BE Seminars & Events

Current Seminar Series: 2016-2017

Bioengineering Seminars are held on Thursdays at 10:30AM in 337 Towne Building unless otherwise noted below. For all Penn Engineering events, visit the Penn Calendar.

September 8
Glen Niebur
Mechanobiology of Bone Marrow and Its Relationship to Bone Physiology
Read the Abstract

Bone marrow is a soft cellular tissue in the human body that supports important physiological functions. It contains two primary cell lineages that derive from two progenitor populations. The hematopoietic lineage provides blood cells and the immune cells. The mesenchymal cell lineage supports the function of the hematopoietic cells, but also provides cells necessary to generate new connective tissue, including the bone itself. The bone and marrow have a symbiotic relationship, with both the hematopoietic and the mesenchymal lineages contributing cells the maintain bone health.

Both bone and bone marrow cells are highly mechanically sensitive, and adapt to typical physiological loading in humans and animals. While we have studied the mechanical response of bone for centuries and of bone cells for 50 years, we know little about the mechanics of bone marrow, or what types of mechanical signals it is subjected to in situ.

I will present our recent studies to quantify the mechanical properties of bone marrow and the mechanical environment during normal physiological activities. Since the marrow resides within sub-millimeter pores inside the bone, direct measurements were supplemented with large-scale computational models to quantify the mechanics based on limited measurement data. Based on our mechanics data, we have used bioreactors with controlled culture conditions to simulate these signals and quantify the physiological response of marrow and identify signaling pathways through which marrow affects bone formation.

Monday, October 17
Joint Seminar
Orion Weiner
Cell Polarity at the Crossroads of Signaling Physical Forces
and the Actin Cytoskeleton

Read the Abstract

Signal transduction networks enable cells to respond to the world around them. To uncover how these signaling networks generate proper responses, we need not only a parts list but also an understanding of how their constituent molecular components work together to process information. I have devoted my lab to developing technologies that will enable us to answer signaling questions that have not been possible to address before. My primary interest is to understand the signaling circuits that organize cell polarity. We take advantage of advanced microscopy techniques in conjunction with techniques to rewire cell signaling or to activate and inhibit signaling on a subcellular level. We aim to move beyond a parts list of components involved in migration to a systems level understanding of cell polarity.

October 20
Jennifer Cochran
Engineering Proteins for Visualizing and Treating Cancer

Read the Abstract

We engineer proteins as therapeutics and diagnostic agents for biomedical applications including cancer and regenerative medicine. I will discuss the discovery and development of novel therapeutic approaches to targeted cancer treatment, spanning a broad range of efforts in the areas of protein engineering, biochemical and biophysical analyses, and preclinical testing.

We also create technologies for protein analysis and engineering, including a high-throughput screening platform that enables massively parallel, quantitative biochemical measurements to be performed on millions of protein variants expressed in yeast or bacteria. My presentation will highlight examples of engineered proteins with translational impact, as well as protein engineering applications performed with this new technology platform.

October 27
Ibrahhim I Cisse
RNA Polymerase II cluster dynamics predict mRNA output in living cells
Read the Abstract

Protein clustering is a hallmark of genome regulation in mammalian cells. However, the dynamic molecular processes involved make it difficult to correlate clustering with functional consequences in vivo. We developed a live-cell super-resolution approach to uncover the correlation between mRNA synthesis and the dynamics of RNA Polymerase II (Pol II) clusters at a gene locus. For endogenous β-actin genes in mouse embryonic fibroblasts, we observe that short-lived (~8 s) Pol II clusters correlate with basal mRNA output. During serum stimulation, a stereotyped increase in Pol II cluster lifetime correlates with a proportionate increase in the number of mRNAs synthesized. Our findings suggest that transient clustering of Pol II may constitute a pre-transcriptional regulatory event that predictably modulates nascent mRNA output.

November 3
Otger Campas
Mechanical Control of Tissue Morphogenesis
Read the Abstract

The sculpting of tissues into their functional morphologies requires a tight spatiotemporal control of their mechanics. While cell-generated mechanical forces power morphogenesis, the resulting tissue movements depend on the local tissue mechanical properties, such as its stiffness and viscosity, which govern the system's response to the internally generated forces. Despite their relevance, the role of mechanical forces and mechanical properties in development processes remains largely unknown, mainly because of a lack in methodologies enabling direct in vivo and in situ measurements of cell-generated forces and mechanical properties within developing 3D tissues and organs. In this talk, I will present two novel microdroplet-based techniques that we have recently developed to quantify local cellular forces and mechanical properties within developing 3D tissues. Using zebrafish as model system, I will show that cellular forces do not vary strongly in space and time, whereas spatiotemporal changes in supra-cellular (tissue level) forces and mechanical properties correlate with morphogenetic events and spatial variations in cellular movements. These results indicate that spatiotemporal changes in tissue mechanical properties (stiffness, fluidity, etc.), rather than just cellular forces, regulate the sculpting of embryonic tissues

November 17
Peter Lelkes
Modulation of Pluripotent Stem Cell Fate Decision by Microenvironmental Cues
Read the Abstract

As part of our ongoing studies into lug tissue engineering we have been focusing on optimizing the efficiency of directed in vitro differentiation of murine embryonic stem cells (mESCs) into lung alveolar epithelial cells. In this presentation I will describe how this differentiative process can be modulated by two microenvironmental cues: oxygen tension and substrate stiffness. Specifically, both these factors, using distinct signaling pathways that involve HIF-1α and Rho/Rock, respectively, independently enhance differentiation of mESCs into definitive endoderm, and subsequently into alveolar epithelium. Augmentation of endodermal differentiation and subsequent alveolar differentiation depend strikingly on the duration of exposure to hypoxia.  Of note is also the marked biphasic nature of the effect of substrate stiffness on endoderm induction. The results of our study will be important in advancing the production of differentiated alveolar cells necessary for cell based therapies of lung diseases and/or for whole lug tissue engineering.

December 1
Eva Marie Collins
Ripping Yourself a New One: Biomechanics of Tissue Rupture in
Regenerating Organisms

Read the Abstract

Biological tissues are an exciting system to study because they are non-equilibrium materials that consist of self-propelled, interacting agents (cells) and as such exhibit interesting phenomena not observed in passive materials. In my talk I will present our recent work on two
examples of active violent morphological restructuring in biological tissues.

The first study explains how Hydra, a simple freshwater animal, opens its mouth to eat. In contrast to humans and most other animals, Hydra does not have a permanent mouth. Instead, it rips a hole in its skin every time it wants to eat. For a preview, see:
http://shows.howstuffworks.com/now/hydra-mouth-video.htm

The second study explains how freshwater planarians rip themselves apart during asexual reproduction using only substrate adhesion and their own musculature. How this feat can be achieved is a complex biomechanics problem which reportedly already bugged the great Michael Faraday, but has
remained a mystery for centuries.

Each study solves a longstanding puzzle about a fundamental biological phenomenon which remained unsolved due to a lack of experimental tools and quantitative measurements. These examples further illustrate how complex biological phenomena can be described by relatively simple physics and
that our quantitative approach provides new insights into the biological mechanisms underlying these phenomena.

December 8
12PM
Jun Song
Telomere Maintenance in Glioma
Read the Abstract

Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations specific to two nucleotide positions. I will describe how we have recently identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant TERT activation in multiple cancers and provides an opportunity for targeting these highly recurrent non-coding mutations.

December 15
Prashant Mali
Therapeutic Strategies via CRISPR-Cas: New Approaches and New Challenges
Read the Abstract

The recent advent of RNA-guided effectors derived from clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems have dramatically transformed our ability to engineer the genomes of diverse organisms. As unique factors capable of co-localizing RNA, DNA, and protein, tools and techniques based on these are paving the way for unprecedented control over cellular organization, regulation, and behavior. Here I will describe some of our ongoing efforts towards engineering this system for enabling therapeutic applications.

January 19
Kimberly Kelly
Hitting the Target: Imaging, Nanotechnology and Drug Delivery in Pancreatic Cancer

Read the Abstract

The era of “omics” has ushered in the hope for personalized medicine.  Proteomic and genomic strategies that allow unbiased identification of genes and proteins and their post-transcriptional and -translation modifications are an essential component to successful understanding of disease and the choice of imaging targets.  However, the enormity of the genome and proteome and limitations in data analysis make it difficult to determine the targets that are particularly relevant to human disease and will be good targets for molecular imaging and targeted drug therapies.  Methods are therefore needed that allow rational identification of targets based on function, relevance to disease, and suitability for molecular imaging and therapy.

Through this lecture, we will explore one clinical scenario: pancreatic ductal adenocarcinoma (PDAC) as an application for target identification, imaging and therapeutic agent development. PDAC is among the most lethal of human cancers due to its marked resistance to existing chemo- and radiotherapies.  Unlike a number of other solid tumors, which have robust methods for early detection, there have been no significant improvements in PDAC survival over the past 40 years despite a large number of clinical trials of both conventional and targeted therapies.  Like other solid cancers, early detection that allows complete surgical resection offers the best hope for longer survival, unfortunately, most patients are diagnosed with metastatic disease due to the lack of specific symptoms and absence of suitable biomarkers for early detection.

January 26
April Kloxin
Designing and Utilizing Responsive Biomaterials to Control Cellular Microenvironments in the Study of Tissue Regeneration and Disease

Read the Abstract

The nano- to macro-scale physical and chemical properties of the environment that surrounds a cell are known to play an important role in cell function and fate. Yet, less is known about how combinations of and changes in these properties influence biological functions. For example, driven by transient bidirectional crosstalk between cells and the extracellular matrix (ECM), cell activation and tissue remodeling are complex processes that often involve the presentation of multiple cues that are tightly regulated over multiple time and size scales. Studying such complex and dynamic processes in vitro can be challenging. Biomaterials, particularly hydrogels, are useful tools for probing how microenvironment cues regulate cell behavior toward directing cellular functions in the treatment of disease and regeneration of tissue. Further, these materials can be utilized to deliver therapeutics, from proteins to cells, to regulate these processes in vivo. Engineering hydrogel-based materials from the bottom up enables controlled presentation of selected cues at the appropriate time and place within the cellular niche. This talk will focus on simple strategies to impart highly-regulated property control by synthesizing monomers capable of forming hydrogels in the presence of cells and subsequently allowing triggered modification (e.g., light, enzymes, or reducing conditions) to tune the physical or chemical properties of the network. In particular, we will highlight recent results toward understanding critical cues that regulate stem cell differentiation down hard-to-achieve lineages, such as mesenchymal stem cells into ligament fibroblasts, and new approaches for the construction of soft, well-defined synthetic extracellular matrices with controlled nanostructure for two- and three-dimensional culture studies, including breast cancer cells in metastatic disease.

February 2
12PM
Long Cai
Spatial genomics and single cell lineage dynamics by seqFISH and MEMOIR

Read the Abstract

Identifying the spatial organization of tissues at cellular resolution from single cell
gene expression profiles is essential to understanding many biological systems. We have developed an in situ 3D multiplexed imaging method to quantify hundreds of genes with single cell resolution via Sequential barcoded Fluorescence in situ hybridization (seqFISH) (Lubeck et al., 2014). We used seqFISH to identify unique transcriptional states by quantifying and clustering up to 249 genes in 16,958 cells. By visualizing these clustered cells in situ, we identified regions within distinct composition of cells in different transcriptional states. Together, these results demonstrate the power of seqFISH in transcriptional profiling of complex tissues.  Lastly, I will discuss our work in writing lineages and cell event history into genome of cells by CRISPR/Cas9 genome editing and reading out the stored information in single cells by seqFISH. 

February 16
Nandan Nerurkar
Molecular Control of Physical Forces During Morphogenesis of the Vertebrate Gut

Read the Abstract

Changes in the shape of a material – be it rubber, concrete, cells, or tissue – requires the action of physical forces. Therefore during embryonic development, the dramatic transformation from a seemingly disorganized mass of cells into the fully patterned adult form necessitates stereotyped regulation of forces at the genetic and molecular level. While great progress has been made in understanding how gene expression and signaling events generate biological pattern, little is known about how molecular cues organize forces to sculpt physical patterns during development. How does the developing embryo ensure that tissues are shaped by the right forces, acting at the right time and location, and with the right orientation and magnitude?  My work begins to address this in two complementary contexts during gastrointestinal morphogenesis in the chick embryo: gut tube formation and intestinal looping. Together these studies demonstrate how secreted signals are converted into tissue-level forces that shape the developing embryo, and yield new insight into important gastrointestinal birth defects. The long-term goal of this work is to provide insight into the fundamental mechanisms of tissue formation, ultimately revealing a molecular-mechanical toolkit of embryonic development that can be redeployed in the context of regenerative medicine and tissue engineering.

March 2
Caleb Bashor, Ph.D.
Bottom-up Engineering of Eukaryotic Regulatory Systems
12 pm

Read the Abstract

A major goal of synthetic biology is to predictively reshape cellular phenotype by introducing artificial regulatory network connections. While the practice of constructing synthetic circuitry is relatively well established in model prokaryotic systems, the pace and progress of engineering has been much slower for eukaryotic cells. In this presentation, I will describe our recent efforts at creating network engineering frameworks for both synthetic transcriptional (genetic circuits) and post-translational (phosphorylation-based signaling circuits) networks that are both inspired by and compatible with native networks found in eukaryotic cells. In each case, we showcase modular, scalable solutions which utilize simple molecular components that can be assembled into circuits that exhibit sophisticated, natural-like behavior. Furthermore, we introduce strategies for rapidly sampling circuit design space to quickly converge on behaviors that fulfill a particular design goal. Our engineering strategies are broadly applicable, and point toward a universal toolkit for reprogramming the ability of eukaryotic cells to sense, process, and transmit information for important industrial or therapeutic purposes.

March 13
Lukasz Bugaj
Interrogating Cell Signal Perception Using Optogenetics
Read the Abstract

Despite decades of cell signaling studies, we have a limited understanding of the cell signaling code: how can cells make diverse and complex decisions using only a small set of intracellular signaling pathways? An intriguing hypothesis is that cells can decode the strength, dynamics, or combinations of intracellular signals. Optogenetic (light-activatable) tools now enable us to test this hypothesis through precise and tunable control over signaling inputs in living cells.  These tools allow us to reverse-engineer the cell, giving fundamental insight into both 1) the cellular machinery and 2) the cell’s ability to process and interpret its dynamic environment. In this talk, I will first describe the engineering of optogenetic proteins for cell signaling, as well as their high-throughput implementation. I will then show how these approaches are revealing principles by which signaling dynamics govern cell fate decisions from neurogenesis to cancer cell proliferation.


March 16
Alex Hughes
Inferring the Design Rules of Development by Tissue Reconstitution

Read the Abstract

The emergence of gut villi, the branching of the airway epithelium, and the wrapping and closure of the neural tube are all developmental transitions that convert flat tissue structures into more complex forms. I believe that a systems-level understanding of tissues sufficient to study their malfunction in disease will come through reconstituting their developmental transitions ex vivo. I will describe our synthetic system for recapitulating the mechanics of mesenchymal condensation, a core vertebrate developmental program that encodes transitions in tissue complexity in diverse contexts. These efforts will enable fundamental
studies on the interplay between tissue mechanics and morphogenesis, and instruct our efforts to bring developmental principles under engineering control for applications in basic science, regenerative medicine, and stimuli-responsive biological materials.

March 20
Michael Mitchell
"Technologies for Engineering Blood and Marrow for Cancer Therapy"

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It has become apparent that the surrounding tumor microenvironment can promote the growth, drug resistance, and metastasis of malignant cells. In this talk, I will discuss how cells within the vascular and bone marrow microenvironments can be engineered and exploited for cancer therapy. I will first discuss an approach to engineer the surface of innate immune cells in the bloodstream with cancer therapeutics in vivo. Mimicking the cytotoxic activity of natural killer cells, the approach exploits the extensive surface area of circulating immune cells to display both the cancer-specific TNF-related apoptosis-inducing ligand (TRAIL) and E-selectin adhesion receptor to metastatic cells in the vascular microenvironment. The resulting “unnatural killer cells” neutralized tumor cells within the circulation in vivo, and prevented metastatic tumor formation in spontaneous metastasis mouse models of prostate cancer. I will then present our most recent work on the development of gene delivery materials that target the bone marrow microenvironment in vivo, as a means to treat cancers that colonize in marrow. Through the synthesis of a diverse library of polymer-lipid hybrids in combination with high throughput in vivo screening methods, we have identified novel biomaterials that efficiently deliver nucleic acid therapeutics to target cells in the bone marrow microenvironment at low dosages. By targeting physical interactions between tumor cells and the surrounding microenvironment, these materials disrupted multiple myeloma progression in clinically relevant, humanized mouse models of the disease.

March 30
Aaron Meyer
"Engineering More Precise and Potent TAMR-Targeted Therapies"
Read the Abstract

Abstract
TAM (Tyro3, AXL, MerTK) receptor tyrosine kinases (TAMRs) are critical regulators of immune response and tissue homeostasis. Immunological dysregulation of the family contributes to a wide range of diseases including lupus, retinal dystrophy, infection, and cancer. TAMR activation in cancer cells serves as a mechanism of resistance to chemotherapies and targeted inhibitors. Further improving our understanding of the molecular events that lead to oncogenic TAMR function will enable rational design of more specific inhibitors with precise effects in vivo and help identify the patients who will benefit from these therapies. In this talk, I will describe our efforts to identify the molecular events leading to TAMR activation, and how these events are tied to the receptors’ physiological function. Using kinetic models of receptor activation, tied to inference techniques that rigorously consider model uncertainty, have helped us to identify new ways of rationally targeting the TAMR family. Using these tools, we are deconvolving the pleiotropic role these receptors play in tumor cell heterogeneity, metastasis, and immune suppression using combinations of these targeted treatments with data-driven modeling. Lastly, I will touch upon how these approaches can inform other areas of innate immune signaling, and opportunities for bioengineering technological development presented by what we have learned.

April 6
Sindy Tang
"Order and Chaos*: Collective Behavior of Crowded Drops in Microfluidic Systems"

Read the Abstract

Droplet microfluidics, in which micro-droplets serve as individual reactors, has enabled a range of high-throughput biochemical processes. The talk will start with our recent application on using droplets to identify microbes, specifically methane-metabolizing bacteria, for the more efficient generation of bioplastics. Unlike solid wells typically used in current biochemical assays, droplets are subject to instability and can break especially at fast flow conditions. Although the physics of single drops has been studied extensively, the flow of crowded drops or concentrated emulsions—where droplet volume fraction exceeds ~80%—is relatively unexplored in microfluidics. Ability to leverage concentrated emulsions is critical for further increasing the throughput of droplet applications. Prior work on concentrated emulsions focused on their bulk rheological properties. The behavior of individual drops within the emulsion is not well understood, but is important as each droplet carries a different reaction.

This talk examines the collective behavior of drops in a concentrated emulsion by tracking the dynamics and the fate of individual drops within the emulsion. At the fast flow limit, we show that droplet breakup within the emulsion is stochastic. This contrasts the deterministic breakup in classical single-drop studies. We further demonstrate that the breakup probability is described by dimensionless numbers including the capillary number and confinement factor, and the stochasticity originates from the time-varying packing configuration of the drops. To mitigate breakup, we design novel amphiphilic nanoparticles, and show they are more effective than surfactant molecules as droplet stabilizers.

At the slow flow limit, we observe an unexpected order, where the velocity of individual drops in the emulsion exhibits spatiotemporal periodicity. Such periodicity is surprising from both fluid and solid mechanics point of view. We show the phenomenon can be explained by treating the emulsion as a soft crystal undergoing plasticity, in a nanoscale system comprising thousands of atoms as modeled by droplets. Our results represent a new type of collective order not described before, and have practical use in on-chip droplet manipulation. From the solid mechanics perspective, the phenomenon directly contrasts the stochasticity of dislocations in microscopic crystals, and suggests a new approach to control the mechanical forming of nanocrystals.

*Chaos stands for Crowded droplet breakup HydrodynAmics not Ordered but Stochastic

April 13
Ahmad Khalil
Epigenetics and Evolution in the Age of Synthetic Biology

Read the Abstract

Cells use genetically-encoded molecular networks to sense and respond to the changing environment. Our lab uses synthetic biology to study the function of these cellular networks, and to predictively engineer them for useful applications. While the synthetic approach has been used to explore a wide range of cellular functions, less has been done on the systems involved in establishing and interfacing with epigenetic processes. In this talk, I will discuss our efforts to apply synthetic biology to engineer epigenetic systems, which are important for expanding the repertoire of cellular responses and establishing the distinct cellular identities that make up multicellular organisms. Specifically, I will discuss the development of synthetic tools and systems for controlling: (1) molecular signatures and changes to chromatin to produce/program distinct gene expression outputs; and (2) an altogether different form of epigenetics, encoded in the self-propagating conformations of prion proteins. A broad goal of this work is quantitatively defining/controlling the molecular properties that underlie cellular responses via engineering. A newer, complementary goal in the lab is using engineering to quantitatively control environmental and selective conditions that can be imposed on organisms in the laboratory. I will discuss these new high-throughput technologies, and show how they can be applied to comprehensively map adaptive cellular phenotypes and evolve new biological functions.

April 27
Ali Khademhosseini
Nano- and Microfabricated Hydrogels for Regenerative Engineering

Read the Abstract

Engineered materials that integrate advances in polymer chemistry, nanotechnology, and biological sciences have the potential to create powerful medical therapies. Our group aims to engineer tissue regenerative therapies using water-containing polymer networks, called hydrogels, that can regulate cell behavior. Specifically, we have developed photocrosslinkable hybrid hydrogels that combine natural biomolecules with nanoparticles to regulate the chemical, biological, mechanical and electrical properties of gels. These functional scaffolds induce the differentiation of stem cells to desired cell types and direct the formation of vascularized heart or bone tissues. Since tissue function is highly dependent on architecture, we have also used microfabrication methods, such as microfluidics, photolithography, bioprinting, and molding, to regulate the architecture of these materials. We have employed these strategies to generate miniaturized tissues. To create tissue complexity, we have also developed directed assembly techniques to compile small tissue modules into larger constructs. It is anticipated that such approaches will lead to the development of next-generation regenerative therapeutics and biomedical devices.