A research team led by engineers at the University of Pennsylvania and Northwestern University scientists has created a new synthetic biology approach, or a “QR code for cancer cells,” to follow tumor cells over time, finding there are meaningful differences in why a cancer cell dies or survives in response to anti-cancer therapies.
Remarkably, what fate cancer cells choose after months of therapy is “entirely predictable” based on seemingly small, yet important, differences that appear even before treatment begins. The researchers also discovered the reason is not genetics, contrary to beliefs held in the field.
The study outlined the team’s new technology platform that developed a QR code for each of the millions of cells for scientists to find and use later — much like tagging swans in a pond. The QR code directs researchers to a genome-wide molecular makeup of these cells and provides information about how they’ve reacted to cancer treatment.
“We think this work stands to really change how we think about therapy resistance,” said Arjun Raj, co-senior author and Professor in Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania. “Rather than drug-resistant cells coming in just one flavor, we show that even in highly controlled conditions, different ‘flavors’ can emerge, raising the possibility that each of these flavors may need to be treated individually.”
In the study, the lab and collaborators sought to apply synthetic biology tools to answer a key question in cancer research: What makes certain tumors come back a few months or years after therapy? In other words, could the lab understand what causes some rare cells to develop therapeutic resistance to a drug?
“There are many ways cells become different from each other,” said Yogesh Goyal, the co-senior author at Northwestern University. “Our lab asks, how do individual cells make decisions? Understanding this in the context of cancer is all the more exciting because there’s a clinically relevant dichotomy: A cell dies or becomes resistant when faced with therapies.”
Using the interdisciplinary team, the scientists put the before-and-after cloned cells through a whole genome sequencing pipeline to compare the populations and found no systematic underlying genetic mutations to investigate the hypothesis. Raj and Goyal helped develop the QR code framework, FateMap, that could identify each unique cell that seemed to develop resistance to drug therapy. “Fate” refers to whether a cell dies or survives (and if so, how), and the scientists “map” the cells across their lifespan, prior to and following anti-cancer therapy. FateMap is the result of work from several research institutions, and it applies an amalgamation of concepts spanning several disciplines, including synthetic biology, genome engineering, bioinformatics, machine learning and thermodynamics.
“Some are different by chance — just as not all leaves on a tree look the same — but we wanted to determine if that matters,” Goyal said. “The cell biology field has a hard time defining if differences have meaning.”
Mustafa Mir, Assistant Professor of Cell and Developmental Biology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was selected as one of Howard Hughes Medical Institute’s 31 new Freeman Hrabowski Scholars. The group consists of outstanding early career faculty in science who have potential to become leaders in their research fields and to create diverse and inclusive lab environments in which everyone can thrive. Mir and his lab develop and apply new microscopes to directly visualize the molecular scale events that underlie gene expression within live embryos.
Spencer Haws, Postdoctoral Research Fellow in the laboratory of Jennifer E. Phillips-Cremins, Associate Professor and Dean’s Faculty Fellow in Bioengineering and in Genetics, was awarded a 2022 Druckenmiller Fellowship from the New York Stem Cell Foundation Research Institute (NYSCF). This prestigious program is the largest dedicated stem cell fellowship program in the world and was developed to train and support young scientists working on groundbreaking research in the field of stem cell research. Haws is one of only five inductees into the 2022 class of fellows.
Haws earned his Ph.D. in Nutritional Sciences in 2021 from the University of Wisconsin-Madison, where he studied metabolism-chromatin connections under the mentorship of John Denu, Professor in Biomolecular Chemistry at the University of Wisconsin-Madison. As a NYSCF – Druckenmiller Fellow in the Cremins Laboratory for Genome Architecture and Spatial Neurobiology, Haws is using this previously developed expertise to frame his investigations into the underlying mechanisms driving the neurodegenerative disorder fragile X syndrome (FXS). “Ultimately, I hope that this work will help guide the development of future FXS-specific therapeutics of which none currently exist,” says Haws.
Jennifer E. Phillips-Cremins, Associate Professor and Dean’s Faculty Fellow in Bioengineering and Genetics, has been awarded the 2022 Dr. Susan Lim Award for Outstanding Young Investigator by the International Society for Stem Cell Research (ISSCR), the preeminent, global organization dedicated to stem cells research.
This award recognizes the exceptional achievements of an investigator in the early part of his or her independent career in stem cell research. Cremins works in the field of epigenetics, and is a pioneer in understanding how chromatin, the substance within a chromosome, works:
“Dr. Phillips-Cremins is a gifted researcher with diverse skills across cell, molecular, and computational biology. She is a shining star in the stem cell field who has already made landmark contributions in bringing long-range chromatin folding mechanisms to stem cell research. In addition to her skills as an outstanding researcher,” ISSCR President Melissa Little, Ph.D., said. “She has flourished as an independent investigator, providing the stem cell field with unique and creative approaches that have facilitated conceptual leaps in our understanding of long-range spatial regulation of stem cell fate. Congratulations, Jennifer, on this prestigious honor.”
Cremins was awarded a NIH Director’s Pioneer Award in 2021 and a Chan Zuckerberg Initiative (CZI) grant as part of the CZI Collaborative Pairs Pilot Project in 2020. The long-term goal of her lab is to understand the mechanisms by which chromatin architecture governs genome function. The ISSCR will recognize Cremins and her research in a plenary session during the ISSCR annual meeting on June 15.
Heatmaps are used by researchers in the lab of Jennifer Phillips-Cremins to visualize which physically distant genes are brought into contact when the genome is in its folded state.
More data is being produced across diverse fields within science, engineering, and medicine than ever before, and our ability to collect, store, and manipulate it grows by the day. With scientists of all stripes reaping the raw materials of the digital age, there is an increasing focus on developing better strategies and techniques for refining this data into knowledge, and that knowledge into action.
Enter data science, where researchers try to sift through and combine this information to understand relevant phenomena, build or augment models, and make predictions.
One powerful technique in data science’s armamentarium is machine learning, a type of artificial intelligence that enables computers to automatically generate insights from data without being explicitly programmed as to which correlations they should attempt to draw.
Advances in computational power, storage, and sharing have enabled machine learning to be more easily and widely applied, but new tools for collecting reams of data from massive, messy, and complex systems—from electron microscopes to smart watches—are what have allowed it to turn entire fields on their heads.
“This is where data science comes in,” says Susan Davidson, Weiss Professor in Computer and Information Science (CIS) at Penn’s School of Engineering and Applied Science. “In contrast to fields where we have well-defined models, like in physics, where we have Newton’s laws and the theory of relativity, the goal of data science is to make predictions where we don’t have good models: a data-first approach using machine learning rather than using simulation.”
Penn Engineering’s formal data science efforts include the establishment of the Warren Center for Network & Data Sciences, which brings together researchers from across Penn with the goal of fostering research and innovation in interconnected social, economic and technological systems. Other research communities, including Penn Research in Machine Learning and the student-run Penn Data Science Group, bridge the gap between schools, as well as between industry and academia. Programmatic opportunities for Penn students include a Data Science minor for undergraduates, and a Master of Science in Engineering in Data Science, which is directed by Davidson and jointly administered by CIS and Electrical and Systems Engineering.
Penn academic programs and researchers on the leading edge of the data science field will soon have a new place to call home: Amy Gutmann Hall. The 116,000-square-foot, six-floor building, located on the northeast corner of 34th and Chestnut Streets near Lauder College House, will centralize resources for researchers and scholars across Penn’s 12 schools and numerous academic centers while making the tools of data analysis more accessible to the entire Penn community.
Faculty from all six departments in Penn Engineering are at the forefront of developing innovative data science solutions, primarily relying on machine learning, to tackle a wide range of challenges. Researchers show how they use data science in their work to answer fundamental questions in topics as diverse as genetics, “information pollution,” medical imaging, nanoscale microscopy, materials design, and the spread of infectious diseases.
Bioengineering: Unraveling the 3D genomic code
Scattered throughout the genomes of healthy people are tens of thousands of repetitive DNA sequences called short tandem repeats (STRs). But the unstable expansion of these repetitions is at the root of dozens of inherited disorders, including Fragile X syndrome, Huntington’s disease, and ALS. Why these STRs are susceptible to this disease-causing expansion, whereas most remain relatively stable, remains a major conundrum.
Complicating this effort is the fact that disease-associated STR tracts exhibit tremendous diversity in sequence, length, and localization in the genome. Moreover, that localization has a three-dimensional element because of how the genome is folded within the nucleus. Mammalian genomes are organized into a hierarchy of structures called topologically associated domains (TADs). Each one spans millions of nucleotides and contains smaller subTADs, which are separated by linker regions called boundaries.
Associate professor and Dean’s Faculty Fellow Jennifer E. Phillips-Cremins.
“The genetic code is made up of three billion base pairs. Stretched out end to end, it is 6 feet 5 inches long, and must be subsequently folded into a nucleus that is roughly the size of a head of a pin,” says Jennifer Phillips-Cremins, associate professor and dean’s faculty fellow in Bioengineering. “Genome folding is an exciting problem for engineers to study because it is a problem of big data. We not only need to look for patterns along the axis of three billion base pairs of letters, but also along the axis of how the letters are folded into higher-order structures.”
To address this challenge, Phillips-Cremins and her team recently developed a new mathematical approach called 3DNetMod to accurately detect these chromatin domains in 3D maps of the genome in collaboration with the lab of Dani Bassett, J. Peter Skirkanich Professor in Bioengineering.
“In our group, we use an integrated, interdisciplinary approach relying on cutting-edge computational and molecular technologies to uncover biologically meaningful patterns in large data sets,” Phillips-Cremins says. “Our approach has enabled us to find patterns in data that classic biology training might overlook.”
In a recent study, Phillips-Cremins and her team used 3DNetMod to identify tens of thousands of subTADs in human brain tissue. They found that nearly all disease-associated STRs are located at boundaries demarcating 3D chromatin domains. Additional analyses of cells and brain tissue from patients with Fragile X syndrome revealed severe boundary disruption at a specific disease-associated STR.
“To our knowledge, these findings represent the first report of a possible link between STR instability and the mammalian genome’s 3D folding patterns,” Phillips-Cremins says. “The knowledge gained may shed new light into how genome structure governs function across development and during the onset and progression of disease. Ultimately, this information could be used to create molecular tools to engineer the 3D genome to control repeat instability.”
Jennifer E. Phillips-Cremins (upper left) and members of her lab.
Each year, the National Institutes of Health (NIH) recognizes exceptionally creative scientists through its High-Risk, High-Reward Research Program. The four awards granted by this program are designed to support researchers whose “out of the box” and “trailblazing” ideas have the potential for broad impact.
Jennifer E. Phillips-Cremins, Associate Professor and Dean’s Faculty Fellow in Penn Engineering’s Department of Bioengineering and the Perelman School of Medicine’s Department of Genetics, is one such researcher. As a recipient of an NIH Director’s Pioneer Award, she will receive $3.5 million over five years to support her work on the role that the physical folding of chromatin plays in the encoding of neural circuit and synapse properties contributing to long-term memory.
Phillips-Cremins’ award is one of 106 grants made through the High-Risk, High-Reward program this year, though she is only one of 10 to receive the Pioneer Award, which is the program’s largest funding opportunity.
“The science put forward by this cohort is exceptionally novel and creative and is sure to push at the boundaries of what is known,” said NIH Director Francis S. Collins.
Phillips-Cremins’ research is in the general field of epigenetics, the molecular and structural modifications that allow the genome — an identical copy of which is found in each cell — to express genes differently at different times and in different parts of the body. Within this field, her lab focuses on higher-order folding patterns of the DNA sequence, which bring distant sets of genes and regulatory elements into close proximity with one another as they are compressed inside the cell’s nucleus.
Previous work from the Cremins lab has investigated severe genome misfolding patterns common across a class of genetic neurological disorders, including fragile X syndrome, Huntington’s disease, ALS and Friedreich’s ataxia.
With the support of the Pioneer Award, she and the members of her lab will extend that research to a more fundamental question of neuroscience: how memory is encoded over decades, despite the rapid turnover of the relevant proteins and RNA sequences within the brain’s synapses.
“Our long-term goals are to understand how, when and why pathologic genome misfolding leads to synaptic dysfunction by way of disrupted gene expression,” said Phillips-Cremins, “as well as to engineer the genome’s structure-function relationship to reverse pathologic synaptic defects in debilitating neurological diseases.”
(Left to right) Top row: Jennifer E. Phillips-Cremins, Rajan Jain, and Eric Joyce. Middle row: Melike Lakadamyali, Golnaz Vahedi, and Gerd Blobel. Bottom row: Bomyi Lim, Arjun Raj, and Stanley Qi.
Popular accounts of the human genome often depict it as a long string of DNA base pairs, but in reality the genome is separated into chromosomes that are tightly twisted and coiled into complex three-dimensional structures. These structures create a myriad of connections between sites on the genome that would be distant from one another if stretched out end-to-end. These “long range interactions” are not incidental — they regulate the activity of our genes during development and can cause disease when disrupted.
Now two teams of researchers at the Perelman School of Medicine at the University of Pennsylvania, each led by Jennifer E. Phillips-Cremins, associate professor and Dean’s Faculty Fellow in the Department of Bioengineering at the School of Engineering and Applied Science and of Genetics at the Perelman School of Medicine have been awarded grants totaling $9 million from the National Institutes of Health (NIH), as part of a major NIH Common Fund initiative to understand such 3D-genomic interactions.
The initiative, known as the 4D Nucleome Program, broadly aims to map higher-order genome structures across space and time, as well as to understand how the twists and loops of the DNA sequence govern genome function and cellular phenotype in health and disease.
N.B.: In addition to Phillips-Cremins, collaborators include Arjun Raj, Professor in Bioengineering and Genetics, and Bioengineering Graduate Group Members Melike Lakadamyali, Associate Professor in Physiology, and Bomyi Lim, Assistant Professor in Chemical and Biomolecular Engineering.
The Chan Zuckerberg Initiative’s Collaborative Pairs Pilot Project Award is part of its Neurodegeneration Challenge Network
Jennifer Phillips-Cremins, Ph.D.
More than 30 inherited disorders are caused by the unstable expansion of repetitive DNA sequences, including Huntington’s disease, ALS, Fragile X syndrome, and Friedreich’s ataxia. Jennifer E. Phillips-Cremins, associate professor in Penn Engineering’s Department of Bioengineering and in the Perelman School of Medicine’s Department of Genetics, has shown another link between these disorders: the location of these expanding genes relative to the complicated folding patterns the genome exhibits to fit inside the nucleus of a cell.
Now, Phillips-Cremins is among 60 researchers taking part in a $4.5 Million Chan Zuckerberg Initiative project that aims to apply novel, interdisciplinary approaches toward investigating neurodegenerative disorders. The CZI Collaborative Pairs Pilot Project will fund 30 teams that combine clinical and basic science expertise and have at least one early- or mid-career researcher.
Jennifer Phillips-Cremins, Ph.D., was recently promoted to the tenured position of Associate Professor in Penn’s Department of Bioengineering. Cremins, leads a lab on campus in 3D Epigenomes and Systems Neurobiology.
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 research team led by engineers at the University of Pennsylvania and Northwestern University scientists has created a new synthetic biology approach, or a “QR code for cancer cells,” to follow tumor cells over time, finding there are meaningful differences in why a cancer cell dies or survives in response to anti-cancer therapies.
