CBC Announces Sixth Lever Award

Chicago Biomedical Consortium Lever Award Supports Center’s New Instrumentation and Shared Resources

Vadim Backman (NU), Lucy Godley (UChicago) and Jack Kaplan (UIC) are co-Principal Investigators on the CBC’s new $1.5M Lever Award:  “Chicago Center for Physical Science-Oncology Innovation and Translation.”  Professors Backman, Godley, and Kaplan are members of a team led by Thomas O’Halloran (NU) and Jonathan Licht (NU) which recently won a $10M NCI U54 grant to fund the Chicago Region Physical Science-Oncology Center.  CBC Lever funds will support the Center’s new instrumentation and shared resources.

Scientists have long known that the transformation of healthy cells to cancer cells involves more than just mutations in our genetic DNA sequence. Now, thanks to a $10M grant from the National Cancer Institute, researchers in the Chicago Region Physical Science–Oncology Center (CR-PSOC) will advance our understanding of this disease by examining the role of physical and chemical forces involved in the transformation of a normal cell into a cancer-causing one. This team will develop new ways to interrogate changes in the “epigenome”— the chemical markers that influence the folding and condensation of DNA within the nucleus, and changes in the “metallome” – the metal ion content of the cell— that support the development of cancer.

The “packaging” of DNA influences the local environment of genes and their regulation. DNA is packaged together with proteins, RNA and metal ions into a structure known as chromatin which is responsible for DNA folding and plays a vital role in gene expression. CR-PSOC investigators will deploy a series of physical science approaches and novel imaging methods to determine whether changes in chromatin folding result in aberrant patterns of gene expression that drive cancer progression. Then, they will translate these advances into a deeper understanding of cancer biology and, eventually, into novel cancer therapy.

The Center is led by a pair of Northwestern researchers. Renowned physical scientist Thomas V. O’Halloran, PhD, Morrison Professor of Chemistry in the Weinberg College of Arts and Science and Director of Northwestern’s Chemistry of Life Processes Institute (CLP), is principal investigator. Collaborating with him is internationally recognized cancer researcher Jonathan D. Licht, MD, Director of the Division of Hematology and Oncology and Dobe Professor of Hematology-Oncology in the Feinberg School of Medicine.  They are both members of Northwestern’s Robert H. Lurie Comprehensive Cancer Center.

The CR-PSOC is composed of a multi-disciplinary team of 12 physical scientists and 8 cancer researchers from fields encompassing physics, chemistry, biomedical engineering, biophysics, biochemistry, pharmacology, and hematology-oncology from the Chicago region’s premier research institutions: Northwestern University, the University of Chicago and University of Illinois at Chicago.  Project leaders recruited additional experts in the physical sciences and chromatin fields from outside Chicago, namely MIT, Memorial-Sloan Kettering Cancer Center, and the University of Massachusetts Medical School.

“Several thought-leaders in the physical sciences and oncology fields have joined forces to bring emergent ideas and cutting-edge methods and focus them on understanding  molecular changes that allow the cancer cell to grow out of control,” said Dr. O’Halloran (right). “By harnessing these combined interdisciplinary strengths, this team will make significant progress in the diagnosis and treatment of several types of cancer.”

Designed around the theme of “Spatio-Temporal Organization of Chromatin and Information Transfer in Cancer,” the Center consists of three interrelated project areas, each focused on different aspects of chromatin structure and function, plus two core facilities, and pilot project, education and outreach programs.

“What we’re trying to do is understand the fundamental rules of misbehavior of cancer cells with a particular class of mutations,” said Dr. Licht (left).

The Center will be a knowledge hub for training the next generations of scholars to make breakthroughs at the convergence of physical sciences and oncology. Center programming will include an extensive series of workshops, student forums, symposia, and journal clubs.  An institutional commitment by Northwestern University to support the training of graduate students and postdocs engaged in CR-PSOC research will further extend the Center’s educational reach.

The Center is part of a cadre of Physical Science-Oncology Centers within the National Cancer Institute’s collaborative Physical Sciences-Oncology Network.

“We will have common cellular platforms, and we’re going to have frequent group meetings, as well as periodic regional and national meetings where these findings are discussed and where inter-program collaboration is encouraged,” said Dr. Licht. “We will have a kickoff meeting in mid-July.”

The Center is supported by the resources and expertise of Northwestern’s foremost engines for transdisciplinary research: CLP and the Robert H. Lurie Comprehensive Cancer Center. The breadth and scope of these resources will be substantially augmented by local consortium partners, the University of Chicago and University of Illinois at Chicago, and through a $1.5M Lever grant from the Chicago Biomedical Consortium that provides additional support for key shared resource facilities (see below). Vadim Backman (NU), Lucy Godley (UChicago) and Jack Kaplan (UIC) are co-Principal Investigators on the CBC’s Lever Award: “Chicago Center for Physical Science-Oncology Innovation and Translation.”

“This new Center is part of a coalition assembled by the National Cancer Institute to address and bring breakthroughs in the physical sciences to bear on the problem of cancer” said Dr. O’Halloran. “Cancer patients expect us to increase the speed with which we apply discoveries in the basic sciences to the prevention, diagnosis and treatment of disease, and the PS-OC teams are embracing this important challenge.”

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Adapted with modifications from: “New $10M Chicago Region Physical Science-Oncology Center Will Expand Personalized Medicine Beyond the Genome”. Press Release, Northwestern’s Office for Research, May 20, 2015. Contact: Sheila Judge s-judge@northwestern.edu  847-491-5868

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The CBC Lever award will support the following resource facilities:

  • Nanocytometry Core (Northwestern)
    Leader: Vadim Backman
    It will include Partial Wave Spectroscopy (PWS) and Stochastic Optical Reconstruction Microscopy (STORM) for high resolution microscopy
  • PDX Core (Northwestern)
    Leader: Andrew Mazar
    a. Patient-derived xenografts will provide meaningful models of human cancer and enable translation of PSOC innovations
    b. Includes funding for investigator pilot studies using PDX models
  • New high precision methylation analysis capabilities through acquisition of an Illumina NextSeq500, to be used in the University of Chicago’s Genomics Core
    Leader: Lucy Godley
  • New ultra-sensitive IC-ICP-mass spectrometer capability to be used in the Quantitative Bioelement Imaging Center at Northwestern
    Leader: Thomas O’Halloran

CR-PSOC Co-Investigator, Job Dekker, named an HHMI Investigator at UMASS

Job Dekker becomes seventh Howard Hughes Medical Institute investigator at UMass Medical School

A pioneer in the study of the three-dimensional structure of the genome, Job Dekker, PhD, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology, was named a Howard Hughes Medical Institute (HHMI) investigator. Dr. Dekker, developer of the chromosome conformation technologies used to map the topography of the genome, was one of 26 scientists chosen for his scientific excellence from a pool of 894 applicants. Over the next five years, HHMI has committed $153 million to support these innovative scientists.

“This is one of the most prestigious and sought-after scientific awards in the world. The Howard Hughes Medical Institute recognizes exceptionally creative thinkers and innovative scientists who are at the forefront of expanding the boundaries of scientific knowledge,” said Chancellor Michael F. Collins. “This award allows Dr. Dekker the freedom to pursue novel ideas that can fundamentally change our understanding of disease. All of us at UMMS are incredibly proud of what he has accomplished.”

“It is a tremendous honor to be named among such an accomplished group of scientists,” said Dekker. “Being an HHMI investigator provides us with the resources to pursue game-changing questions about how chromosome structure affects disease formation. With this support we’ll be able to investigate high-risk, high-reward research, such as the kind that led to the initial development of chromosome conformation capture technology.”

Although DNA is comprised of a linear sequence of bases, it doesn’t exist inside the cell nucleus in a simple, straight form. More like a ball of cooked spaghetti, the genome folds and loops back on itself so it can fit inside the tight confines of the nucleus. How the genome is packed inside the nucleus is tightly controlled and varies from cell type to cell type. And each unique shape has a profound influence on which genes in a cell are turned on or turned off.

Seeking tools and technology for mapping the three-dimensional structure of the genome in detail, Dekker developed a biochemical technique for determining how DNA segments interact and are linked to one another. The result, akin to a “molecular microscope,” can be used to detect physical interactions between DNA segments. The more interactions between segments, the more closely associated in space they are, due to chromosome folding. This breakthrough discovery was the genesis of what are now termed “3C,” “5C” and “Hi-C” tools, used by researchers worldwide interested in mapping the structure and organization of chromosomes inside cells.

“Before 3C, we could see that genomes looked different across cell types, but limitations in imaging technologies meant we couldn’t study these differences in a meaningful way,” said Dekker. “Chromosome conformation capture technologies have rapidly taken hold and allowed our lab and others to explore the structure of the genome in a way that wasn’t previously available to scientists.”

Since joining UMMS, Dekker has refined and enhanced the initial chromosome conformation techniques to visualize whole genomes, combining it with next-generation sequencing to create high through put versions.

Dekker has made a number of key discoveries related to how the structure of a genome may influence genetic function and contribute to human disease. Included among these discoveries is the identification of a new mechanism involving chromatin loops that is responsible for controlling genomic structure and activating genes to generate specific cell types. He has also found that chromosomes fold in a series of contiguous “yarns” that harbor groups of genes and regulatory elements, bringing them in contact with each other and allowing them to work in a coordinated manner during development. Recently Dekker and co-workers also uncovered how chromosomes are condensed inside mitotic chromosomes, which are among the most iconic structures in the cell.

In 2012, a team led by Dekker offered conclusive evidence that the three-dimensional structure of the chromosome strongly influences patterns of chromosome rearrangements and translocations, shedding light on a fundamental process related to cancer and our understanding of cancer genomics.

A member of the UMMS faculty since 2003, Dekker received his doctoral degree in biochemistry from Utrecht University in the Netherlands. He trained as a postdoctoral fellow at Harvard University with Nancy Kleckner, PhD, studying chromosome structure and developing the techniques that led to the 3C technology.

Dekker was elected to the American Association for the Advancement of Science in 2014. In 2007, he was named a Keck Foundation Distinguished Young Scholar in Biomedical Research, and he received the 2011 ASBMB Young Investigator Award from the American Society of Biochemistry and Molecular Biology.

HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators—rather than awarding them research grants—HHMI gives scientists the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition—even if that process takes many years.

“Scientific discovery requires original thinking and creativity,” says HHMI President Robert Tjian. “Every scientist selected has demonstrated these qualities. One of the most important things we can do at HHMI is to continue to support and encourage the best discovery research. We don’t know this for certain, but the ideas that emerge from these labs might one day change the world, and it’s our privilege to help make that happen.”

HHMI will provide each investigator with his or her salary, benefits and a research budget over an initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. HHMI appointments may be renewed for additional five-year terms, contingent on a successful scientific review.

Mid-career researchers with five to 15 years of experience as faculty members at more than 200 institutions were eligible to apply. Applications from the 894 eligible applicants were evaluated by distinguished biomedical researchers, who narrowed the field to 59 semifinalists. The semifinalists attended a scientific symposium at HHMI’s Janelia Research Campus in April and presented a brief research talk to members of the review panel. The 26 new HHMI investigators were selected shortly after the scientific symposium.

Through its flagship HHMI Investigator Program, the Institute has joined with more than 70 distinguished U.S. universities, hospitals, institutes and medical schools to create an environment that provides flexible, long-term support for approximately 330 Hughes investigators and members of their research teams. HHMI investigators are widely recognized for their creativity and research accomplishments: 182 HHMI investigators are members of the National Academy of Sciences and there are currently 17 Nobel laureates within the investigator community.

Written by Jim Fessenden and originally posted by the UMASS Medical School Communications

Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg

A Northwestern University Physical Sciences-Oncology Center outreach pilot project lead to a novel physical approach that shows aging-related changes in the micromechanical properties of meiotic metaphase II chromosomes in mouse oocytes are associated with deleterious in chromosome duplication and egg quality.  In collaboration with UC Berkeley, National University of Singapore and the University of Kansas Medical Center, scientists from the Woodruff and Marko research groups designed and implemented a novel approach to measure the stiffness of chromosomes.

Using this technique, the scientists discovered a correlation between the stiffness of chromosomes and the reproductive age of a model organism. It is widely accepted that signs of aging of the female reproductive system include errors in chromosome segregation leading to a phenomenon named aneuploidy, a condition where there are more or less chromosomes than is normal for that species. In order to investigate the biophysical properties of chromosomes, scientists utilized this stress technique to determine how “stiff” the chromosomes are for both reproductively aged organisms (where there is a high incidence of aneuploidy) and young organisms (where there is a low incidence of aneuploidy). The correlation, as it was discovered, suggests that as the reproductive age of the organism increases, the stiffness of the chromosome also increases. In fact, chromosomes of reproductively old mice required 2.5 times more force to be stretched than the chromosomes of young mice.

This new finding adds great value to the understanding of cancer biology and age related diseases in which errors of chromosome segregation and aneuploidy play crucial roles.

J Assist Reprod Genet. 2015 Mar 11. [Epub ahead of print] Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg. Hornick JE1, Duncan FESun MKawamura RMarko JFWoodruff TK.

Read full study here.

Jiping Wang to speak at 1st Modeling Cancer Meeting

jiping-wang.jpgJiping Wang, leader of the NU-PSOC Bioinformatics Core, will speak on Modeling causalities of mixed features in TCGA data using Bayesian network analysis at the 1st Annual ICBP/PSOC Mathematical and computational modeling meeting entitled, Modeling Cancer: Integrating Scales, Disciplines and Programs on February 25th in Tampa, FL. The three day meeting is sponsored by NCI¹s Integrative Cancer Biology Program (ICBP) & Physical Sciences in Oncology programs. The limited attendance format will enable participants to discuss theoretical tools and approaches in greater depth than is usually possible in larger program meetings with the goal of building a community resource in this topic area.

Wang is an associate professor and director of graduate studies in the department of physics. His NU-PSOC-funded research has deployed bioinformatics and computational biology aims to develop complex statistical methods for analysis of high throughput genomic and genetic data. His current projects include Expressed Sequence Tag (EST) data analysis, nucleosome sequence alignment and positioning prediction, human brain mapping, DNA methylation differentiation and tRNA inter-positional association. He has developed multiple software tools to support these efforts that he freely shares, including: ESTstat (EST), NuPoP (nucleosome) and SPECIES (species number estimation). Sample publications associated with his role in the NU-PSOC include:

1. Popovic, R., Martinez-Garcia, E., Giannopoulou, E., Zhang, Q., Ezponda, T., Shah, M.Y., Zheng, Y., Will, C.M., Small, E.C., Hua, Y., Bulic, M., Jiang, Y., Carrara, M., Calogero, R.A., Kath, W.L., Kelleher, N.L., Wang, J.-P., Elemento, O. and Licht, J.D., Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation, PLoS Genetics 2014,10(9): e1004566, doi: 10.1371/journal.pgen.1004566 .

2. Small, E.C., Xi, L., Wang, J.-P., Widom, J., and Licht, J.D., Single-cell nucleosome mapping reveals the molecular basis of gene expression heterogeneity. PNAS 2014,111(24):E2462-71,doi: 10.1073/pnas. 1400517111.

3. Henikoff, S., Ramachandran, S., Krassovsky, K., Bryson, E.D., Codomo, C.A., Brogaard, K., Widom, J., Wang, J.-P., Henikoff, J.G., The budding yeast centromere DNA element II wraps a stable Cse4 hemisome in either orientation in vivo, eLife, 2014, 3:e01861.

4. Xi, L., Brogaard,K., Zhang, Q., Lindsay, B.G., Widom, J., and Wang, J.-P., A locally convoluted cluster model for nucleosome positioning signals in chemical map, Journal of American Statistical Association 2014, 109 (505):48-62, DOI:10.1080/01621459.2013.862169

5. Moyle-Heyrman, G., Zaichuk, T., Xi, L., Zhang, Q., Uhlenbeck, O.C., Holmgren, R., Widom, J. and Wang, J.-P., Chemical map of Schizosaccharomyces pombe reveals species-specific features in nucleosome positioning. PNAS 2013,110(50),20158-20163 pdf; Supplementary materials

6. McCallum, K.J. and Wang, J.-P., Quantifying copy number variations using a hidden Markov model with inhomogeneous emission distributions. Biostatistics 2013, Jul;14(3):600-11. doi: 10.1093/ biostatistics/kxt003

7. Nalabothula,N., Xi,L., Bhattacharyya,S., Widom,J., Wang, J.-P., Reeve,NJ, Santangelo, JT, Fondufe-Mittendorf, NY, Archaeal nucleosome positioning in vivo and in vitro is directed by primary sequence motifs. BMC Genomics 2013, 14:391 PDF

8. Yigit, E., Zhang, Q., Xi, L., Grilley, D., Widom, J., Wang, J.-P., Rao, A. and Pipkin, M.E. High-resolution nucleosome mapping of targeted regions using BAC-based enrichment. Nucleic Acids Res. 2013;doi: 10.1093/ nar/gkt081 PDF;Supplementary materials

9. Brogaard, K., Xi, L., Wang, J.-P., and Widom, J., A chemical approach to mapping nucleosomes at base pair resolution. Methods Enzymol. 2012;513:315-34

10. Brogaard, K., Xi, L., Wang, J.-P., and Widom, J., A map of nucleosome positions in yeast at base-pair resolution Nature, 2012, 486: 496­501. Online Supplementary Methods; Other supplementary materials

Trainee Nir Yungster Wins Poster Award

nir_0Trainee Nir Yungster (Project 4), a graduate student working in the Research on Complex Systems group, received an award for his poster “Optimizing Rate Constants in Epigenetic Markov Models” at the 2013 PS-OC Annual Investigators’ Meeting.  Yungster was one of six recipients of the award out of 129 presenters.  Here is Nir’s research in his own words:

Describe your research in general terms.

I presented work on a mathematical model that describes the dynamics of histone modifications in cancer cells.  Histones are proteins that act as spools, allowing DNA to coil into a more compact form.  Through a number of mechanisms, these proteins can significantly impact gene expression in a manner dependent on chemical modifications made to them.  Cancers such as B-cell lymphoma and multiple myeloma have both been linked to proteins that modify these histones, and thus understanding the dynamics of this system can provide important insight into possible treatments for patients.  Our model uses experimental data to quantify the rates at which modifications occur in cancer cells, and allows for dependence on the current modified state of the histone.

How did the PS-OC help shape or develop this research?

My advisor and Project-4 leader Bill Kath and I have been fortunate to find a terrific set of collaborators in Neil Kelleher and Yupeng Zheng, without whom this work would not be possible. The model I presented was a natural outgrowth of their groundbreaking ‘M4K’ approach for tracking the kinetics of histone modification in human multiple myeloma cells as part of a PSOC Pilot Project. Bringing together their top-down proteomics expertise with our mathematical modeling background has made for a fruitful partnership, and our work together continues to grow as both the experimental and modeling sides of the project mature.


What is the next step?

While thus far we have only modeled a small subset of possible histone modifications, our model can be robustly extended to include a larger number of modifications in order to provide a fuller picture of histone modification kinetics. Additionally, by comparing the histone kinetics in cancer cells to the kinetics in normal ones, we hope to use our model to predict treatments that could promote transitions of cancer cells to their non-cancerous forms.

Full Abstract: Recently, a method was developed for conducting M4K – mass spectrometry-based measurement and modeling of histone methylation kinetics (Zheng 2012). We have made improvements to this method by incorporating previously unused experimental statistics into our model-optimization procedure that results in significantly improved fits to experimental data. Accurately modeling methylation changes to histone proteins is essential to understanding the activities of methyltransferases such as EZH2, which has been linked to human B-cell lymphoma, or MMSET, which has been linked to multiple myeloma (MM). Among MM patients, 15-20% show a t(4:14) chromosomal translocation which leads to the overexpression of MMSET. Zheng et. al. used MM cells with high MMSET expression to demonstrate the potency of their M4K approach. By comparing the results from a targeted knock-out of MMSET to a non-targeted knock-out, they obtain a measured decrease in methylation rates. Our model, with its improved modeling of such rates, can be incorporated in testing the effectiveness of drug therapies that might target the activities of methyltransferases. Among the adjustments we made to improve the calculation of these rates was an alteration to the optimization cost function to weigh deviations between our model and individual data points based on the precision of those experimental values. Additionally, we imposed new error terms to the optimization cost function to ensure that for large time, our dynamical model agrees with the steady-state behavior observed in experiment.

Northwestern Grad Students Contribute to Novel, Networked Physical Sciences Approach to Cancer Research

Northwestern Grad Students Contribute to Novel, Networked Physical Sciences Approach to Cancer Research

Dhwanil Damania

Dhwanil Damania

Two Northwestern graduate students, Dhwanil Damania (Biomedical Engineering) and Yolanda Stypula (Interdepartmental Biological Sciences) are co-authors on an important new paper just published in Scientific Reports. The paper is the outcome of a ground-breaking collaborative effort by a network of 12 National Cancer Institute-funded Physical Sciences-Oncology Centers (PS-OC).

The goal of this effort was to compare the molecular and biophysical attributes of non-tumorigenic (MCF-10A) cells and metastatic breast cancer cells (MDA-MB-231) in culture to determine the nature of physical changes in cell structure and activity associated with metastasis.  PS-OC investigators found dramatic differences in the capacity of the metastatic cells for migration and adhesion compared to non-metastatic cells.  Cell shape, oxygen stress response and protein profiles also differed markedly between these cell types.

Overall, the metastatic cells were found to be more physically flexible and stress-tolerant than the non-tumorigenic cells.  PS-OC investigators were able to model potential linkages between the molecular and physical characteristics of the cell lines using molecular network analysis.

This pilot study, created by a large array of physical and life scientists and clinicians, demonstrates the potential of a large scale team approach, such as the Physical Science-Oncology Centers network, to address the “big questions” of cancer research.

Yolanda Stypula

Yolanda Stypula

Damania, who was recently awarded a doctorate in biomedical engineering and Stypula contributed to this work using a unique imaging technique developed in Professor Vadim Backman’s lab (Biomedical Engineering), called partial wave spectroscopic (PWS) microscopy, to compare the nanoscale architecture of the nuclei of the two different cancer cell types which is otherwise invisible by traditional microscopy/histopathology.  They found that the nuclei of the metastatic cells were significantly more disorganized than those of the non-metastatic cells.    Previous studies by the Backman group have shown that these nuclear alterations are a marker for early stage carcinogenesis in solid tumors.

According to Damania and Stypula “From a logistic perspective, it is exciting and rewarding to see how the final paper came together as an end-result of all the hard work of many researchers, coordinators and PSOC/NCI staff.  We believe that this manuscript would serve as an example for other groups to carry out multi-institutional studies.”

Both Damania and Stypula have been supported by Northwestern PS-OC and have made significant contributions to the work of the Center.  Damania previously won a PSOC Young Investigator Trans-Network award in 2010 for a collaborative project with the Scripps Research Institute.  Their work intercalates with the efforts of the Northwestern PS-OC to determine the fundamental rules governing how DNA is configured, modified and expressed in normal and tumor cells.

Trainees Win Young Investigators’ Trans-network Award

Northwestern University Physical Sciences-Oncology Center (NU PS-OC) trainees Joo Sang Lee, Behnam Nabet, and Eliza Small, along with team member Subhayjyoti De of the Dana Farber Cancer Institute PS-OC, have won a one-year, $15,000 Young Investigators’ Trans-network Award from the National Cancer Institute.

The award supports the team’s innovative project “Identifying the impact of nuclear architecture in the regulation of metabolic pathways,” where they will investigate how genes involved in the regulation of metabolic pathways are spatially distributed in the cell nucleus and how this distribution is altered in cancer cells compared to their normal counterparts. The collaboration brings together both computational biologists and cancer biologists from the two centers.

“This project is a mosaic of orthogonal approaches mastered in three very diverse labs in the two PS-OCs, said Joo Sang Lee, project leader. “It not only brings together computational biologists and experimental cancer biologists, but it also integrates the studies on cancer genomics and epigenetics with those on cancer metabolism.”

The team formulated their proposal over the course of the 4-day Annual PS-OC Network Investigators’ Meeting in April of this year. Selected proposals were submitted by each center for review by the PS-OC Steering Committee, who evaluated proposals on their innovative physical sciences perspective, relevance to major cancer issues, and trans-network collaboration.

Trainees Lee and De will use their computational biology and mathematical modeling expertise to computationally analyze the human metabolic network model and genomic proximity data to identify how the genes encoding enzymes for the metabolic pathways are distributed in the three dimensional genomic packaging. This analysis will allow cancer biologists Nabet and Small to test predictions on the altered proximity of a set of enzyme-coding genes responsible for deregulation of metabolic pathways in cancer.

“I am very excited that the NCI recognized our efforts to bring together computational biologists and cancer biologists within the PS-OCs. By combining these disciplines to work on a common goal, we will model the disease, ask new questions, and then directly test them in the lab,” said Nabet. By identifying the key differences in cancer cells, the team hopes to elucidate the role of chromatin organization in the deregulated metabolism seen in cancer.

Lee and his team are grateful not only for the award, but also of the experience in developing the proposal. “I had the opportunity to sharpen my skills through all the steps of the process, such as organizing a competitive and interdisciplinary team of fellow young investigators, designing a creative and at the same time feasible research project, and writing a clear and strong research proposal,” Lee said. “With this exceptional collaboration, I am confident our team will be able to unveil strategies used by cancer cells to control their metabolism through alterations in their nuclear architecture.”

New Discoveries from NU Physical Sciences-Oncology Center Uncover the “Rules” Governing Gene Transcription

A trio of ground-breaking publications from researchers in Northwestern’s Physical Sciences-Oncology Center (NU-PSOC) has revealed important new methodological advances that have led to a new understanding of the forces governing the regulation of gene expression.   This field is the bedrock for understanding the fundamental aspects of health and disease as it is the “decryption” of the messages carried in our genes that is the important first step in determining which proteins, the major “working” molecules in our cells, are produced in response to changes in the cellular environment.  Regulation of the expression of genes is very tightly controlled in normal cells and aberrant expression is associated with a broad range of diseases, especially cancer.  The length and complexity of DNA requires that it be tightly bundled in cells and the question of how specific genes are accesses by the cell’s decrypting molecules has been a question that has long tantalized researchers.

These new studies produced by the laboratories of Dr. Eran Segal, a collaborator from the Weizmann Institute in Israel, and Drs. Jonathan Widom and Ji-Ping Wang have succeeded in pulling back the curtain on these most fundamental aspects of biology by developing highly sensitive methods to examine how genes are packed in the cell and the factors in terms of location, orientation, and organization of specific genes that affect the conditions under which genes are expressed.   Prof. Segal and colleagues, publishing in a June edition of Nature Biotechnology (volume 30: no. 6, pp. 521-530) has developed a method for high-throughput measurements of carefully designed large-scale promoter (DNA sequences that precede protein-coding regions of genes) libraries that will allow researchers to uncover the ‘regulatory code’ that translates DNA sequence into expression.  His lab has also demonstrated a mechanism for fine-tuning gene expression by changing DNA promoter sequences to disfavor the binding of proteins, known as histones which wrap DNA into inaccessible balls, can increase gene expression (Raveh-Sadka et al. Nature Genetics vol. 44 no. 7:  pp. 743-750, 2012).

This work is complemented by the recent publication in Nature(vol. 486 pp. 497-501, 2012) by Kristin Brogaard, a recent NU PhD working in collaboration with the NU-PSOC Bioinformatics Core, describing a new, highly sensitive method for examining the rules governing how DNA is wound up around histone proteins for compaction into cells.  The profound influence of Prof. Jonathan Widom, founding director of Northwestern’s Physical Science-Oncology Center, on this work is not diminished by his untimely death last July.   He guided the intellectual foundation and methodological approaches that led to these breakthroughs.

Jonathan Licht MD, Johanna Dobe Professor and Chief of the Division of Hematology/ Oncology in the Robert H. Lurie Comprehensive Cancer Center in the Northwestern University Feinberg School of Medicine and the NU-PSOC’s Senior Investigator commented “It is becoming increasingly clear that acquired mutations in the machinery that underlies the way in which DNA is packaged into chromatin are major drivers of the development of tumors in humans.  The work of the PSOC has allowed the elucidation of the normal rules by which chromatin is arranged in the cell.  This will allow us to understand what’s going wrong in cancer and how that might be remedied.”

The Northwestern Physical Sciences-Oncology Center, a collaboration between the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center, is funded by the National Cancer Institute with the goal of applying physical sciences approaches to understanding the fundamental principles underlying aberrant gene expression in cancer.

Pulitzer Prize-winning Author, Dr. Siddhartha Mukherjee, Lectures on the History of Cancer at Northwestern University

On May 1, 2012, nearly 600 guests from the Northwestern University and Evanston community gathered in the Ryan Family Auditorium to journey through the history of cancer with oncologist and Pulitzer-prize winning author, Siddhartha Mukherjee, M.D., Ph.D. Dr. Mukherjee is well-known for ambitiously tackling the 4,000-year recorded history of cancer in his first book, The Emperor of All Maladies: A Biography of Cancer. The book has been widely hailed by critics as an ambitious, important, and unique contribution to the history of the social and scientific responses to cancer.

Mukherjee regaled a captivated audience with vignettes from both his own work and those of historically significant characters of cancer research, illustrating the often surprising and seemingly antithetical origins of treatment and diagnosis. At times both humorous and weighty, Mukherjee’s talk highlighted the intricate nature of both cancer and its effect on patients’ lives. A lively Q&A session followed the talk.
Mukherjee is an assistant professor of medicine at Columbia University and a staff cancer physician at Columbia University Medical Center. In addition to the 2011 Pulitzer Prize in general nonfiction, “The Emperor of All Maladies” (Scribner, 2010) was named by The New York Times as one of the “10 Best Books of 2010.”
The free public lecture was offered by the Northwestern University Physical Sciences-Oncology Center (PS-OC) as part of an effort to enrich the intellectual life on campus and to engage the larger community in the discussion regarding the future of cancer research.
The PS-OC, one of 12 established nationwide by the National Cancer Institute in 2009, is a joint effort between the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. As Mukherjee’s book illustrates, many of the most important breakthroughs in cancer research have arisen from discoveries outside of the field of cancer research.
Brought together through the PS-OC, physical scientists and cancer biologists from across the University are focused on genes and their role in cancer. The unique perspective of physical scientists broadens the lens with which the PS-OC addresses most fundamental questions regarding the regulation of gene expression in normal health and development and in cancer. A better understanding of these mechanisms could lead to better diagnostics and therapeutics as well as open up new directions for research.

Symposium to Celebrate Contributions of Jonathan Widom

EVANSTON, Ill. — Colleagues, friends and family of Northwestern University professor Jonathan Widom will gather at a special symposium Friday, March 16, to celebrate his life, creativity and scientific accomplishments. Widom died suddenly last year at age 55.

Widom, an expert in the field of chromatin biology, was the William Deering Professor of Molecular Biosciences in the Weinberg College of Arts and Sciences and principal investigator of Northwestern’s Physical Sciences-Oncology Center.

“It will be a fabulous day of science,” said Richard I. Morimoto, the Bill and Gayle Cook Professor of Biology in Weinberg and an organizer of the symposium. “Speakers will reflect intellectually and scientifically about the impact Jon and his work have had on them. He made his mark on a wide range of fields, such as physical biochemistry, genetics and molecular biology, and on the molecular basis of diseases, including cancer.”

Unraveling the Mysteries of Life: Recognizing the Life of Jon Widom” will be held from 9 a.m. to 4:30 p.m. at the James Allen Center, 2169 Campus Drive, on the Evanston campus. Attendees are welcome to attend all or part of the public symposium but reservations are required.

Leaders in the fields of chromatin biology and gene expression will focus on the biological consequences of Widom’s discoveries as well as discuss the ongoing work in his research group. (Chromatin is the combination of DNA and proteins that make up the contents of a cell’s nucleus.)

“Jon Widom is greatly missed as he was a wonderful colleague at Northwestern who always listened to the scientific questions of others and then offered thoughtful and knowledgeable advice, usually from a quantitative viewpoint,” said Robert A. Lamb, chair of the department of molecular biosciences. “His broad knowledge made him highly sought after by colleagues, and he was always most generous with his time.”

In his research, Widom focused on how DNA is packaged into chromosomes — and the location of nucleosomes specifically. The work has had profound implications for how genes are able to be read in the cell and how mutations outside of the regions that encode proteins can lead to errors and disease.

“Jon’s contributions to the fields of chromatin packaging and gene regulation are unquestioned and reflected in his outstanding international reputation,” said colleague Kelly E. Mayo, professor of molecular biosciences.

Symposium speakers include Eran Segal of the Weizmann Institute of Science in Israel discussing “The Genomic Code for Nucleosome Positioning” and Northwestern’s Kristin Brogaard of the Widom lab discussing “A Chemical Biology Approach to Mapping Nucleosomes at Base Pair Resolution.” Other speakers whose research was influenced by Widom’s discoveries are: Carl Wu from the National Cancer Institute, John Lis from Cornell University, Barbara Meyer from the University of California at Berkeley and David Shore from the University of Geneva.

Jonathan Widom’s parents and siblings will attend the event. His brother, Michael Widom, of Carnegie Mellon University, is chair of the session “The Dynamic Interplay of Transcription Regulation and Chromatin Structure.”

Q-and-A time will allow for audience interaction with the speakers.

Sponsors of the symposium are the Office of the Provost, Weinberg College of Arts and Sciences, Chemistry of Life Processes Institute, department of molecular biosciences, the Physical Sciences-Oncology Center and the Cellular and Molecular Basis of Disease and the Molecular Biophysics training programs.

For more information, a schedule and to RSVP, go to the symposium’s website.


Article written by Megan Fellman, science and engineering editor for NU NewsCenter. Contact her at fellman@northwestern.edu.

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