We would like to congratulate Penn Bioengineering faculty members Arjun Raj, Ph.D., and Danielle Bassett, Ph.D., on their promotions from associate to full professors.
The Raj lab studies how biological processes work at the level of individual cells. Their work combines quantitative tools from genomics, imaging, biology, math, and computer science to develop models for how individual cells function, and in particular, how these individual cells can behave differently from each other. One major interest is in cancer, in which the lab is studying how individual cells can drive resistance to anti-cancer drugs. He and his lab also have a regularly updated blog discussing general topics related to scientific academia.
The Bassett lab takes an in-depth look at the use of network science and complex systems theory to study computational neuroscience in projects that involve the architecture of knowledge networks, the controllability of brain networks, and the dynamic networks in neuroscience. This fall, she will teach an elective course in network neuroscience open to graduate and undergraduate students that covers the use of network science in understanding overall brain circuitry. Bassett was recently profiled in Science Magazine.
The Drug Delivery Special Interest Group will deal with the science and technology of controlled release of active agents from delivery systems. Controlled drug release is achieved by the use of diffusion, chemical reactions, dissolutions or osmosis, used either singly or in combination. While the vast majority of such delivery devices are based on polymers, controlled release can also be achieved by the use of mechanical pumps. In a broader sense, controlled release also involves control over the site of action of the active agent, using the active agent using pro-drugs, targetable water soluble polymers or various microparticulate systems. Relevant aspects of toxicology, bioavailability, pharmacokinetics, and biocompatibility are also included.
The Society for Biomaterials is an interdisciplinary organization comprised of academic, industry, health care, and governmental professionals dedicated to promoting advancements in all aspects of biomaterial science and engineering, education, and professional standards to enhance human health and quality of life. The Society for Biomaterials was established in 1974, and is the oldest scientific organization in the field of biomaterials.
Mitchell joined the Department of Bioengineering at Penn in 2018 as Skirkanich Assistant Professor of Innovation. Previously, he was an NIH Ruth L. Kirschstein Postdoctoral Fellow with Institute Professor Robert Langer at the Koch Institute for Integrative Cancer Research at MIT. His research interests include biomaterials, drug delivery, and cellular and molecular bioengineering for applications in cancer research, immunotherapy, and gene therapy. Since joining Penn in 2018, Mitchell has received the NIH Director’s New Innovator Award, the Burroughs Wellcome Fund Career Award at the Scientific Interface, a Rising Star Award from the Biomedical Engineering Society, and the T. Nagai Award from the Controlled Release Society.
Mitchell’s new role as the Chair of the SFB’s Drug Delivery Special Interest Group will allow him to lead conversations across academia on the future of drug delivery as it relates to biomaterials. With his fellow officers, Mitchell will help spread knowledge about the field of controlled drug release by hosting research forums, helping to publish news and activities of the SFB in Biomaterials Forum, and foster connections and mentorship among members of his and other Special Interest Groups. We can’t wait to see where Mitchell’s leadership will help take the community of research on areas like toxicology, pharmacokinetics, and biocompatibility next!
DNA Microscopy Gives a Better Look at Cell and Tissue Organization
A new technique that researchers from the Broad Institute of MIT and Harvard University are calling DNA microscopy could help map cells for better understanding of genetic and molecular complexities. Joshua Weinstein, Ph.D., a postdoctoral associate at the Broad Institute, who is also an alumnus of Penn’s Physics and Biophysics department and former student in Penn Bioengineering Professor Ravi Radhakrishnan’s lab, is the first author of this paper on optics-free imaging published in Cell.
The primary goal of the study was to find a way of improving analysis of the spatial organization of cells and tissues in terms of their molecules like DNA and RNA. The DNA microscopy method that Weinstein and his team designed involves first tagging DNA, and allowing the DNA to replicate with those tags, which eventually creates a cloud of sorts that diffuses throughout the cell. The DNA tags subsequent interactions with molecules throughout the cell allowed Weinstein and his team to calculate the locations of those molecules within the cell using basic lab equipment. While the researchers on this project focused their application of DNA microscopy on tracking human cancer cells through RNA tags, this new method opens the door to future study of any condition in which the organization of cells is important.
Penn Engineers Demonstrate Superstrong, Reversible Adhesive that Works like Snail Slime
If you’ve ever pressed a picture-hanging strip onto the wall only to realize it’s slightly off-center, you know the disappointment behind adhesion as we typically experience it: it may be strong, but it’s mostly irreversible. While you can un-stick the used strip from the wall, you can’t turn its stickiness back on to adjust its placement; you have to start over with a new strip or tolerate your mistake. Beyond its relevance to interior decorating, durable, reversible adhesion could allow for reusable envelopes, gravity-defying boots, and more heavy-duty industrial applications like car assembly.
Such adhesion has eluded scientists for years but is naturally found in snail slime. A snail’s epiphragm — a slimy layer of moisture that can harden to protect its body from dryness — allows the snail to cement itself in place for long periods of time, making it the ultimate model in adhesion that can be switched on and off as needed. In a new study, Penn Engineers demonstrate a strong, reversible adhesive that uses the same mechanisms that snails do.
Low-Dose Radiation CT Scans Could Be Improved by Machine Learning
Machine learning is a type of artificial intelligence growing more and more popular for applications in bioengineering and therapeutics. Based on learning from patterns in a way similar to the way we do as humans, machine learning is the study of statistical models that can perform specific tasks without explicit instructions. Now, researchers at Rensselaer Polytechnic Institute (RPI) want to use these kinds of models in computerized tomography (CT) scanning by lowering radiation dosage and improving imaging techniques.
A recent paper published in Nature Machine Intelligence details the use of modularized neural networks in low-dose CT scans by RPI bioengineering faculty member Ge Wang, Ph.D., and his lab. Since decreasing the amount of radiation used in a scan will also decrease the quality of the final image, Wang and his team focused on a more optimized approach of image reconstruction with machine learning, so that as little data as possible would be altered or lost in the reconstruction. When tested on CT scans from Massachusetts General Hospital and compared to current image reconstruction methods for the scans, Wang and his team’s method performed just as well if not better than scans performed without the use of machine learning, giving promise to future improvements in low-dose CT scans.
A Mind-Controlled Robotic Arm That Requires No Implants
A new mind-controlled robotic arm designed by researchers at Carnegie Mellon University is the first successful noninvasive brain-computer interface (BCI) of its kind. While BCIs have been around for a while now, this new design from the lab of Bin He, Ph.D., a Trustee Professor and the Department Head of Biomedical Engineering at CMU, hopes to eliminate the brain implant that most interfaces currently use. The key to doing this isn’t in trying to replace the implants with noninvasive sensors, but in improving noisy EEG signals through machine learning, neural decoding, and neural imaging. Paired with increased user engagement and training for the new device, He and his team demonstrated that their design enhanced continuous tracking of a target on a computer screen by 500% when compared to typical noninvasive BCIs. He and his team hope that their innovation will help make BCIs more accessible to the patients that need them by reducing the cost and risk of a surgical implant while also improving interface performance.
KIChE is an organization that aims “to promote constructive and mutually beneficial interactions among Korean Chemical Engineers in the U.S. and facilitate international collaboration between engineers in U.S. and Korea.”
We would also like to congratulate Natalia Trayanova, Ph.D., of the Department of Biomedical Engineering at Johns Hopkins University on being inducted into the Women in Tech International (WITI) Hall of Fame. Beginning in 1996, the Hall of Fame recognizes significant contributions to science and technology from women. Trayanova’s research specializes in computational cardiology with a focus on virtual heart models for the study of individualized heart irregularities in patients. Her research helps to improve treatment plans for patients with cardiac problems by creating virtual simulations that help reduce uncertainty in either diagnosis or courses of therapy.
Every cell in your body has a copy of your genome, tightly coiled and packed into its nucleus. Since every copy is effectively identical, the difference between cell types and their biological functions comes down to which, how and when the individual genes in the genome are expressed, or translated into proteins.
Scientists are increasingly understanding the role that genome folding plays in this process. The way in which that linear sequence of genes are packed into the nucleus determines which genes come into physical contact with each other, which in turn influences gene expression.
Jennifer Phillips-Cremins, assistant professor in Penn Engineering’s Department of Bioengineering, is a pioneer in this field, known as “3-D Epigenetics.” She and her colleagues have now demonstrated a new technique for quickly creating specific folding patterns on demand, using light as a trigger.
The technique, known as LADL or light-activated dynamic looping, combines aspects of two other powerful biotechnological tools: CRISPR/Cas9 and optogenetics. By using the former to target the ends of a specific genome fold, or loop, and then using the latter to snap the ends together like a magnet, the researchers can temporarily create loops between exact genomic segments in a matter of hours.
The ability to make these genome folds, and undo them, on such a short timeframe makes LADL a promising tool for studying 3D-epigenetic mechanisms in more detail. With previous research from the Phillips-Cremins lab implicating these mechanisms in a variety of neurodevelopmental diseases, they hope LADL will eventually play a role in future studies, or even treatments.
Alongside Phillips-Cremins, lab members Ji Hun Kim and Mayuri Rege led the study, and Jacqueline Valeri, Aryeh Metzger, Katelyn R. Titus, Thomas G. Gilgenast, Wanfeng Gong and Jonathan A. Beagan contributed to it. They collaborated with associate professor of Bioengineering Arjun Raj and Margaret C. Dunagin, a member of his lab.
“In recent years,” Phillips-Cremins says, “scientists in our fields have overcome technical and experimental challenges in order to create ultra-high resolution maps of how the DNA folds into intricate 3D patterns within the nucleus. Although we are now capable of visualizing the topological structures, such as loops, there is a critical gap in knowledge in how genome structure configurations contribute to genome function.”
In order to conduct experiments on these relationships, researchers studying these 3D patterns were in need of tools that could manipulate specific loops on command. Beyond the intrinsic physical challenges — putting two distant parts of the linear genome in physical contact is quite literally like threading a needle with a thread that is only a few atoms thick — such a technique would need to be rapid, reversible and work on the target regions with a minimum of disturbance to neighboring sequences.
The advent of CRISPR/Cas9 solved the targeting problem. A modification of the gene editing tool allowed researchers to home in on the desired sequences of DNA on either end of the loop they wanted to form. If those sequences could be engineered to seek one another out and snap together under the other necessary conditions, the loop could be formed on demand.
Cremins Lab members then sought out biological mechanisms that could bind the ends of the loops together, and found an ideal one in the toolkit of optogenetics. The proteins CIB1 and CRY2, found in Arabidopsis, a flowering plant that’s a common model organism for geneticists, are known to bind together when exposed to blue light.
“Once we turn the light on, these mechanisms begin working in a matter of milliseconds and make loops within four hours,” says Rege. “And when we turn the light off, the proteins disassociate, meaning that we expect the loop to fall apart.”
“There are tens of thousands of DNA loops formed in a cell,” Kim says. “Some are formed slowly, but many are fast, occurring within the span of a second. If we want to study those faster looping mechanisms, we need tools that can act on a comparable time scales.”
Fast acting folding mechanisms also have an advantage in that they lead to fewer perturbations of the surrounding genome, reducing the potential for unintended effects that would add noise to an experiment’s results.
The researchers tested LADL’s ability to create the desired loops using their high-definition 3D genome mapping techniques. With the help of Arjun Raj, an expert in measuring the activity of transcriptional RNA sequences, they also were able to demonstrate that the newly created loops were impacting gene expression.
The promise of the field of 3D-epigenetics is in investigating the relationships between these long-range loops and mechanisms that determine the timing and quantity of the proteins they code for. Being able to engineer those loops means researchers will be able to mimic those mechanisms in experimental conditions, making LADL a critical tool for studying the role of genome folding on a variety of diseases and disorders.
“It is critical to understand the genome structure-function relationship on short timescales because the spatiotemporal regulation of gene expression is essential to faithful human development and because the mis-expression of genes often goes wrong in human disease,” Phillips-Cremins says. “The engineering of genome topology with light opens up new possibilities to understanding the cause-and-effect of this relationship. Moreover we anticipate that, over the long term, the use of light will allow us to target specific human tissues and even to control looping in specific neuron subtypes in the brain.”
The research was supported by the New York Stem Cell Foundation; Alfred P. Sloan Foundation; the National Institutes of Health through its Director’s New Innovator Award from the National Institute of Mental Health, grant no. 1DP2MH11024701, and a 4D Nucleome Common Fund, grant no. 1U01HL1299980; and the National Science Foundation through a joint NSF-National Institute of General Medical Sciences grant to support research at the interface of the biological and mathematical sciences, grant no. 1562665, and a Graduate Research Fellowship, grant no. DGE-1321851.
“It’s part of our ethos that technology can and should be a force for good. Our annual list of 35 innovators under 35 is a way of putting faces on that idea,” reads the 2019 award announcement. “This year’s list shows that even in our hard, cynical world, there are still lots of smart people willing to dedicate their lives to the idea that technology can make a safer, fairer world.”
De la Fuente was named in the list’s “Pioneers” category for his work researching antibiotics with a computational approach. Using algorithms, he creates artificial antibiotics to better understand how bacteria will evolve and how scientists can optimize treatments. De la Fuente, who was also recently featured in GEN’s Top 10 Under 40 list, further expands his search for medical solutions by extensively studying a variety of proteins, searching for molecules to develop into antimicrobials.
Included in the honor of being named on the 2019 Innovators List is an invitation for de la Fuente to speak at the EmTech MIT conference in September, an event that reflects on the potential impacts of the year’s biggest developments.
The NAE describes the Frontiers of Engineering program as one that “brings together outstanding early-career engineers from industry, academia, and government to discuss pioneering technical work and leading-edge research in various engineering fields and industry sectors. The goal is to facilitate interactions and exchange of techniques and approaches across fields and facilitate networking among the next generation of engineering leaders.”
Bassett and Tsourkas fit the grant’s description, as their proposed research requires them to combine their different areas of expertise to push the state of the art in engineering. The pair plans to engineer a new class of nanoparticles that can sense and differentially react to particular chemicals in their biochemical environment. This new class of nanoparticles could allow scientists to better study cellular processes and could eventually have important applications in medicine, potentially allowing for more personalized diagnoses and targeted treatment of disease.
To design and create this type of nanoparticle is no small task. The research demands Bassett’s background in engineering quantum-mechanical systems for use as environmental sensors, and Tsourkas’ ability to apply these properties to nanoscale “theranostic” agents, which are designed to target treatments based on a patient’s specific diagnostic test results.
By combining forces, Bassett and Tsourkas hope to introduce a new nanoparticle tool into their fields and to connect even more people in their different areas to promote future interdisciplinary work.
Chip Diagnostics is a Philadelphia-based device company founded in 2016 based on research from the lab of David Issadore, Assistant Professor of Bioengineering and Electrical and Systems Engineering in the School of Engineering and Applied Science. The startup combines microelectronics, microfluidics, and nanomaterials with the aim to better diagnose cancer. The company is developing technologies and digital assays for minimally-invasive early cancer detection and screening that can be done using mobile devices.
There has been a long interest in diagnosing cancer using blood tests by looking for proteins, cells, or DNA molecules shed by tumors, but these tests have not worked well for many cancers since the molecules shed tend to be either nonspecific or very rare.
Issadore’s group aims to target different particles called exosomes: Tiny particles shed by cells that contain similar proteins and RNA as the parent cancer cell. The problem, explains Issadore, is that because of the small size of the exosomes, conventional methods such as microscopy and flow cytometry wouldn’t work. “As an engineering lab, we saw an opportunity to build devices on a nanoscale that could specifically sort the cancer exosomes versus the background exosomes of other cells,” he explains.
After Issadore was approached by the IP group at PCI Ventures in the early stages of their research, Chip Diagnostics has since made huge strides as a company. Now, as the awardee of the JPOD @ Philadelphia QuickFire Challenge, Chip Diagnostics will receive $30,000 in grant funding to further develop the first-in-class, ultra-high-definition exosomal-based cancer diagnostic. The award also includes one year of residency at Pennovation Works as well as access to educational programs and mentoring provided by Johnson & Johnson Family of Companies global network of experts.
To treat large gaps in long bones, like the femur, which result from bone tumor removal or a shattering trauma, researchers at Penn Medicine and the University of Illinois at Chicago developed a process that partially recreates the bone growth process that occurs before birth. A bone defect of more than two centimeters is considered substantial, and current successful healing rates stand at 50% or less, with failure often resulting in amputation. The team hopes that their method, which they’ve developed in rodent models to mimic the process of rapid fetal bone growth, can substantially improve success rates. Their findings are published in Science Translational Medicine.
“When bones are originally formed in the embryo, they’re first generated from cartilage, like a template,” says senior author Joel Boerckel, an assistant professor of orthopaedic surgery and bioengineering. “In order to regenerate bone within defects that otherwise won’t heal in grown people, we are seeking to recreate the embryonic bone development process.”
To do that, the researchers’ process begins with the delivery of specially engineered stem cells (called a condensation of mesenchymal cells) to the rodents’ bone defect, which sparks endochondral ossification, the specific term for embryonic bone development.
Bio-inspiration Informs New Football Helmet Design from IUPUI Students
Art, design, biology, and engineering all interact with each other in a recent design for a football helmet from two students— one of media arts and the other of engineering — at the Indiana University – Purdue University Indianapolis. Directed by Lecturer in Media Arts and Science Zebulun Wood, M.S., and Associate Professor of Mechanical and Energy Engineering and Assistant Professor of Biomedical Engineering Andres Tovar, Ph.D., the students found inspiration in biological structures like a pomelo peel, nautilus shell, and woodpecker skull to create energy-absorbing helmet liners. The resulting design took these natural concussion-reducing structures and created compliant mechanism lattice-based liners the replace the foam traditionally placed in between two harder shells of a typical helmet. Their work not only exemplifies the benefits of bio-inspiration, but demonstrates the way that several different domains of study can overlap in the innovation of a new product.
Study of Mechanical Properties of Hyaluronic Acid Could Help Inform Current Debates Over Treatment Regulation for Osteoarthritis
Arthritis is an extremely common condition, especially in older patients, in which inflammation of the joints can cause high amounts of stiffness and pain. Osteoarthritis in particular is the result of the degradation of flexible tissue between the bones of a joint, which increases friction in joint motion. A common treatment of this form of arthritis is the injection of hyaluronic acid, which is meant to provide joint lubrication, and decreases this friction between bones. Recently, however, there has been a debate over hyaluronic acid’s classification by the FDA and whether it should remain based on the knowledge of the mechanical actions of the acid in treatment for osteoarthritis or if potential chemical action of the acid should be considered as well.
Because of limited ways of testing the mechanical properties of the acid, many researchers felt that there could be more to hyaluronic acid’s role in pain relief for arthritic patients. But Lawrence Bonassar, Ph.D., the Daljit S. and Elaine Sarkaria Professor in Biomedical Engineering at the Meinig School of Bioengineering of Cornell University, had another idea. With his lab, he created a custom-made tribometer to measure the coefficient of friction of a given lubricant by rubbing a piece of cartilage back and forth across a smooth glass plate. The research demonstrated that hyaluronic acid’s ability to reduce the coefficient of friction aligned with patients’ pain relief. Bonassar and his team hope that these results will demonstrate the heavy contribution of mechanical action that hyaluronic acid has in osteoarthritis treatment, and help bring an end to the debate over its FDA classification.
A New Way of Mapping the Heart Could Lead to Better Understanding of Contractile Activity
Celebrity Cat Lil Bub Helps Penn and German Researchers Draw Public Attention to Genetics
In 2015, a group of curious researchers set out to sequence the genome of a celebrity cat named Lil Bub. They were hoping to understand the genetics behind Lil Bub’s extra toes and unique skeletal structure, which contribute to her heart-warming, kitten-like appearance. However, an equally important goal of their “LilBUBome” project was to invite the general public into the world of genetics.
Because of Lil Bub’s online fame, the project garnered attention from her fans and the media, all hoping to discover the secret to Lil Bub’s charm. As early as 2015, Gizmodo’s Kiona Smith-Strickland reported on the team’s intentions to sequence Lil Bub’s genome, and, since then, many have been awaiting the results of the LilBUBome.
We would like to congratulate Jean Paul Allain, Ph.D., on being named the first head of the new Ken and Mary Alice Lindquist Department of Nuclear Engineering at Penn State. Allain, who is currently a Professor and head of graduate programs in the University of Illinois at Urbana-Champaign’s Department of Nuclear, Plasma, and Radiological Engineering, conducts research in models of particle-surface interactions. In addition to being head of the new department at Penn State, Allain will also hold a position as a Professor of Biomedical Engineering at the university.
We would also like to congratulate Andrew Douglas, Ph.D., on his appointment as the Vice Provost for Faculty Affairs at Johns Hopkins University. Douglas currently holds the position of Vice Dean for Faculty at the Whiting School of Engineering, and has joint appointments in Mechanical and Biomedical Engineering. Douglas’s research at Hopkins focuses on mechanical properties and responses of compliant biological tissue and on the nonlinear mechanics of solids, with a focus on soft tissues and organs like the heart and tongue.
Dan Huh, the Wilf Family Term Assistant Professor in the Department of Bioengineering, focuses his research on creating organs-on-chips: specially manufactured micro-devices with human cells that mimic the natural cellular processes of organs. Huh’s lab has engineered chips that approximate the functioning of placentas and lung disease, some of which were launched into space in May. Most recently, Huh published a review of organ-on-a-chip technology in the journal Science with graduate students Sunghee Estelle Park and Andrei Georgescu.
The June 2019 issue of Science is a special issue centered around the science of growing human organ models in the laboratory. Such in vitro organs are known as organoids; they grow and develop much like organs do in the body, as opposed to Huh’s organs-on-chips, in which cells from the relevant organs are grown within a fabricated device that imitates some of the organ’s functions and natural environment.
In a video accompanying the review article, Huh explains how organoid and organ-on-a-chip technologies differ and the advantages that accompany each approach:
Unlike Organ-on-a-Chip, which are heavily engineered man-made systems, organoids allow us to mimic the complex of the human body in a more natural way. So organoids represent a more realistic model, but they have problems because they develop in a highly variable fashion and it’s not very easy to control their environment. So we think that Organ-on-a-Chip Technology is a promising solution to many of these problems.
Read Huh, Park, and Georgescu’s review article at Science.