Latest Publications
Mitchell Lab and Walhout Lab collaboration paper published
December, 2020
Brewster Lab
Lee Lab
Although the activity of the epidermal growth factor receptor (EGFR) pathway is increased in triple-negative breast cancers (TNBC), patients are generally insensitive to EGFR inhibitors. Peter Cruz-Gordillo, Megan Honeywell, and colleagues found that this is because TNBC cells produced the prosurvival protein Mcl-1. A gene deletion screen revealed that insensitivity to the EGFR inhibitor erlotinib required MCL1 expression promoted by the ELP family of transcription-elongation regulators, particularly ELP4. The findings suggest that an ELP4–Mcl-1 mechanism masks erlotinib sensitivity in TNBC and that combining erlotinib with an Mcl-1 inhibitor might be effective in patients with TNBC.
Shank Lab
 |
A new study shows that transparent soil substitutes can be used to replicate the interactions of bacteria and fungi in soil, opening up a new approach to learning how soil microbes contribute to a healthy ecosystem. Elizabeth Shank, PhD, associate professor of microbiology & physiological systems and senior author on the study, describes how using two transparent soil substitutes allowed scientists to follow how soil bacteria rely on fungi to help them survive extended dry periods.
Walhout Lab
Youk Lab
Laman Trip DS, Youk H. (2020) Yeasts collectively extend the limits of habitable temperatures by secreting glutathione, Nature Microbiology 5:943-954.
Program in Systems Biology News
Top Story
UMMS scientists to expand 4D nucleome research with $13 million NIH grants
Job Dekker and Paul Kaufman to investigate architecture of genome as it changes over time
October 23, 2020
Hyun Youk, PhD, has received the CIFAR AI Catalyst Grant
November 2, 2020This grant will support of his collaborative project, “Mechanisms of bacterial spatial localization in response to oxidative stress in the gut.”This is a joint award with Professor Carolina Tropini, School of Biomedical Engineering, University of British Columbia.
Hyun Youk, PhD, has been selected as a member for the EMBO Young Investigator Programme
November 2, 2020EMBO identifies and supports some of the best young researchers in the life sciences. EMBO Young Investigators are group leaders in the early stages of setting up an independent laboratory and the programme helps them develop skills and connections that will help them during this career stage.
Hyun Youk, PhD, joins the Program in Systems Biology
November 2, 2020
We welcome Dr. Hyun Youk to UMass Medical School as an Associate Professor in the Program in Systems Biology. Hyun and his lab study how living systems transition between being alive and being either truly dead or seemingly dead. They hope to discover common, quantitative principles that underlie life or death transitions. The Youk Lab is particularly eager to unveil principles that allow life to be restarted after it has nearly ceased. Their studies use microbes and mammalian cells (e.g., yeasts and mouse embryonic stem cells), and combine experimental approaches, mathematical models, and ideas rooted in statistical physics to achieve their goal.
Despite the remarkable advances in science, "what is life?" is a long-standing, deceptively simple-to-state question that still remains difficult to address at a deep level. The same is true for the related questions, "what is death?" and "can we revive any dead things?". Every molecule in a cell (e.g., DNA, RNA, protein) is governed by the same laws and principles of physics and chemistry as non-living systems. Yet, unlike non-living systems such as rocks and metals, biomolecules can interact amongst themselves to somehow endow a cell with "life" and all the remarkable behaviors associated with a living state (e.g., making decisions, processing information, cognition). Microscopic cells, too, can interact amongst them to endow life to macroscopic beings. How does a state of living emerge from interacting molecules and cells? The Youk Lab hopes that their work can reveal how small and large-scale networks of molecules and cells engender life, death, and revival. Beneath the molecular mechanisms that are specific to each organism, they believe that there may be quantitative principles that are common to many different cell types and organisms.
Welcome to the PSB!
Job Dekker elected to European Molecular Biology Organization
July 07, 2020
The European Molecular Biology Organization (EMBO) has elected Job Dekker, PhD, Howard Hughes Medical Institute investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology, and co-director of the Program in Systems Biology, to lifetime membership in the organization. Dr. Dekker and 62 other leading scientists from around the world were elected in recognition of their remarkable achievements in the life sciences.
“The new members have contributed to the success of research in the life sciences in Europe and around the world,” said EMBO Director Maria Leptin. “As EMBO members, they can help to shape the future through EMBO’s work to support talented researchers, bring ideas together, and promote an international research environment conducive to excellent science.”
UMMS students produce hand sanitizer for nearby hospitals amid COVID-19 pandemic
April 10, 2020In a time of dire need, as medical professionals are working to care for patients during the COVID-19 pandemic and critical supplies of protective gear are running low, students in the Graduate School of Biomedical Sciences at UMass Medical School produced nearly 130 gallons of hand sanitizer in less than three days to help sustain local hospitals.
“We wanted to find a way to get the graduate students involved in this effort,” said MD/PhD student Peter Cruz-Gordillo, a member of the UMMS COVID-19 student task force. “By the day, COVID-19 cases are increasing. There’s a great need for sanitizer not just for hands, but also to clean off the PPE. We thought this would be a great opportunity to help.”
Elizabeth Shank, PhD, joins the Program in Systems Biology
January 2, 2020
PSB welcomes Dr. Elizabeth Shank to UMass Medical School as an Associate Professor of Microbiology & Physiological Systems. Beth and her lab study microbiolal activities and how they impact their hosts and ecosystem. They are particularly fascinated by the idea that microbes are able to generate and secrete chemical cues (specialized or secondary metabolites) that can act as interspecies signals to influence the physiology and metabolism of their microbial neighbors, and thus contribute to the stability and functioning of complex microbial communities.
The Shank lab's research dissects microbial interactions using traditional microbiology, fluorescent co-culture, bioinformatics, mass spectrometry imaging, and native-like microcosms. They aim to define the molecular basis of how microbial specialized metabolites impact bacterial cellular differentiation, discover chemical tools to kill and modulate pathogens, and dynamically visualize microbial interactions at the single-cell level. Their goal is to gain insights into microbial ecology as well as identifying novel bioactive compounds as potential therapeutics and chemical tools to achieve our long-term goal of manipulating microbial communities to improve host health and the environment.
Welcome to PSB!
Amir Mitchell to study cellular decoding of extracellular information with new NIH grant
October 9, 2019
Amir Mitchell, PhD, assistant professor of molecular medicine in the Program in Systems Biology, has received the Maximizing Investigators' Research Award from the National Institute of General Medical Sciences to support research into cellular decoding of signaling dynamics.
Dr. Mitchell will use the five-year, nearly $2.1 million grant to study how intracellular dysfunctions, as mutations, corrupt information encoding and which cellular processes need to be targeted in order to restore proper encoding.
“Healthy cells in the human body use temporal patterns of activity in signaling pathways to encode information about the extracellular environment. Many diseases, foremost cancer, stem from corruption of these temporal signaling patterns which culminates in maladaptive outcomes as uncontrolled cell proliferation,” Mitchell said.
Job Dekker receives the Chancellor’s Medal for Distinguished Scholarship at the 2019 Convocation
September 13, 2019
Job Dekker, PhD, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology, received the Chancellor’s Medal for Distinguished Scholarship. As recipient of the honor, Dr. Dekker will present the plenary lecture at the 20th Annual Research Retreat next month.
Chancellor Michael Collins (pictured right with Dr. Dekker) said Dekker was described by his peers as an “unselfish collaborator,” an “intellectual leader,” and as one who “inspires loyalty in his collaborators.”
Amir Mitchell lab engages high school classes in superbug research via online portal
May 14, 2019
Under the guidance of Amir Mitchell, PhD, assistant professor of molecular medicine in the Program in Systems Biology, 250 high school students from Massachusetts, California and Israel have had the opportunity to research one of medicine’s biggest challenges today—the emergence of superbugs. While students often learn about strains of drug-resistant bacteria in school, Dr. Mitchell’s innovative program is allowing these students to conduct their own investigations into the phenomenon. Mitchell’s lab collaborated with Anat Yarden, PhD, of the Weizmann Institute of Science in Israel, to develop an approach to educate high school students on the emergence of antibiotics resistance through natural selection and rapid evolutionary adaptation. This year, Worcester Tech students (pictured left) were joined by peers in Brockton and San Francisco to monitor, in real-time through live video streams on YouTube and the project’s website, how drug resistance gradually emerged. The educational framework for this project was published in PLoS Biology.
Job Dekker and colleagues develop new model to examine large mutations in cells
September 11, 2018
Scientists at UMass Medical School, Pennsylvania State University and Florida State University have developed a new computational framework combining three methods of finding large mutations in cancer cells into a single, more complete model. The new method, described in a study published in Nature Genetics, will help researchers find what are called “structural variants” within cancer genomes and learn more about how such cancers begin.
Each of the three methods alone only reveals a portion of the structural variations found in cancer cells, but when the results of all methodologies are integrated using the new model, a more comprehensive view of the genome emerges, said study authors Job Dekker, PhD, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology at UMMS, and Feng Yue, PhD, assistant professor of biochemistry and molecular biology at Penn State.
Ben Landry, Mike Lee and colleagues publish their findings on the diversity in tumor-stromal cell interactions that modulate chemotherapeutic drug sensitivity in Molecular Systems Biology
June 28, 2018
Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor-stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.
PSB faculty receive award for outstanding contribution to curricular development for the Systems and Computational Biology course
April 19, 2018
The faculty members of the Program in Systems Biology received an award for outstanding contribution to curricular development at the 20th annual Educational Recognition Awards ceremony. The Systems and Computational Biology course was cited for excellence in teaching concepts and ideas needed for modern biological analysis. All faculty members from the program contributed to the course development: A.J. Marian Walhout, PhD, Robert C. Brewster, PhD, Job Dekker, PhD, Michael J. Lee, PhD, Amir Z. Mitchell, PhD, and Lutfu Safak Yilmaz, PhD.
Job Dekker receives 2018 Edward Novitski Prize
February 9, 2018
The Genetics Society of America (GSA) has named Job Dekker, PhD, the recipient of the 2018 Edward Novitski Prize. The award honors investigators who have exhibited “an extraordinary level of creativity and intellectual ingenuity in the solution of significant problems in genetics research.”
Dr. Dekker, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology at UMass Medical School, is recognized for scientific contributions that include the development of chromosome conformation capture—a technique that has revolutionized chromosome research.
Chromosome conformation capture, or 3C, allows researchers to study the interactions of chromosomes at resolutions and scales previously impossible to attain. In 3C, chromatin is treated with a crosslinking chemical that causes chromosomal regions that are near each other to be chemically linked together. By isolating these crosslinked regions of chromatin and determining their DNA sequences, geneticists can deduce which parts of the genome are in proximity to each other. Although the foundation of the technique seems simple, no one before Dekker had formulated a practical way to take advantage of it for a high-throughput molecular assay like 3C.
Study from the Dekker lab and colleagues answers 100-year-old question about how chromosomes get their distinctive X-shape
January 18, 2018
A multi-disciplinary team at UMass Medical School led by Job Dekker, PhD, has unraveled how chromosomes are packaged into their iconic X-shape during cell division. Packaging the genome inside mitotic chromosomes is critical to the faithful transmission of DNA from parent to daughter cells; these findings shed new light on the inner workings of cell division and may provide novel targets for potential cancer treatments.
“Cancer cells are experts at dividing. They do it well, and they do it very fast,” said Dr. Dekker, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology at UMMS. “Many cancer therapies take advantage of this fact and attack dividing cells specifically in the hopes of eliminating the cancer. The more we understand about how this process works, the more ways we have to throw a wrench into this machine and disrupt this process.”
Job Dekker appointed inaugural Joseph J. Byne Chair in Biomedical Research
July 17, 2017
Two newly established endowed chairs at UMass Medical School—the Joseph J. Byrne Chair in Biomedical Research and the Herman G. Berkman Chair in Diabetes Care Innovation—were approved by the UMass Board of Trustees on Monday, July 17, according to Chancellor Michael F. Collins.
Job Dekker, PhD, Howard Hughes Medical Institute Investigator, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology, and Michael J. Thompson, MD, clinical professor of medicine and chief of adult diabetes clinical research, were appointed to the positions, respectively.
The purpose of The Joseph J. Byrne Chair in Biomedical Research is to support the research activities of an accomplished faculty member whose work is advancing the fundamental understanding of human biological systems and offering new and innovative pathways to treat human disease. Dr. Dekker is one of the medical school’s most dynamic and cutting-edge researchers and is the inaugural holder of The Joseph J. Byrne Chair in Biomedical Research.
Aurian García-González, Marian Walhout, and colleagues publish study in Cell showing that bacteria modulate host chemotherapeutic drug responses
April 21, 2017
The bacteria residing in your digestive tract, or your gut microbiota, may play an important role in your ability to respond to chemotherapy drugs, according to a new study by scientists at UMass Medical School. Published in Cell, the study by Marian Walhout, PhD, and colleagues shows that when a common research model, the roundworm Caenorhabditis elegans, was fed a diet of E.coli bacteria, the worms were 100 times more sensitive to the chemotherapy drug floxuridine (FUDR) than worms who were fed different bacteria. FUDR is a commonly used drug to treat colorectal cancer.
Cancer doctors have long been puzzled by how dramatically patients with the same disease can respond differently to the same treatment—even in cases where identical twins have the same diagnosis. “Two twins, genetically identical, who have colorectal cancer could potentially respond very differently to the same treatment because of their microbiome,” said Dr. Walhout, the Maroun Semaan Chair in Biomedical Research, professor of molecular medicine and co-director of the Program in Systems Biology. “If we can learn how bacteria affect the efficacy or toxicity of chemotherapies, it’s not hard to imagine developing personalized medicine built on probiotics that could improve the clinical benefits of some cancer treatments.”
Rob Brewster and colleagues publish a kinetic model of transcription that incorporates the interplay between transcription factor copy number and its binding sites in PLoS Computational Biology
April 17, 2017
Gene expression is intrinsically a stochastic (noisy) process with important implications for cellular functions. Deciphering the underlying mechanisms of gene expression noise remains one of the key challenges of regulatory biology. Theoretical models of transcription often incorporate the kinetics of how transcription factors (TFs) interact with a single promoter to impact gene expression noise. However, inside single cells multiple identical gene copies as well as additional binding sites can compete for a limiting pool of TFs. Here we develop a simple kinetic model of transcription, which explicitly incorporates this interplay between TF copy number and its binding sites. We show that TF sharing enhances noise in mRNA distribution across an isogenic population of cells. Moreover, when a single gene copy shares its TFs with multiple competitor sites, the mRNA variance as a function of the mean remains unaltered by their presence. Hence, all the data for variance as a function of mean expression collapse onto a single master curve independent of the strength and number of competitor sites. However, this result does not hold true when the competition stems from multiple copies of the same gene. Therefore, although previous studies showed that the mean expression follows a universal master curve, our findings suggest that different scenarios of competition bear distinct signatures at the level of variance. Intriguingly, the introduction of competitor sites can transform a unimodal mRNA distribution into a multimodal distribution. These results demonstrate the impact of limited availability of TF resource on the regulation of noise in gene expression.
Marian Walhout appointed inaugural Maroun Semaan Chair in Biomedical Research
April 12, 2017
UMass Medical School will invest three faculty members into newly endowed chairs and three more to existing endowed chairs, according to a vote by the University of Massachusetts Board of Trustees at its April 12 meeting.
Marian Walhout, PhD, professor of molecular medicine and co-director of the Program in Systems Biology, has been appointed the inaugural recipient of The Maroun Semaan Chair in Biomedical Research. Dr. Walhout is a pioneer among those working to understand how genes are expressed on a system level, and how these complex biological networks adapt to various conditions. Her research, which combines large-scale data sets and uses computational modeling to unravel regulatory networks involved in metabolic and genetic development, has advanced the fundamental understanding of these systems and offers potentially new and innovative pathways to treat human disease.
Latest Publications
Mitchell Lab and Walhout Lab collaboration paper published
December, 2020
Brewster Lab
Lee Lab
Although the activity of the epidermal growth factor receptor (EGFR) pathway is increased in triple-negative breast cancers (TNBC), patients are generally insensitive to EGFR inhibitors. Peter Cruz-Gordillo, Megan Honeywell, and colleagues found that this is because TNBC cells produced the prosurvival protein Mcl-1. A gene deletion screen revealed that insensitivity to the EGFR inhibitor erlotinib required MCL1 expression promoted by the ELP family of transcription-elongation regulators, particularly ELP4. The findings suggest that an ELP4–Mcl-1 mechanism masks erlotinib sensitivity in TNBC and that combining erlotinib with an Mcl-1 inhibitor might be effective in patients with TNBC.
Shank Lab
|
A new study shows that transparent soil substitutes can be used to replicate the interactions of bacteria and fungi in soil, opening up a new approach to learning how soil microbes contribute to a healthy ecosystem. Elizabeth Shank, PhD, associate professor of microbiology & physiological systems and senior author on the study, describes how using two transparent soil substitutes allowed scientists to follow how soil bacteria rely on fungi to help them survive extended dry periods.
Walhout Lab
Youk Lab
Laman Trip DS, Youk H. (2020) Yeasts collectively extend the limits of habitable temperatures by secreting glutathione, Nature Microbiology 5:943-954.