Tag: faculty

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Herman P. Schwan Distinguished Lecture: “Nucleoside-modified mRNA-LNP therapeutics” (Drew Weissman, Perelman School of Medicine)

We hope you will join us for the Spring 2022 Herman P. Schwan Distinguished Lecture by Dr. Drew Weissman, hosted by the Department of Bioengineering.

Date: Tuesday, March 29, 2022
Time: 3:30-5:00 PM
Location: Bodek Lounge, Houston Hall
Reception to follow
Zoom Link
Password: schwan22

Drew Weissman, M.D., Ph.D.

Speaker: Drew Weissman, M.D., Ph.D.
Roberts Family Professor in Vaccine Research, Department of Medicine
Perelman School of Medicine
University of Pennsylvania

Abstract:

Vaccines prevent 4-5 million deaths a year making them the principal tool of medical intervention worldwide. Nucleoside-modified mRNA was developed over 15 years ago and has become the darling of the COVID-19 pandemic with the first 2 FDA approved vaccines based on it. These vaccines show greater than 90% efficacy and outstanding safety in clinical use. The mechanism for the outstanding immune response induction are the prolonged production of antigen leading to continuous loading of germinal centers and the adjuvant effect of the LNPs, which selectively stimulate T follicular helper cells that drive germinal center responses. Vaccine against many pathogens, including HIV, HCV, HSV2, CMV, universal influenza, coronavirus variants, pancoronavirus, nipah, norovirus, malaria, TB, and many others are currently in development. Nucleoside-modified mRNA is also being developed for therapeutic protein delivery. Clinical trials with mRNA encoded monoclonal antibodies are underway and many other therapeutic or genetic deficient proteins are being developed. Finally, nucleoside-modified mRNA-LNPs are being developed and used for gene therapy. Cas9 knockout to treat transthyretin amyloidosis has shown success in phase 1 trials. We have developed the ability to target specific cells and organs, including lung, brain, heart, CD4+ cells, all T cells, and bone marrow stem cells, with LNPs allowing specific delivery of gene editing and insertion systems to treat diseases such as sickle cell anemia, Nucleoside-modified mRNA will have an enormous potential in the development of new medical therapies.

Bio:

Drew Weissman, M.D., Ph.D. is a professor of Medicine at the Perelman School of Medicine, University of Pennsylvania. He received his graduate degrees from Boston University School of Medicine. Dr. Weissman, in collaboration with Dr. Katalin Karikó, discovered the ability of modified nucleosides in RNA to suppress activation of innate immune sensors and increase the translation of mRNA containing certain modified nucleosides. The nucleoside-modified mRNA-lipid nanoparticle vaccine platform Dr. Weissman’s lab created is used in the first 2 approved COVID-19 vaccines by Pfizer/BioNTech and Moderna. They continue to develop other vaccines that induce potent antibody and T cell responses with mRNA–based vaccines. Dr. Weissman’s lab also develops methods to replace genetically deficient proteins, edit the genome, and specifically target cells and organs with mRNA-LNPs, including lung, heart, brain, CD4+ cells, all T cells, and bone marrow stem cells.

About the Schwan Lecture:

The Herman P. Schwan Distinguished Lecture is in honor of one of the founding members of the Department of Bioengineering, who emigrated from Germany after World War II and helped create the field of bioengineering in the US. It recognizes people with a similar transformative impact on the field of bioengineering.

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Bionegineering Spin-off Vivodyne on Fast Company’s ‘Most Innovative’ List

Andrei Georgescu (left) and Dan Huh developed several organ-on-a-chip platforms in Huh’s lab. Their spin-off company, Vivodyne, aims to use the technology as a scalable alternative to animal testing in the pharmaceutical industry.

With Vivodyne, Associate Professor in the Department of Bioengineering Dan Huh is translating the organs-on-chips technology into a promising industry venture. Using microfluidic structures that mimic aspects of human physiology, organs-on-chips allow scientists to test therapies on lab-grown human cells. Vivodyne specifically focuses on designing organs-on-chips to create a scalable alternative for pharmaceutical drug testing on animals.

Last year, the company raised $4 million dollars in seed money. This year, it’s topping influential lists of small companies making big impacts.

Fast Company now lists it as one of “the 10 most innovative companies with fewer than 10 employees,”  saying “Vivodyne is helping major pharmaceutical companies like GlaxoSmithKline quickly adopt viable alternatives for testing drugs on monkeys.”

Vivodyne, launched in 2021, has created a platform that allows fully automated, complex studies at a far larger scale and lower cost than would be possible with manual experimentation, so pharmaceutical companies can actually test lab-made organs instead of animals in their drug-development processes. When done by hand, only 20 to 40 living tissue samples can be managed in parallel; Vivodyne’s instrument can cultivate, dose, and image more than 2,000 living tissues at once. The company, which raised $4 million in seed funding last year, says its instruments currently play pivotal roles in clinical drug testing for respiratory diseases, cancer treatment, vaccine development, diabetes therapies, and maternal medicine. GlaxoSmithKline, one of Vivodyne’s clients, estimates that for some projects the lab-grown tissues may displace as much as 80% of its animal testing. The company’s ultimate goal? “To supplant the vast majority of animal testing within the next decade,” says CEO Andrei Georgescu.

Continue reading “The 10 most innovative companies with fewer than 10 employees” at Fast Company.

Originally posted in Penn Engineering today.

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Konrad Kording Appointed Co-Director the CIFAR Learning in Machines & Brains Program

Konrad Kording, PhD (Photo by Eric Sucar)

Konrad Kording, Nathan Francis Mossell University Professor in Bioengineering, Neuroscience, and Computer and Information Sciences, was appointed the Co-Director of the CIFAR Program in Learning in Machines & Brains. The appointment will start April 1, 2022.

CIFAR is a global research organization that convenes extraordinary minds to address the most important questions facing science and humanity. CIFAR was founded in 1982 and now includes over 400 interdisciplinary fellows and scholars, representing over 130 institutions and 22 countries. CIFAR supports research at all levels of development in areas ranging from Artificial Intelligence and child and brain development, to astrophysics and quantum computing. The program in Learning in Machines & Brains brings together international scientists to examine “how artificial neural networks could be inspired by the human brain, and developing the powerful technique of deep learning.” Scientists, industry experts, and policymakers in the program are working to understand the computational and mathematical principles behind learning, whether in brains or in machines, in order to understand human intelligence and improve the engineering of machine learning. As Co-Director, Kording will oversee the collective intellectual development of the LMB program which includes over 30 Fellows, Advisors, and Global Scholars. The program is also co-directed by Yoshua Benigo, the Canada CIFAR AI Chair and Professor in Computer Science and Operations Research at Université de Montréal.

Kording, a Penn Integrates Knowledge (PIK) Professor, was previously named an associate fellow of CIFAR in 2017. Kording’s groundbreaking interdisciplinary research uses data science to advance a broad range of topics that include understanding brain function, improving personalized medicine, collaborating with clinicians to diagnose diseases based on mobile phone data and even understanding the careers of professors. Across many areas of biomedical research, his group analyzes large datasets to test new models and thus get closer to an understanding of complex problems in bioengineering, neuroscience and beyond.

Visit Kording’s lab website and CIFAR profile page to learn more about his work in neuroscience, data science, and deep learning.

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Decade-long Remission After CAR T Cell Therapy

Bill Ludwig, left, was the first patient to receive CAR T cells as part of clinical trials at Abramson Cancer Center. Carl June, right, has played a pioneering roll in the therapeutic use of CAR T cells. (Image: Penn Medicine)

Carl H. June, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine at Penn Medicine, director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group at the University of Pennsylvania, has led a new analytical study published in Nature that explains the longest persistence of CAR T cell therapy recorded to date against chronic lymphocytic leukemia (CLL), and shows that the CAR T cells remained detectable at least a decade after infusion, with sustained remission in both patients. June’s pioneering work in gene therapy led to the FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating leukemia and transforming the fight against cancer. His lab develops new forms of T cell based therapies.

Read the story in Penn Today

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Understanding Optimal Resource Allocation in the Brain

by Erica K. Brockmeier

A processed image representative of the types of images used in this study. Natural landscapes were transformed into binary images, ones made of black and white pixels, that were decomposed into different textures defined by specific statistics. (Image: Eugenio Piasini)

The human brain uses more energy than any other organ in the body, requiring as much as 20% of the body’s total energy. While this may sound like a lot, the amount of energy would be even higher if the brain were not equipped with an efficient way to represent only the most essential information within the vast, constant stream of stimuli taken in by the five senses. The hypothesis for how this works, known as efficient coding, was first proposed in the 1960s by vision scientist Horace Barlow.

Now, new research from the Scuola Internazionale Superiore di Studi Avanzati (SISSA) and the University of Pennsylvania provides evidence of efficient visual information coding in the rodent brain, adding support to this theory and its role in sensory perception. Published in eLife, these results also pave the way for experiments that can help understand how the brain works and can aid in developing novel artificial intelligence (AI) systems based on similar principles.

According to information theory—the study of how information is quantified, stored, and communicated—an efficient sensory system should only allocate resources to how it represents, or encodes, the features of the environment that are the most informative. For visual information, this means encoding only the most useful features that our eyes detect while surveying the world around us.

Vijay Balasubramanian, a computational neuroscientist at Penn, has been working on this topic for the past decade. “We analyzed thousands of images of natural landscapes by transforming them into binary images, made up of black and white pixels, and decomposing them into different textures defined by specific statistics,” he says. “We noticed that different kinds of textures have different variability in nature, and human subjects are better at recognizing those which vary the most. It is as if our brains assign resources where they are most necessary.”

Read the full story in 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. He is a member of the Penn Bioengineering Graduate Group.

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Jennifer Phillips-Cremins Wins ISSCR Dr. Susan Lim Award for Outstanding Young Investigator

Jennifer Phillips-Cremins, Ph.D.

Jennifer E. Phillips-Cremins, Associate Professor and Dean’s Faculty Fellow in Bioengineering and Genetics, has been awarded the 2022 Dr. Susan Lim Award for Outstanding Young Investigator by the International Society for Stem Cell Research (ISSCR), the preeminent, global organization dedicated to stem cells research.

This award recognizes the exceptional achievements of an investigator in the early part of his or her independent career in stem cell research. Cremins works in the field of epigenetics, and is a pioneer in understanding how chromatin,  the substance within a chromosome, works:

“Dr. Phillips-Cremins is a gifted researcher with diverse skills across cell, molecular, and computational biology. She is a shining star in the stem cell field who has already made landmark contributions in bringing long-range chromatin folding mechanisms to stem cell research. In addition to her skills as an outstanding researcher,” ISSCR President Melissa Little, Ph.D., said. “She has flourished as an independent investigator, providing the stem cell field with unique and creative approaches that have facilitated conceptual leaps in our understanding of long-range spatial regulation of stem cell fate. Congratulations, Jennifer, on this prestigious honor.”

Cremins was awarded a NIH Director’s Pioneer Award in 2021 and a Chan Zuckerberg Initiative (CZI) grant as part of the CZI Collaborative Pairs Pilot Project in 2020. The long-term goal of her lab is to understand the mechanisms by which chromatin architecture governs genome function. The ISSCR will recognize Cremins and her research in a plenary session during the ISSCR annual meeting on June 15.

Read the full press release on the ISSCR website.

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Penn Engineers Secure Wellcome Leap Contract for Lipid Nanoparticle Research Essential in Delivery of RNA Therapies

by Melissa Pappas

The Very Large Scale Microfluidic Integration (VLSMI) platform, a technology developed by the Penn researchers, contains hundreds of mixing channels for mass-producing mRNA-carrying lipid nanoparticles.

Penn Engineering secured a multi-million-dollar contract with Wellcome Leap under the organization’s $60 million RNA Readiness + Response (R3) program, which is jointly funded with the Coalition for Epidemic Preparedness Innovations (CEPI). Penn Engineers aim to create “on-demand” manufacturing technology that can produce a range of RNA-based vaccines.

The Penn Engineering team features Daeyeon Lee, Evan C Thompson Term Chair for Excellence in Teaching and Professor in Chemical and Biomolecular Engineering, Michael Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering, David Issadore, Associate Professor in Bioengineering and Electrical and Systems Engineering, and Sagar Yadavali, a former postdoctoral researcher in the Issadore and Lee labs and now the CEO of InfiniFluidics, a spinoff company based on their research. Drew Weissman of the Perelman School of Medicine, whose foundational research directly continued to the development of mRNA-based COVID-19 vaccines, is also a part of this interdisciplinary team.

The success of these COVID-19 vaccines has inspired a fresh perspective and wave of research funding for RNA therapeutics across a wide range of difficult diseases and health issues. These therapeutics now need to be equitably and efficiently distributed, something currently limited by the inefficient mRNA vaccine manufacturing processes which would rapidly translate technologies from the lab to the clinic.

Read more in Penn Engineering Today.

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New Lipid Nanoparticles Improve mRNA Delivery for Engineering CAR T Cells

by Melissa Pappas

The Penn researchers’ latest paper on the design of lipid nanoparticles was featured on the cover of the most recent edition of the journal Nano Letters.

From COVID vaccines to cancer immunotherapies to the potential for correcting developmental disorders in utero, mRNA-based approaches are a promising tool in the fight against a wide range of diseases. These treatments all depend on providing a patient’s cells with genetic instructions for custom proteins and other small molecules, meaning that getting those instructions inside the target cells is of critical importance.

The current delivery method of choice uses lipid nanoparticles (LNPs). Thanks to surfaces customized with binding and signaling molecules, they encapsulate mRNA sequences and smuggle them through the cell membrane. But with a practically unlimited number of variables in the makeup of those surfaces and molecules, figuring out how to design the most effective LNP is a fundamental challenge.

Now, in a study featured on the cover of the journal Nano Letters, researchers from the University of Pennsylvania’s School of Engineering and Applied Science and Perelman School of Medicine have now shown how to computationally optimize the design of these delivery vehicles.

Using an established methodology for comparing a wide range of variables known as “orthogonal design of experiments,” the researchers simultaneously tested 256 candidate LNPs. They found the frontrunner was three times better at delivering mRNA sequences into T cells than the current standard LNP formulation for mRNA delivery.

The study was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering in Penn’s School of Engineering and Applied Science, and Margaret Billingsley, a graduate student in his lab.

Read the full story in Penn Engineering Today.

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Newly Discovered ‘Encrypted Peptides’ Found in Human Plasma Exhibit Antibiotic Properties

by Melissa Pappas

The antimicrobial peptides the researchers studied are “encrypted” in that they are contained within Apolipoprotein B, a blood plasma protein that is not directly involved in the immune response, but are not normally expressed on their own.

The rise of drug-resistant bacteria infections is one of the world’s most severe global health issues, estimated to cause 10 million deaths annually by the year 2050. Some of the most virulent and antibiotic-resistant bacterial pathogens are the leading cause of life-threatening, hospital-acquired infections, particularly dangerous for immunocompromised and critically ill patients. Traditional and continual synthesis of antibiotics will simply not be able to keep up with bacteria evolution.

To avoid the continual process of synthesizing new antibiotics to target bacteria as they evolve, Penn Engineers have looked at a new, natural resource for antibiotic molecules.

César de la Fuente, Ph.D.

A recent study on the search for encrypted peptides with antimicrobial properties in the human proteome has located naturally occurring antibiotics within our own bodies. By using an algorithm to pinpoint specific sequences in our protein code, a team of Penn researchers along with collaborators, led by César de la Fuente, Presidential Assistant Professor in Psychiatry, Bioengineering, Microbiology, and Chemical and Biomolecular Engineering, and Marcelo Torres, a post doc in de la Fuente’s lab, were able to locate novel peptides, or amino acid chains, that when cleaved, indicated their potential to fend off harmful bacteria.

Now, in a new study published in ACS Nano, the team along with Angela Cesaro, the lead author and post doc in de la Fuente’s lab, have identified three distinct antimicrobial peptides derived from a protein in human plasma and demonstrate their abilities in mouse models. Angela Cesaro performed a great part of the activities during her PhD under the supervision of corresponding author, Professor Angela Arciello, from the University of Naples Federico II. The collaborative study also includes Utrecht University in the Netherlands.

“We identified the cardiovascular system as a hot spot for potential antimicrobials using an algorithmic approach,” says de la Fuente. “Then we looked closer at a specific protein in the plasma.”

Read the full story in Penn Engineering Today.

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A New Way to Profile T Cells Can Aid in Personalized Immunotherapy

by Melissa Pappas

A scanning electron micrograph of a healthy human T cell. A better understanding the wide variety of antigen receptors that appear on the surfaces of these critical components of the immune system is necessary for improving a new class of therapies. (Credit: NIAID)

Our bodies are equipped with specialized white blood cells that protect us from foreign invaders, such as viruses and bacteria. These T cells identify threats using antigen receptors, proteins expressed on the surface of individual T cells that recognize specific amino acid sequences found in or on those invaders. Once a T cell’s antigen receptors bind to the corresponding antigen, it can directly kill infected cells or call for backup from the rest of the immune system.

We have hundreds of billions of T cells, each with unique receptors that recognize unique antigens, so profiling this T cell antigen specificity is essential in our understanding of the immune response. It is especially critical in developing targeted immunotherapies, which equip T cells with custom antigen receptors that recognize threats they would otherwise miss, such as the body’s own mutated cancer cells.

Jenny Jiang, Ph.D.

Jenny Jiang, Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, along with lab members and colleagues at the University of Texas, Austin, recently published a study in Nature Immunology that describes their technology, which simultaneously provides information in four dimensions of T cell profiling. Ke-Yue Ma and Yu-Wan Guo, a former post doc and current graduate student in Jiang’s Penn Engineering lab, respectively, also contributed to this study.

This technology, called TetTCR-SeqHD, is the first to provide such detailed information about single T cells in a high-throughput manner, opening doors for personalized immune diagnostics and immunotherapy development.

There are many pieces of information needed to comprehensively understand the immune response of T cells, and gathering all of these measurements simultaneously has been a challenge in the field. Comprehensive profiling of T cells includes sequencing the antigen receptors, understanding how specific those receptors are in their recognition of invading antigens, and understanding T cell gene and protein expression. Current technologies only screen for one or two of these dimensions due to various constraints.

“Current technologies that measure T cell immune response all have limitations,” says Jiang. “Those that use cultured or engineered T cells cannot tell us about their original phenotype, because once you take a cell out of the body to culture, its gene and protein expression will change. The technologies that address T cell and antigen sequencing with mass spectrometry damage genetic information of the sample. And current technologies that do provide information on antigen specificity use a very expensive binding ligand that can cost more than a thousand dollars per antigen, so it is not feasible if we want to look at hundreds of antigens. There is clearly room for advancement here.”

The TetTCR-SeqHD technology combines Jiang’s previously developed T cell receptor sequencing tool, TetTCR-Seq, described in a Nature Biotechnology paper published in 2018, with the new ability of characterizing both gene and protein expression.

Read the full story in Penn Engineering Today.