellular matrix environment to support the in vitro development of vessels from human umbilical vein endothelial cells (HUVEC) coated on cytodex beads. In order to confirm the success of angiogenesis, immunostaining for Phalloidin and CD31 will be conducted. After confirmation that fibrin gel bead assays can produce in vitro tubules, sgRNA CRISPR knockout of Tbc1d2b will be performed on HUVEC cells which will then be used to conduct more fibrin gel bead assays. We hypothesize that HUVEC with the Tbc1d2b knockout phenotype will be unable to form tubules while wild type HUVEC will be able to.
Gloria Lee is a rising senior studying Bioengineering and Physics in the VIPER program from Denver, Colorado. Her research in Dr. Yi Fan’s lab focuses on the role that proteins play in cardiovascular tubule formation.
Abraham Noordergraaf Student Summer Bioengineering Research Fund (Noordergraaf Fellows)
Gary Lin
Student: Gary Lin (Master’s in MEAM Class of 2023)
PI: Michelle J. Johnson, Associate Professor in Physical Medicine and Rehabilitation, Perelman School of Medicine, and in Bioengineering
“Development and Integration of Dynamically Modulating Control Systems in the Rehabilitation Using Community-Based Affordable Robotic Exercise System (Rehab CARES)”
As the number of stroke patients requiring rehabilitative care continues to increase, strain is being put onto the US health infrastructure which already has a shortage of rehabilitation practitioners. To help alleviate this pressure, a cost-effective robotic rehabilitative platform was developed to increase access to rehabilitative care. The haptic TheraDrive, a one-degree of freedom actuated hand crank that can apply assistive and resistive forces, was modified to train pronation and supination at the elbow and pinching of the fingers in addition to flexion and extension of the elbow and shoulder. Two controllers were created including an open-loop force controller and a closed-loop proportional-integral (PI) with adaptive control gains based on subject performance in therapy-game tasks as well as galvanic skin response. Stroke subjects (n=11) with a range of cognitive and motor impairment completed 4 therapy games in both adaptive and non-adaptive versions of the controllers (n=8) while measuring force applied on the TheraDrive handle. Resulting normalized average power versus Upper Extremity Fugl-Meyer (UE-FM) and Montreal Cognitive Assessment (MoCA) correlation analyses showed that power was strongly correlated with UE-FM in 2 of the conditions and moderately correlated with the other 6 while MoCA was moderate correlated to 2 of the conditions and weakly correlated to the rest. Mann-Whitney U-tests between adaptive and non-adaptive versions of each therapy game showed no significant differences with regards to power between controller types (p<0.05).
Gary is a master’s student in the School of Engineering studying Mechanical Engineering and Applied Mechanics with a concentration in Robotic and Mechatronic systems. His research primarily focuses on developing affordable rehabilitation robotics for use in assessment and game-based therapies post neural injury. Many of his interests revolve around the design of mechatronic systems and the algorithms used to control them for use in healthcare spaces.
Priya Shah
Student: Priya Shah (BE Class of 2024)
PI: Alex J. Hughes, Assistant Professor in Bioengineering
“Optogenetic Control of Developing Kidney Cells for Future Treatment of End-Stage Renal Disease”
This project sought to build from prior research in the Hughes Lab on the geometric and mechanical consequences of kidney form on cell and tissue-scale function. While the developmental trajectory of the kidney is well understood, little is currently known about many factors affecting nephron progenitor differentiation rate. Insufficient differentiation of nephron progenitor cells during kidney formation can result in lower nephron number and glomerular density, which is a risk factor for progression to end-stage renal disease later in life. Prior studies indicated that the amount of nephron differentiation – and thus function of the adult kidney – is correlated to the packing of ureteric tubule tips present at the surface of the kidney. Building off of research conducted in the Bugaj Lab, we found that inserting an optogenetic construct into the genome of human embryonic kidney (HEK) cells allowed us to manipulate the contraction of those cells through exposing them to blue light. Manipulating the contraction of the cells allows for the manipulation of the packing of ureteric tubule tips at the kidney surface. We used a lentiviral vector to transduce HEK293 cells with the optogenetic construct and witnessed visible contraction of the cells when they were exposed to blue light. Future work will include using CRISPR-Cas9 to introduce the optogenetic construct into IPS cells.
Priya is a junior studying bioengineering and had the opportunity to work on manipulating developing kidney cells using an optogenetic construct in the Hughes Lab this summer. She is thrilled to continue this research throughout the coming school year. Outside of the lab, Priya is involved with the PENNaach dance team and the Society of Women Engineers, as well as other mentorship roles.
Cosette Tomita
Student: Cosette Tomita (Master’s in MEAM Class of 2023)
“Expression and Characterization of an Anti-Aβ42 scFv”
Background: Amyloid Beta (Aβ42) fibrils contribute to the pathology of Alzheimer’s Disease. Numerous monoclonal antibodies have been developed against Aβ42. In this study we have designed and expressed a short chain variable fragment specific to Aβ42 (Anti-Aβ42 scFv). To characterize our anti-Aβ42 scFv we have performed structural analysis using transmission electron microscopy (TEM) and binding kinetics using microscale thermophoresis (MST) compared to commercially available antibodies 6E10, Aducanumab, and an IgG isotype control. The goal of this study is to determine if labeling densities and binding constants for Aducanumab and anti-Aβ42 scFv are not significantly different.
Method: To characterize Aβ42 fibril associated antibodies we used negative stain TEM. Aβ42 fibrils were stained on a glow discharged copper grid, and incubated with gold conjugated anti-Aβ42 scFv, 6E10—which binds all Aβ species, aducanumab, or IgG isotype control. Labeling densities were calculated as the number of fibril-associated gold particles per 1 μm2 for each image. Next, we used microscale thermophoresis determine the binding kinetics. Antibodies or anti-Aβ42 scFv were labeled with Alexa Fluor-647 and unlabeled Aβ42 was titrated in a serial dilution over 16 capillaries. The average fluorescence intensity was plotted against the antibody or scFv concentration and the curves were analyzed using the GraphPad Prism software to calculate the dissociation constant (KD) values.
Results: We found a significant difference, tested with a one-way ANOVA (P <0.0001), in gold particle associated Aβ fibrils per 1 μm2 between anti-Aβ42 scFv, 6E10, aducanumab, and IgG isotype control. Further analysis of aducanumab and 6CO3 with unpaired student t-test indicates significant differences in fibril associated gold particles between aducanumab vs. 6E10 (P=0.0003), Aducanumab vs. Isotype control (P <0.0001), anti-Aβ42 scFv vs 6E10 (p=0.0072), and anti-Aβ42 scFv vs Isotype Control (P=0.0029) with no significant difference in labeling densities between Aducanumab and anti-Aβ42 scFv. The expected KD values from MST were 1.8μM for Aducanumab and anti-Aβ42 scFv, 10.3nM for 6E10 and no expected binding for the isotype control. The experimental KD values for anti-Aβ42 scFv and 6E10 are 0.1132μM and 1.467μM respectively. The KD value for Isotype control was undetermined, as expected, however, the KD for Aducanumab was undetermined due to suboptimal assay conditions. Due to confounding variables in the experimental set up such as the use of Aβ1-16 compared to Aβ42 and the use of different fluorophores—5-TAMRA, Alexa Fluor 647 or FITC— the experimental KD values were off by several orders of magnitude.
Conclusion: We have illustrated similar labeling densities between Aducanumab and our anti-Aβ42 scFv. In the future, we will further optimize the MST assay conditions and compare the KD values obtained by MST with other techniques such as surface plasma resonance.
Cosette was born and raised in Chicago land area. Go Sox! She attended University of Missouri where she majored in Chemistry and Biology. She synthesized sigma-2 radiotracers and developed advanced skills in biochemical techniques in Dr. Susan Lever’s lab. After graduation, she moved to NJ to work at Lantheus, a radiopharmaceutical company. She missed academia and the independence of program and project development, so she came to work at the Penn Cyclotron facility before entering the Bioengineering master’s program.
A cross-kingdom partnership between bacteria and fungi can result in the two joining to form a “superorganism” with unusual strength and resilience. It may sound like the stuff of science fiction, but these microbial groupings are very much part of the here and now.
Found in the saliva of toddlers with severe childhood tooth decay, these assemblages can effectively colonize teeth. They were stickier, more resistant to antimicrobials, and more difficult to remove from teeth than either the bacteria or the fungi alone, according to the research team, led by University of PennsylvaniaSchool of Dental Medicine scientists.
What’s more, the assemblages unexpectedly sprout “limbs” that propel them to “walk” and “leap” to quickly spread on the tooth surface, despite each microbe on its own being non-motile, the team reported in the journal Proceedings of the National Academy of Sciences.
“This started with a very simple, almost accidental discovery, while looking at saliva samples from toddlers who develop aggressive tooth decay,” says Hyun (Michel) Koo, a professor at Penn Dental Medicine and a co-corresponding author on the paper. “Looking under the microscope, we noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. They have a lot of what we call ‘emergent functions’ that bring new benefits to this assemblage that they could not achieve on their own. It’s almost like a new organism—a superorganism—with new functions.”
Hyun (Michel) Koo is a professor in the Department of Orthodontics and the divisions of Community Oral Health and Pediatric Dentistry in the School of Dental Medicine, co-founder of the Center for Innovation & Precision Dentistry (CiPD) at the University of Pennsylvania, and member of the Penn Bioengineering Graduate Group.
(From left to right) Startup Challenge sponsor Eric Aroesty with members of Toxisense: Aravind Krishnan, Udit Garg, Andrew Diep-Tran, and Aarush Sahni. (Image: The Wharton School)
Penn’s Venture LabStartup Challenge awarded its 2022 prize to a sustainable and cost-effective water-testing startup. The venture, ToxiSense, was awarded at a ceremony on April 29, at Tangen Hall, Penn’s hub for student entrepreneurship and innovation.
Co-founded by four first-year students—Aravind Krishnan, Udit Garg, Andrew Diep-Tran, and Aarush Sahni—ToxiSense aims to improve the endotoxin testing required for drinking water and biopharma products through genetically engineering plants with bioluminescent properties. Biopharmaceutical products and drinking water must be tested for endotoxins, the sickness-causing molecule from bacteria. The current method relies on expensive horseshoe crab blood and is environmentally damaging. ToxiSense genetically engineered the Arabidopsis plant to luminesce based on the endotoxin concentration applied to it, serving as a sustainable, cost-effective solution.
ToxiSense was selected from a field of eight finalist teams—including DeToXyFi, Groov, Impact Local, Miren, Nemu, Ossum Technologies, and Shinkei Systems Corp.—who advanced from 30 ventures during the semi-finals portion of the competition, which consisted of a day of virtual pitching and Q&A in front of alumni entrepreneur and investor panels. For the finals, teams pitched to a panel of alumni judges and in front of a live audience of nearly 200 attendees as they competed for over $150,000 in cash and prizes to launch their startups.
“The Startup Challenge is Venture Lab’s premier yearly event, showcasing Penn’s most promising teams of student entrepreneurs,” says Lori Rosenkopf, vice dean of entrepreneurship and Simon and Midge Palley Professor at the Wharton School. “This year’s finalists included undergraduate and graduate students from across the University, and their products offered solutions for environmental, financial, health, and social challenges. These motivated teams capture the spirit of Penn entrepreneurship—innovative, interdisciplinary, inclusive—and we offer our congratulations and our optimistic wishes for their futures.”
A group of bacteriophages, viruses that infect bacteria, imaged using transmission electron microscopy. New research sheds light on how bacteria fight off these invaders without triggering an autoimmune response. (Image: ZEISS Microscopy, CC BY-NC-ND 2.0)
During the last few years, CRISPR has grabbed headlines for helping treat patients with conditions as varied as blindness and sickle cell disease. However, long before humans co-opted CRISPR to fight genetic disorders, bacteria were using CRISPR as an immune system to fight off viruses.
In bacteria, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) works by stealing small pieces of DNA from infecting viruses and storing those chunks in the genes of the bacteria. These chunks of DNA, called spacers, are then copied to form little tags, which attach to proteins that float around until they find a matching piece of DNA. When they find a match, they recognize it as a virus and cut it up.
Now, a paper published in Current Biology by researchers from the University of Pennsylvania Department of Physics and Astronomy shows that the risk of autoimmunity plays a key role in shaping how CRISPR stores viral information, guiding how many spacers bacteria keep in their genes, and how long those spacers are.
Ideally, spacers should only match DNA belonging to the virus, but there is a small statistical chance that the spacer matches another chunk of DNA in the bacteria itself. That could spell death from an autoimmune response.
“The adaptive immune system in vertebrates can produce autoimmune disorders. They’re very serious and dangerous, but people hadn’t really considered that carefully for bacteria,” says Vijay Balasubramanian, principal investigator for the paper and the Cathy and Marc Lasry Professor of Physics in the School of Arts & Sciences.
Balancing this risk can put the bacteria in something of an evolutionary bind. Having more spacers means they can store more information and fend off more types of viruses, but it also increases the likelihood that one of the spacers might match the DNA in the bacteria and trigger an autoimmune response.
Vijay Balasubramanian is the Cathy and Marc Lasry Professor of Physics at the Department of Physics and Astronomy of the University of Pennsylvania, a visiting professor at Vrije Universiteit Brussel, and a member of the Penn Bioengineering Graduate Group.
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.
