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.

New Review Blazes the TRAIL

TRAIL
Drawing of tumor necrosis factor alpha

Cell signaling and the proteins involved in it participate in virtually every process in the body, whether normal or pathological. Much of this signaling involves proteins called cytokines, and of particular interest among them are tumor necrosis factors (TNFs), whose job it is to carry out apoptosis — the process by which cells die at predetermined time points as part of their normal life cycle. Among this family of cytokines, TNF-related apoptosis-inducing ligand (TRAIL) has been of particular interest to oncologists.

The process by which TRAIL combines with or binds to other molecules that modulate the life cycle of cancer cells can interfere with the ability of these molecules to facilitate the growth of cancer cells into tumors. However, attempts to deploy the cytokine to interfere in the process that produces cancer have been unsuccessful because of issues regarding inefficient delivery of TRAIL to the relevant sites, poor circulation of the cytokine in the blood, and the development of resistance to TRAIL. Bioengineers have been hard at work attempting to overcome these barriers.

In a new article published in ACS Nano coauthored by Michael J. Mitchell, Ph.D., Skirkanich Assistant Professor of Innovation at Penn Bioengineering, and Robert Langer, Ph.D., David H. Koch Institute Professor at MIT, these engineered solutions are reviewed and assessed. The review covers nanoparticle technologies with potential to solve the problems encountered thus far, including a range of materials (polymers, lipids, inorganic), cell-nanoparticle hybrids, and therapeutic cells genetically engineered using nanoparticles.

“The TRAIL protein is a essential component of our immune system,” Dr. Mitchell says, “and it kills tumor cells without harming normal ones. However, it remains challenging to deliver the protein into tumors, and tumors can also be resistant to the protein. We and others are now exploiting nanotechnology, genetic engineering, and immune cell-biomaterial hybrids to overcome these key biological barriers to cancer therapy.”

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.

Tissue Folding Processes Further Unraveled

tissue folding
Alex Hughes, Ph.D.

One of the key processes in embryonic development and growth through childhood and adolescence is that of how tissue folds into the specific shapes required for them to function in the body.  For instance, mesenchymal stem cells, which form a variety of tissues including bones, muscles, and fat, are required to “know” what shapes to take on as they form organ systems and other structures. Therefore, a big concern in tissue engineering is determining how to control these processes of tissue folding.

Just in time for his arrival at Penn Bioengineering, Dr. Alex Hughes, a new assistant professor in the department, is the lead author on a new paper in Developmental Cell that explores this concern. The study was coauthored with Dr. Zev Gartner of the University of California, Berkeley, where Dr. Hughes just finished a postdoctoral fellowship. In the paper, the authors used three-dimensional cell-patterning techniques, embryonic tissue explants, and finite element modeling to determine that the folding process involves the interaction of a protein called myosin II with the extracellular matrix, itself the molecular material that provides a structural framework for developing tissues. With the knowledge gained in the initial experiments, the authors were then able to reproduce the tissue folding process in the lab.

“Bioengineers are currently thinking about building tissues,” Dr. Hughes says, “not just at the level of organoids, but at the level of organs in the body. One of my interests at Penn is to harness developmental principles that link these length scales, allowing us to design medically relevant scaffolds and machines.”

Equipped with the knowledge gleaned from this research, future studies could contribute further to the ability to generate tissues and even organ systems in laboratories. Ultimately, this knowledge could revolutionize transplant medicine, as well as variety of other fields.

CIFAR Names Kording Associate Fellow

CIFAR
Konrad Kording, Ph.D.

Dr. Konrad Kording, a University of Pennsylvania PIK Professor in Bioengineering and Neuroscience, has been named an associate fellow by the Canadian Institute for Advanced Research (CIFAR), an advanced study institute headquartered in Toronto and partially funded by the government of Canada. Dr. Kording’s fellowship is in the institute’s Learning in Machines & Brains area, which has been one of CIFAR’s 14 interdisciplinary study fields since 2004. He joins 32 other fellows currently supported by the institute for their work in this area.

“The CIFAR program in Learning in Machines & Brains brings together many of the world’s leading deep learning scientists,” Dr. Kording says. “I look forward to collaborate with them to figure out how the brain learns.”

CIFAR was founded in 1982. Over the last 35 years, the institute has supported the work of scientists in 133 countries, including 18 Nobel Prize laureates.

Penn Bioengineering at BMES 2017

BMES 2017

The annual meeting of the Biomedical Engineering Society (BMES) was held in Phoenix on October 11-14. The professional society for bioengineers and biomedical engineers this year played host not only to faculty from Penn’s Bioengineering Department but also to several undergraduate and graduate students, as well as staff

As previously mentioned here, three of the undergraduate students from the Center for Engineering MechanoBiology (CEMB) presented their work at the BMES meeting. The three students – Kimberly DeLuca from New Jersey Institute of Technology; John Durel from the University of Virginia; and Olivia Leavitt from Worcester Polytechnic Institute – spent 10 weeks over the summer at Penn working on individual research projects in the labs of Penn faculty.

Olivia worked in the laboratory of Beth Winkelstein, Ph.D., Professor of Bioengineering and Vice Provost for Education at Penn. Olivia’s project studied how matrix proteases influence the nerve impulses, but not the structure, of connective tissue. Jacob’s project, developed with Professor Jason Burdick, Ph.D., generated new insights into how single stem cells sense the mechanical environment and ‘make decisions’ about which type of cell they will become.  Kimberly’s work was done in the lab of Robert Mauck, Ph.D., Professor of Orthopaedic Surgery at Penn’s Perelman School of Medicine, and it studies how to make materials with unique mechanical properties that could eventually find use in tissue engineering applications.

“I am very pleased to have been a part of the CEMB’s first round of undergraduate summer interns, and while there are certainly some small kinks to be worked out around the edges, the CEMB offered an invaluable experience. If I had to go back and decide again whether or not to chose this internship versus others, I would do it again in a heart-beat,” John Durel said.

BMES 2017
(left to right) Bioengineering Department Chair David Meaney, BMES Co-president Olivia Teter, and GABE board members Meagan Ita and Varsha Viswanath.

Also attending BMES were officers of the undergraduate chapter of BMES at Penn. As we previously reported, the chapter won the Student Outreach Achievement Award for the year, repeating its win from 2015. Penn’s contingent from the BMES chapter, as well as from the Graduate Association of Bioengineers (GABE), were on hand to receive awards and recognition (see photo above).

BMES 2017
Sevile Mannickarottu

Finally, Sevile Mannickarottu, instructional laboratories director for the Bioengineering Department, presented a paper at one of the conference sessions. Alongside presenters from MIT, Johns Hopkins, Berkeley, UCSD, UIUC, and Stanford, Sevile (see photo right) participated in a special sessions on curricular innovation held on Friday, October 13. Sevile did a great job explaining the innovations introduced to Penn’s undergraduate lab over the course of the last few years, and the presentation was very well received.

Next year’s BMES conference will be held in Atlanta on October 17-20, followed by the 2019 meeting in Philadelphia, to be co-chaired by Penn BE’s Jason Burdick.

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.”

Lagrange Goes to Dani Bassett

Lagrange
Danielle Bassett, Ph.D.

Danielle S. Bassett, Eduardo D. Glandt Faculty Fellow and Associate Professor in the University of Pennsylvania’s Department of Bioengineering, is the recipient of the 2017 Lagrange-CRT Foundation Prize. The prize, given by the Institute for Scientific Interchange Foundation in Turin, Italy, was created to encourage and honor researchers working in the field of complex systems.

Complex systems feature many interconnected parts whose individual behavior influences the outcomes of the whole. Examples include social media networks, ecological webs, stock markets, and in Bassett’s case, the brain. Her research maps and analyzes the networks of neurons that enable all manners of cognitive abilities, as well as how those networks evolve during development or malfunction in disease.

The prize comes with an award of €50,000, or roughly $60,000. It will be formally presented to Bassett at a ceremony in Turin next week. Bassett is the first woman to be the sole recipient of the prize since its inception in 2008. Lada Adamic won it alongside Xavier Gabaix in 2012.

Read more at the SEAS blog on Medium.

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.”