In a recent piece profiling top technologies to watch in 2020, Cremins spoke to Nature about which technological trends she saw as being important for the year to come. In the panel, which highlighted perspectives from a panel of researchers across several fields, Cremins discussed the increasing relevance of innovations that would allow researchers to study the way that folding patterns within the human genome can influence how genes are expressed in healthy individuals and misregulated in human disease.
One such innovation is actually employed by the Cremins Lab: light-activated dynamic looping (LADL). This technique uses both CRISPR/Cas9 and optogenetics to induce folding patterns into the genome on demand, using light as a trigger. In doing so, Cremins and her fellow researchers can more efficiently study the patterns of the human genome, and what effects certain folding patterns can have on the gene expression state of the cell.
Now, with her new promotion, Cremins can continue advancing her research in understanding the genetic and epigenetic mechanisms that regulate neural connections during brain development, with a focus on how that understanding can eventually lead to better treatments of neurological disease. Beyond the lab, she’ll now lead a new Spatial Epigenetics program, bringing together scientists across Penn’s campus to understand how the spatial connections between biomolecules influence biological behavior. She will also continue teaching her hallmark course for Penn Bioengineering undergraduate students, Biological Data Science, and her more advanced graduate-level course in epigenomics. Congratulations, Dr. Cremins!
Nature, one of the world’s most prestigious scientific journals, recently reached out to a panel of researchers from a variety of fields, asking them what technological trends they see as having the most impact on their disciplines in the coming year.
Jennifer Phillips-Cremins, assistant professor in the Department of Bioengineering, was among these panelists. As an expert in “3D epigenetics,” or the way the genome’s highly specific folding patterns influence how and when individual genes are expressed, she highlighted a slate of new techniques that will allow researchers to take a closer look at those relationships.
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.
Electrode Arrays and Star Wars Help to Inspire a New Prosthetic Arm
After nearly fifteen years of work, a new high-tech prosthetic arm from researchers at the University of Utah allows hand amputees to pluck grapes, pick up eggs without breaking them, and even put on their wedding rings. Named after Luke Skywalker’s robotic hand in the Star Wars saga, the LUKE Arm includes sensors that better mimic the way the human body sends information to the brain, allowing users to distinguish between soft and hard surfaces and to perform more complicated tasks. The arm relies heavily on an electrode array invented by University of Utah biomedical engineering professor Richard A. Normann, Ph.D., which is a bundle of microelectrodes that enable a computer to read signals from connected nerves in the user’s forearm.
But the biggest innovation in the use of these electrode arrays for the LUKE Arm is in the way they allow the prosthetic to mimic the sense of feeling on the surface of an object that indicates how much pressure should be applied when handling it. Gregory Clark, Ph.D., an associate professor of biomedical engineering at the University of Utah and the leader of the LUKE Arm project, says the key to improving these functions in the prosthetic was by more closely mimicking the path that this information takes to the brain, as opposed to merely what comprises that sensory information. In the future, Clark hopes to improve upon the LUKE Arm by including more inputs, like one for temperature data, and on making them more portable by eliminating the device’s need for computer connection.
Philly Voice Recognizes the Cremins Lab’s Innovations in Light-Activated Gene-Folding
While technological advancements over the past few decades have opened doors to understanding the topological structures of DNA, we still have far more to learn about how these structures impact and contribute to genome function. But here at Penn, the Cremins Laboratory in 3D Epigenomes and Systems Neurobiology hopes to fix that. Led by Jennifer E. Phillips-Cremins, Ph.D., members of the lab use light-activated dynamic looping (LADL) to better understand the way that genome topological properties and folding can affect protein translation. Cremins and her lab use this technique to force specific genome folds to interact with each other, and create temporary DNA loops that can then be bound together in the presence of blue light for certain proteins in the Arabidopsis plant. Using the data from these tests, researchers can better understand the genome structure-function relationships, and hopefully open the door to new treatments for diseases in which expression or mis-expression of certain genes is the cause.
Artificial Cells Can Deliver Molecules Better than the Real Thing
From pills to vaccines, ways to deliver drugs into the body have been constantly evolving since the early days of medicine.
Now, a new study from an interdisciplinary team led by researchers at the University of Pennsylvania provides a new platform for how drugs could be delivered to their targets in the future. Their work was published in the Proceedings of the National Academy of Sciences.
The research focuses on a dendrimersome, a compartment with a lamellar structure and size that mimic a living cell. It can be thought of as the shipping box of the cellular world that carries an assortment of molecules as cargo.
The scientists found that these dendrimersomes, which have a multilayered, onion-like structure, were able to “carry” high concentrations of molecules that don’t like water, which is common in pharmaceutical drugs. They were also able to carry these molecules more efficiently than other commercially available vessels. Additionally, the building block of the cell-like compartment, a janus dendrimer, is classified as an amphiphile, meaning it contains molecules that don’t like water and also molecules that are soluble in water, like lipids, that make up natural membranes.
“This is a different amphiphile that makes really cool self-assembled onions into which we were able to load a bunch of molecular cargos,” says co-author Matthew Good.
In a recent review of over 5,000 sleep studies, biomedical engineering researchers at the University of Texas at Austin found a connection between water-based passive body heating and sleep onset latency, efficiency, and quality. Using meta-analytical tools to compare all of the studies and patient data, lead author and Ph.D. candidate Shahab Haghayegh and his team found that a warm bath in the temperature range of 104-109 degrees Fahrenheit taken 1-2 hours before bed has the ability to improve all three considered sleep categories. This makes sense considering that our body’s Circadian rhythms govern both our sleep cycles and temperature, bringing us to a higher temperature during the day and a lower one at night during sleep. In fact, this lowering of body temperature before sleep is what helps to trigger the onset of sleep, so taking a warm bath and allowing your body to cool down from it before going to sleep enhances the body’s own efforts of naturally cooling down before we go to bed. With this new and comprehensive review, those who suffer from poor sleep quality may soon find solace in temperature regulation therapy systems.
People & Places
With the recent 50th anniversary of the first moon landing by Americans Neil Armstrong, Buzz Aldrin, and Michael Collins in 1969, ABC News looked back at one of the women involved in the project. Judy Sullivan was a biomedical engineer at the time of the project, and served as the lead engineer of the biomedical system for Apollo 11. In this role, she led studies on the astronauts’ breathing rates and sensor capabilities for the devices being sent into space to help the astronauts monitor their health. For the Apollo 11 mission and a lot of Sullivan’s early work at NASA, she worked on teams of all men, as women were often encouraged to become teachers, secretaries, or homemakers over other professions. Today, Sullivan says she’s thrilled that women have more career options to choose from, and wants to continue seeing more women getting involved in math and science.
We would like to congratulate Sanjay Kumar, M.D., Ph.D., on his appointment as the new Department Chair of Bioengineering at the University of California, Berkeley. Since joining the faculty in 2005, Kumar has received several prestigious awards including the NSF Career Award, the NIH Director’s New Innovator Award, the Presidential Early Career Award for Scientists and Engineers, and the Berkeley student-voted Outstanding Teacher Award.
Every cell in your body has a copy of your genome, tightly coiled and packed into its nucleus. Since every copy is effectively identical, the difference between cell types and their biological functions comes down to which, how and when the individual genes in the genome are expressed, or translated into proteins.
Scientists are increasingly understanding the role that genome folding plays in this process. The way in which that linear sequence of genes are packed into the nucleus determines which genes come into physical contact with each other, which in turn influences gene expression.
Jennifer Phillips-Cremins, assistant professor in Penn Engineering’s Department of Bioengineering, is a pioneer in this field, known as “3-D Epigenetics.” She and her colleagues have now demonstrated a new technique for quickly creating specific folding patterns on demand, using light as a trigger.
The technique, known as LADL or light-activated dynamic looping, combines aspects of two other powerful biotechnological tools: CRISPR/Cas9 and optogenetics. By using the former to target the ends of a specific genome fold, or loop, and then using the latter to snap the ends together like a magnet, the researchers can temporarily create loops between exact genomic segments in a matter of hours.
The ability to make these genome folds, and undo them, on such a short timeframe makes LADL a promising tool for studying 3D-epigenetic mechanisms in more detail. With previous research from the Phillips-Cremins lab implicating these mechanisms in a variety of neurodevelopmental diseases, they hope LADL will eventually play a role in future studies, or even treatments.
Alongside Phillips-Cremins, lab members Ji Hun Kim and Mayuri Rege led the study, and Jacqueline Valeri, Aryeh Metzger, Katelyn R. Titus, Thomas G. Gilgenast, Wanfeng Gong and Jonathan A. Beagan contributed to it. They collaborated with associate professor of Bioengineering Arjun Raj and Margaret C. Dunagin, a member of his lab.
“In recent years,” Phillips-Cremins says, “scientists in our fields have overcome technical and experimental challenges in order to create ultra-high resolution maps of how the DNA folds into intricate 3D patterns within the nucleus. Although we are now capable of visualizing the topological structures, such as loops, there is a critical gap in knowledge in how genome structure configurations contribute to genome function.”
In order to conduct experiments on these relationships, researchers studying these 3D patterns were in need of tools that could manipulate specific loops on command. Beyond the intrinsic physical challenges — putting two distant parts of the linear genome in physical contact is quite literally like threading a needle with a thread that is only a few atoms thick — such a technique would need to be rapid, reversible and work on the target regions with a minimum of disturbance to neighboring sequences.
The advent of CRISPR/Cas9 solved the targeting problem. A modification of the gene editing tool allowed researchers to home in on the desired sequences of DNA on either end of the loop they wanted to form. If those sequences could be engineered to seek one another out and snap together under the other necessary conditions, the loop could be formed on demand.
Cremins Lab members then sought out biological mechanisms that could bind the ends of the loops together, and found an ideal one in the toolkit of optogenetics. The proteins CIB1 and CRY2, found in Arabidopsis, a flowering plant that’s a common model organism for geneticists, are known to bind together when exposed to blue light.
“Once we turn the light on, these mechanisms begin working in a matter of milliseconds and make loops within four hours,” says Rege. “And when we turn the light off, the proteins disassociate, meaning that we expect the loop to fall apart.”
“There are tens of thousands of DNA loops formed in a cell,” Kim says. “Some are formed slowly, but many are fast, occurring within the span of a second. If we want to study those faster looping mechanisms, we need tools that can act on a comparable time scales.”
Fast acting folding mechanisms also have an advantage in that they lead to fewer perturbations of the surrounding genome, reducing the potential for unintended effects that would add noise to an experiment’s results.
The researchers tested LADL’s ability to create the desired loops using their high-definition 3D genome mapping techniques. With the help of Arjun Raj, an expert in measuring the activity of transcriptional RNA sequences, they also were able to demonstrate that the newly created loops were impacting gene expression.
The promise of the field of 3D-epigenetics is in investigating the relationships between these long-range loops and mechanisms that determine the timing and quantity of the proteins they code for. Being able to engineer those loops means researchers will be able to mimic those mechanisms in experimental conditions, making LADL a critical tool for studying the role of genome folding on a variety of diseases and disorders.
“It is critical to understand the genome structure-function relationship on short timescales because the spatiotemporal regulation of gene expression is essential to faithful human development and because the mis-expression of genes often goes wrong in human disease,” Phillips-Cremins says. “The engineering of genome topology with light opens up new possibilities to understanding the cause-and-effect of this relationship. Moreover we anticipate that, over the long term, the use of light will allow us to target specific human tissues and even to control looping in specific neuron subtypes in the brain.”
The research was supported by the New York Stem Cell Foundation; Alfred P. Sloan Foundation; the National Institutes of Health through its Director’s New Innovator Award from the National Institute of Mental Health, grant no. 1DP2MH11024701, and a 4D Nucleome Common Fund, grant no. 1U01HL1299980; and the National Science Foundation through a joint NSF-National Institute of General Medical Sciences grant to support research at the interface of the biological and mathematical sciences, grant no. 1562665, and a Graduate Research Fellowship, grant no. DGE-1321851.
There are two types of fat in the human body: brown and white. Brown fat, the “good” fat, is rich in mitochondria, which gives it its brown appearance. Whereas white fat stores calories and acts as an insulator, mitochondria-rich brown fat burns energy to produce heat throughout the body and maintains body temperature. White fat, conversely, uses its stored energy to insulate the body and keep its temperature level. While all fat serves a purpose in the body, an excess of white fat cells causes obesity, a condition affecting one in three adults in the U.S. and the root cause of many potential health problems. Finding ways to convert white fat to brown opens a possibility of treating this problem naturally.
A new study in Scientific Reports proposes a clever way to convert fat types. Professor of Biomedical Engineering Samuel Sia, PhD, of the Columbia University School of Engineering and Applied Science, led a team which developed a method of converting white fat into brown using a tissue-grafting technique. After extracting and converting the fat, it can then be transplanted back into the patient. White fat is hard-wired to convert to brown under certain conditions, such as exposure to cold temperatures, so the trick for Dr. Sia’s team was finding a way to make the conversion last for long periods. The studies conducted with mice suggested that using these methods, newly-converted fat stayed brown for a period of two months.
Dr. Sia’s team will proceed to conduct further tests, especially on the subjects’ metabolism and overall weight after undergoing the procedure, and they hope that eventual clinical trials will result in new methods to treat or even prevent obesity in humans.
Cremins Lab Student Appointed Blavatnik Fellow
The Perelman School of Medicine named Linda Zhou, a student in BE’s Cremins Laboratory, a Blavatnik Fellow for the 2018-2019 academic year. The selection process for this award is highly competitive, and Linda’s selection speaks to the excellent quality of her scholarship and academic performance. The fellows will be honored in a special ceremony at the Museum of Natural History in New York City.
Linda received her B.S. in Biophysics and Biochemistry from Yale University and is currently pursuing her M.D./Ph.D. in the Genomics and Computational Biology Program at Penn. “I am honored to be named a Blavatnik Fellow and am extremely excited to continue my graduate studies investigating neurological disorders and the 3D genome,” she said. “This support will be integral to achieving my long term goal of driving scientific discovery that will help treat human disease.”
Linda’s research is overseen by Penn Bioengineering Assistant Professor Jennifer Phillips-Cremins, PhD. “Linda is an outstanding graduate student,” said Dr. Cremins. “It is a true delight to work with her. She is hard working, intelligent, kind, and has extraordinary leadership ability. Her unrelenting search for ground-state truth makes her a shining star.”
The Blavatnik Family Fellowship in Biomedical Research is a new award announced by the Perelman School of Medicine in May of this year. This generous gift from the Blavatnik Family Foundation awards $2 million to six recipients in the Biomedical Graduate Studies Program at Penn for each of the next four years.
Growing Lungs in a Lab
As the demand for lung transplants continues to rise, so does the need for safe and effective transplanted lungs. Bioengineered lungs grown or created in labs are one way of meeting this demand. The problem – as is ever the case with transplants – is the high rate of rejection. The results of success are always better when cells from the patient herself (or autologous cells) are used in the transplanted organ.
Recently Joan Nichols, PhD, Professor of Internal Medicine, and Microbiology and Immunology, at the University of Texas Medical Branch at Galveston, successfully bioengineered the first human lung. Her latest study published in Science Translational Medicine describes the next milestone for Dr. Nichols’ lab: successfully transplanting a bioengineered lung into a pig.
These advances are possible due to Dr. Nichols’ work with autologous cells, continuing the trend of “on demand” medicine (i.e. medicine tailor for a specific patient) which we track on this blog. Dr. Nichols’ particular method is to build the structure of a lung (using the harvested organs of dead pigs in this case), de-cellularize the tissue, and then repopulate it with autologous cells from the intended recipient. This way, the host body recognizes the cells as friendly and the likelihood of acceptance increases. While further study is needed before clinical trials can begin, Dr. Nichols and her team see the results as extremely promising and believe that we are on the way to bioengineered human lungs.
Nanoparticles Combat Dental Plaque
Combine a diet high in sugar with poor oral hygiene habits and dental cavities likely result. The sugar triggers the formation of an acidic biofilm (plaque) on the teeth, eroding the surface. Early childhood dental cavities affect one in every four children in the United States and hundreds of millions more globally. It’s a particularly severe problem in underprivileged populations.
The flu virus is notoriously contagious, but there may be a way to stop it before it starts. In order for the influenza virus to successfully transport itself into the cells of a human host, it needs a certain protein called hemagglutinin which mediates its entry. By interfering with this vital ingredient, researchers can effectively kill the virus.
A new study in the Proceedings of the National Academy of Sciences discusses a method of disrupting the process by which this protein causes the virus to infect its host cells. This discovery could lead to more effective flu vaccines that target the flu virus at its root, rather than current ones which have to keep up with the ongoing changes and mutations of the virus itself. Indeed, the need for different vaccines to address various “strains” of the flu is moot if a vaccine can stop the virus from infecting people in the first place.
This breakthrough results from grants provided by the NSF, the Welch Foundation, and the NIH to Rice University and Baylor College of Medicine. Lead researchers José Onuchic, PhD, Harry C. and Olga K. Wiess Chair of Physics and Professor of Chemistry and BioSciences at Rice University; Jianpeng Ma, PhD, Professor of Bioengineering at Rice University and Lodwick T. Bolin Professor of Biochemistry at Baylor College of Medicine; and Qinghua Wang, PhD, Assistant Professor of Biochemistry at Baylor College of Medicine. Their team will continue to study the important role proteins play in how the flu virus operates.
People and Places
This week, we congratulate a few new leadership appointments in bioengineering. First, the Georgia Institute of Technology appointed Penn BE alumnus Andréas García, PhD, the new Executive Director of the Parker H. Petit Institute for Bioengineering and Bioscience. In addition to his new role, Dr. García is also the George W. Woodruff School of Mechanical Engineering Regents Professor. He conducts research in biomolecular, cellular, and tissue engineering and collaborates with a number of research centers across Georgia Tech. Dr. García graduated with both his M.S.E. and Ph.D. from the University of Pennsylvania’s Department of Bioengineering.
Secondly, the University of Minnesota Institute for Engineering in Medicine (IEM) named the Distinguished McKnight University Professor John Bischof, PhD, their new director. This follows Dr. Bischof’s recent position as interim director for the IEM. Dr. Bischof earned his Ph.D. in Mechanical Engineering at the University of California at Berkeley, and is currently a faculty member in both the Mechanical Engineering and Biomedical Engineering Departments at the University of Minnesota. Dr. Bischof holds the Carl and Janet Kuhrmeyer Chair in Mechanical Engineering.
At an earlier, but no less impressive, point in his academic career, Tanishq Abraham became the youngest person to graduate with a degree in biomedical engineering. The fifteen year old recently graduated summa cum laude from the University of California, Davis. As part of his graduating research, Abraham – a first-generation Indian-American – designed a device to measure the heart rates of burn victims. Abraham has already been accepted by U.C. Davis for his Ph.D. and plans to continue on to his M.D.
Finally, the work continues to create affordable and well-fitted prosthetics, especially for remote, rural, and underfunded areas both in the U.S. and abroad. Unfortunately, recent studies published by the Centre for Biomedical Engineering at the India Institute of Technology Delhi (IIT) demonstrate the uphill nature of this battle; stating that India alone contains over half a million upper limb amputees. To address this explosive population, researchers and entrepreneurs are using new bioengineering technologies such as digital manufacturing, 3D scanning and printing, and more. The best innovations are those that save time, resources, and money, without sacrificing quality in the prosthetic or patient comfort. Penn Engineering’s Global Biomedical Service (GBS) program similarly responds to this need, as each year students follow an academically rigorous course with a two-week immersive trip to China, where they learn how to create and fit prosthetic limbs for local children in conjunction with Hong Kong Polytechnic University.
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 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.