How HIV Infection Shrinks the Brain’s White Matter

by Katherine Unger Baillie

Researchers from Penn and CHOP detail the mechanism by which HIV infection blocks the maturation process of brain cells that produce myelin, a fatty substance that insulates neurons.

A confocal microscope image shows an oligodendrocyte in cell culture, labeled to show the cell nucleus in blue and myelin proteins in red, green, and yellow. Researchers from Penn and CHOP have shown that HIV infection prevents oligodendrocytes from maturing, leading to a reduction in white matter in the brain. (Image: Raj Putatunda)

It’s long been known that people living with HIV experience a loss of white matter in their brains. As opposed to gray matter, which is composed of the cell bodies of neurons, white matter is made up of a fatty substance called myelin that coats neurons, offering protection and helping them transmit signals quickly and efficiently. A reduction in white matter is associated with motor and cognitive impairment.

Earlier work by a team from the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found that antiretroviral therapy (ART)—the lifesaving suite of drugs that many people with HIV use daily—can reduce white matter, but it wasn’t clear how the virus itself contributed to this loss.

In a new study using both human and rodent cells, the team has hammered out a detailed mechanism, revealing how HIV prevents the myelin-making brain cells called oligodendrocytes from maturing, thus putting a wrench in white matter production. When the researchers applied a compound blocking this process, the cells were once again able to mature.

The work is published in the journal Glia.

“Even when people with HIV have their disease well-controlled by antiretrovirals, they still have the virus present in their bodies, so this study came out of our interest in understanding how HIV infection itself affects white matter,” says Kelly Jordan-Sciutto, a professor in Penn’s School of Dental Medicine and co-senior author on the study. “By understanding those mechanisms, we can take the next step to protect people with HIV infection from these impacts.”

“When people think about the brain, they think of neurons, but they often don’t think about white matter, as important as it is,” says Judith Grinspan, a research scientist at CHOP and the study’s other co-senior author. “But it’s clear that myelination is playing key roles in various stages of life: in infancy, in adolescence, and likely during learning in adulthood too. The more we find out about this biology, the more we can do to prevent white matter loss and the harms that can cause.”

Jordan-Sciutto and Grinspan have been collaborating for several years to elucidate how ART and HIV affect the brain, and specifically oligodendrocytes, a focus of Grinspan’s research. Their previous work on antiretrovirals had shown that commonly used drugs disrupted the function of oligodendrocytes, reducing myelin formation.

In the current study, they aimed to isolate the effect of HIV on this process. Led by Lindsay Roth, who recently earned her doctoral degree within the Biomedical Graduate Studies group at Penn and completed a postdoctoral fellowship working with Jordan-Sciutto and Grinspan, the investigation began by looking at human macrophages, one of the major cell types that HIV infects.

Read the full story in Penn Today.

Kelly Jordan-Sciutto is vice chair and professor in the University of Pennsylvania School of Dental Medicine’s Department of Basic & Translational Sciences and is director of Biomedical Graduate Studies. She is a member of the Penn Bioengineering Graduate Group.

Katherine Reuther Appointed Practice Associate Professor in Bioengineering

Katie Reuther, PhD, MBA

Katherine (Katie) Reuther, Ph.D., M.B.A. will return to Penn Engineering in July 2021 as the new Executive Director of Penn Health-Tech (PHT) and as Practice Associate Professor in Bioengineering. Reuther is an alumna of Penn Bioengineering, having obtained her Ph.D. at Penn in the laboratory of Louis Soslowsky, Fairhill Professor in Bioengineering and Orthopaedic Surgery.

“Dr. Reuther is a role model for biomedical innovation, linking formal training in engineering and entrepreneurship with deep practical experience in leading technologies through the commercialization pipeline. Dr. Reuther graduated with her Bachelor of Science in Biomedical Engineering, Magna cum Laude, from the College of New Jersey; she obtained her Ph.D. in Bioengineering at Penn in the laboratory of Dr. Louis Soslowsky and completed her MBA at Columbia, where she currently is a Senior Lecturer in Design, Innovation, and Entrepreneurship in the Department of Biomedical Engineering. During her tenure at Columbia, Dr. Reuther helped create and led Columbia’s Biomedical Engineering Technology Accelerator (BiomedX), overseeing more than 60 technologies leading to $80M in follow-on funding and 18 licenses to start-ups or start-ups industry.  Introducing both new courses and a new curriculum in biomedical innovation, Dr. Reuther was recently awarded Columbia’s highest teaching honor, the ‘2021 Presidential Award for Outstanding Teaching,’ this Spring as a recognition of her excellence in teaching and dedication to students.

Katie has extensive experience in developing and translating early-stage medical technologies and discoveries and providing formal educational training for aspiring medical entrepreneurs.  Dr. Reuther served as Director of Masters’ Studies for the Department of Biomedical Engineering and spearheaded the development of a graduate-level medical innovation program, including an interdisciplinary course available to scientists, engineers, and clinicians. Dr. Reuther provided advising and educational support to more than 100 student/faculty teams and start-ups, as they worked to develop and commercialize medical technologies. She will bring these extensive skills to PHT and Penn Bioengineering in two new, hands-on graduate courses in medical innovation centered around Penn Health-Tech ventures.”

Read the full announcement in OVPR news.

César de la Fuente Featured in “40 Under 40” List

César de la Fuente, Ph.D.

César de la Fuente, PhD, Presidential Assistant Professor in Bioengineering, Chemical and Biomolecular Engineering, Psychiatry, and Microbiology, was featured in the Philadelphia Business Journal’s Class of 2021 “40 Under 40” list. Currently focused on antibiotic discovery, creating tools for microbiome engineering, and low-cost diagnostics, de le Fuente pioneered the world’s first computer-designed antibiotic with efficacy in animal models.

De la Fuente was previously included in the AIChE’s “35 Under 35” list in 2020 and most recently published his work demonstrating a rapid COVID-19 diagnostic test which delivers highly accurate results within four minutes.

Read “40 Under 40: Philadelphia Business Journal’s complete Class of 2021” here.

Read other BE blog posts featuring Dr. de la Fuente here.

Rapid COVID-19 Diagnostic Test Delivers Results Within 4 Minutes With 90 Percent Accuracy

RAPID, a low-cost COVID-19 diagnostic test, can detect SARS-CoV-2 within four minutes with 90 percent accuracy

Even as COVID-19 vaccinations are being rolled out, testing for active infections remains a critical tool in fighting the pandemic. Existing rapid tests that can directly detect the virus rely on reverse transcription polymerase chain reaction (RT-PCR), a common genetic assay that nevertheless requires trained technicians and lab space to conduct.

Alternative testing methods that can be scaled up and deployed in places where those are in short supply are therefore in high demand.

Penn researchers have now demonstrated such a method, which senses the virus by measuring the change in an electrical signal when a piece of the SARS-CoV-2 virus binds to a biosensor in their device, which they call RAPID 1.0.

The work, published in the journal Matter, was led by César de la Fuente, a Presidential Assistant Professor who has appointments in Engineering’s departments of Chemical and Biomolecular Engineering, and Bioengineering, as well as in Psychiatry and Microbiology in the Perelman School of Medicine.

“Prior to the pandemic, our lab was working on diagnostics for bacterial infections. But then, COVID-19 hit. We felt a responsibility to use our expertise to help—and the diagnostic space was ripe for improvements,” de la Fuente said. “We feel strongly about the health inequities witnessed during the pandemic, with testing access and the vaccine rollout, for example. We believe inexpensive diagnostic tests like RAPID could help bridge some of those gaps.”

The RAPID technology uses electrochemical impedance spectroscopy (EIS), which transforms the binding event between the SARS-CoV-2 viral spike protein and its receptor in the human body, the protein ACE2 (which provides the entry point for the coronavirus to hook into and infect human cells), into an electrical signal that clinicians and technicians can detect. That signal allows the test to discriminate between infected and healthy human samples. The signal can be read through a desktop instrument or a smartphone.

Read more about RAPID at Penn Medicine News.

Originally posted on Penn Engineering Today.

Carl June Receives the Sanford Lorraine Cross Award

Carl June, MD

Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania, director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center, and member of the Penn Bioengineering Graduate Group, received the $1 million Sanford Lorraine Cross Award for his groundbreaking work in developing chimeric antigen receptor (CAR) T cell therapy. June is a world renowned cancer cell therapy pioneer.

“Sanford Health, the only health system in the country to award a $1 million prize for achievements in the medical sciences, announced the award on April 13 at a special ceremony in Sioux Falls, South Dakota. The biennial award recognizes life-changing breakthroughs and bringing emerging transformative medical innovations to patients.

‘This is a well-deserved and exciting award for one of Penn’s most distinguished faculty members, whose pioneering research has reshaped the fight against cancer and brought fresh hope for both adults and children with the disease,’ said J. Larry Jameson, MD, PhD, Executive Vice President of the University of Pennsylvania for the Health System and Dean of the Perelman School of Medicine. ‘His contributions truly have been transformative for patients across the globe and taken the field of oncology in new and powerful directions.'”

Read the full story in Penn Medicine News.

Modified Nanoparticles Can Stop Osteoarthritis Development

Zhiliang Cheng

As we age, the cushioning cartilage between our joints begins to wear down, making it harder and more painful to move. Known as osteoathritis, this extremely common condition has no known cure; if the symptoms can’t be managed, the affected joints must be surgically replaced.

Now, researchers are exploring whether their specially designed nanoparticles can deliver a new inflammation inhibitor to joints, targeting a previously overlooked enzyme called sPLA2.

Zhiliang Cheng, a research associate professor in the Department of Bioengineering, recently collaborated with members of Penn Medicine’s McKay Orthopaedic Research Laboratory, on a study of this approach, published in the journal Science Advances.

The normal function of sPLA2 is to provide lipids (fats) that promote a variety of inflammation processes. The enzyme is always present in cartilage tissue, but typically in low levels. However, when the researchers examined mouse and human cartilage taken from those with osteoarthritis, disproportionately high levels of the enzyme were discovered within the tissue’s structure and cells.

“This marked increase strongly suggests that sPLA2 plays a role in the development of osteoarthritis,” said the study’s corresponding author, Zhiliang Cheng, PhD, a research associate professor of Bioengineering. “Being able to demonstrate this showed that we were on the right track for what could be a potent target for the disease.”

The next step was for the study team – which included lead author Yulong Wei, MD, a researcher in Penn Medicine’s McKay Orthopaedic Research Laboratory – to put together a nanoparticle loaded with an sPLA2 inhibitor. This would block the activity of sPLA2 enzyme and, they believed, inflammation. These nanoparticles were mixed with animal knee cartilage in a lab, then observed as they diffused deeply into the dense cartilage tissue. As time progressed, the team saw that the nanoparticles stayed there and did not degrade significantly or disappear. This was important for the type of treatment the team envisioned.

Continue reading at Penn Medicine News.

Originally posted in Penn Engineering Today.

Engineering and Medicine Researchers Collaborate on Studies of Genome Folding in Health and Disease

(Left to right) Top row: Jennifer E. Phillips-Cremins, Rajan Jain, and Eric Joyce. Middle row: Melike Lakadamyali, Golnaz Vahedi, and Gerd Blobel. Bottom row: Bomyi Lim, Arjun Raj, and Stanley Qi.

Popular accounts of the human genome often depict it as a long string of DNA base pairs, but in reality the genome is separated into chromosomes that are tightly twisted and coiled into complex three-dimensional structures. These structures create a myriad of connections between sites on the genome that would be distant from one another if stretched out end-to-end. These “long range interactions” are not incidental — they regulate the activity of our genes during development and can cause disease when disrupted.

Now two teams of researchers at the Perelman School of Medicine at the University of Pennsylvania, each led by Jennifer E. Phillips-Cremins,  associate professor and Dean’s Faculty Fellow in the Department of Bioengineering at the School of Engineering and Applied Science and of Genetics at the Perelman School of Medicine have been awarded grants totaling $9 million from the National Institutes of Health (NIH), as part of a major NIH Common Fund initiative to understand such 3D-genomic interactions.

The initiative, known as the 4D Nucleome Program, broadly aims to map higher-order genome structures across space and time, as well as to understand how the twists and loops of the DNA sequence govern genome function and cellular phenotype in health and disease.

Read the full story in Penn Engineering Today.

N.B.: In addition to Phillips-Cremins, collaborators include Arjun Raj, Professor in Bioengineering and Genetics, and Bioengineering Graduate Group Members Melike Lakadamyali, Associate Professor in Physiology, and Bomyi Lim, Assistant Professor in Chemical and Biomolecular Engineering.

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.

Using Lung-on-a-chip Technology to Find Treatments for Chlorine Gas Exposure

Huh’s organ-on-a-chip devices contain human cells, allowing for experiments that could not otherwise be practically or ethically performed.

Chlorine gas is a commonly used industrial chemical. It is also highly toxic and potentially deadly; it was used as a chemical weapon in both World War I and the Syrian Civil War and has led to multiple deaths from industrial accidents. Mixing certain household cleaners can also produce the toxic gas, leading to lasting lung injuries for which there are currently no effective treatments.

Now, researchers at Penn Engineering and Penn’s Perelman School of Medicine are collaborating with BARDA, the U.S. Office of Health and Human Services’ Biomedical Advanced Research and Development Authority, to address this need using their lung-on-a-chip technology.

The laboratory of Dan Huh, associate professor in the Department of Bioengineering, has developed a series of organ-on-a-chip platforms. These devices incorporate human cells into precisely engineered microfluidic channels that mimic an organ’s natural environment, providing a way to conduct experiments that would not otherwise be feasible.

Dan Huh
Dan Huh, PhD

Huh’s previous research has involved using a placenta-on-a-chip to study which drugs are able to reach a developing fetus; investigating microgravity’s effect on the immune system by sending one of his chips to the International Space Station; and testing treatments for dry eye disease using an eye-on-a-chip, complete with a mechanical blinking eyelid.

Read the full story on Penn Engineering Today. Media contact Evan Lerner.

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.