A collaborative study conducted by researchers at the Children’s Hospital of Philadelphia (CHOP), Penn Engineering and Pennsylvania State University has uncovered new information about how chromosomal material in cell nuclei reorganizes itself after cell division.
While a deep understanding of the cell cycle is a cornerstone of biology and health sciences, research into the complex relationship between three-dimensional chromatin structure and gene transcription is still in its infancy. The results of this study will contribute to a more robust understanding of chromatin rebuilding after mitosis and potentially aid in the treatment of genetic diseases.
Phillips-Cremins’ research uses genetic engineering approaches to discover the mechanisms regulating chromatin organizing principles in cells, as well as computational approaches to investigate cellular function. Her lab’s techniques provide ways of mapping the three-dimensional organization of genes while they are folded together in the genome and how those spatial relationships impact gene expression.
The research team performed their experiments in blood-forming cells from a well-established mouse model. They used sophisticated techniques called high throughput chromosome conformation capture (Hi-C) that detect and map interactions across three-dimensional space between specific sites in chromosomal DNA. These maps also allowed the scientists to measure such interactions at different time points in the cell cycle. In all, the tools detected roughly 2 billion interactions during mitosis and thereafter, when the daughter nuclei are rebuilt.
Members of the Cremins Lab, Daniel J. Emerson, Thomas G. Gilgenast and Katelyn R. Titus, also contributed to the study, which was published in Nature.
Jason Burdick, Robert D. Bent Professor in the Department of Bioengineering, has been named a Fellow of the National Academy of Inventors (NAI), an award of high professional distinction accorded to academic inventors. Elected Fellows have demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.
Burdick’s research interests include developing degradable polymeric biomaterials that can be used for tissue engineering, drug delivery, and fundamental polymer studies. His lab focuses on developing polymeric materials for biomedical applications with specific emphasis on tissue regeneration and drug delivery. Burdick believes that advances in synthetic chemistry and materials processing could be the answer to organ and tissue shortages in medicine. The specific targets of his research include: scaffolding for cartilage regeneration, controlling stem cell differentiation through material signals, electrospinning and 3D printing for scaffold fabrication, and injectable hydrogels for therapies after a heart attack.
Danielle Bassett has been named the J. Peter Skirkanich Professor of Bioengineering.
Dr. Bassett is a Professor in the department of Bioengineering at the School of Engineering and Applied Science. She holds a Ph.D. in Physics from the University of Cambridge and completed her postdoctoral training at the University of California, Santa Barbara, before joining Penn in 2013.
Dr. Bassett has received numerous awards for her research, including an Alfred P Sloan Research Fellowship, a MacArthur Fellowship, an Office of Naval Research Young Investigator Award, a National Science Foundation CAREER Award and, most recently, an Erdos-Renyi Prize in Network Science to name but a few. She has authored over 190 peer-reviewed publications as well as numerous book chapters and teaching materials. She is the founding director of the Penn Network Visualization Program, a combined undergraduate art internship and K-12 outreach program bridging network science and the visual arts.
Positive results in first-in-U.S. trial of CRISPR-edited immune cells
Genetically editing a cancer patient’s immune cells using CRISPR/Cas9 technology, then infusing those cells back into the patient appears safe and feasible based on early data from the first-ever clinical trial to test the approach in humans in the United States. Researchers from the Abramson Cancer Center have infused three participants in the trial thus far—two with multiple myeloma and one with sarcoma—and have observed the edited T cells expand and bind to their tumor target with no serious side effects related to the investigational approach. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics.
“This trial is primarily concerned with three questions: Can we edit T cells in this specific way? Are the resulting T cells functional? And are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes,” says the study’s principal investigator Edward A. Stadtmauer, section chief of Hematologic Malignancies at Penn. Stadtmauer will present the findings next month at the 61st American Society of Hematology Annual Meeting and Exposition.
Because of the opioid epidemic sweeping the nation, Moore notes that there’s a rapid search going on to develop non-addictive painkiller options. However, he also sees a gap in adequate models to test those new drugs before human clinical trials are allowed to take place. Here is where he hopes to step in and bring some innovation to the field, by integrating living human cells into a computer chip for modeling pain mechanisms. Through his research, Moore wants to better understand not only how some drugs can induce pain, but also how patients can grow tolerant to some drugs over time. If successful, Moore’s work will lead to a more rapid and less expensive screening option for experimental drug advancements.
New machine learning-assisted microscope yields improved diagnostics
Researchers at Duke University recently developed a microscope that uses machine learning to adapt its lighting angles, colors, and patterns for diagnostic tests as needed. Most microscopes have lighting tailored to human vision, with an equal distribution of light that’s optimized for human eyes. But by prioritizing the computer’s vision in this new microscope, researchers enable it to see aspects of samples that humans simply can’t, allowing for a more accurate and efficient diagnostic approach.
Led by Roarke W. Horstmeyer, Ph.D., the computer-assisted microscope will diffuse light through a bowl-shaped source, allowing for a much wider range of illumination angles than traditional microscopes. With the help of convolutional neural networks — a special kind of machine learning algorithm — Horstmeyer and his team were able to tailor the microscope to accurately diagnose malaria in red blood cell samples. Where human physicians typically perform similar diagnostics with a rate of 75 percent accuracy, this new microscope can do the same work with 90 percent accuracy, making the diagnostic process for many diseases much more efficient.
Case Western Reserve University researchers create first-ever holographic map of brain
A Case Western Reserve University team of researchers recently spearheaded a project in creating an interactive holographic mapping system of the human brain. The design, which is believed to be the first of its kind, involves the use of the Microsoft HoloLens mixed reality platform. Lead researcher Cameron McIntyre, Ph.D., sees this mapping system as a better way of creating holographic navigational routes for deep brain stimulation. Recent beta tests with the map by clinicians give McIntyre hope that the holographic representation will help them better understand some of the uncertainties behind targeted brain surgeries.
More than merely providing a useful tool, McIntyre’s project also brings together decades’ worth of neurological data that has not yet been seriously studied together in one system. The three-dimensional atlas, called “HoloDBS” by his lab, provides a way of finally seeing the way all of existing neuro-anatomical data relates to each other, allowing clinicians who use the tool to better understand the brain on both an analytical and visual basis.
Implantable cancer traps reduce biopsy incidence and improve diagnostic
Biopsies are one of the most common procedures used for cancer diagnostics, involving a painful and invasive surgery. Researchers at the University of Michigan are trying to change that. Lonnie Shea, Ph.D., a professor of biomedical engineering at the university, worked with his lab to develop implants with the ability to attract any cancer cells within the body. The implant can be inserted through a scaffold placed under the patient’s skin, making it a more ideal option than biopsy for inaccessible organs like lungs.
The lab’s latest work on the project, published in Cancer Research, details its ability to capture metastatic breast cancer cells in vivo. Instead of needing to take biopsies from areas deeper within the body, the implant allows for a much simpler surgical procedure, as biopsies can be taken from the implant itself. Beyond its initial diagnostic advantages, the implant also has the ability to attract immune cells with tumor cells. By studying both types of cells, the implant can give information about the current state of cancer in a patient’s body and about how it might progress. Finally, by attracting tumor and immune cells, the implant has the ability to draw them away from the area of concern, acting in some ways as a treatment for cancer itself.
People and Places
The Philadelphia Inquirer recently published an article detailing the research of Penn’s Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering, Cesar de la Fuente, Ph.D. In response to a growing level of worldwide deaths due to antibiotic-resistant bacteria, de la Fuente and his lab use synthetic biology, computation, and artificial intelligence to test hundreds of millions of variations in bacteria-killing proteins in the same experiment. Through his research, de la Fuente opens the door to new ways of finding and testing future antibiotics that might be the only viable options in a world with an increasing level of drug-resistant bacteria
Emily Eastburn, a Ph.D. candidate in Bioengineering at Penn and a member of the Boerckel lab of the McKay Orthopaedic Research Laboratory, recently won the Ashton fellowship. The Ashton fellowship is an award for postdoctoral students in any field of engineering that are under the age of 25, third-generation American citizens, and residents of either Pennsylvania or New Jersey. A new member of the Boerckel lab, having joined earlier this fall, Eastburn will have the opportunity to conduct research throughout her Ph.D. program in the developmental mechanobiology and regeneration that the Boerckel lab focuses on.
Cesar de la Fuente, Ph.D., a Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering at Penn, recently published a literature review in Trends in Immunology entitled, “Emerging Frontiers in Microbiome Engineering.” The microbiome, in simple terms, consists of the genetic material of microorganisms in the gut, including bacteria, fungi, protozoa, viruses, and oral, vaginal, and skin microbiomes. Each human has a unique microbiome that depends both on predetermined factors like exposure to microorganisms within a mother’s birth canal or breastmilk in early life as well as environmental factors and diet in later life. The health of someone’s microbiome is extremely important, as an unhealthy microbiome with an imbalance of symbiotic and pathogenic microbes can make a person more susceptible to various diseases. The most common diseases or disorders associated with a problematic microbiome are rather far-reaching, including some of the most afflicting diseases of today like inflammatory bowel disease, diabetes, obesity, cardiovascular diseases, and neurological disorders.
In his recent literature review, de la Fuente provides an overview of microbiome engineering, and what the future might hold for the field. He defines microbiome engineering initially as a way of studying the “contribution of individual microbes and generating potential therapies against metabolic, inflammatory, and immunological diseases.” Currently, most treatments for issues with the microbiome are broad solutions like dietary adjustments to include more probiotics, antibiotics, or prebiotics, while more serious cases may require a fecal microbiota transplant. While these therapies may work for some patients, de la Fuente emphasizes the need for greater specificity in treatment targets and a need for precision in reprogramming existing microbial communities as an alternative to transplants.
De la Fuente highlights the current methods and tools in microbiome engineering such as the use of bacteriocins and bacteriophages to knock out specific bacteria within the microbiome. However, there are very few bacteriocins or bacteriophages commercially available on today’s market. Another common approach to microbiome engineering is in synthetic biology, or the use of “chassis” — a type of cell that maintains DNA constructs for different functions — to engineering interactions within the microbiome. De la Fuente continues his discussion of current methods by naming and describing several specific examples of these approaches, particularly in relation to synthetic biology options before moving on to examine future directions for these methods.
Before bringing up potential new frontiers for microbiome engineering, de la Fuente also outlines the way that microbiome engineering works in the first place, and dedicates sections of the review to the microbiome’s influence on its host’s immune system and how to engineer the microbiome to modulate that immune system. The main future methods for microbiome engineering that de la Fuente points out in his review include more precise regulation of gene expression through commensal organisms and the use of CRISPRi to find genes involved in bacterial maintenance. The conclusion of de la Fuente’s review brings up the notion of new personalized medicine or therapy for the microbiome that could come with further advances in the field. However, he also makes sure to bring up some still-outstanding questions about the human microbiome that require further research, most notably, what exactly makes a healthy human microbiome? Here’s hoping the research de la Fuente mentions can illuminate a path to the answer.
When the immune system detects a foreign pathogen, a cascade of chemical signals call white blood cells to the scene. Neutrophils are the most common and abundant type of these cells and while they start accumulating at the site of an infection within minutes, they are essentially at the mercy of the circulatory system’s one-way flow of traffic to get them where they need to go.
Now, research from the University of Pennsylvania’s School of Engineering and Applied Science shows how these cells can be coaxed to fight the direction of blood flow, crawling upstream along the walls of veins and arteries.
The in vitro study suggested that this technique could get neutrophils to the sites of infections faster when they are restricted to the direction of blood flow.
Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in the Department of Bioengineering, and Alexander Buffone, Jr., a research associate in his lab, led the research. Nicholas R. Anderson, a graduate student in the Hammer lab, also contributed to the study.
For almost any conceivable protein, corresponding antibodies can be developed to block it from binding or changing shape, which ultimately prevents it from carrying out its normal function. As such, scientists have looked to antibodies as a way of shutting down proteins inside cells for decades, but there is still no consistent way to get them past the cell membrane in meaningful numbers.
Now, Penn Engineering researchers have figured out a way for antibodies to hitch a ride with transfection agents, positively charged bubbles of fat that biologists routinely use to transport DNA and RNA into cells. These delivery vehicles only accept cargo with a highly negative charge, a quality that nucleic acids have but antibodies lack. By designing a negatively charged amino acid chain that can be attached to any antibody without disrupting its function, they have made antibodies broadly compatible with common transfection agents.
Beyond the technique’s usefulness towards studying intracellular dynamics, the researchers conducted functional experiments with antibodies that highlight the technique’s potential for therapeutic applications. One antibody blocked a protein that decreases the efficacy of certain drugs by prematurely ejecting them from cells. Another blocked a protein involved in the transcription process, which could be an even more fundamental way of knocking out proteins with unwanted effects.
Tissue gets stiffer when it’s compressed. That property can become even more pronounced with injury or disease, which is why doctors palpate tissue as part of a diagnosis, such as when they check for lumps in a cancer screening. That stiffening response is a long-standing biomedical paradox, however: tissue consists of cells within a complex network of fibers, and common sense dictates that when you push the ends of a string together, it loosens tension, rather than increasing it.
Now, in a study published in Nature, University of Pennsylvania’s School of Engineering and Applied Science researchers have solved this mystery by better understanding the mechanical interplay between that fiber network and the cells it contains.
The researchers found that when tissue is compressed, the cells inside expand laterally, pulling on attached fibers and putting more overall tension on the network. Targeting the proteins that connect cells to the surrounding fiber network might therefore be the optimal way of reducing overall tissue stiffness, a goal in medical treatments for everything from cancer to obesity.
The study was led by Paul Janmey, Professor in the Perelman School of Medicine’s Department of Physiology and in Penn Engineering’s Department of Bioengineering, and Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Materials Science and Engineering, Mechanical Engineering and Applied Mechanics, and Bioengineering, along with Anne van Oosten and Xingyu Chen, graduate students in Janmey’s and Shenoy’s labs. Van Oosten is now a postdoctoral fellow at Leiden University in The Netherlands.
Shenoy is Director of Penn’s Center for Engineering Mechanobiology, which studies how physical forces influence the behavior of biological systems; Janmey is the co-director of one of the Center’s working groups, organized around the question, “How do cells adapt to and change their mechanical environment?”
Together, they have been interested in solving the paradox surrounding tissue stiffness.
Diabetes is one of the more common diseases among Americans today, with the American Diabetes Association estimating that approximately 9.5 percent of the population battles the condition today. Though symptoms and causes may vary across types and patients, diabetes generally results from the body’s inability to produce enough insulin to keep blood sugar levels in check. A new experimental treatment from the lab of Sha Jin, Ph.D., a biomedical engineering professor at Binghamton University, aims to use about $1.2 million in recent federal grants to develop a method for pancreatic islet cell transplantation, as those are the cells responsible for producing insulin.
But the catch to this new approach is that relying on healthy donors of these islet cells won’t easily meet the vast need for them in diabetic patients. Sha Jin wants to use her grants to consider the molecular mechanisms that can lead pluripotent stem cells to become islet-like organoids. Because pluripotent stem cells have the capability to evolve into nearly any kind of cell in the human body, the key to Jin’s research is learning how to control their mechanisms and signaling pathways so that they only become islet cells. Jin also wants to improve the eventual culture of these islet cells into three-dimensional scaffolds by finding ways of circulating appropriate levels of oxygen to all parts of the scaffold, particularly those at the center, which are notoriously difficult to accommodate. If successful in her tissue engineering efforts, Jin will not only be able to help diabetic patients, but also open the door to new methods of evolving pluripotent stem cells into mini-organ models for clinical testing of other diseases as well.
A Treatment to Help Others See Better
Permanently crossed eyes, a medical condition called strabismus, affects almost 18 million people in the United States, and is particularly common among children. For a person with strabismus, the eyes don’t line up to look at the same place at the same time, which can cause blurriness, double vision, and eye strain, among other symptoms. Associate professor of bioengineering at George Mason University, Qi Wei, Ph.D., hopes to use almost $2 million in recent funding from the National Institute of Health to treat and diagnose strabismus with a data-driven computer model of the condition. Currently, the most common method of treating strabismus is through surgery on one of the extraocular muscles that contribute to it, but Wei wants her model to eventually offer a noninvasive approach. Using data from patient MRIs, current surgical procedures, and the outcomes of those procedures, Wei hopes to advance and innovate knowledge on treating strabismus.
A Newly Analyzed Brain Mechanism Could be the Key to Stopping Seizures
Among neurological disorders, epilepsy is one of the most common. An umbrella term for a lot of different seizure-inducing conditions, many versions of epilepsy can be treated pharmaceutically. Some, however, are resistant to the drugs used for treatment, and require surgical intervention. Bin He, Ph. D., the Head of the Department of Biomedical Engineering at Carnegie Mellon University, recently published a paper in collaboration with researchers at Mayo Clinic that describes the way that seizures originating at a single point in the brain can be regulated by what he calls “push-pull” dynamics within the brain. This means that the propagation of a seizure through the brain relies on the impact of surrounding tissue. The “pull” he refers to is of the surrounding tissue towards the seizure onset zone, while the “push” is what propagates from the seizure onset zone. Thus, the strength of the “pull” largely dictates whether or not a seizure will spread. He and his lab looked at different speeds of brain rhythms to perform analysis of functional networks for each rhythm band. They found that this “push-pull” mechanism dictated the propagation of seizures in the brain, and suggest future pathways of treatment options for epilepsy focused on this mechanism.
Hyperspectral Imaging Might Provide New Ways of Finding Cancer
A new method of imaging called hyperspectral imaging could help improve the prediction of cancerous cells in tissue specimens. A recent study from a University of Texas Dallas team of researchers led by professor of bioengineering Baowei Fei, Ph.D., found that a combination of hyperspectral imaging and artificial intelligence led to an 80% to 90% level of accuracy in identifying the presence of cancer cells in a sample of 293 tissue specimens from 102 patients. With a $1.6 million grant from the Cancer Prevention and Research Institute of Texas, Fei wants to develop a smart surgical microscope that will help surgeons better detect cancer during surgery.
Fei’s use of hyperspectral imaging allows him to see the unique cellular reflections and absorptions of light across the electromagnetic spectrum, giving each cell its own specific marker and mode of identification. When paired with artificial intelligence algorithms, the microscope Fei has in mind can be trained to specifically recognize cancerous cells based on their hyperspectral imaging patterns. If successful, Fei’s innovations will speed the process of diagnosis, and potentially improve cancer treatments.
People and Places
A group of Penn engineering seniors won the Pioneer Award at the Rothberg Catalyzer Makerthon led be Penn Health-Tech that took place from October 19-20, 2019. SchistoSpot is a senior design project created by students Vishal Tien (BE ‘20), Justin Swirbul (CIS ‘20), Alec Bayliff (BE ‘20), and Bram Bruno (CIS ‘20) in which the group will design a low-cost microscopy dianostic tool that uses computer vision capabilities to automate the diagnosis of schistosomiasis, which is a common parasitic disease. Read about all the winners here.
Virginia Tech University will launch a new Cancer Research Initiative with the hope of creating an intellectual community across engineers, veterinarians, biomedical researchers, and other relevant scientists. The initiative will focus not only on building better connections throughout departments at the university, but also in working with local hospitals like the Carilion Clinic and the Children’s National Hospital in Washington, D.C. Through these new connections, people from all different areas of science and engineering and come together to share ideas.
Associate Professor of Penn Bioengineering Dani Bassett, Ph.D., recently sat down with the Penn Integrates Knowledge University Professor Duncan Watts, Ph.D., for an interview published in Penn Engineering. Bassett discusses the origins of network science, her research in small-world brain networks, academic teamwork, and the pedagogy of science and engineering. You can read the full interview here.
We would like to congratulate Brit Shields, Ph.D., of the Penn Department of Bioengineering, on her recent promotion to Senior Lecturer. Shields got her start at Penn by completing her Ph.D. here in 2015 in History and Sociology of Science, with a dissertation on scientific diplomacy through the example of Richard Courant and New York University, where Shields completed an M.A. in Humanities and Social Thought: Science Studies. Following the conclusion of her doctorate, Shields immediately joined Penn as a lecturer in the Department of Bioengineering, teaching core undergraduate classes like the Senior Thesis course for B.A.S. degree candidates, and Engineering Ethics, one of the courses that fulfills the ethics requirement for all Penn engineering students. Furthermore, Shields has served as an advisor for undergraduate students on senior thesis in the History and Sociology of Science as well as Bioengineering.
In her new position, Shields will have the chance to further develop the engineering ethics curriculum for SEAS students. She will also take on a direct role with freshman bioengineering students as one of two bioengineering faculty members in charge of advising the incoming classes. Through these opportunities to better connect with students, Shields will be able to continue improving the ethics curriculum for all engineering majors, and increase its efficacy in imparting lessons that all engineers should take to the workforce with them. Beyond her roles in the classroom and as an advisor, Shields will also continue her research in the history and sociology of science and technology focusing on both scientific diplomacy and educational programs for engineers. She says that she “look[s] forward to collaborating with the school’s administration, faculty and students to further develop the engineering ethics curriculum. Being able to innovate in this field with such talented students is incredibly rewarding.”