Week in BioE (July 9, 2018)

A New Treatment for Joint Dysfunction

TMD is a common condition affecting movement of the jaw

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 Science Robotics.

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.

 

Shoddy Science Uncovered in New Research

by Linda Tunesi

shoddy science
Konrad Kording, Ph.D.

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.

Continued at the Penn Engineering Medium blog.

Collaboration in Research by Bioengineering Faculty

Jennifer Phillips-Cremins
Danielle Bassett

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.

A Call to Understand Brain Network Mechanisms of Mental Disorders

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.

mental disorders
Rat microglia and neurons stained for different proteins

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.”

Brain Network Control Emerges over Childhood and Adolescence

network control

 

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.

Oncology/Engineering Review Published

oncology
Mike Mitchell, Ph.D.

Michael Mitchell, Ph.D., who will arrive in the Spring 2018 semester as assistant professor in the Department of Bioengineering, is the first author on a new review published in Nature Reviews Cancer on the topic of engineering and the physical sciences and their contributions to oncology. The review was authored with Rakesh K. Jain, Ph.D., who is Andrew Werk Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School, and Robert Langer, Sc.D., who is Institute Professor in Chemical Engineering at the David H. Koch Institute for Integrative Cancer Research at MIT. Dr. Mitchell is currently in his final semester as a postdoctoral fellow at the Koch Institute and is a member of Dr. Langer’s lab at MIT.

The review focuses on four key areas of development for oncology in recent years: the physical microenvironment of the tumor; technological advances in drug delivery; cellular and molecular imaging; and microfluidics and microfabrication. Asked about the review, Dr. Mitchell said, “We’ve seen exponential growth at the interface of engineering and physical sciences over the last decade, specifically through these advances. These novel tools and technologies have not only advanced our fundamental understanding of the basic biology of cancer but also have accelerated the discovery and translation of new cancer therapeutics.”

Chairs for BMES ’19 to Include Burdick

chairsJason Burdick, Ph.D., who is a professor in the University of Pennsylvania’s Department of Bioengineering, has been named one of the three chairs of the 2019 annual meeting of the Biomedical Engineering Society (BMES), which be held here in Philadelphia on October 16-19. Dr. Burdick will share this position with two other Philadelphians: Alisa Morss Clyne, Ph.D., an associate professor of mechanical engineering and mechanics at Drexel University; and Ruth Ochia, Ph.D., an associate professor of instruction in bioengineering at Temple University. Drs. Burdick, Clyne, and Ochia will share the responsibility for planning the meeting and chairing it once it is in session.

“I am very happy to be appointed as a program chair for the 2019 BMES meeting in Philadelphia, along with Alisa Morss Clyne of Drexel University and Ruth Ochia of Temple University,” Dr. Burdick said when asked about the honor. “The three of us felt that it was important to represent the various biomedical engineering research and education programs within the city of Philadelphia, since the meeting will be held here.  There is such a wealth of biomedical engineering efforts in Philly that provides great opportunities to engage in outreach and interaction with both the community and local industry during the meeting.”

Undergraduates Converge at Penn for REU

REU
This year’s summer students

This past summer, 10 undergraduate from 10 colleges came to Penn for 10 weeks (May 30 to August 4) for the Summer Undergraduate Research Experience (SURE), also known as the Research Experience for Undergraduates (REU). During the program, the students were hosted in the laboratories of faculty in Penn’s Schools of Engineering and Applied Science (including Penn Bioengineering faculty Beth Winkelstein, Dan Huh, and Jason Burdick) and Arts and Sciences and the Perelman School of Medicine. These students were hosted under the aegis of the Center for Engineering MechanoBiology (CEMB), a National Science Foundation-funded collaboration among Penn, Washington University (WashU) in St. Louis, New Jersey Institute of Technology (NJIT), Alabama State University, Bryn Mawr College, Boston University, and the University of Texas at Austin.

The students all worked on individual research projects. At the end of the 10-week term, three abstracts from this research were chosen for presentation at the forthcoming annual meeting of the Biomedical Engineering Society (BMES), which will be held October 11-14 in Phoenix. The three students are Kimberly DeLuca (NJIT), John Durel (Univ. of Virginia), and Olivia Leavitt (Worcester Polytech).

The CEMB Web site at WashU has a nice page up featuring the program and this summer’s students.

Penn’s 2017 Summer Undergraduate Research Experience At-a-Glance

Bioengineers Get Support to Study Chronic Pain

chronic pain
Zhiliang Cheng, Ph.D.

Zhiliang Cheng, Ph.D., a research assistant professor in the Department of Bioengineering at the University of Pennsylvania, has received an R01 grant from the National Institute of Neurological Disorders and Stroke to study chronic pain. The grant, which provides nearly $1.7 million over the next five years, will support the work of Dr. Cheng, Bioengineering Professor Andrew Tsourkas, and Vice Provost for Education and Professor Beth Winkelstein, in developing a novel nanotechnology platform for greater effectiveness in radiculopathy treatment.

Based on the idea that phospholipase-A2 (PLA2) enzymes, which modulate inflammation, play an important role in pain due to nerve damage, the group’s research seeks to develop PLA2-responsive multifunctional nanoparticles (PRMNs) that could both deliver anti-inflammatory drugs and magnetic resonance contrast agents to sites of pain so that the molecular mechanisms at work in producing chronic pain can be imaged, as well as allowing for the closer monitoring of treatment.

This research builds on previous findings by Drs. Cheng, Tsourkas, and Winkelstein. In a 2011 paper, Drs. Tsourkas and Winkelstein used superparamagnetic iron oxide nanoparticles to enhance magnetic resonance imaging of neurological injury in a rat model. Based on the theory of reactive oxygen species playing a role in pain following neural trauma, a subsequent paper published in July with Sonia Kartha as first author and Dr. Cheng as a coauthor found that a type of nanoparticle called polymersomes could be used to deploy superoxide dismutase, an antioxidant, to sites of neuropathic pain. The current grant-supported study combines the technologies developed in the previous studies.

“To the best of our knowledge, no studies have sought to combine and/or leverage this aspect of the inflammatory and PLA2 response for developing effective pain treatment. We hypothesize that this theranostic agent, which integrates both diagnostic and therapeutic functions into a single system, offers a unique opportunity and tremendous potential for monitoring and treating patients with direct, clinically translational impact,” Dr. Cheng said.

Phillips-Cremins Research Identifies Protein Involved in Brain Development

Phillips-Cremins
Jennifer Phillips-Cremins, Ph.D.

The vast majority of genetic mutations that are associated with disease occur at sites in the genome that aren’t genes. These sequences of DNA don’t code for proteins themselves, but provide an additional layer of instructions that determine if and when particular genes are expressed. Researchers are only beginning to understand how the non-coding regions of the genome influence gene expression and might be disrupted in disease.

​​​​​​​​​​​​Jennifer Phillips-Cremins, assistant professor in the Department of Bioengineering in the University of Pennsylvania’s School of Engineering and Applied Science, studies the three-dimensional folding of the genome and the role it plays in brain development. When a stretch of DNA folds, it creates a higher-order structure called a looping interaction, or “loop.” In doing so, it brings non-coding sites into physical contact with their target genes, precisely regulating gene expression in space and time during development.

Phillips-Cremins and lab member Jonathan Beagan have led a new study identifying a new protein that connects loops in embryonic stem cells as they begin to differentiate into types of neurons. Though the study was conducted in mice, these findings inform aspects of human brain development, including how the genetic material folds in the 3-D nucleus and is reconfigured as stem cells become specialized. Better understanding of these mechanisms may be relevant to a wide range of neurodevelopmental disorders.

Cremins lab members Michael Duong, Katelyn Titus, Linda Zhou, Zhendong Cao, Jingjing Ma, Caroline Lachanski and Daniel Gillis also contributed to the study, which was published in the journal Genome Research.​​​​​​

Continue reading at the SEAS blog.