About

Casim A. Sarkar, PhD, is an Associate Professor of Bioengineering in the Department of Bioengineering at the University of Pennsylvania's Perelman School of Medicine. His research expertise includes the integration of extrinsic and intrinsic cues into models of lineage commitment for hematopoietic progenitors, as well as the directed evolution of G protein-coupled receptors for expression, stability, and binding selectivity. Dr. Sarkar's work involves understanding cellular signaling pathways and designing cytokines with increased lifetime and enhanced potency through pH-activated mechanisms. He completed his BS in Chemical Engineering at the University of Texas at Austin in 1997 and earned his PhD in Chemical Engineering from the Massachusetts Institute of Technology in 2002. His research contributions include developing cell-level pharmacokinetic models and exploring protein PEGylation effects, with numerous publications in biophysical and biochemical journals. Dr. Sarkar's work is focused on advancing biomedical engineering through innovative modeling and protein engineering techniques.

Research topics

• Computer Science
• Biology
• Genetics
• Computational biology
• Physics
• Biological system
• Mathematics
• Cell biology
• Ecology
• Immunology
• Statistical physics

Selected publications

• Syncytial therapeutics: Receptor-specific and direct-to-cytosol biologic drug delivery mediated by measles fusion complex

  Journal of Controlled Release · 2025-02-22

  articleOpen access
  PublisherOA PDFDOI

• Pulsed stimuli enable p53 phase resetting to synchronize single cells and modulate cell fate

  Molecular Systems Biology · 2025-03-03 · 2 citations

  articleOpen access

  Oscillatory p53 expression occurs in individual cells responding to DNA breaks. While the majority of cells exhibit the same qualitative response, quantitative features of the oscillations (e.g., amplitude or period) can be highly variable between cells, generating heterogeneity in downstream cell fate responses. Since heterogeneity can be detrimental to therapies based on DNA damage, methods to induce synchronization of p53 oscillations across cells in a population have the potential to generate more predictable responses to DNA-damaging treatments. Using mathematical modeling and time-lapse microscopy, we demonstrated that p53 oscillations can be synchronized through the phenomenon of phase resetting. Surprisingly, p53 oscillations were synchronized over a wider range of damage-induction frequencies than predicted computationally. Recapitulating the range of synchronizing frequencies required, non-intuitively, a less robust oscillator. We showed that p53 phase resetting altered the expression of downstream targets responsible for cell fate depending on target mRNA stability. This study demonstrates that p53 oscillations can be phase reset and highlights the potential of driving p53 dynamics to reduce cellular variability and synchronize cell fate responses to DNA damage.

  PublisherOA PDFDOI

• Valency-affinity mapping of multivalent liposomes for tunable target cell discrimination

  Drug Delivery · 2025-06-23 · 1 citations

  articleOpen accessSenior authorCorresponding

  can be rationally increased or decreased by adjusting DARPin valency and affinity (separately or synergistically) to lower or higher values, respectively. The approach outlined here enables rapid testing and optimization of ligand parameters for nanoparticle binding toward a given therapeutic target.

  PublisherDOI

• 982 Targeting glycans for cancer immunotherapy

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• Antibody-lectin chimeras for glyco-immune checkpoint blockade

  Nature Biotechnology · 2025-12-16 · 4 citations

  articleOpen access

  Despite the curative potential of checkpoint blockade immunotherapy, many patients remain unresponsive to existing treatments. Glyco-immune checkpoints, which involve interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors, have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular system for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin 'decoy receptor' domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate cancer cell destruction by primary human immune cells in vitro and reduce tumour burden in a humanized, immunocompetent mouse model, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumours and immune cell subsets as well as glyco-immune checkpoints, thus representing a potential modality for cancer immunotherapy.

  PublisherDOI

• Rapid retinoic acid-induced trophoblast cell model from human induced pluripotent stem cells

  Scientific Reports · 2024-08-06 · 2 citations

  articleOpen access

  A limited number of accessible and representative models of human trophoblast cells currently exist for the study of placentation. Current stem cell models involve either a transition through a naïve stem cell state or precise dynamic control of multiple growth factors and small-molecule cues. Here, we demonstrated that a simple five-day treatment of human induced pluripotent stem cells with two small molecules, retinoic acid (RA) and Wnt agonist CHIR 99021 (CHIR), resulted in rapid, synergistic upregulation of CDX2. Transcriptomic analysis of RA + CHIR-treated cells showed high similarity to primary trophectoderm cells. Multipotency was verified via further differentiation towards cells with syncytiotrophoblast or extravillous trophoblast features. RA + CHIR-treated cells were also assessed for the established criteria defining a trophoblast cell model, and they possess all the features necessary to be considered valid. Collectively, our data demonstrate a facile, scalable method for generating functional trophoblast-like cells in vitro to better understand the placenta.

  PublisherOA PDFDOI

• Inertial effect of cell state velocity on the quiescence-proliferation fate decision

  npj Systems Biology and Applications · 2024-10-02 · 3 citations

  articleOpen accessSenior author

  Energy landscapes can provide intuitive depictions of population heterogeneity and dynamics. However, it is unclear whether individual cell behavior, hypothesized to be determined by initial position and noise, is faithfully recapitulated. Using the p21-/Cdk2-dependent quiescence-proliferation decision in breast cancer dormancy as a testbed, we examined single-cell dynamics on the landscape when perturbed by hypoxia, a dormancy-inducing stress. Combining trajectory-based energy landscape generation with single-cell time-lapse microscopy, we found that a combination of initial position and velocity on a p21/Cdk2 landscape, but not position alone, was required to explain the observed cell fate heterogeneity under hypoxia. This is likely due to additional cell state information such as epigenetic features and/or other species encoded in velocity but missing in instantaneous position determined by p21 and Cdk2 levels alone. Here, velocity dependence manifested as inertia: cells with higher cell cycle velocities prior to hypoxia continued progressing along the cell cycle under hypoxia, resisting the change in landscape towards cell cycle exit. Such inertial effects may markedly influence cell fate trajectories in tumors and other dynamically changing microenvironments where cell state transitions are governed by coordination across several biochemical species.

  PublisherOA PDFDOI

• Pulsed stimuli entrain p53 to synchronize single cells and modulate cell-fate determination

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-27

  preprintOpen accessCorresponding

  Entrainment to an external stimulus enables a synchronized oscillatory response across a population of cells, increasing coherent responses by reducing cell-to-cell heterogeneity. It is unclear whether the property of entrainability extends to systems where responses are intrinsic to the individual cell, rather than dependent on coherence across a population of cells. Using a combination of mathematical modeling, time-lapse fluorescence microscopy, and single-cell tracking, we demonstrated that p53 oscillations triggered by DNA double-strand breaks (DSBs) can be entrained with a periodic damage stimulus, despite such synchrony not known to function in effective DNA damage responses. Surprisingly, p53 oscillations were experimentally entrained over a wider range of DSB frequencies than predicted by an established computational model for the system. We determined that recapitulating the increased range of entrainment frequencies required, non-intuitively, a less robust oscillator and wider steady-state valley on the energy landscape. Further, we show that p53 entrainment can lead to altered expression dynamics of downstream targets responsible for cell fate in a manner dependent on target mRNA stability. Overall, this study demonstrates that entrainment can occur in a biological oscillator despite the apparent lack of an evolutionary advantage conferred through synchronized responses and highlights the potential of externally entraining p53 dynamics to reduce cellular variability and synchronize cell-fate responses for therapeutic outcomes.

  PublisherOA PDFDOI

• Inertial effect of cell state velocity on the quiescence-proliferation fate decision in breast cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-05-24 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Energy landscapes can provide intuitive depictions of population heterogeneity and dynamics. However, it is unclear whether individual cell behavior, hypothesized to be determined by initial position and noise, is faithfully recapitulated. Using the p21-/Cdk2-dependent quiescence-proliferation decision in breast cancer dormancy as a testbed, we examined single-cell dynamics on the landscape when perturbed by hypoxia, a dormancy-inducing stress. Combining trajectory-based energy landscape generation with single-cell time-lapse microscopy, we found that initial position on a p21/Cdk2 landscape did not fully explain the observed cell-fate heterogeneity under hypoxia. Instead, cells with higher cell state velocities prior to hypoxia, influenced by epigenetic parameters, tended to remain proliferative under hypoxia. Thus, the fate decision on this landscape is significantly influenced by "inertia", a velocity-dependent ability to resist directional changes despite reshaping of the underlying landscape, superseding positional effects. Such inertial effects may markedly influence cell-fate trajectories in tumors and other dynamically changing microenvironments.

  PublisherOA PDFDOI

• Facile Display of Homomultivalent Proteins for <i>In Vitro</i> Selections

  ACS Synthetic Biology · 2023-01-19 · 4 citations

  articleOpen accessSenior authorCorresponding

  Low-affinity protein binders are emerging as valuable domains for therapeutic applications because of their higher specificity when presented in multivalent ligands that increase the overall strength and selectivity of receptor binding. De novo discovery of low-affinity binders would be enhanced by the large library sizes attainable with in vitro selection systems, but these platforms generally maximize recovery of high-affinity monovalent binders. Here, we present a facile technology that uses rolling circle amplification to create homomultivalent libraries. We show proof of principle of this approach in ribosome display with off-rate selections of a bivalent ligand against monovalent and bivalent targets, thereby demonstrating high enrichment (up to 166-fold) against a low-affinity target that is bivalent but not monovalent. This approach to homomultivalent library construction can be applied to any binder tolerant of N- and C-terminal fusions and provides a platform for performing in vitro display selections with controlled protein valency and orientation.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32GM069267

  NIH · $100k · 2006

• Analysis and Engineering of Cell Signaling

  NIH · $2.3M · 2020–2031

• Interplay between signaling and noise in cellular decision making

  NIH · $1.7M · 2015–2021

• CAREER: Engineering Biomolecules and Cells for Oral Protein Delivery

  NSF · $247k · 2011–2014

• Rapid discovery of new biologics and cell-surface targets to direct cell behavior

  NIH · $402k · 2016–2019

Frequent coauthors

• Najaf A. Shah

  9 shared

• Jeffrey A. Gralnick

  Biotechnology Institute

  9 shared

• Seth J. Corey

  Cleveland Clinic

  7 shared

• Zakary L. Whichard

  7 shared

• Pamela A. Barendt

  University of Pennsylvania

  7 shared

• Samira M. Azarin

  7 shared

• Patrick V. Holec

  Allen Institute

  6 shared

• Kelly G. Aukema

  University of Minnesota

  6 shared

Labs

• Casim A. Sarkar LabPI