Massachusetts Institute of Technology Physical Sciences-Oncology Center (MIT PS-OC) will assemble renowned investigators from cancer biology, experimental physics/engineering and theoretical/computational physics to address critical issues in cancer biology. These investigators will employ experimental and theoretical approaches to construct innovative technology and analytical and computational tools to explore the process of carcinogenesis at the single cell level. This group theorizes that the intersection of these varied disciplines will yield major breakthroughs in the principles of cancer formation. These investigators will utilize pioneering single-cell mRNA counting techniques to model stem cell differentiation and reprogramming signaling networks as well as to probe the connection between cell growth and the cell cycle. Gene expression of various transcripts in individual cells will be surveyed over time to measure the quantity and pattern during these processes. Likewise, Ras-regulated signaling networks and neoplastic progression will be explored and used to establish computational models. Overall, these studies will provide a better understanding of the complexity of cancer and should facilitate the discovery of novel therapeutic targets.
Principal Investigator: Scott Manalis, Ph.D.
Senior Scientific Investigator: Tyler Jacks, Ph.D.
Collaborators: Boston University, Brigham and Women's Hospital, Broad Institute, Harvard Medical School, Hubrecht Institute, Stanford University, University of California-San Francisco, Whitehead Institute
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Scott Manalis, Ph.D.
Scott Manalis is a professor of biological and mechanical engineering at MIT and has been a faculty member at MIT since 1999. He is also a member of the Koch Institute for Integrative Cancer Research at MIT. Dr. Manalis was the recipient of the Presidential Early Career Award for Scientists and Engineers (PECASE) from the Department of Defense. He has also been selected by Technology Review magazine as one of the 100 innovators under the age of 35. Dr. Manalis received his B.S. degree in physics from the University of California at Santa Barbara and his Ph.D. degree in applied physics from Stanford University.
Tyler Jacks, Ph.D.
Dr. Tyler Jacks is the David H. Koch Professor of Biology and the Director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. He is also an Investigator of the Howard Hughes Medical Institute. Dr. Jacks received his B.A. in Biology from Harvard College in 1983. His Ph.D. thesis was performed with Harold Varmus at the University of California, San Francisco. He was a post-doctoral fellow with Robert Weinberg at the Whitehead Institute at MIT. Dr. Jacks joined the faculty at MIT in 1992. He has pioneered the use of gene targeting technology in the mouse to study cancer-associated genes and to construct mouse models of many human cancer types, including cancers of the lung, brain and ovary. His laboratory has made seminal contributions to the understanding of the effects of mutations of several common cancer-associated genes. This research has led to novel insights into tumor development, normal development and other cellular processes. In addition to mouse modeling, a major focus of research in Dr. Jacks’ laboratory has been the role of p53 in the elimination of damaged and pre-cancerous cells by programmed cell death, a form of cellular suicide. He has published more than 200 scientific papers. Dr. Jacks has served on the Board of Scientific Advisors of the National Cancer Institute (NCI) and the Board of Directors of the American Association of Cancer Research (AACR); he is currently President of the AACR and was elected to the National Academy of Sciences in 2009.
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Alexander van Oudenaarden, Ph.D.
Alexander van Oudenaarden performed his PhD research in the field of experimental solid state physics at Delft University of Technology. He obtained his PhD degree in 1998 and received the 'Andries Miedema' Award for best PhD-research in the field of condensed matter physics in the Netherlands. From 1998 to 1999, he was a postdoctoral fellow at Stanford University collaborating with Steven Boxer and Julie Theriot. He joined the MIT faculty in 2000 and in 2001, he was named an Alfred Sloan Research Fellow, a Keck Career Development Professor in Biomedical Engineering, and received the NSF CAREER award. He was promoted to Associate Professor with tenure in 2004. In 2008 he was promoted to full Professor of Physics at MIT and received a John Simon Guggenheim Fellowship and the NIH Director’s Pioneer Award. From 2009 to 2012, Alexander was the principal investigator of the Physical Sciences-Oncology center at MIT. In 2012 he accepted a position as the Director of the Hubrecht Institute in the Netherlands, where he is currently, and was awarded an ERC Advanced Investigator award and NWO VICI award.
Arup K. Chakraborty, Ph.D.
Arup K. Chakraborty is the Robert T. Haslam Professor of Chemical Engineering, Chemistry, Physics, and Biological Engineering at MIT. He is the founding Director of MIT's new Institute of Medical Engineering and Science. He is also a founding member of the Ragon Institute of MIT, MGH, and Harvard, which is focused on multi-disciplinary approaches to understand human immunology and develop a vaccine against HIV and other scourges on the planet. After obtaining his PhD in chemical engineering at the University of Delaware, and postdoctoral studies at the University of Minnesota, he joined the faculty at the University of California at Berkeley in December 1988. He rose through the ranks, and ultimately served as the Warren and Katherine Schlinger Distinguished Professor and Chair of Chemical Engineering, Professor of Chemistry, and Professor of Biophysics at Berkeley. He was also Head of Theoretical and Computational Biology at Lawrence Berkeley National Laboratory. In September 2005, Arup moved to MIT. For over twelve years, the central theme of his research has been the development and application of theoretical/computational approaches, rooted in physics and engineering, to study how T lymphocytes, orchestrators of the adaptive immune response, function. In recent years, this has included efforts to study the human immune response to HIV and vaccine design. A characteristic of his work is the impact of his studies on experimental immunology and clinical studies (he collaborates extensively with leading immunologists). Arup's work at the interface of the physical, life, and engineering sciences has been recognized by many honors that include a NIH Director's Pioneer Award, the E.O. Lawrence Memorial Award for Life Sciences, the Allan P. Colburn and Professional Progress awards of the American Institute of Chemical Engineers, a Camille Dreyfus Teacher-Scholar award, a Miller Research Professorship, and a National Young Investigator award. Arup is a member of the National Academy of Engineering and a Fellow of the American Academy of Arts & Sciences and the American Association for the Advancement of Science.
Leonid Mirny, Ph.D.
Dr. Mirny is an Associate Professor of Health Sciences and Technology at MIT, with a joined appointment at Physics Department. He holds Ph.D. in Biophysics from Harvard University, served as a Junior Fellow at Harvard Society of Fellows. Mirny lab has been working on a range of problems in biophysics and genomics. Those include protein folding and protein-DNA interactions, higher-order chromatin architecture and its role in genome function, and more recently cancer evolution and cancer genomics. While at MIT, Dr. Mirny has developed several classes, including a course in Quantitative Genomics, and collaborated with Prof. Mehran Kardar, with whom they developed and taught a class "Statistical Physics in Biology". Dr.Mirny has been recently elected an Associate Member of Dana-Farber Harvard Cancer Center and the Broad Institute at Harvard and MIT.
Jeroen Roose, Ph.D.
Dr. Roose received his PhD in Immunology at the University of Utrecht, where he studied the Wnt pathway with Hans Clevers. While in the Clevers laboratory he identified two Tcf-1 interacting proteins, ß-catenin and Groucho. Dr. Roose then joined the laboratory of Dr. Art Weiss at UCSF and studied the regulation of Ras signal transduction in normal lymphocytes. He had a prolific period with three first author manuscripts in PLoS Biology and MCB, two transitional career grants (K01 and Arthritis Investigator Award), and a program for future research that was distinct from Dr. Weiss' interests. In the course of his postdoctoral work in Art Weiss' laboratory, Dr. Roose became interested in the regulation of Ras signal transduction and in the cellular abnormalities and disease states that arise from aberrant Ras signals.
Using lymphocytes as a model system, they first unraveled the mechanism of Ras activation via two types of Ras activators, RasGRP and SOS. Through synergistic in silico and in vitro studies Dr. Roose established that lymphocytes possess a complex Ras signaling network that allows for high-level, digital Ras signaling without loss of control. This research was published in Cell, PNAS, and Science Signaling in 2009. They are currently investigating how abnormal basal and induced Ras signals relate to development of autoimmunity. His laboratory's most recent efforts demonstrate that unregulated expression of the Ras activator RasGRP1 is potently oncogenic in mouse models and in patient samples of T cell leukemia. Similarly, RasGRP1 confers resistance to MEK inhibition in mouse models of acute myeloid leukemia, a collaborative effort with Dr. Kevin Shannon's laboratory (Nature, 2009). His team is actively investigating the different mechanisms of oncogenic Ras signals in T cell malignancies with a focus on understanding the heterogeneity in this disease to pursue the goal of successful, specific blockade of these oncogenic signals.
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Project 1 - Single-Cell Transcript Counting of Stem Cell Differentiation and Reprogramming
Project Leader: Alexander van Oudenaarden (Massachusetts Institute of Technology)
The general objective of this project, led by Dr. Alexander van Oudenaarden, is to develop quantitative models of stem cell differentiation and reprogramming by obtaining absolute measurements of the transcript abundance in individual stem cells and their progeny in healthy tissue and cancer. Two complementary experimental systems will be explored: the intestinal epithelium and induced pluripotent stem cells.
Project 2 - Complementary in silico, in vitro, and in vivo Studies to Deconvolute Ras Signaling Networks in T Cell Lymphoma
Project Leader: Arup Chakraborty (Massachusetts Institute of Technology)
The central theme of this project, led by Dr. Arup Chakraborty, is to employ complementary theoretical and experimental studies at the crossroads of the physical and life sciences to deconvolute the origins of aberrant Ras signaling in the context of a specific T cell lymphoma observed in the clinic. We will especially try to understand the mechanisms underlying our recent observation of complex and heterogeneous responses.
Project 3 - Coordination of Cell Growth and Division in Normal and Cancer Cells
Project Leader: Scott Manalis (Massachusetts Institute of Technology)
The replication and segregation of the genome (the cell cycle) and the increase in bio-mass of individual cells (cell growth) must be coordinated in all cells. Many tumor suppressors and oncogenes can alter the normal balance between growth and division and some cancers are characterized by abnormal cell size. The goal of this project, led by Dr. Scott Manalis, is to deconvolve cell growth and the cell division cycle, determine the molecular basis for the coordination of these two processes, and determine how these two processes and their coordination are altered in cancer.
Project 4 - Modeling Neoplastic Progression and Analyzing Genomic Data to Characterize the Load of Driver and Passenger Mutations in Cancer
Project Leader: Leonid Mirny (Massachusetts Institute of Technology)
The development of cancer can be considered as an evolutionary process within an organism. During neoplastic progression, cells acquire mutations, compete for resources, and are subject of selection for ability to grow fast in a complex and dynamic environment. The goal of the project, led by Dr. Leonid Mirny, is to develop a theory of neoplastic evolution informed by cancer genomic and experimental data; use it as a framework for characterization of driver and passenger mutations by original statistical techniques, and to test feasibility of pushing a cancer into a population meltdown due to elevated mutation load.
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Core 1 - Single-Cell Transcript Counting Core
Core Leader: Alexander van Oudenaarden (Massachusetts Institute of Technology)
The Single-Cell Transcript Counting Core will provide the investigators of the MIT PS-OC and investigators of other PS-OCs in the network with the infrastructure to image individual mRNA molecules in single cells, both in culture and in tissue. In addition to the exceptional sensitivity and spatial resolution, superior to other existing mRNA imaging methods, this technique allows measurements of absolute quantities of up to three different mRNAs in a single cell.
Core 2 - Cell Sorting and Physical Measurement
Core Leader: Scott Manalis (Massachusetts Institute of Technology)
This Core comprises novel technologies for measuring a wide range of physical properties of single cells, including mass, growth rate, density and deformability. These technologies are based on the suspended microchannel resonant (SMR) mass sensor, which is capable of measuring the buoyant mass and growth rate of single cells with high precision.
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Profile of Scott Manalis in Nature Methods:
Seeing cancer in three dimensions:
The impact of deleterious passenger mutations on cancer progression:
van Oudenaarden Lab recent publications:
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