Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy. The proof-of-concept study, published today in Science Advances, engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.
“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”
Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, is the other co-senior author of the study. The co-first authors are Mitchell Lab members Rachel Riley, a postdoctoral fellow, and Margaret Billingsley, a graduate student, and Peranteau Lab member Meghana Kashyap, a research fellow.
Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.
The nature of scientific progress is often summarized by the Isaac Newton quotation, “If I have seen further it is by standing on the shoulders of giants.” Each new study draws on dozens of earlier ones, forming a chain of knowledge stretching back to Newton and the scientific giants his work referenced.
Scientific publishing and referencing has become more formal since Newton’s time, with databases of citations allowing for sophisticated quantitative analyses of that flow of information between researchers.
The Institute for Scientific Information and the Web of Science Group provide a yearly snapshot of this flow, publishing a list of the researchers who are in the top 1 percent of their respective fields when it comes to the number of times their work has been cited.
Danielle Bassett, J. Peter Skirkanich Professor in the departments of Bioengineering and Electrical and Systems Engineering, and Jason Burdick, Robert D. Bent Professor in the department of Bioengineering, are among the 6,389 researchers named to the 2020 list.
Bassett is a pioneer in the field of network neuroscience, which incorporates elements of mathematics, physics, biology and systems engineering to better understand how the overall shape of connections between individual neurons influences cognitive traits. Burdick is an expert in tissue engineering and the design of biomaterials for regenerative medicine; by precisely tailoring the microenvironment within these materials, they can influence stem cell differentiation or trigger the release of therapeutics.
The Chan Zuckerberg Initiative’s Collaborative Pairs Pilot Project Award is part of its Neurodegeneration Challenge Network
More than 30 inherited disorders are caused by the unstable expansion of repetitive DNA sequences, including Huntington’s disease, ALS, Fragile X syndrome, and Friedreich’s ataxia. Jennifer E. Phillips-Cremins, associate professor in Penn Engineering’s Department of Bioengineering and in the Perelman School of Medicine’s Department of Genetics, has shown another link between these disorders: the location of these expanding genes relative to the complicated folding patterns the genome exhibits to fit inside the nucleus of a cell.
Now, Phillips-Cremins is among 60 researchers taking part in a $4.5 Million Chan Zuckerberg Initiative project that aims to apply novel, interdisciplinary approaches toward investigating neurodegenerative disorders. The CZI Collaborative Pairs Pilot Project will fund 30 teams that combine clinical and basic science expertise and have at least one early- or mid-career researcher.
The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. Further information about the program can be found on the NSF website. BE is thrilled to congratulate our excellent students on these well-deserved accolades! Continue reading below for a list of 2020 recipients and descriptions of their research.
William Benman is a Ph.D. student in the lab of Assistant Professor of Bioengineering, Lukasz Bugaj. His work in the Bugaj lab focuses on developing novel optogenetic tools to control and study cell function.
Paul Gehret is a Ph.D. student and Ashton Fellow in the lab of Riccardo Gottardi, Assistant Professor of Pediatrics at the Perelman School of Medicine. Paul works on pediatric cartilage and airway tissue engineering for children with subglottic stenosis. He and his team apply classic tissue engineering principles to the airway.
Rebecca Haley is a Ph.D. student in the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering. Her current project aims to use polymer and/or lipid nanoparticles for the intracellular delivery of proteins. Successful delivery of proteins (such as antibodies) in this fashion may allow for targeting of previously undruggable intracellular targets.
Patrick John Mulcahey is a Research Assistant and Graduate Student in the Children’s Hospital of Philadelphia (CHOP) Epilepsy Research Lab of Douglas A. Coulter, Professor of Pediatrics at the Perelman School of Medicine. His work focuses on developing techniques that combine electrophysiology with two-photon excitation microscopy to study a potential biomarker of the seizure onset zone in models of drug-refractory epilepsy.
Catherine Porter is a Ph.D. student in the lab of Alex J. Hughes, Assistant Professor of Bioengineering. She is working on developing high-throughput methods to produce and characterize human-cell-derived kidney organoids for disease modeling and genetic screening. Currently, she is focused on engineering physicochemical control to improve organoid homogeneity.
Sarah Shepherd is a Ph.D. student who is co-advised in the Michael J. Mitchell lab and the lab of David Issadore, Associate Professor of Bioengineering and Electrical and Systems Engineering (ESE). Her research aims to combine microfabrication with biomaterial design of lipid nanoparticles to address major shortcomings in the field of nanomedicine. Currently, she is prototyping a scale-up microfluidic device to produce lipid nanoparticles for gene therapy.
Spencer Glantz, a graduate of the Penn Bioengineering doctoral program and former member of the Brian Chow Lab, was mentioned in a recent WHYY piece highlighting the efforts of Penn labs to develop rapid, at-home testing for COVID-19. Glantz is currently a co-leader of the molecular biology team for 4Catalyzer, a medical device incubator founded by National Medal of Technology and Innovation recipient, and sponsor of the annual Rothberg Catalyzer Makerthon competition, Jonathan Rothberg. 4Catalyzer is developing the testing technology while Penn researchers are working to evaluate its effectiveness.
Medical researchers have long been baffled by the need to find safe and effective treatment for a common condition called temporomandibular joint dysfunction (TMD). Affecting around twenty-five percent of the adult population worldwide, TMD appears overwhelmingly in adolescent, premenopausal women. Many different factors such as injury, arthritis, or grinding of the teeth can lead to the disintegration of or damage to the temporomandibular joint (TMJ), which leads to TMD, although the root cause is not always clear. A type of temporomandibular disorder, TMD can result in chronic pain in the jaw and ears, create difficulty eating and talking, and even cause occasional locking of the joint, making it difficult to open or close one’s mouth. Surgery is often considered a last resort because the results are often short-lasting or even dangerous.
The state of TMD treatment may change with the publication of a study in Science Translational Medicine. With contributions from researchers at the University of California, Irvine (UCI), UC Davis, and the University of Texas School of Dentistry at Houston, this new study has successfully implanted engineered discs made from rib cartilage cells into a TMJ model. The biological properties of the discs are similar enough to native TMJ cells to more fully reduce further degeneration of the joint as well as potentially pave the way for regeneration of joints with TMD.
Senior author Kyriacos Athanasiou, PhD, Distinguished Professor of Biomedical Engineering at UCI, states the next steps for the team of researchers include a long-term study to ensure ongoing effectiveness and safety of the implants followed by eventual clinical trials. In the long run, this technique may also prove useful and relevant to the treatment of other types of arthritis and joint dysfunction.
Advances in Autism Research
Currently, diagnosis of autism spectrum disorders (ASD) has been limited entirely to clinical observation and examination by medical professionals. This makes the early identification and treatment of ASD difficult as most children cannot be accurately diagnosed until around the age of four, delaying the treatment they might receive. A recent study published in the journal of Bioengineering & Translational Medicine, however, suggests that new blood tests may be able to identify ASD with a high level of accuracy, increasing the early identification that is key to helping autistic children and their families. The researchers, led by Juergen Hahn, PhD, Professor and Department Head of Biomedical Engineering at the Rensselaer Polytechnic Institute, hope that after clinical trials this blood test will become commercially available.
In addition to work that shows methods to detect autism earlier, the most recent issue of Nature Biomedical Engineering includes a study to understand the possible causes of autism and, in turn, develop treatments for the disease. The breakthrough technology of Cas9 enzymes allowed researchers to edit the genome, correcting for symptoms that appeared in mice which resembled autism, including exaggerated and repetitive behaviors. This advance comes from a team at the University of California, Berkeley, which developed the gene-editing technique known as CRISPR-Gold to treat symptoms of ASD by injecting the Cas9 enzyme into the brain without the need for viral delivery. The UC Berkeley researchers suggest in the article’s abstract that these safe gene-editing technologies “may revolutionize the treatment of neurological diseases and the understanding of brain function.” These treatments may have practical benefits for the understanding and treatment of such diverse conditions as addiction and epilepsy as well as ASD.
Penn Professor’s Groundbreaking Bioengineering Technology
Our own D. Kacy Cullen, PhD, was recently featured in Penn Today for his groundbreaking research which has led to the first implantable tissue-engineered brain pathways. This technology could lead to the reversal of certain neurodegenerative disorders, such as Parkinson’s disease.
With three patents, at least eight published papers, $3.3 million in funding, and a productive go with the Penn Center for Innovation’s I-Corps program this past fall, Dr. Cullen is ready to take this project’s findings to the next level with the creation of a brand new startup company: Innervace. “It’s really surreal to think that I’ve been working on this project, this approach, for 10 years now,” he says. “It really was doggedness to just keep pushing in the lab, despite the challenges in getting extramural funding, despite the skepticism of peer reviewers. But we’ve shown that we’re able to do it, and that this is a viable technology.” Several Penn bioengineering students are involved in the research conducted in Dr. Cullen’s lab, including doctoral candidate Laura Struzyna and recent graduate Kate Panzer, who worked in the lab all four years of her undergraduate career.
In addition to his appointment as a Research Associate Professor of Neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, Dr. Cullen also serves as a member of Penn’s Department of Bioengineering Graduate Group Faculty, and will teach the graduate course BE 502 (From Lab to Market Place) for the BE Department this fall 2018 semester. He also serves as the director for the Center of Neurotrauma, Neurodegeneration, and Restoration at the VA Medical Center.
New Prosthetics Will Have the Ability to Feel Pain
New research from the Department of Biomedical Engineering at Johns Hopkins University (JHU) has found a way to address one of the difficult aspects of amputation: the inability for prosthetic limbs to feel. This innovative electronic dermis is worn over the prosthetic, and can detect sensations (such as pain or even a light touch), which are conveyed to the user’s nervous system, closing mimicking skin. The findings of this study were recently published in the journal ScienceRobotics.
While one might wonder at the value of feeling pain, both researchers and amputees verify that physical sensory reception is important both for the desired realism of the prosthetic or bionic limb, and also to alert the wearer of any potential harm or damage, the same way that heat can remind a person to remove her hand from a hot surface, preventing a potential burn. Professor Nitish Thakor, PhD, and his team hope to make this exciting new technology readily available to amputees.
People and Places
Women are still vastly outnumbered in STEM, making up only twenty percent of the field, and given the need for diversification, researchers, educators, and companies are brainstorming ways to proactively solve this problem by promoting STEM subjects to young women. One current initiative has been spearheaded by GE Healthcare and Milwaukee School of Engineering University (MSOE) who are partnering to give middle school girls access to programs in engineering during their summer break at the MSOE Summer STEM Camp, hoping to reduce the stigma of these subjects for young women. GE Girls also hosts STEM programs with a number of institutions across the U.S.
The National Science Policy Network (NSPN) “works to provide a collaborative resource portal for early-career scientists and engineers involved in science policy, diplomacy, and advocacy.” The NSPN offers platforms and support including grant funding, internships, and competitions. Chaired and led by emerging researchers and professors from around the country, including biomedical engineering PhD student Michaela Rikard of the University of Virginia, the NSPN seeks to provide a network for young scientists in the current political climate in which scientific issues and the very importance of the sciences as a whole are hotly contested and debated by politicians and the public. The NSPN looks to provide a way for scientists to have a voice in policy-making. This new initiative was recently featured in the Scientific American.
Upon its original founding in 2000, the Bill and Melinda Gates Foundation has included the eradication of malaria as part of its mission, pledging around $2 billion to the cause in the years since. One of its most recent initiatives is the funding of a bioengineering project which targets the type of mosquitoes which carry the deadly disease. Engineered mosquitoes (so-called “Friendly Mosquitoes”) would mate in the wild, passing on a mosquito-killing gene to their female offspring (only females bite humans) before they reach maturity. While previous versions of “Friendly Mosquitoes” have been met with success, concerns have been raised about the potential long-term ecological effects to the mosquito population. UK-based partner Oxitec expects to have the new group ready for trials in two years.
Konrad Kording, professor in the Department of Bioengineering, and colleagues have a new technique for identifying fraudulent scientific papers by spotting reused images. Rather than scrap a failed study, for example, a researcher might attempt to pass off images from a different experiment to give the false impression that their own was a success.
Kording, a Penn Integrates Knowledge (PIK) Professor who also has an appointment in the Department of Neuroscience in Penn’s Perelman School of Medicine, and his collaborators developed an algorithm that can compare images across journal articles and detect such replicas, even if the image has been resized, rotated, or cropped.
They describe their technique in a paper recently published on the BioRxiv preprint server.
“Any fraudulent paper damages science,” Kording says. “In biology, many times fraud is detected when someone looks at a few papers and says ‘hey, these images look a little similar.’ We reckoned we could make an algorithm that does the same thing.”
“Science depends on building upon other people’s work,” adds Daniel Acuna, lead author on the paper, and a student in Kording’s lab at Northwestern University at the time the study was conducted. “If you cannot trust other people’s work, the scientific process collapses and, worse, the general public loses trust in us. Some websites were doing this, anonymously, but at a painstakingly slow rate.” Acuna is now an assistant professor in the School of Information Studies at Syracuse University.
While much of Kording’s work focuses on using data science to understand the brain, he is also curious about the process of research itself, or, as he puts it, “the science of science.” One of the Kording lab’s previous projects closely analyzed common methods of neuroscience research, and another turned a mirror on itself, describing how to structure a scientific paper.
In faculty matters, specialization is the name of game. The areas in which individual professors conduct their research and teach are highly specific, with often no overlap between the areas of expertise of people in the same departments. Given the broad range of topics covered by the term, bioengineering is particularly complex in the array of subjects researched by faculty.
Now and then, however, these paths converge. Most recently, Jennifer Phillips-Cremins, Ph.D., Assistant Professor of Bioengineering, and Danielle Bassett, Ph.D., Eduardo D. Glandt Faculty Fellow and Associate Professor of Bioengineering, collaborated on a paper published in Nature Methods. Dr. Cremins’s research has focused on genome folding, an intricate process by which DNA in the nuclei of cells creates loops that result in specific forms of gene regulation. Dr. Bassett’s area is network science and systems theory. Both professors apply their research in the area of central nervous development.
In the new paper, Drs. Cremins and Bassett, along with members of both their labs and colleagues from the Department of Genetics, developed a a graph theory-based method for detecting genome folding, called 3DNetMod, which outperformed earlier models used for the same purpose. In addition, Dr. Cremins is profiled in the same issue of Nature Methods, where she discusses how her past education and experience have resulted in her career achievements thus far.
The sheer complexity of the human brain means that, despite the tremendous advances made in neuroscience, there is still much we don’t know about what goes on inside our heads and how it goes awry in mental disorders. Even with the most advanced techniques, much of what we’ve learned about the brain is descriptive — telling that something is different between health and unhealthy function — but not why that something is different or how we could change it.
Among the approaches that have provided important insights into these questions is network science, which seeks to understand the brain as a complex system of multiple interacting components. Now, in a review published recently in Neuron, Danielle Bassett, Ph.D., Eduardo D. Glandt Faculty Fellow and Associate Professor of Bioengineering, and Richard Betzel, Ph.D., a postdoc in Dr. Bassett’s lab, have collaborated with scientists from the University of Heidelberg in Germany. The review covers a broad range of discoveries and innovations, moving from earlier, two-dimensional approaches to understanding the brain, such as graph theory, to newer approaches including multilayer networks, generative network models, and network control theory.
“Stating what is different in brain networks of individuals with disorders of mental health is not the same as identifying why” says Bassett. “Here we propose that emerging tools from network science can be used to identify true mechanisms of mental health disorders, and bridge molecular and genetic mechanisms through brain physiology, thus informing interventions in the form of pharmacological manipulations and brain stimulation.”
The developing human brain contains a cacophony of electrical and chemical signals from which emerge the powerful adult capacities for decision-making, strategizing, and critical thinking. These signals support the trafficking of information across brain regions, in patterns that share many similarities with traffic patterns in railway and airline transportation systems. Yet while air traffic is guided by airport control towers, and railway routes are guided by signal control rooms, it remains a mystery how the information traffic in the brain is guided and how that guidance changes as kids grow.
In part, this mystery has been complicated by the fact that, unlike transportation systems, the brain is not hooked up to external controllers. Control must happen internally. The problem becomes even more complicated when we think about the sheer number of routes that must exist in the brain to support the full range of human cognitive capabilities. Thus, the controllers would need to produce a large set of control signals or use different control strategies. Where internal controllers might be, how they produce large variations in routing, and whether those controllers and their function change with age are important open questions.
A recent paper published in Nature Communications – a product of collaboration among the Departments of Bioengineering and Electrical & Systems Engineering at the University of Pennsylvania and the Department of Psychiatry of Penn’s Perelman School of Medicine – offers some interesting answers. In their article, Danielle Bassett, Ph.D., Eduardo D. Glandt Faculty Fellow and Associate Professor in the Penn BE Department, Theodore D. Satterthwaite, M.D., Assistant Professor in the Penn Psychiatry Department, postdoctoral fellow Evelyn Tang, and their colleagues suggest that control in the human brain works in a similar way to control in man-made robotic and other mechanical systems. Specifically, controllers exist inside each human brain, each region of the brain can perform multiple types of control, and this control grows as children grow.
As part of this study, the authors applied network control theory — an emerging area of systems engineering – to explain how the pattern of connections (or network) between brain areas directly informs the brain’s control functions. For example, hubs of the brain’s information trafficking system (like Grand Central Station in New York City) show quite different capacities for and sensitivities to control than non-hubs (like Newton Station, Kansas). Applying these ideas to a large set of brain imaging data from 882 youths in the Philadelphia area between the ages of 8 and 22 years old, the authors found that the brain’s predicted capacity for control increases over development. Older youths have a greater predicted capacity to push their brains into nearby mental states, as well as into distant mental states, indicating a greater potential for diversity of mental operations than in younger youths.
The investigators then asked whether the principles of network control could explain the specific manner in which connections in the brain change as youths age. They used tools from evolutionary game theory – traditionally used to study Darwinian competition and evolving populations in biology – to ‘evolve’ brain networks in silico from their 8-year old state to their 22-year-old state. The results demonstrated that the optimization of network control is a principle that explains the observed changes in brain connectivity as youths develop over childhood and adolescence. “One of the observations that I think is particularly striking about this study,” Bassett says, “is that the principles of network controllability are sufficient to explain the observed evolution in development, suggesting that we have identified a quintessential rule of developmental rewiring.”
This research informs many possible future directions in scientific research. “Showing that network control properties evolve during adolescence also suggests that abnormalities of this developmental process could be related to cognitive deficits that are present in many neuropsychiatric disorders,” says Satterthwaite. The discovery that the brain optimizes certain network control functions over time could have important implications for better understanding of neuroplasticity, skill acquisition, and developmental psychopathology.