Charting a Path Forward with Unifying Definition of Cytokine Storm

by Melissa Moody

Penn Medicine researchers have developed a unifying definition of ‘cytokine storm’ to provide a framework to assess and treat patients whose immune systems have gone rogue.

Penn Medicine’s David Fajgenbaum (left) and Carl June (right). (Image: Penn Medicine News)

One of the most elusive aspects for clinicians treating COVID-19 is the body’s immune response to the virus. In the most severe cases of COVID-19, the immune system goes into overdrive, resulting in a fever, multiorgan system damage, and often death—a cytokine storm. But how to detect and treat a cytokine storm requires that clinicians can identify it as such.

Two Penn Medicine researchers have developed a unifying definition of “cytokine storm” to provide physicians with a framework to assess and treat severely-ill patients whose immune systems have gone rogue. Cytokine storms can be triggered by different pathogens, disorders, or treatments, from COVID-19 to Castleman disease to CAR T cell therapy.

In a paper published in the New England Journal of Medicine, David Fajgenbaum, an assistant professor of translational medicine & human genetics and director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), and Carl June, a professor of pathology and laboratory medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center, and the Parker Institute for Cancer Immunotherapies define a cytokine storm as requiring elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond what could be attributed to a normal response to a pathogen, if a pathogen is present.

“There has never been a defining central review of what a cytokine storm is and how to treat one, and now with COVID-19, that is a major issue,” says Fajgenbaum, a Castleman disease patient who has previously experienced five cytokine storms himself. “I’ve spent the last 10 years of my life as a cytokine storm patient and researcher, so I know the importance of having a comprehensive unified definition to find therapies that work across the various types of cytokine storms.”

There is widespread recognition that the immune response to a pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and other symptoms. Additionally, similar cytokine storm syndromes can occur with no obvious infection.

Read more at Penn Medicine News.

NB: Carl June is a member of the Penn Bioengineering Graduate Group.

Yale Cohen and Douglas Smith Awarded 2020 Penn Medicine Awards of Excellence

Yale Cohen, Ph.D.
Douglas H. Smith, M.D.

The Perelman School of Medicine has announced the winners of the 2020 Penn Medicine Awards of Excellence. The Office of the Dean says:

“These awardees exemplify our profession’s highest values of scholarship, teaching, innovation, commitment to service, leadership, professionalism and dedication to patient care. They epitomize the preeminence and impact we all strive to achieve. The awardees range from those at the beginning of their highly promising careers to those whose distinguished work has spanned decades.

Each recipient was chosen by a committee of distinguished faculty from the Perelman School of Medicine or the University of Pennsylvania. The contributions of these clinicians and scientists exemplify the outstanding quality of patient care, mentoring, research, and teaching of our world-class faculty.”

Two faculty members affiliated with Penn Bioengineering are among this year’s recipients.

Yale Cohen, PhD, Professor of Otorhinolaryngology with secondary appointments in Neuroscience and Bioengineering, is the recipient of the Jane M. Glick Graduate Student Teaching Award. Cohen is an alumnus of the Penn Bioengineering doctoral program and is currently the department’s Graduate Chair.

“Dr. Cohen’s commitment to educating and training the next generation of scientists exemplifies the type of scientist and educator that Jane Glick represented. His students value his highly engaging and supportive approach to teaching, praising his enthusiasm, energy, honesty, and compassion.”

Douglas H. Smith, MD, Robert A. Groff Endowed Professor of Research and Teaching in Neurosurgery and member of the Penn Bioengineering Graduate Group, is the recipient of this year’s William Osler Patient Oriented Research Award:

“Dr. Smith is the foremost authority on diffuse axonal injury (DAI) as the unifying hypothesis behind the short- and long-term consequences of concussion.  After realizing early in his career that concussion, or mild traumatic brain injury (TBI), was a much more serious event than broadly appreciated, Dr. Smith and his team have used computer biomechanical modeling, in vitro and in vivo testing in parallel with seminal human studies to elucidate mechanisms of concussion.”

Read the full story in Penn Medicine Communications.

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

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

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

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

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

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

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

Language in Tweets Offers Insight Into Community-level Well-being

In a Q&A, researcher Lyle Ungar discusses why counties that frequently use words like ‘love’ aren’t necessarily happier, plus how techniques from this work led to a real-time COVID-19 wellness map.

By Michele W. Berger

Lyle Ungar, Ph.D. (Photo: Eric Sucar)

People in different areas across the United States reacted differently to the threat of COVID-19. Some imposed strict restrictions, closing down most businesses deemed nonessential; others remained partially open.

Such regional distinctions are relatively easy to quantify, with their effects generally understandable through the lens of economic health. What’s harder to grasp is the emotional satisfaction and happiness specific to each place, a notion ’s has been working on for more than five years.

In 2017, the group published the , a free, interactive tool that displays characteristics of well-being by county based on Census data and billions of tweets. Recently, WWBP partnered with ’s Center for Digital Health to create a , which reveals in real time how people across the country perceive COVID-19 and how it’s affecting their mental health.

That map falls squarely in line with a paper published this week in the by computer scientist , one of the principal investigators of the World Well-Being Project, and colleagues from Stanford University, Stony Brook University, the National University of Singapore, and the University of Melbourne.

By analyzing 1.5 billion tweets and controlling for common words like “love” or “good,” which frequently get used to connote a missing aspect of someone’s life rather than a part that’s fulfilled, the researchers found they could discern subjective well-being at the county level. “We have a long history of collecting people’s language and asking people who are happier or sadder what words they use on Facebook and on Twitter,” Ungar says. “Those are mostly individual-level models. Here, we’re looking at community-level models.”

In a conversation with Penn Today, Ungar describes the latest work, plus how it’s useful in the time of COVID-19 and social distancing.

Read Ungar’s Q&A at .

Dr. Lyle Ungar is a Professor of Computer and Information Science and a member of the Department of Bioengineering Graduate Group.

Bomyi Lim Receives KIChE President Young Investigator

Bomyi Lim, Ph.D.

Bomyi Lim, Assistant Professor in the Department of Chemical Biomolecular Engineering, has been selected by the U.S. Chapter of the Korean Institute of Chemical Engineers (KIChE) as the recipient of the KIChE President Young Investigator Award. As a recipient of this Award, Lim will be invited to present a research talk at the KIChE Open Forum during the AIChE Conference.

KIChE is an organization that aims “to promote constructive and mutually beneficial interactions among Korean Chemical Engineers in the U.S. and facilitate international collaboration between engineers in the U.S. and Korea.”

Read more on the Penn Engineering blog. Dr. Lim is a member of the Department of Bioengineering Graduate Group.

The Optimal Immune Repertoire for Bacteria

by Erica K. Brockmeier

Transmission electron micrograph of multiple bacteriophages, viruses that infect bacteria, attached to a cell wall. New research describes how bacteria can optimize their “memory” of past viral infections in order to launch an effective immune response against a new invader. (Image: Graham Beards)

Before CRISPR became a household name as a tool for gene editing, researchers had been studying this unique family of DNA sequences and its role in the bacterial immune response to viruses. The region of the bacterial genome known as the CRISPR cassette contains pieces of viral genomes, a genomic “memory” of previous infections. But what was surprising to researchers is that rather than storing remnants of every single virus encountered, bacteria only keep a small portion of what they could hold within their relatively large genomes.

Work published in the Proceedings of the National Academy of Sciences provides a new physical model that explains this phenomenon as a tradeoff between how much memory bacteria can keep versus how efficiently they can respond to new viral infections. Conducted by researchers at the American Physical Society, Max Planck Institute, University of Pennsylvania, and University of Toronto, the model found an optimal size for a bacteria’s immune repertoire and provides fundamental theoretical insights into how CRISPR works.

In recent years, CRISPR has become the go-to biotechnology platform, with the potential to transform medicine and bioengineering. In bacteria, CRISPR is a heritable and adaptive immune system that allows cells to fight viral infections: As bacteria come into contact with viruses, they acquire chunks of viral DNA called spacers that are incorporated into the bacteria’s genome. When the bacteria are attacked by a new virus, spacers are copied from the genome and linked onto molecular machines known as Cas proteins. If the attached sequence matches that of the viral invader, the Cas proteins will destroy the virus.

Bacteria have a different type of immune system than vertebrates, explains senior author Vijay Balasubramanian, but studying bacteria is an opportunity for researchers to learn more about the fundamentals of adaptive immunity. “Bacteria are simpler, so if you want to understand the logic of immune systems, the way to do that would be in bacteria,” he says. “We may be able to understand the statistical principles of effective immunity within the broader question of how to organize an immune system.”

Read more on Penn Today.

Vijay Balasubramanian is the Cathy and Marc Lasry Professor in the Department of Physics and Astronomy in the School of Arts & Sciences at the University of Pennsylvania and a member of the Department of Bioengineering Graduate Group

This research was supported by the Simons Foundation (Grant 400425) and National Science Foundation Center for the Physics of Biological Function (Grant PHY-1734030). 

BE Welcomes New Grad Chair Dr. Yale Cohen

by Sophie Burkholder

Yale Cohen, Ph.D.

We would like to congratulate Dr. Yale Cohen, Ph.D., on his recent appointment as the new Graduate Group Chair for Penn’s Department of Bioengineering. The Graduate Group is a group of faculty that graduate students in bioengineering can choose from to collaborate with on lab research. The Group includes members from nearly all of Penn’s schools, including Penn Engineering, Penn Dental, Penn Medicine, Penn Vet, and the School of Arts and Sciences.

Dr. Cohen specializes in otorhinolaryngology as his primary department, with research areas in computational and experimental neuroengineering. He will take over the role of Graduate Group Chair from Dr. Ravi Radhakrishnan, Ph.D, professor of bioengineering and chemical and biomolecular engineering, whose research specializes in cellular, molecular, and theoretical and computational bioengineering. During his tenure as Graduate Group Chair, Dr. Radhakrishnan says that “the most enjoyable part was the student talks during bioengineering seminars, and the talks at the bioengineering graduate student research symposium,” noting the way they made him realize the “depth and breadth of our graduate group, and how accomplished our students are.”

Also during his time as chair, Dr. Radhakrishnan says he was proud to expand the course BE 699 — the Bioengineering Department’s required seminar for all Ph.D. candidates — to include discussions of leadership and soft-skills, as well as instituting individualized development plans to help students track their work. In looking forward to Dr. Cohen’s appointment to the role, Dr. Radhakrishnan says that he is “a natural and accomplished scientist, educator, and amazing leader who connects so readily and well with our students and faculty.”

Dr. Cohen, looking forward to taking on his new role, says that he hopes to improve programs like the Graduate Association of Bioengineers (GABE) and the mentoring of graduate students so that they can access the wide range of wisdom that comprises the faculty, students, staff, and alumni associated with the Graduate Group. “I am thrilled to be the new chair of the BE Graduate Group and welcome your input and comments on how to improve an already outstanding program,” says Dr. Cohen.