Penn Nanoparticles are Less Toxic to T Cells Engineered for Cancer Immunotherapy

An artist’s illustration of nanoparticles transporting mRNA into a T cell (blue), allowing the latter to express surface receptors that recognize cancer cells (red). (Credit: Ryan Allen, Second Bay Studios)

New cancer immunotherapies involve extracting a patient’s T cells and genetically engineering them so they will recognize and attack tumors. This type of therapy is not without challenges, however. Engineering a patient’s T cells is laborious and expensive. And when successful, the alterations to the immune system immediately make patients very sick for a short period of time, with symptoms including fever, nausea and neurological effects.

Now, Penn researchers have demonstrated a new engineering technique that, because it is less toxic to the T cells, could enable a different mechanism for altering the way they recognize cancer, and could have fewer side effects for patients.

The technique involves ferrying messenger RNA (mRNA) across the T cell’s membrane via a lipid-based nanoparticle, rather than using a modified HIV virus to rewrite the cell’s DNA. Using the former approach would be preferable, as it only confers a temporary change to the patient’s immune system, but the current standard method for getting mRNA past the cell membrane can be too toxic to use on the limited number of T cells that can be extracted from a patient.

Michael Mitchell, Margaret Billingsley, and Carl June

The researchers demonstrated their technique in a study published in the journal Nano Letters. It was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation of bioengineering in the School of Engineering and Applied Science, and Margaret Billingsley, a graduate student in his lab.

They collaborated with one of the pioneers of CAR T therapy: Carl June, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and the director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine.

Read more at Penn Engineering blog.

Bioengineering Round-Up (January 2020)

by Sophie Burkholder

University of Washington Researchers Engineer a New Way to Study Circulatory Obstruction

Capillaries are one of the most important forms of vasculature in our body, as they allow our blood to transfer nutrients to other parts of our body. But for how much effect capillary functionality can have on our health, their small size makes them extremely difficult to engineer into models for a variety of diseases. Now, researchers at the University of Washington led by Ying Zheng, Ph. D., engineered a three-dimensional microvessel model with living cells to study the mechanisms of microcirculatory obstruction involved with malaria.

Rather than just achieving a physical model of capillaries, these researchers created a model that allowed them to study typical flow and motion through capillaries, before comparing it to deficiencies in this behavior involved with diseases like malaria. The shape of the engineered model is similar to that of an hourglass, allowing the researchers to study instances where red blood cell transit may encounter bottlenecks between the capillaries and other vessels. Using multiphoton technology, Zheng and her team created 100mm capillary models with etched-in channels and a collagen base, to closely model the typical size and rigidity of the vessels. Tested with malaria-infected blood cells, the model showed similar circulatory obstructive behavior to that which occurs in patients, giving hope that this model can be transferred to other diseases involving such obstruction, like sickle cell anemia, diabetes, and cardiovascular conditions.

Understanding a Cell Membrane Protein Could Be the Key to New Cancer Treatments

Almost every cell in the body has integrins, a form of proteins, on its membrane, allowing cells to sense biological information from beyond their membranes while also using this feedback information to initiate signals within cells themselves. Bioengineers at the Imperial College of London recently looked at the way another membrane protein, called syndecan-4, interacts with integrins as a potential form of future cancer treatment. Referred to as “cellular hands” by lead researcher of the study Armando del Rio Hernandez, Ph.D., syndecan-4 sometimes controls the  development of diseases or conditions like cancer and fibrosis. Hernandez and his team specifically studied the ties of syndecan-4 to yes-associated protein (YAP) and enzyme called P13K, both of which are affiliated with qualities of cancer progression like halted apoptosis or cell stiffening. Knowing this, Hernandez and his team hope to continue research into understanding the mechanisms of syndecan-4 throughout the cell, in search of new mechanisms and targets to focus on with future developments of cancer treatments.

A New Medical Device Could Improve Nerve Functionality After Severe Damage

Serious nerve damage remains difficult to repair surgically, often involving the stretching of nerves for localized damage, or the transfer of healthy nerve cells from another part of the body to fill larger gaps in nerve damage. But these imperfect solutions limit the return of full nerve function and movement to the damaged part of the body, and in more serious cases with large areas of nerve damage, can also risk damage in other areas of the body that healthy nerves are borrowed from for treatment. A new study from the University of Pittsburgh published in Science Translational Medicine led by Kacey Marra, Ph. D., has successfully repaired nerve damage in mice and monkeys using a biodegradable tube that releases growth factors called glial-cell-derived neurotrophic factors over time.

Marra and her team showed that this new device restored nerve function up to 80% in nonhuman primates, where current methods of nerve replacement often only achieve 50-60% functionality restoration. The device might have an easier time getting FDA-approval, since it doesn’t involve the use of stem cells in its repair mechanisms. Hoping to start human clinical trials in 2021, Marra and her team hope that the device will help both injured veterans and typical patients with nerve damage, and see potential future applications in facial nerve damage as well.

A New Computational Model Could Improve Treatments for Cancer, HIV, and Autoimmune Diseases

With cancer, HIV, and other autoimmune diseases, the best treatment options for patients are often determined with trial-and-error methods, leading to prolonged instances of ineffective approaches and sometimes unnecessary side effects. A group of researchers led by Wesley Errington, Ph.D., at the University of Minnesota decided to take a computational approach this problem, in an effort to more quickly and efficiently determine the most appropriate treatment for a given patient. Based on parameters controlling interactions between molecules with multiple binding sites, the team’s new model looks primarily at binding strength, linkage rigidity, and size of linkage arrays. Because diseases can often involve issues in molecular binding, the model aimed to model the 78 unique binding configurations for cases of when interacting molecules only have three binding sites, which are often difficult to observe experimentally. This new approach will allow for faster and easier determination of treatments for patients with diseases involving these molecular interactions.

Improved Drug Screening for Glioblastoma Patients

A new microfluidic brain chip from researchers at the University of Houston could help improve treatment evaluations for brain tumors. Glioblastoma patients, who have a five-year survival rate of a little over 5%, are some of the most common patients suffering from malignant brain tumors. This new chip, developed by the lab of Yasemin Akay, Ph.D., can quickly determine cancer drug effectiveness by analyzing a piece of cultured tumor biopsy from a patient by incorporating different chemotherapy treatments through the microfluidic vessels. Overall, Akay and her team found that this new chip holds hope as a future efficient and inexpensive form of drug screening for glioblastoma patients.

People and Places

The brain constructs maps to guide people, not just of physical spaces but also to connect stimuli around them, like conversations and other people. It’s long been known that the brain area responsible for this spatial navigation—the medial temporal lobe—is also involved in recalling memories.

Michael Kahana (left) is principal investigator in the Defense Advanced Research Projects Agency’s RAM program and a professor in the Department of Psychology. Ethan Solomon is an M.D./Ph.D. student in the Department of Bioengineering of the School of Engineering and Applied Science and in the Perelman School of Medicine.

Now, neuroscientists at the University of Pennsylvania have discovered that the signals the brain produces during spatial navigation and episodic memory recall look similar. Low-frequency brain waves called the theta rhythm appear as people jump from one memory to the next, as many prior studies looking only at human navigation have shown. The new findings, which suggest that the brain structures responsible for helping people navigate the world may also “navigate” a mental map of prior experiences, appear in the Proceedings of the National Academy of Sciences.

Read the rest of this story featuring Penn Bioengineering’s Graduate Group member Michael Kahana and M.D./Ph.D. student Ethan Solomon on Penn Today.

The Florida Institute of Technology recently announced plans to start construction in spring 2020 on a new Health Sciences Research Center, set to further establish biomedical engineering and pre-medical coursework and research at the institute. With plans to open the new center in 2022, Florida Tech anticipates increased enrollment in the two programs, and hopes that the center will offer more opportunities in a growing professional field.

Anson Ong, Ph.D., the Associate Dean of Administration and Graduate Programs at the University of Texas at San Antonio, was recently elected to the International College of Fellows of Biomaterials Science and Engineering. With a focus on research in biomaterial implants for orthopaedic applications, Ong’s election to the college honors his advancement and contribution to the field of biomaterials research.

Penn Bioengineers Help Unlock Secrets of Cell Nuclei after Mitosis

By Izzy Lopez

A collaborative study conducted by researchers at the Children’s Hospital of Philadelphia (CHOP), Penn Engineering and Pennsylvania State University has uncovered new information about how chromosomal material in cell nuclei reorganizes itself after cell division.

While a deep understanding of the cell cycle is a cornerstone of biology and health sciences, research into the complex relationship between three-dimensional chromatin structure and gene transcription is still in its infancy. The results of this study will contribute to a more robust understanding of chromatin rebuilding after mitosis and potentially aid in the treatment of genetic diseases.

Jennifer E. Phillips-Cremins, Ph.D.

Jennifer E. Phillips-Cremins, Assistant Professor in the Department of Bioengineering, contributed to the study alongside Gerd A. Blobel, Frank E. Weise III Endowed Chair in Pediatric Hematology at CHOP and Ross C. Hardison, an expert in gene regulation at Penn State.

Phillips-Cremins’ research uses genetic engineering approaches to discover the mechanisms regulating chromatin organizing principles in cells, as well as computational approaches to investigate cellular function. Her lab’s techniques provide ways of mapping the three-dimensional organization of genes while they are folded together in the genome and how those spatial relationships impact gene expression.

The research team performed their experiments in blood-forming cells from a well-established mouse model. They used sophisticated techniques called high throughput chromosome conformation capture (Hi-C) that detect and map interactions across three-dimensional space between specific sites in chromosomal DNA. These maps also allowed the scientists to measure such interactions at different time points in the cell cycle. In all, the tools detected roughly 2 billion interactions during mitosis and thereafter, when the daughter nuclei are rebuilt.

Members of the Cremins Lab, Daniel J. Emerson, Thomas G. Gilgenast and Katelyn R. Titus, also contributed to the study, which was published in Nature.

Read more about this study in CHOP News.

Bioengineering Round-Up (December 2019)

by Sophie Burkholder

Positive results in first-in-U.S. trial of CRISPR-edited immune cells

3D render of the CRISPR-Cas9 genome editing system

Genetically editing a cancer patient’s immune cells using CRISPR/Cas9 technology, then infusing those cells back into the patient appears safe and feasible based on early data from the first-ever clinical trial to test the approach in humans in the United States. Researchers from the Abramson Cancer Center have infused three participants in the trial thus far—two with multiple myeloma and one with sarcoma—and have observed the edited T cells expand and bind to their tumor target with no serious side effects related to the investigational approach. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics.

“This trial is primarily concerned with three questions: Can we edit T cells in this specific way? Are the resulting T cells functional? And are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes,” says the study’s principal investigator Edward A. Stadtmauer, section chief of Hematologic Malignancies at Penn. Stadtmauer will present the findings next month at the 61st American Society of Hematology Annual Meeting and Exposition.

Read the rest of the story on Penn Today.

Tulane researchers join NIH HEAL initiative for research into opioid crisis

A Tulane University professor and researcher of biomedical engineering will join fellow researchers from over 40 other institutions in the National Institute of Health’s Help to End Addiction Long-Term (HEAL) Initiative. Of the $945 million that make up the project, Michael J. Moore, Ph.D. will receive a share of $1.2 million to advance research in modeling human pain through computer chips, with the help of fellow Tulane researchers Jeffrey Tasker, Ph.D., and James Zadina, Ph.D., each with backgrounds in neuroscience.

Because of the opioid epidemic sweeping the nation, Moore notes that there’s a rapid search going on to develop non-addictive painkiller options. However, he also sees a gap in adequate models to test those new drugs before human clinical trials are allowed to take place. Here is where he hopes to step in and bring some innovation to the field, by integrating living human cells into a computer chip for modeling pain mechanisms. Through his research, Moore wants to better understand not only how some drugs can induce pain, but also how patients can grow tolerant to some drugs over time. If successful, Moore’s work will lead to a more rapid and less expensive screening option for experimental drug advancements.

New machine learning-assisted microscope yields improved diagnostics

Researchers at Duke University recently developed a microscope that uses machine learning to adapt its lighting angles, colors, and patterns for diagnostic tests as needed. Most microscopes have lighting tailored to human vision, with an equal distribution of light that’s optimized for human eyes. But by prioritizing the computer’s vision in this new microscope, researchers enable it to see aspects of samples that humans simply can’t, allowing for a more accurate and efficient diagnostic approach.

Led by Roarke W. Horstmeyer, Ph.D., the computer-assisted microscope will diffuse light through a bowl-shaped source, allowing for a much wider range of illumination angles than traditional microscopes. With the help of convolutional neural networks — a special kind of machine learning algorithm — Horstmeyer and his team were able to tailor the microscope to accurately diagnose malaria in red blood cell samples. Where human physicians typically perform similar diagnostics with a rate of 75 percent accuracy, this new microscope can do the same work with 90 percent accuracy, making the diagnostic process for many diseases much more efficient.

Case Western Reserve University researchers create first-ever holographic map of brain

A Case Western Reserve University team of researchers recently spearheaded a project in creating an interactive holographic mapping system of the human brain. The design, which is believed to be the first of its kind, involves the use of the Microsoft HoloLens mixed reality platform. Lead researcher Cameron McIntyre, Ph.D., sees this mapping system as a better way of creating holographic navigational routes for deep brain stimulation. Recent beta tests with the map by clinicians give McIntyre hope that the holographic representation will help them better understand some of the uncertainties behind targeted brain surgeries.

More than merely providing a useful tool, McIntyre’s project also brings together decades’ worth of neurological data that has not yet been seriously studied together in one system. The three-dimensional atlas, called “HoloDBS” by his lab, provides a way of finally seeing the way all of existing neuro-anatomical data relates to each other, allowing clinicians who use the tool to better understand the brain on both an analytical and visual basis.

Implantable cancer traps reduce biopsy incidence and improve diagnostic

Biopsies are one of the most common procedures used for cancer diagnostics, involving a painful and invasive surgery. Researchers at the University of Michigan are trying to change that. Lonnie Shea, Ph.D., a professor of biomedical engineering at the university, worked with his lab to develop implants with the ability to attract any cancer cells within the body. The implant can be inserted through a scaffold placed under the patient’s skin, making it a more ideal option than biopsy for inaccessible organs like lungs.

The lab’s latest work on the project, published in Cancer Research, details its ability to capture metastatic breast cancer cells in vivo. Instead of needing to take biopsies from areas deeper within the body, the implant allows for a much simpler surgical procedure, as biopsies can be taken from the implant itself. Beyond its initial diagnostic advantages, the implant also has the ability to attract immune cells with tumor cells. By studying both types of cells, the implant can give information about the current state of cancer in a patient’s body and about how it might progress. Finally, by attracting tumor and immune cells, the implant has the ability to draw them away from the area of concern, acting in some ways as a treatment for cancer itself.

People and Places

Cesar de la Fuente-Nunez, PhD

The Philadelphia Inquirer recently published an article detailing the research of Penn’s Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering, Cesar de la Fuente, Ph.D. In response to a growing level of worldwide deaths due to antibiotic-resistant bacteria, de la Fuente and his lab use synthetic biology, computation, and artificial intelligence to test hundreds of millions of variations in bacteria-killing proteins in the same experiment. Through his research, de la Fuente opens the door to new ways of finding and testing future antibiotics that might be the only viable options in a world with an increasing level of drug-resistant bacteria

Emily Eastburn, a Ph.D. candidate in Bioengineering at Penn and a member of the Boerckel lab of the McKay Orthopaedic Research Laboratory, recently won the Ashton fellowship. The Ashton fellowship is an award for postdoctoral students in any field of engineering that are under the age of 25, third-generation American citizens, and residents of either Pennsylvania or New Jersey. A new member of the Boerckel lab, having joined earlier this fall, Eastburn will have the opportunity to conduct research throughout her Ph.D. program in the developmental mechanobiology and regeneration that the Boerckel lab focuses on.

Cesar de la Fuente ‘Trends in Immunology’ Literature Review

by Sophie Burkholder

 

Cesar de la Fuente, PhD

Cesar de la Fuente, Ph.D., a Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering at Penn, recently published a literature review in Trends in Immunology entitled, “Emerging Frontiers in Microbiome Engineering.” The microbiome, in simple terms, consists of the genetic material of microorganisms in the gut, including bacteria, fungi, protozoa,  viruses, and oral, vaginal, and skin microbiomes. Each human has a unique microbiome that depends both on predetermined factors like exposure to microorganisms within a mother’s birth canal or breastmilk in early life as well as environmental factors and diet in later life. The health of someone’s microbiome is extremely important, as an unhealthy microbiome with an imbalance of symbiotic and pathogenic microbes can make a person more susceptible to various diseases. The most common diseases or disorders associated with a problematic microbiome are rather far-reaching, including some of the most afflicting diseases of today like inflammatory bowel disease, diabetes, obesity, cardiovascular diseases, and neurological disorders.

In his recent literature review, de la Fuente provides an overview of microbiome engineering, and what the future might hold for the field. He defines microbiome engineering initially as a way of studying the “contribution of individual microbes and generating potential therapies against metabolic, inflammatory, and immunological diseases.” Currently, most treatments for issues with the microbiome are broad solutions like dietary adjustments to include more probiotics, antibiotics, or prebiotics, while more serious cases may require a fecal microbiota transplant. While these therapies may work for some patients, de la Fuente emphasizes the need for greater specificity in treatment targets and a need for precision in reprogramming existing microbial communities as an alternative to transplants.

De la Fuente highlights the current methods and tools in microbiome engineering such as the use of bacteriocins and bacteriophages to knock out specific bacteria within the microbiome. However, there are very few bacteriocins or bacteriophages commercially available on today’s market. Another common approach to microbiome engineering is in synthetic biology, or the use of “chassis” — a type of cell that maintains DNA constructs for different functions — to engineering interactions within the microbiome. De la Fuente continues his discussion of current methods by naming and describing several specific examples of these approaches, particularly in relation to synthetic biology options before moving on to examine future directions for these methods.

Before bringing up potential new frontiers for microbiome engineering, de la Fuente also outlines the way that microbiome engineering works in the first place, and dedicates sections of the review to the microbiome’s influence on its host’s immune system and how to engineer the microbiome to modulate that immune system. The main future methods for microbiome engineering that de la Fuente points out in his review include more precise regulation of gene expression through commensal organisms and the use of CRISPRi to find genes involved in bacterial maintenance. The conclusion of de la Fuente’s review brings up the notion of new personalized medicine or therapy for the microbiome that could come with further advances in the field. However, he also makes sure to bring up some still-outstanding questions about the human microbiome that require further research, most notably, what exactly makes a healthy human microbiome? Here’s hoping the research de la Fuente mentions can illuminate a path to the answer.

Penn Engineers Coax White Blood Cells to Crawl Upstream, Enabling Faster Route to Infections

When the immune system detects a foreign pathogen, a cascade of chemical signals call white blood cells to the scene. Neutrophils are the most common and abundant type of these cells and while they start accumulating at the site of an infection within minutes, they are essentially at the mercy of the circulatory system’s one-way flow of traffic to get them where they need to go.

Now, research from the University of Pennsylvania’s School of Engineering and Applied Science shows how these cells can be coaxed to fight the direction of blood flow, crawling upstream along the walls of veins and arteries.

The in vitro study suggested that this technique could get neutrophils to the sites of infections faster when they are restricted to the direction of blood flow.

Alexander Buffone and Daniel Hammer

Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in the Department of Bioengineering, and Alexander Buffone, Jr., a research associate in his lab, led the research. Nicholas R. Anderson, a graduate student in the Hammer lab, also contributed to the study.

They published their findings in Biophysical Journal.

Read the full post on the Penn Engineering Blog.

How to Build Your Own Makerspace for Under $1500

By Sophie Burkholder

As technology and hands-on activities continue to become a larger part of education at all levels, a new movement of do-it-yourself projects is on the rise. Known as the “MakerSpace Movement,” the idea is that with the use of devices like 3-D printers, laser cutters, and simple circuitry materials, students, classes and communities can apply topics discussed in the classroom to real-life projects. Especially popular among STEM educators, the MakerSpace Movement is one that’s taken over labs in engineering schools around the country. Here at Penn, our own Stephenson Foundation Bioengineering Educational Lab and Bio-MakerSpace is equipped with all of the tools needed to bring student designs to fruition. In particular, the Stephenson Lab is the only lab on Penn’s campus that is open to all students and has both mechanical and electrical rapid prototyping equipment, as well as tools for biological and chemistry work.

Though Penn helps to fund the lab’s operation, many of the technologies and materials used in the Stephenson Lab and Bio-MakerSpace to help students throughout different class and independent projects are actually relatively affordable. Sevile Mannickarottu, Director of the Educational Laboratories, recently presented a paper describing the innovations and opportunities available to students through the MakerSpace attributes of the lab.

The Stephenson Lab mostly looks to support bioengineering majors, particularly in their lab courses and seniors design projects, but also encourages students of all disciplines to use the space for whatever MakerSpace-inspired ideas they might have, whether it be fixing a bike or measuring EMG signals for use in a mechanical engineering design.

Believe it or not, however, some of the best parts of the Bio-MakerSpace can actually be purchased for a total of under $1500. Though that number is probably far beyond the individual budget of most students, it might be more affordable for a student club or dorm floor that receives additional funding from Penn. While the idea of building a MakerSpace from nothing might sound intimidating, the popularity of the movement actually helps to provide a wide range of technology and affordable options.

One of the hallmarks of the MakerSpace at the Stephenson Lab, and of any MakerSpace, is the 3-D printer. Certainly, the highest quality 3-D printers on the market are incredibly expensive, but the ones used in the Stephenson Lab are actually only $750 per printer. Even better, most spools of the PLA filaments used in printers like this one can be found online for under a price of $30 each. With access to free CAD-modeling services like OpenScad and SketchUp, all you need is a computer to start 3-D printing on your own.

But if you can’t afford a 3-D printer, or want to add more electric components to the plastic designs the printer can make, the Stephenson Lab also has NI myDAQ devices, external power sources, wires, resistors, voltage meters, Arduino kits, and other equipment that can all be purchased by students for less than $500.

The most expensive device is the NI myDAQ, which costs $200 for students, but $400 for everyone else. With access to software that includes a digital multimeter, oscilloscope, function generator, Bode analyzer, and several other applications, the myDAQ is essential to any project that involves data with electronic signals. But even without the myDAQ, components like breadboards, wire cutters, resistors, voltage regulators, and all of the other basic elements of circuitry can typically be found online for a total price of under $100.

The Stephenson Lab also provides students with Arduino Kits, which are a combination of hardware and software in circuitry and programming that can be purchased for under $100 from the Arduino website. With sensors, breadboards, and other essential circuit elements, the Arduino Kits also allow users to control their designs through a software code that corresponds to hands-on setup. Particularly for those new to understanding the relationship between codes and circuitry, an Arduino Kit can be a great place to start.

Using all of these items, you can easily start your own MakerSpace for under $1500, especially if you can take advantage of student pricing. At the heart of the MakerSpace movement is the notion that anyone, anywhere can bring their own ideas and innovations to reality with the right equipment. So if you have a project in mind, get started on building your own MakerSpace, with these tools or your own — it’s cheaper than you’d think!

Penn Engineers Devise Easier Way of Sneaking Antibodies into Cells

Getting a complex protein like an antibody through the membrane of a cell without damaging either is a long-standing challenge in the life sciences. Penn Engineers have found a plug-and-play solution that makes antibodies compatible with the delivery vehicles commonly used to ferry nucleic acids across that barrier.

For almost any conceivable protein, corresponding antibodies can be developed to block it from binding or changing shape, which ultimately prevents it from carrying out its normal function. As such, scientists have looked to antibodies as a way of shutting down proteins inside cells for decades, but there is still no consistent way to get them past the cell membrane in meaningful numbers.

Now, Penn Engineering researchers have figured out a way for antibodies to hitch a ride with transfection agents, positively charged bubbles of fat that biologists routinely use to transport DNA and RNA into cells. These delivery vehicles only accept cargo with a highly negative charge, a quality that nucleic acids have but antibodies lack. By designing a negatively charged amino acid chain that can be attached to any antibody without disrupting its function, they have made antibodies broadly compatible with common transfection agents.

Beyond the technique’s usefulness towards studying intracellular dynamics, the researchers conducted functional experiments with antibodies that highlight the technique’s potential for therapeutic applications. One antibody blocked a protein that decreases the efficacy of certain drugs by prematurely ejecting them from cells. Another blocked a protein involved in the transcription process, which could be an even more fundamental way of knocking out proteins with unwanted effects.

Andrew Tsourkas and Hejia Henry Wang

The study, published in the Proceedings of the National Academy of Sciences, was conducted by Andrew Tsourkas, professor in the Department of Bioengineering, and Hejia Henry Wang, a graduate student in his lab.

Read the full story at the Penn Engineering Medium Blog. Media contact Evan Lerner.

Penn Engineers Solve the Paradox of Why Tissue Gets Stiffer When Compressed

The researchers’ experiments involved making synthetic tissues with artificial “cells.” The fibrin network that surrounds these beads pull on them when compressed; by changing the number of beads in their experimental tissues, the researchers could suss out how cell-fiber interplay contributes to the tissue’s overall properties.

Tissue gets stiffer when it’s compressed. That property can become even more pronounced with injury or disease, which is why doctors palpate tissue as part of a diagnosis, such as when they check for lumps in a cancer screening. That stiffening response is a long-standing biomedical paradox, however: tissue consists of cells within a complex network of fibers, and common sense dictates that when you push the ends of a string together, it loosens tension, rather than increasing it.

Now, in a study published in Nature, University of Pennsylvania’s School of Engineering and Applied Science researchers have solved this mystery by better understanding the mechanical interplay between that fiber network and the cells it contains.

The researchers found that when tissue is compressed, the cells inside expand laterally, pulling on attached fibers and putting more overall tension on the network. Targeting the proteins that connect cells to the surrounding fiber network might therefore be the optimal way of reducing overall tissue stiffness, a goal in medical treatments for everything from cancer to obesity.

Headshots of Paul Janmey and Vivek Shenoy

Paul Janmey and Vivek Shenoy

The study was led by Paul Janmey, Professor in the Perelman School of Medicine’s Department of Physiology and in Penn Engineering’s Department of Bioengineering, and Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Materials Science and Engineering, Mechanical Engineering and Applied Mechanics, and Bioengineering, along with Anne van Oosten and Xingyu Chen, graduate students in Janmey’s and Shenoy’s labs. Van Oosten is now a postdoctoral fellow at Leiden University in The Netherlands.

Shenoy is Director of Penn’s Center for Engineering Mechanobiology, which studies how physical forces influence the behavior of biological systems; Janmey is the co-director of one of the Center’s working groups, organized around the question, “How do cells adapt to and change their mechanical environment?”

Together, they have been interested in solving the paradox surrounding tissue stiffness.

Read the full story on the Penn Engineering Medium Blog.

Bioengineering Round-Up (October 2019)

by Sophie Burkholder

Innovations in Advancing a Cure for Diabetes

The blue circle is the global symbol for diabetes. Wikimedia Commons.

Diabetes is one of the more common diseases among Americans today, with the American Diabetes Association estimating that approximately 9.5 percent of the population battles the condition today. Though symptoms and causes may vary across types and patients, diabetes generally results from the body’s inability to produce enough insulin to keep blood sugar levels in check. A new experimental treatment from the lab of Sha Jin, Ph.D., a biomedical engineering professor at Binghamton University, aims to use about $1.2 million in recent federal grants to develop a method for pancreatic islet cell transplantation, as those are the cells responsible for producing insulin.

But the catch to this new approach is that relying on healthy donors of these islet cells won’t easily meet the vast need for them in diabetic patients. Sha Jin wants to use her grants to consider the molecular mechanisms that can lead pluripotent stem cells to become islet-like organoids. Because pluripotent stem cells have the capability to evolve into nearly any kind of cell in the human body, the key to Jin’s research is learning how to control their mechanisms and signaling pathways so that they only become islet cells. Jin also wants to improve the eventual culture of these islet cells into three-dimensional scaffolds by finding ways of circulating appropriate levels of oxygen to all parts of the scaffold, particularly those at the center, which are notoriously difficult to accommodate. If successful in her tissue engineering efforts, Jin will not only be able to help diabetic patients, but also open the door to new methods of evolving pluripotent stem cells into mini-organ models for clinical testing of other diseases as well.

A Treatment to Help Others See Better

Permanently crossed eyes, a medical condition called strabismus, affects almost 18 million people in the United States, and is particularly common among children. For a person with strabismus, the eyes don’t line up to look at the same place at the same time, which can cause blurriness, double vision, and eye strain, among other symptoms. Associate professor of bioengineering at George Mason University, Qi Wei, Ph.D., hopes to use almost $2 million in recent funding from the National Institute of Health to treat and diagnose strabismus with a data-driven computer model of the condition. Currently, the most common method of treating strabismus is through surgery on one of the extraocular muscles that contribute to it, but Wei wants her model to eventually offer a noninvasive approach. Using data from patient MRIs, current surgical procedures, and the outcomes of those procedures, Wei hopes to advance and innovate knowledge on treating strabismus.

A Newly Analyzed Brain Mechanism Could be the Key to Stopping Seizures

Among neurological disorders, epilepsy is one of the most common. An umbrella term for a lot of different seizure-inducing conditions, many versions of epilepsy can be treated pharmaceutically. Some, however, are resistant to the drugs used for treatment, and require surgical intervention. Bin He, Ph. D., the Head of the Department of Biomedical Engineering at Carnegie Mellon University, recently published a paper in collaboration with researchers at Mayo Clinic that describes the way that seizures originating at a single point in the brain can be regulated by what he calls “push-pull” dynamics within the brain. This means that the propagation of a seizure through the brain relies on the impact of surrounding tissue. The “pull” he refers to is of the surrounding tissue towards the seizure onset zone, while the “push” is what propagates from the seizure onset zone. Thus, the strength of the “pull” largely dictates whether or not a seizure will spread. He and his lab looked at different speeds of brain rhythms to perform analysis of functional networks for each rhythm band. They found that this “push-pull” mechanism dictated the propagation of seizures in the brain, and suggest future pathways of treatment options for epilepsy focused on this mechanism.

Hyperspectral Imaging Might Provide New Ways of Finding Cancer

A new method of imaging called hyperspectral imaging could help improve the prediction of cancerous cells in tissue specimens. A recent study from a University of Texas Dallas team of researchers led by professor of bioengineering Baowei Fei, Ph.D., found that a combination of hyperspectral imaging and artificial intelligence led to an 80% to 90% level of accuracy in identifying the presence of cancer cells in a sample of 293 tissue specimens from 102 patients. With a $1.6 million grant from the Cancer Prevention and Research Institute of Texas, Fei wants to develop a smart surgical microscope that will help surgeons better detect cancer during surgery.

Fei’s use of hyperspectral imaging allows him to see the unique cellular reflections and absorptions of light across the electromagnetic spectrum, giving each cell its own specific marker and mode of identification. When paired with artificial intelligence algorithms, the microscope Fei has in mind can be trained to specifically recognize cancerous cells based on their hyperspectral imaging patterns. If successful, Fei’s innovations will speed the process of diagnosis, and potentially improve cancer treatments.

People and Places

A group of Penn engineering seniors won the Pioneer Award at the Rothberg Catalyzer Makerthon led be Penn Health-Tech that took place from October 19-20, 2019. SchistoSpot is a senior design project created by students Vishal Tien (BE ‘20), Justin Swirbul (CIS ‘20), Alec Bayliff (BE ‘20), and Bram Bruno (CIS ‘20) in which the group will design a low-cost microscopy dianostic tool that uses computer vision capabilities to automate the diagnosis of schistosomiasis, which is a common parasitic disease. Read about all the winners here.

Virginia Tech University will launch a new Cancer Research Initiative with the hope of creating an intellectual community across engineers, veterinarians, biomedical researchers, and other relevant scientists. The initiative will focus not only on building better connections throughout departments at the university, but also in working with local hospitals like the Carilion Clinic and the Children’s National Hospital in Washington, D.C. Through these new connections, people from all different areas of science and engineering and come together to share ideas.

Associate Professor of Penn Bioengineering Dani Bassett, Ph.D., recently sat down with the Penn Integrates Knowledge University Professor Duncan Watts, Ph.D., for an interview published in Penn Engineering. Bassett discusses the origins of network science, her research in small-world brain networks, academic teamwork, and the pedagogy of science and engineering. You can read the full interview here.

An all-female group of researchers from Northern Illinois University developed a device for use by occupational therapists that can capture three-dimensional images of a patient’s hand, helping to more accurately measure the hand or wrist’s range of motion. The group presented the abstract for their design at this year’s meeting of the Biomedical Engineering Society here in Philadelphia, where Penn students and researchers presented as well.