Tag: synthetic biology

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BE Seminar: “Engineering Synthetic Biomaterials for Islet Transplantation” (María M. Coronel)

Speaker: María M. Coronel, Ph.D.
Postdoctoral Fellow, the George W. Woodruff School of Mechanical Engineering
Georgia Institute of Technology

Date: Thursday, February 18, 2021
Time: 3:00-4:00 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “Engineering Synthetic Biomaterials for Islet Transplantation”

Abstract:

Two major challenges to the translation of cellular-based tissue-engineered therapies are the lack of adequate oxygen support post-implantation and the need for systemic immunosuppression to halt the strong inflammatory and immunological response of the host. As such, strategies that aim at addressing oxygen demand, and local immunological responses can be highly beneficial in the translation of these therapies. In this seminar, I will focus on two biomaterial strategies to create a more favorable transplant niche for pancreatic islet transplantation. The first half will describe an in-situ oxygen-releasing biomaterial fabricated through the incorporation of solid peroxides in a silicone polymer. The implementation of this localized, controlled and sustained oxygen-generator mitigates the activation of detrimental hypoxia-induced pathways in islets and enhances the potency of extrahepatic 3D islet-loaded devices in a diabetic animal model. In the second part, I will focus on engineering synthetic biomaterials for the delivery of immunomodulatory signals for transplant acceptance. Biomaterial carriers fabricated with polyethylene glycol microgels are used to deliver immunomodulatory signals to regulate the local microenvironment and prevent allograft rejection in a clinically relevant pre-clinical transplant model. The use of synthetic materials as an off-the-shelf platform, without the need for manipulating the biological cell product, improves the clinical translatability of this engineered approach. Designing safer, responsive biomaterials to boost the delivery of targeted therapeutics will significantly reinvigorate interventional cell-based tissue-engineered therapies.

Bio:

Dr. María M. Coronel is currently a Juvenile Diabetes Research Foundation postdoctoral fellow at the Georgia Institute of Technology. Dr. Coronel completed her BS degree in Biomedical Engineering from the University of Miami, and her Ph.D. degree in Biomedical Engineering from the University of Florida as a National Institute of Health predoctoral fellow. Her doctoral work focused on engineering oxygen-generating materials for addressing the universal challenge of hypoxia within three-dimensional tissue-engineered implants. As a postdoctoral fellow, her research interest focus on engineering tools and principles to understand, stimulate, and modulate the immune system to develop controlled targeted interventional therapies. In addition to research, Dr. Coronel aims to be an advocate for diversity and inclusion in STEM as the co-president of the postdoctoral group and a founding member of the diversity, equity, and inclusion committee in bioengineering at Georgia Tech. Outside of the lab María enjoys cooking, baking, and traveling.

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BE/MEAM Seminar: “Microbes in Biomechanics” (Christopher J. Hernandez)

Speaker: Christopher J. Hernandez, Ph.D.
Professor, Sibley School of Mechanical and Aerospace Engineering, Cornell University
Adjunct Scientist, Hospital for Special Surgery

Date: Thursday, February 4, 2021
Time: 3:00-4:00 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “Microbes in Biomechanics”

This seminar is jointly hosted by the Department of Bioengineering and the Department of Mechanical Engineering and Applied Mechanics.

Abstract:

The idea that mechanical stresses influence the growth and form of organs and organisms originated in the 1800s and is the basis for the modern study of biomechanics and mechanobiology. Biomechanics and mechanobiology are well studied in eukaryotic systems, yet eukaryotes represent only a small portion of the diversity and abundance of life on Earth. Bacteria exhibit broad influences on human health (as both pathogens and as beneficial components of the gut microbiome) and processes used in biotechnology and synthetic biology. Over the past eight years my group has explored mechanobiology within individual bacteria and the effects of changes in the composition of commensal bacterial communities on the biomechanics in the musculoskeletal system.

The ability of the bacteria to not only resist mechanical loads (biomechanics) but also to respond to changes in the mechanical environment (mechanobiology) is necessary for survival. Here I describe a novel microfluidic platform used to explore the biomechanics and mechanobiology of individual, live bacteria. I discuss work from my group demonstrating that mechanical stress within the bacterial cell envelope can influence the assembly and function of multicomponent efflux pumps used by bacteria to resist toxins and antibiotics. Additionally, I share some of our more recent work showing that mechanical stress and strain within the bacterial cell envelope can stimulate a bacterial two-component system controlling gene expression. Our findings demonstrate that bacteria, like mammalian cells, have mechanosensitive systems that are key to survival.

In musculoskeletal disease, bacteria are commonly viewed as sources of infection. However, in the past decade the studies by my group and others have suggested that commensal bacteria – the microbiome – can modulate the pathogenesis of musculoskeletal disorders. My group is among the first to study the effects of the gut microbiome on orthopaedic disorders. Here I provide an introduction to the microbiome and current concepts of how modifications to the gut microbiome could influence the musculoskeletal system. Specifically, I discuss studies from my group which are the first to demonstrate that the gut microbiome influences bone biomechanics and the development of infection of orthopaedic implants.

Bio:

Dr. Hernandez is Professor in the Sibley School of Mechanical and Aerospace Engineering at Cornell University and is an Adjunct Scientist at the Hospital for Special Surgery. Dr. Hernandez is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE), the American Society of Mechanical Engineers (ASME), and the American Society for Bone and Mineral Research (ASBMR). He is the 2018 recipient of the Fuller Albright Award for Scientific Excellence from the American Society for Bone and Mineral Research. He has served on the Board of Directors of the Orthopaedic Research Society and the American Society for Bone and Mineral Research. His laboratory’s research currently focuses on the effects of the microbiome on bone and joint disorders, periprosthetic joint infection and the biomechanics and mechanobiology of bacteria.

hernandezresearch.com

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BE Seminar: “High-throughput Screening of a Combinatorial CAR Co-stimulatory Domain Library” (Kyle Daniels)

Kyle Daniels, PhD

Speaker: Kyle Daniels, Ph.D.
Postdoctoral Scholar, Cellular Molecular Pharmacology
University of California, San Francisco

Date: Thursday, October 22, 2020
Time: 3:00-4:00 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “High-throughput Screening of a Combinatorial CAR Co-stimulatory Domain Library”

Abstract:

CAR T cells—T cells engineered to express a chimeric antigen receptor that redirects their function to a specific antigen—have proven to be an effective therapy for certain B cell cancers, but many issues remain in order to apply CAR T cells to a broader range of cancers. The activity of CAR T cells can be modulated by varying their co-stimulatory domains. Most CARs use co-stimulatory domains from natural proteins such as 41BB or CD28, each of which contains motifs that recruit unique signaling molecules and elicit a corresponding T cell response. One strategy to achieve increased control over T cell function is to engineer synthetic co-stimulatory domains composed of novel combinations of motifs from natural co-stimulatory proteins. We constructed libraries of CARs containing synthetic co-stimulatory domains and screened these library in primary human T cells for the ability to promote proliferation, degranulation, and memory formation. The results of the screens give insights into how signaling motifs dictate cell function and offer clues on how to engineer co-stimulatory domains that promote desired CAR T cell functions.

Bio:

Kyle completed his BS in Biochemistry at University of Maryland-College Park, and did undergraduate research in the lab of Dorothy Beckett where he studied ligand binding to biotin protein ligases. He did his graduate work at Duke University with Terry Oas working to understand the mechanism of coupled binding and folding in the protein subunit of B. subtilis RNase P. He is currently a postdoctoral fellow in Wendell Lim’s lab at UCSF studying how combinations of linear motifs in receptors dictate cell function. He was an HHMI undergraduate researcher, an NSF graduate research fellow, and a Damon Runyon Cancer Research Foundation postdoctoral fellow. His research interests include synthetic biology, how cells process information and make decisions, and cellular therapy. Outside of lab, he enjoys swimming, videogames, and quality time with friends.

See the full list of upcoming Penn Bioengineering fall seminars here.

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BE Seminar: “Predicting the Effects of Engineering Immune Cells Using Systems Biology Modeling” (Stacey Finley, USC)

The Penn Bioengineering virtual seminar series continues on October 1st.

Stacey Finley, PhD

 

Speaker: Stacey Finley, Ph.D.
Gordon S. Marshall Early Career Chair and Associate Professor of Biomedical Engineering and Biological Sciences
University of Southern California

 

Date: Thursday, October 1, 2020
Time: 3:00-4:00 pm
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “Predicting the Effects of Engineering Immune Cells Using Systems Biology Modeling”

Abstract:

Systems biology approaches, including computational models, provide a framework to test biological hypotheses and optimize effective therapeutic strategies to treat human diseases. In this talk, I present recent work in modeling signaling in cancer-targeting immune cells, including CAR T cells at Natural Killer cells. Chimeric antigen receptors (CARs) are comprised of a variety of different activating domains and co-stimulatory domains that initiate signaling required for T cell activation. There is a lack of understanding of the mechanisms by which activation occurs. We apply mathematical modeling to investigate how CAR structure influences downstream T cell signaling and develop new hypotheses for the optimal design of CAR-engineered T cell systems. Natural Killer cells also provide a useful platform for targeting cancer cells. However, NK cells have been shown to exhibit reduced killing ability with prolonged stimulation by cancer cells. We use a combination of mechanistic model, optimal control theory and in silico synthetic biology to investigate strategies to enhance NK cell-mediated killing.

Bio:

Stacey D. Finley is the Gordon S. Marshall Early Career Chair and Associate Professor of Biomedical Engineering at the University of Southern California. Dr. Finley received her B.S. in Chemical Engineering from Florida A & M University and obtained her Ph.D. in Chemical Engineering from Northwestern University. She completed postdoctoral training at Johns Hopkins University in the Department of Biomedical Engineering. Dr. Finley joined the faculty at USC in 2013, and she leads the Computational Systems Biology Laboratory. Dr. Finley has joint appointments in the Departments of Chemical Engineering and Materials Science and Biological Science, and she is a member of the USC Norris Comprehensive Cancer Center. Dr. Finley is also the Director of the Center for Computational Modeling of Cancer at USC. Her research is supported by grants from NSF, NIH, and the American Cancer Society.

Selected honors: 2016 NSF Faculty Early CAREER Award; 2016 Young Innovator by the Cellular and Molecular Bioengineering journal; Leah Edelstein-Keshet Prize from the Society of Mathematical Biology; Junior Research Award from the USC Viterbi School of Engineering; the Hanna Reisler Mentorship Award; 2018 AACR NextGen Star; 2018 Orange County Engineering Council Outstanding Young Engineer

See the full list of upcoming Penn Bioengineering fall seminars here.

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César de la Fuente Wins Inaugural NEMO Prize, Will Develop Rapid COVID Virus Breath Tests

The paper-based tests could be integrated directly into facemasks and provide instant results at testing sites.

Cesar de la Fuente-Nunez, PhD

When Penn Health-Tech announced its Nemirovsky Engineering and Medicine Opportunity, or NEMO Prize, in February, the center’s researchers could only begin to imagine the impact the looming COVID-19 pandemic was about to unleash. But with the promise of $80,000 to support early-stage ideas at the intersection of engineering and medicine, the contest quickly sparked a winning innovation aimed at combating the crisis.

Judges from the University of Pennsylvania’s School of Engineering and Applied Sciences and Perelman School of Medicine awarded its first NEMO Prize to César de la Fuente, PhD, who proposed a paper-based COVID diagnostic system that could capture viral particles on a person’s breath, then give a result in a matter of seconds when taken to a testing site.

Similar tests for bacteria cost less than a dollar each to make. De la Fuente, a Presidential Assistant Professor in the departments of Psychiatry, Microbiology, and Bioengineering, is aiming to make COVID tests at a similar price point and with a smaller footprint so that they could be directly integrated into facemasks, providing further incentive for their regular use.

“Wearing a facemask is vital to containing the spread of COVID because, before you know you’re sick, they block your virus-carrying droplets so those droplets can’t infect others,” de la Fuente says. “What we’re proposing could eventually lead to a mask that can be infected by the virus and let you know that you’re infected, too.”

De la Fuente’s lab has conducted molecular dynamic simulations of the regions of the SARS-COV-2 spike protein (blue) that bind to the human ACE2 receptor (red and yellow).

De la Fuente’s expertise is in synthetic biology and molecular-scale simulations of disease-causing viruses and bacteria. Having such fine-grained computational models of these microbes’ binding sites allow de la Fuente to test them against massive libraries of proteins, seeing which bind best. Other machine learning techniques can then further narrow down the minimum molecular structures responsible for binding, resulting in functional protein fragments that are easier to synthesize and manipulate.

The spike-shaped proteins that give coronaviruses their crown-like appearance and name bind to a human receptor known as ACE2. De la Fuente and his colleagues are now aiming to characterize the molecular elements and environmental factors that would allow for the most precise, reliable detection of the virus.

Read the full story on the Penn Engineering blog.

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BE Seminar Series: March 5th with Tara L. Deans, Ph.D.

Our next Penn Bioengineering seminar will be held this Thursday. We hope to see you there!

Speaker: Tara L. Deans, Ph.D.
Assistant Professor
Biomedical Engineering
University of Utah

Date: Thursday, March 5, 2020
Time: 12:00-1:00 pm
Location: Room 337, Towne Building

Title: “Engineering Stem Cells to Create Novel Delivery Vehicles”

 

Abstract:

Synthetic biology has transformed how cells can be reprogrammed, providing a means to reliably and predictably control cell behavior with the assembly of genetic parts into more complex gene circuits. Using approaches and tools in synthetic biology, we are programming stem cells with novel genetic tools to control genes and pathways that result in changes in stem cell fate decisions, in addition to reprogramming terminally differentiated cells to function as unique therapeutic diagnostic and delivery vehicles.

Bio:

Dr. Tara Deans received her PhD from Boston University in Biomedical Engineering. Following her postdoctoral training at Johns Hopkins University, she became an Assistant Professor in Biomedical Engineering at the University of Utah. Currently, Dr. Deans runs an applied mammalian synthetic biology laboratory where her lab focuses on building novel genetic tools to study the mechanisms of stem cell differentiation for the purpose of directing cell fate decisions. Recently, Dr. Deans received four prestigious awards to support this area of research: the NSF CAREER Award, the Office of Naval Research (ONR) Young Investigator Award, the NIH Trailblazer Award and an NIH Director’s New Innovator Award. In addition to her research, Dr. Deans was recently named a STEM Ambassador in the STEM Ambassador Program (STEMAP) at the University of Utah to engage underrepresented groups in STEM fields.

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BE Seminar Series: February 13th with Jeffrey J. Tabor, Ph.D.

Our next Penn Bioengineering seminar is coming up soon. We hope to see you there!

Jeffrey J. Tabor, Ph.D.

Speaker: Jeffrey J. Tabor, Ph.D.
Associate Professor of Bioengineering and BioSciences
Rice University

Date: Thursday, February 13, 2020
Time: 12:00-1:00 pm
Location: Room 337, Towne Building

 

Title: “Repurposing bacterial two-component systems as sensors for synthetic biology applications”

Abstract:

Two-component systems (TCSs) are the largest family of signal transduction pathways in biology, and a treasure trove of biosensors for engineering applications. Though present in plants and other eukaryotes, TCSs are ubiquitous in bacteria. Bacteria use TCSs to sense everything from metal ions to carbohydrates and light, and activate responses such as biofilm formation, antibiotic-resistance, and virulence. Despite their importance, the vast majority of TCSs remain uncharacterized. The major challenges are that most bacteria cannot be cultured nor genetically manipulated in the laboratory, and that many TCSs are silenced by poorly-understood gene regulatory networks in laboratory conditions. We have recently developed synthetic biology technologies to address these challenges. In particular, we have developed dual inducible promoter systems that allow us simultaneously express both TCS proteins to optimal levels in the model Gram-negative and Gram-positive bacteria E. coli and B. subtilis. In addition, we have developed a method to modularly interchange the DNA-binding domains of response regulator proteins, enabling unknown or silent TCS output promoters to be replaced with well-characterized alternatives. Finally, we have developed a method to rationally tune the amount of input signal required to activate a TCS over several orders of magnitude by introducing mutations that specifically alter the intrinsic phosphatase activity of the sensor histidine kinase protein. Using these methods, we have repurposed cyanobacterial TCSs to function as optogenetic tools with wavelength specificities from the ultraviolet (380 nm) to the near infrared (770 nm), engineered gut bacteria that diagnose colon inflammation in mice, and discovered a novel pH-sensing TCS in the genome of Yersinia pestis, the causative agent of bubonic plague. Additionally, we have constructed a library of >500 uncharacterized TCSs from the human gut microbiome, which we are screening for novel sensors of gut metabolites and diseases in humans. Finally, we are using our methods to develop new anti-virulence compounds that inhibit TCSs that regulate pathogenesis in major human pathogens. Our work is accelerating fundamental microbiological discoveries and has broad applications in synthetic biology.

Bio:

Since coming to Rice in 2010, Tabor’s work at the interface of synthetic chemistry and molecular/cell biology has led to more than 30 peer-reviewed journal publications and five patent applications. Additional awards he has received include a Collaborative Research Award from the John S. Dunn Foundation (2016), a Michel Systems Biology Innovation Award (2013), a Hamill Innovation Award (2011) by Rice’s Institute of Biosciences and Bioengineering, and a National Academies Keck Futures Initiative (NAKFI) award (2009). Tabor is an affiliated investigator of the NSF Synthetic Biology Engineering Research Center (SynBERC), a member of the editorial board of ACS Synthetic Biology, and has served on an NIH study section and five NSF panels. He also co-organized Synthetic Biology 5.0 – the leading conference in the field.

 

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Penn BE Undergrads Make Biology More Accessible with Open-Source Plate Reader

The annual International Genetically Engineered Machine (iGEM) competition challenges students to expand the field of synthetic biology to solve tangible problems. While most iGEM projects involve imbuing microorganisms with useful new traits and adding them to a global toolkit, Penn Engineering students took a unique approach to the iGEM challenge by creating an open-source blueprint for a mechanical instrument that could make biological research more accessible.

Penn Bioengineering undergraduate Andrew Clark and recent graduates Karol Szymula, now a research assistant in Penn’s Complex Systems Lab, and Michael Patterson, now the lab engineer for Penn Bioengineering’s Instructional Laboratories, contributed to the project that originated through the 2017 iGEM challenge. Graduate student Michael Magaraci, who started Penn’s iGEM program as an undergraduate, and Sevile Mannickarottu, director of Instructional Laboratories, also participated. Brian Chow, Assistant Professor in Bioengineering at Penn, who helped create the iGEM competition when he was an MIT graduate student, oversaw the project.

Read the full story at Penn Engineering’s Medium Blog. Media contacts Evan Lerner and Lauren Salig.

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Week in BioE (August 18, 2017)

SynBio
An embryonic stem cell

SynBio News

Synthetic biology (SynBio) is an important field within bioengineering. Now, SynBio and its relationships with nanotechnology and microbiology will get a big boost with a $6 million grant from the National Science Foundation awarded to the lab of Jason Gleghorn, Ph.D., assistant professor of biomedical engineering at the University of Delaware. The grant, which comes from the NSF’s Established Program to Stimulate Competitive Research, will fund research to determine the interactions between a single virus and single microbe, using microfluidics technology so that the lab staff can examine the interactions in tiny droplets of fluid, rather than using pipettes and test tubes. They believe their research could impact healthcare broadly, as well as perhaps help agriculture by increasing crop yields.

While must SynBio research is medical, the technology is now also being used in making commercial products that will compete with other natural or chemically synthesized products. Antony Evans’s company Taxa Biotechnologies has developed a fragrant moss that he hopes can compete against the sprays and other chemicals you see on the store shelves. Using SynBio principles, Taxa isolates the gene in plants causing odor and transplants these genes to a simple moss in a glass terrarium that, with sufficient sunlight, water, carbon dioxide, will provide one of three scents completely naturally. Technically, the mosses are genetically modified organisms (GMOs), but since people aren’t eating them, they aren’t likely to generate the controversy raised by GMO foods. Taxa has also been working on transplanting bioluminescence genes to plants to provide light without requiring electricity, all as a part of a larger green campaign.

A Few Good Brains

A division of the U.S. Department of Defense, the Targeted Neuroplasticity Training (TNT) program of the Defense Advanced Research Projects Agency (DARPA) will fund the research of Stephen Helms Tillery, Ph.D., of the School of Biological & Health Systems Engineering at Arizona State University, who is investigating methods of enhancing cognitive performance using external stimulation. The ASU project is using transdermal electrical neuromodulation to apply electrical stimulation via electrodes placed on the scalp to determine the effects on awareness and concentration. DARPA hopes to obtain insight into how to improve decision making among troops who are actively deployed. The high-stress environment of a military deployment, combined with the fact that soldiers tend to get suboptimal amounts of sleep, leaves them with fatigue that can cloud judgment in moments of life or death. If the DARPA can find a way to alleviate that fatigue and clarify decision-making processes, it would likely save lives.

Circulatory Science

End-stage organ failure can be treated by transplantation, but waiting lists are long and the number of donors still insufficient, so alternatives are continually sought. In the field of regenerative medicine, which is partly dedicated to finding alternatives, scientists at Ohio State have developed a technology called tissue nanotransfection, which can generate any cell type within a patient’s own body. In a paper published in Nature Nanotechnology, professors Chandan Sen and James Lee and their research team describe how they used nanochip technology to reprogram skin cells into vascular cells. After injecting these cells into the injured legs and brains of mice and pigs, they found the cells could help to restore blood flow. The applications to organ systems is potentially limitless.

For cardiac patients whose conditions can be treated without need for a transplant, who make up the vast majority of this cohort,  stents and valve prostheses are crucial tools. However, these devices and the procedures to implant them have high complication rates. Currently, patients receiving prosthetic valves made in part of metal must take blood thinners to prevent clots, and these drugs can greatly diminish quality of life and limit activity, particularly in younger patients. At Cornell, Jonathan Butcher, Ph.D., associate professor of biomedical engineering, is developing a prosthetic heart valve with small niches in the material loaded with biomaterials to maintain normal heart function and prevent clotting. While it has been possible for some time to coat the surface of an implant with a drug or chemical to facilitate its integration and function, these niches allow for a larger depot of such a material to be distributed over a longer period of time, increasing the durability of the positive effects of these procedures.

Smartphone Spectrometry

A number of medical diagnoses are accomplished by testing of bodily fluids, and spectrometry is a key technology in this process. However, spectrometers are expensive and usually not very portable, posing a challenge for health professionals working outside of traditional care settings. Now, a team led by Brian Cunningham, Ph.D., from the University of Illinois, Urbana-Champaign, has published in Lab on a Chip a paper detailing their creation of a smartphone-integrated spectroscope. Called the spectral Transmission-Reflectance-Intensity (TRI)-Analyzer, it uses microfluidics technology to provide point-of-care analysis to facilitate treatment decisions. The authors liken it to a Swiss army knife in terms of versatility and stress that the TRI Analyzer is less a specialized device than a mobile laboratory. The device costs $550, which is several times less than common lab-based instruments.

New Chair at Stanford

Stanford’s Department of Bioengineering has announced that Jennifer Cochran, Ph.D., will begin a five-year term as department chair beginning on September 1. Dr. Cochran arrived at Stanford in 2005 after earning degrees at the University of Delaware and MIT. Cochran has two connections to Penn – she is currently serving as a member of our department advisory board and completed her postdoctoral training in Penn Medicine. Our heartiest congratulations to her!