A girl stops by an image of the cosmic microwave background (CMB) at Shanghai Astrology Museum in Shanghai, China Sunday, Jul. 18, 2021. The planetarium, with a total floor space of 38,000 square meters and claimed to be the world’s largest, opens to visitors from July 18. (FeatureChina via AP Images)
There was a time before time when the universe was tiny, dense, and hot. In this world, time didn’t even exist. Space didn’t exist. That’s what current theories about the Big Bang posit, says Vijay Balasubramanian, the Cathy and Marc Lasry Professor of Physics. But what does this mean? What did the beginning of the universe look like? “I don’t know, maybe there was a timeless, spaceless soup,” Balasubramanian says. When we try to describe the beginning of everything, “our words fail us,” he says.
Yet, for thousands of years, humans have been trying to do just that. One attempt came 75 years ago from physicists George Gamow and Ralph Alpher. In a paper published on April 1, 1948, Alpher and Gamow imagined the universe starts in a hot, dense state that cools as it expands. After some time, they argued, there should have been a gas of neutrons, protons, electrons, and neutrinos reacting with each other and congealing into atomic nuclei as the universe aged and cooled. As the universe changed, so did the rates of decay and the ratios of protons to neutrons. Alpher and Gamow were able to mathematically calculate how this process might have occurred.
Now known as the alpha-beta-gamma theory, the paper predicted the surprisingly large fraction of helium and hydrogen in the universe. (By weight, hydrogen comprises 74% of nuclear matter, helium 24%, and heavier elements less than 1%.)
The findings of Gamow and Alpher hold up today, Balasubramanian says, part of an increasingly complex picture of matter, time and space. Penn Today spoke with Balasubramanian about the paper, the Big Bang, and the origin of the universe.
Balasubramanian is Cathy and Marc Lasry Professor in the Department of Physics and Astronomy in the Penn School of Arts and Sciences and a member of the Penn Bioengineering Graduate Group.
Throughout his career, Brian Litt has fabricated tools that support international collaboration, produced findings that have led to significant breakthroughs, and mentored the next generation of researchers tackling neurological disorders. (Image: iStock Photo/Alona Siniehina)
When Brian Litt of the Perelman School of Medicine and School of Engineering and Applied Science began treating patients as a neurologist, he found that the therapies and treatments for epilepsy were mostly reliant on traditional pharmacological interventions, which had limited success in changing the course of the disease.
People with epilepsy are often prescribed anti-seizure medications, and, while they are effective for many, about 30% of patients still continue to experience seizures. Litt sought new ways to offer patients better treatment options by investigating a class of devices that electronically stimulate cells in the brain to modulate activity known as neurostimulation devices.
Litt’s research on implantable neurostimulation devices has led to significant breakthroughs in the technology and has broadened scientists’ understanding of the brain. This work started not long after he came to Penn in 2002 with licensing algorithms to help drive a groundbreaking device by NeuroPace, the first closed-loop, responsive neurostimulator to treat epilepsy.
Building on this work, Litt noted in 2011 how the implantable neurostimulation devices being used at the time had rigid wires that didn’t conform to the brain’s surface, and he received support from CURE Epilepsy to accelerate the development of newer, flexible wires to monitor and stimulate the brain.
“CURE is one of the epilepsy community’s most influential funding organizations,” Litt says. “Their support for my lab has been incredibly helpful in enabling the cutting-edge research that we hope will change epilepsy care for our patients.”
Penn Engineering announced the faculty recipients of the 2023 Student Choice Awards (formerly the Teaching and Advising Awards). Each year, the Penn Engineering undergraduate student body thoughtfully selects the recipients of these awards for their dedication in teaching, mentorship and student advocacy. This year also features two new awards, the Student Advocacy Award and the Undergraduate Research Mentoring Award.
Brit Shields, Senior Lecturer in Bioengineering, is the inaugural recipient of the Student Advocacy Award. This award is presented to a member of the Penn Engineering faculty by the Underrepresented Student Advisory Board in Engineering in recognition of their outstanding commitment to women and underrepresented student advocacy, equity and inclusion.
Dr. Shields poses with her award at the annual Penn Engineering Awards Ceremony.
Shields completed a Ph.D. at Penn in 2015 in History and Sociology of Science, with a dissertation on scientific diplomacy through the example of Richard Courant and New York University, where Shields completed an M.A. in Humanities and Social Thought: Science Studies.
She was promoted to Senior Lecturer in Bioengineering in 2019. She has brought her expertise in the history and sociology of science to her leading role in developing and improving the ethics curriculum for all students in the School of Engineering and Applied Science.
Read other stories featuring Brit Shields in the BE Blog.
Read the full list of 2023 Penn Engineering Student Choice Award Winners in Penn Engineering Today.
Gregory Bowman, the Louis Heyman University Professor, has joint appointments in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science. (Image: Courtesy of School of Engineering and Applied Sciences)
His research aims to combat global health threats such as COVID-19 and Alzheimer’s disease by better understanding how proteins function and malfunction, especially through new computational and experimental methods that map protein structures. This understanding of protein dynamics can lead to effective new treatments for even the most seemingly resistant diseases.
“Delivering the right treatment to the right person at the right time is vital to sustaining—and saving—lives,” Magill said. “Greg Bowman’s novel work holds enormous promise and potential to advance new forms of personalized medicine, an area of considerable strength for Penn. A gifted researcher and consummate collaborator, we are delighted to count him among our distinguished PIK University Professors.”
Bowman came to Penn from the Washington University School of Medicine’s Department of Biochemistry and Molecular Biophysics, where he served on the faculty since 2014. He previously completed a three-year postdoctoral fellowship at the University of California, Berkeley.
Bowman’s research utilizes high-performance supercomputers for simulations that can better explain how mutations and disease change a protein’s functions. These simulations are enabled in part through the innovative Folding@home project, which Bowman directs. Folding@home empowers anyone with a computer to run simulations alongside a consortium of universities, with more than 200,000 participants worldwide.
His research has been supported by the National Science Foundation, National Institutes of Health, National Institute on Aging, and Packard Foundation, among others, and he has received a CAREER Award from the NSF, Career Award at the Scientific Interface from the Burroughs Wellcome Fund, and Thomas Kuhn Paradigm Shift Award from the American Chemical Society. He received a Ph.D. in biophysics from Stanford University and a B.S. (summa cum laude) in computer science, with a minor in biomedical engineering, from Cornell University.
“Greg Bowman’s highly innovative work,” Winkelstein said, “exemplifies the power of our interdisciplinary mission at Penn. He brings together supercomputers, biophysics, and biochemistry to make a vital impact on public health. This brilliant fusion of methods—in the service of improving people’s lives around the world—will be a tremendous model for the research of our faculty, students, and postdocs in the years ahead.”
The Penn Integrates Knowledge program is a University-wide initiative to recruit exceptional faculty members whose research and teaching exemplify the integration of knowledge across disciplines and who are appointed in at least two schools at Penn.
The Louis Heyman University Professorship is a gift of Stephen J. Heyman, a 1959 graduate of the Wharton School, and his wife, Barbara Heyman, in honor of Stephen Heyman’s uncle. Stephen Heyman is a University Emeritus Trustee and member of the School of Nursing Board of Advisors. He is Managing Partner at Nadel and Gussman LLC in Tulsa, Oklahoma.
nucleus and membrane of pathogen micro organisms in blue background
Up to 50 percent of cancer-signaling proteins once believed to be immune to drug treatments due to a lack of targetable protein regions may actually be treatable, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The findings, published this month in Nature Communications, suggest there may be new opportunities to treat cancer with new or existing drugs.
Researchers, clinicians, and pharmacologists looking to identify new ways to treat medical conditions—from cancer to autoimmune diseases—often focus on protein pockets, areas within protein structures to which certain proteins or molecules can bind. While some pockets are easily identifiable within a protein structure, others are not. Those hidden pockets, referred to as cryptic pockets, can provide new opportunities for drugs to bind to. The more pockets scientists and clinicians have to target with drugs, the more opportunities they have to control disease.
The research team identified new pockets using a Penn-designed neural network, called PocketMiner, which is artificial intelligence that predicts where cryptic pockets are likely to form from a single protein structure and learns from itself. Using PocketMiner—which was trained on simulations run on the world’s largest super computer—researchers simulated single protein structures and successfully predicted the locations of cryptic pockets in 35 cancer-related protein structures in thousands of areas of the body. These once-hidden targets, now identified, open up new approaches for potentially treating existing cancer.
What’s more, while successfully predicting the cryptic pockets, the method scientists used in this study was much faster than previous simulation or machine-learning methods. The network allows researchers to nearly instantaneously decide if a protein is likely to have cryptic pockets before investing in more expensive simulations or experiments to pursue a predicted pocket further.
“More than half of human proteins are considered undruggable due to an apparent lack of binding proteins in the snapshots we have,” said Gregory R. Bowman, PhD, a professor of Biochemistry and Biophysics and Bioengineering at Penn and the lead author of the study. “This PocketMiner research and other research like it not only predict druggable pockets in critical protein structures related to cancer but suggest most human proteins likely have druggable pockets, too. It’s a finding that offers hope to those with currently untreatable diseases.”
Penn Bioengineering juniors work on their ECG devices in BE 3100, Bioengineering Modeling, Analysis and Design Laboratory II (aka BE MAD)
The George H. Stephenson Foundation Educational Laboratory & Bio-MakerSpace (aka the Penn BE Labs) played host last week to Sarah Huffman, a local journalist writing for Technical.ly Philly. During her visit to the lab, she chatted with third year undergraduates working on their ECG devices for monitoring breathing and heart rates, and senior design students applying all they’ve learned in their previous three years to their graduation capstone projects. She also got a chance to discuss the classes and learn about the lab’s vision to be a bio-makerspace with Sevile Mannickarottu, Director of Educational Labs for BE, and with David Issadore, Associate Professor in Bioengineering and in Electrical and Systems Engineering and professor of the third year spring lab course:
Journalist Sarah Huffman interviews BE 3100 professor David Issadore.
“’The students all come here and they hang out and they build stuff,’ said David Issadore, associate professor of bioengineering and electrical and systems engineering. ‘This junior-level course is kind of an entry point for their senior design. So next year, all these students are going to take on new projects, and then they all kind of hang around here and they build incredible stuff.’”
The profile of the BE Labs is part of Technical.ly’s 2023 Universities Month, a series focusing on the latest trends and tech in higher education.
A new Penn Medicine preclinical study demonstrates a simultaneous ‘knockout’ of two inflammatory regulators boosts T cell expansion to attack solid tumors.
by Meagan Raeke
Image: Courtesy of Penn Medicine News
A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine. The findings, published in the Proceedings of the National Academy of Sciences, show that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased anti-tumor immune activity and durability.
“We want to unlock CAR T cell therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” says June, the new study’s senior author. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”
One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an anti-tumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don’t multiply enough or remember their task as well.
Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells—reviving them to produce an anti-tumor response. The research team, including lead author David Mai, a bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further.
“Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anti-cancer effects than disrupting them individually,” Mai says. “By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumor context.”
Interim Provost Beth A. Winkelstein has announced the appointment of Russell J. Composto as Faculty Co-Director of Penn First Plus (P1P), beginning July 1, 2023. Composto is currently Professor of Materials Science and Engineering with secondary appointments in Bioengineering and Chemical and Biomolecular Engineering, Howell Family Faculty Fellow, and Associate Dean for Undergraduate Education in Penn Engineering.
“Russ Composto has long been one of our campus leaders in advancing support and mentoring for our students,” said Interim Provost Winkelstein, “including new programs for student wellness, community service, and research and mentoring for first-generation and/or low-income students. He is one of the leaders of our exciting new initiative to increase inclusivity in STEM education at Penn, which just received a major six-year grant from the Inclusive Excellence initiative of the Howard Hughes Medical Institute. Within Penn Engineering, he led the development of a new engineering curriculum and a new program of individualized student advising, both of which have been highly successful in enhancing the academic experiences of our undergraduates.
“I am extremely grateful to Robert Ghrist for his longstanding dedication to Penn’s undergraduates and his leadership over the past five years as an inaugural Faculty Co-Director of P1P, as well as to ongoing Faculty Co-Director Camille Charles, Executive Director Marc Lo, and the outstanding P1P staff and extended team for their work in sustaining P1P’s invaluable mission on our campus.”
Penn First Plus, founded in 2018, provides support, resources and community-building for undergraduate students who identify as lower- to middle-income and/or are the first in their families to attend college. It includes the Shleifer Family Penn First Plus Center in College Hall and the Pre-First Year Program, an intensive four-week summer program for select incoming first-year students, preceding New Student Orientation, that offers comprehensive support services which continue throughout students’ undergraduate experiences at Penn.
Composto has served as Associate Dean for Undergraduate Education in Penn Engineering since 2015. In more than thirty years at Penn, he has also served as both Undergraduate Chair and Graduate Group Chair of Materials Science and Engineering and has been awarded the Provost’s Award for Distinguished Ph.D. Teaching and Mentoring, the Geoffrey Marshall Mentoring Award of the Northeastern Association of Graduate Schools, and the Ford Motor Company Award for Faculty Advising.
He is a world-leading pioneer of polymer science who is a Fellow and former Chair of the Division of Polymer Physics of the American Physical Society, has received a Special Creativity Award from the National Science Foundation, and recently became Co-Director of a major NSF-funded initiative to bring together soft matter, data science, and science policy as part of the NSF Research Traineeship Program, which encourages transformative models for training of STEM graduate students, especially in new, high-priority interdisciplinary research areas. He received a Ph.D. and M.S. from Cornell University and a B.A. in Physics from Gettysburg College.
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.”
The research team from left to right includes Kelsey Swingle, Hannah Safford, Alex Hamilton, Ajay Thatte, Hannah Geisler, and Mike Mitchell.
New research on reproductive health demonstrates the first successful delivery of mRNA to placental cells to treat pre-eclampsia at its root.
Pre-eclampsia is a leading cause of stillbirths and prematurity worldwide, occurring in 3 – 8 % of pregnancies. A disorder characterized by high maternal blood pressure, it results from insufficient vasodilation in the placenta, restricting blood flow from the mother to the fetus.
Currently, a health-care plan for someone with pre-eclampsia involves diet and movement changes, frequent monitoring, blood pressure management, and sometimes early delivery of the baby. These standards of care address symptoms of the condition, not the root cause, and further perpetuate health inequity.
Now, Penn engineers are addressing this longstanding gap in reproductive health care with targeted RNA therapy.
The COVID vaccines demonstrated how lipid nanoparticles (LNPs) efficiently deliver mRNA to target cells. The success of LNPs is opening doors for a variety of RNA therapies aiming to treat the root causes of illness and disease. However, drug development and health care have consistently neglected a portion of the population in need of targeted care the most – pregnant people and their babies.
In one of the first studies of its kind, published in the Journal of the American Chemical Society,Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, and Kelsey Swingle, Ph.D. student in the Mitchell Lab and lead author, describe their development of an LNP with the ability to target and deliver mRNA to trophoblasts, endothelial cells, and immune cells in the placenta.
Once these cells receive the mRNA, they create vascular endothelial growth factor (VEGF), a protein that helps expand the blood vessels in the placenta to reduce the mother’s blood pressure and restore adequate circulation to the fetus. The researchers’ successful trials in mice may lead to promising treatments for pre-eclampsia in humans.
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