Quantitative Biology: From Molecules to Man

Quantitative Biology: From Molecules to Man

Thursday, June 18, 2015

The New York Academy of Sciences

Presented By

Presented by The University of Southern California and the New York Academy of Sciences

 

Quantitative Biology: From Molecules to Man will bring together professionals in science, medicine, and engineering to articulate a vision for the future of improving patient health outcomes.  Convergence science provides for a data-driven understanding of intricate biological processes across spatial and temporal scales.  Achieving breakthroughs in healthcare requires a specific progression of steps from molecular-level experiments to manipulations and observations in model systems to human-scale investigations, all followed by major epidemiological studies.  This one-day meeting will provide a forum for individuals involved in every stage of the process to engage in thought-provoking conversations and to generate actionable ideas for new approaches to finding solutions to some of humanity's most intractable health challenges.

*Networking Reception to follow.

Registration Pricing

 By 06/01/2015After 06/01/2015Onsite
Member$100$125$150
Member (Student / Postdoc / Resident / Fellow)$50$75$100
Nonmember (Academia)$150$200$250
Nonmember (Corporate)$225$275$325
Nonmember (Non-profit)$150$200$250
Nonmember (Student / Postdoc / Fellow)$75$100$125

 

USC faculty and students are eligible to register at Academy member rates. To access this discounted pricing, please select "Nonmember (Academia)" or "Nonmember (Student / Postdoc / Fellow)" and use the codes USCfaculty and USCstudent, respectively. Please note that a valid USC ID must be presented upon check-in at the conference. Those without a valid ID will be billed onsite for the difference between the member and regular rates.

 


 

This symposium is made possible with support from

Agenda

* Presentation titles and times are subject to change.


June 18, 2015

8:00 AM

Registration, Breakfast, and Poster Setup

9:00 AM

Welcome Remarks
Representative, the New York Academy of Sciences
Peter Kuhn, PhD, University of Southern California (USC)

Session 1: Lifetime Dynamics in Model Systems and In-silico

9:20 AM

Keynote Address
Time to Change: Circadian Rhythms in Health and Disease
Steve Kay, PhD, DSc, University of Southern California (USC)

10:00 AM

Networks and Control in Systems Biology
Francis J. Doyle, III, Department of Chemical Engineering, University of California Santa Barbara

10:40 AM

Networking Coffee Break

11:10 AM

Clonal Evolution Models of Breast Tumor Growth, Resistance, and Migration
Paul Newton, PhD, University of Southern California (USC)

11:50 AM

Human Scale Fluid Dynamics: How a Millisecond Can Help Us Understand a Lifetime
Amanda Randles, PhD, Harvard University; Lawrence Livermore National Laboratory

12:30 PM

Networking Lunch

Session 2: Convergent Science and Precision Science in Medicine

1:40 PM

Quantitative Real-Time Analysis of Collective Cancer Invasion and Dissemination
Andrew Ewald, PhD, Johns Hopkins University

2:20 PM

Integrative Genomics for Tumor Clonality, Entire Cities, and the International Space Station
Christopher Mason, PhD, Weill Cornell School of Medicine

3:00 PM

Networking Coffee Break

3:30 PM

Perturbation Science: From Physics to Molecular Biology to the Design of Combination Cancer Therapy
Chris Sander, PhD, Memorial Sloan Kettering Cancer Center

4:10 PM

Building and Breaking Hearts, and Other Organs
Scott E. Fraser, PhD, University of Southern California (USC)

4:50 PM

Closing Roundtable: The Disruptive New Science and Engineering that Displaces Translational Science and Personalized Medicine
Scott E. Fraser, PhD, University of Southern California (USC)

5:30 PM

Networking Reception & Poster Session

6:30 PM

Conference and Reception Concludes

Speakers

Scientific Organizing Committee

Melanie Brickman Stynes, MSc, PhD

The New York Academy of Sciences

Melanie Brickman Stynes serves as the Director of Life Sciences Conferences at the New York Academy of Sciences. Dr. Brickman Stynes has nearly 15 years of experience in public health, primarily as a researcher focused on the juncture of health, demography, policy, and geography.

Prior to joining the Academy, Dr. Brickman Stynes was Associate Director of the Institute on Science for Global Policy (ISGP). Additionally, Dr. Brickman Stynes spent nearly a decade as a Research Associate for the Center for International Earth Science Information Network (CIESIN) of Columbia University, where she worked on a range of projects related to health, disease, poverty, urbanization, and population issues. She also taught as an adjunct Professor at Baruch College’s School of Public Affairs for five years.

She received her Ph.D. in medical geography from University College London (UCL) and her M.Sc. in medical demography from the London School of Hygiene and Tropical Medicine (LSHTM).

Scott E. Fraser, PhD

University of Southern California

Professor Fraser has a long-standing commitment to quantitative biology, applying the tools of chemistry, engineering, and physics to problems in biology and medicine. His personal research centers on imaging and molecular analyses of intact biological systems, with an emphasis on studies of early animal development, organogenesis, and medical diagnostics. After receiving training in physics (BS, Harvey Mudd College, 1976) and biophysics (PhD, Johns Hopkins University, 1979), Dr. Fraser joined the University of California, Irvine faculty, and rose through the ranks to become Chair of the Department of Physiology and Biophysics. In 1990 he moved to Caltech as the Anna L. Rosen Professor of Biology, and the Director of the Biological Imaging Center. He is deeply committed to interdisciplinary training and translational research, having helped to found the Caltech Brain Imaging Center, the Kavli Institute of Nanoscience, and the Director of the Rosen Center for Biological Engineering. In Fall 2012, Dr. Fraser moved to University of Southern California (USC) to take a Provost Professorship in the Dornsife College of Letters, Arts, and Sciences, the Children’s Hospital Los Angeles, Keck School of Medicine and the Viterbi School of Engineering. He remains active in interdisciplinary research and serves as the Director of Science Initiatives for the USC campuses.

Brooke Grindlinger, PhD

The New York Academy of Sciences

Dr. Grindlinger serves as the Executive Director of Scientific Programs at the New York Academy of Sciences, providing strategic development and oversight of the Academy’s international portfolio of scientific workshops, conferences, symposia, and related multimedia publications across the broad spectrum of Life Sciences, Physical Sciences, Computer Science, and Engineering. Through this platform – and via strategic alliances with external organizations, foundations, and individuals – the Academy convenes leading international scientists from academia, industry, and government sectors in focused efforts to catalyze advances in science, medicine, engineering, and innovation for the benefit of society. Dr. Grindlinger also serves as a member of the board of the Sackler Institute for Nutrition Science at the New York Academy of Sciences, established in 2010 in partnership with The Mortimer D. Sackler Foundation, Inc., to advance nutrition science research.

Dr. Grindlinger has more than 12 years’ experience in scientific research, academic publishing, and science communication. Prior to joining the Academy, she served for 8 years as Science Editor for The Journal of Clinical Investigation, managing the review and publication of state-of-the-art basic and clinical biomedical research across the continuum of human physiology and disease, in addition to authoring journal News features, Editorials, Book Reviews, and Press Releases.

Dr. Grindlinger received her Bachelor of Science (First Class Honours) degree and PhD in molecular and microbial biosciences from the University of Sydney, Australia, studying the pathogenesis of the tuberculosis-causing organism Mycobacterium tuberculosis and ways in which to boost the efficacy of the tuberculosis vaccine. For this postgraduate work, Dr. Grindlinger was the recipient of an Australian Postgraduate Award. Dr. Grindlinger also regularly conducts local, national, and international workshops on science communication skills and alternative science careers for early career scientists.

Peter Kuhn, PhD

University of Southern California

Dr. Kuhn is a scientist and entrepreneur with a career long commitment in personalized medicine and individualized patient care. He is focused on the redesign of cancer care.

Dr. Kuhn is the Dean’s Professor of Biological Sciences and Professor of Medicine and Engineering at USC, a founding member of the Michelson Center for Convergent Biosciences, a co-founder of the BRIDGE @ USC and director of the Southern California Physics Oncology Center. Prof. Kuhn’s strategy is to advance our understanding of the human body to improve the human condition. His research is shedding new light at how cancer spreads through the body. This new science will lead to a personalized care strategy that is biologically informed and clinically actionable.

Dr. Kuhn is a physicist who trained initially at the Julius Maximilians Universität Würzburg, Germany, before receiving his Masters in Physics at the University of Albany, Albany, NY in 1993 and his PhD in 1995. He then moved to Stanford University where he later joined the faculties of Medicine and Accelerator Physics. From 2002 to 2014 he established a translational science program at the Scripps Research in La Jolla, CA that brought together over forty scientists from basic, engineering and medical sciences to work on understanding the spread of cancer in the human body. He has published over 200 peer scientific articles and patents as a result of his research. He founded Epic Sciences, Inc. in 2009 to develop cancer diagnostic products. Today Epic Sciences is a premier partner to most pharmaceutical and biotech companies in the development of precision companion diagnostics for cancer care.

The University of Southern California (USC) recruited Dr. Kuhn in 2014 to advance the next frontier of human scale science that can improve the human condition. At the convergence of biological, engineering and medical sciences will we learn how major diseases from cancer to neurodegenerative

Maria Watson

University of Southern California

Maria Watson was promoted to Associate Vice President for Development at University of Southern California (USC) on January 1, 2014 after her successful tenure building philanthropic support for the university throughout the Northeast as the inaugural director of USC’s New York Advancement office since 2011.

Ms. Watson’s non-profit executive career spans over 20 years as a leader in fundraising, marketing and public relations for leading higher education institutions, national arts funders and policy makers, and performing arts organizations and public media, including: Lincoln Center, Fordham University-WFUV public radio, New World Symphony, and the National Endowment for the Arts.

In support of USC’s $6 Billion campaign, she leads the university’s regional advancement offices in New York and San Francisco, and serves as the central liaison with five professional art schools of USC: School of Architecture, School of Dramatic Arts, Kaufman School of Dance, Roski School of Art and Design, Thornton School of Music, along with Classical radio KUSC/KDFC, and USC’s libraries and family of museums.

A native New Yorker, Watson earned a bachelor of musical arts degree from the University of Michigan in Ann Arbor, as a merit scholarship recipient in clarinet performance. She was a featured soloist with the Florida Philharmonic.

An avid motorcyclist, she is a proud Ducatista on the street and track.

Keynote Speaker

Steve Kay, PhD, DSc

University of Southern California

Dr. Steve Kay’s research has contributed significantly to the understanding of the molecular basis for circadian rhythms. In exploring the ties between circadian rhythms and glucose metabolism, Dr. Kay and his collaborators discovered a chemical that regulates our biological clock and that could be used to develop new drugs to treat metabolic disorders such as type 2 diabetes. Recently, Dr. Kay and his researchers identified a genetic switch that regulates a plant’s internal clock based on temperature and that may lead to developing plants that can better adapt to climate change.

Dr. Kay has served as dean of the University of Southern California (USC) Dornsife College of Letters, Arts and Sciences since 2012. In addition, he holds faculty appointments in molecular and computational biology at USC Dornsife as well as in neurology, physiology and biophysics and the Keck School of Medicine of USC’s Zilkha Neurogenetics Institute. He also served as the vice president of discovery research at Novartis Research Foundation’s Genomics Institute and has founded several biotechnology companies.

Dr. Kay is an elected member of the National Academy of Sciences and a fellow of the American Association for the Advancement of Science. He was awarded the American Society of Plant Biologists’ 2011 Martin Gibbs Medal and named by Thomson Reuters as one of “The World’s Most Influential Scientific Minds” in 2014.

Speakers

Francis J. Doyle, III, PhD

Department of Chemical Engineering, University of California Santa Barbara

Dr. Francis J. Doyle III is the Duncan and Suzanne Mellichamp Chair in Process Control and the chair of the Department of Chemical Engineering at University of California, Santa Barbara (UCSB), where he is also the associate dean for research in the College of Engineering and is the co-director of the Army Institute for Collaborative Biotechnologies. He holds appointments in the Electrical Engineering Department, the Biomolecular Science and Engineering Program, the Dynamical Neuroscience Program, and the Marine Science Program. He received his BSE from Princeton (1985), CPGS from Cambridge (1986), and PhD from Caltech (1991), all in Chemical Engineering. Prior to his appointment at UCSB, he has held faculty appointments at Purdue University and the University of Delaware, and held visiting positions at DuPont, Weyerhaeuser, and Stuttgart University. He is the recipient of several research awards, including the National Science Foundation National Young Investigator, Office of Naval Research Young Investigator, Humboldt Research Fellowship, and the American Institute of Chemical Engineers/Computing and Systems Technology (AICE/CAST) Computing in Chemical Engineering Award; as well as teaching awards, including the Purdue Potter Award, the American Society for Engineering Education (ASEE) Ray Fahien Award, the ASEE Chemstations Lectureship Award, and the AIChE/CAST David Himmelblau Award. He is a fellow of multiple professional societies including Institute of Electrical and Electronics Engineers (IEEE), International Federation of Automatic Control (IFAC), American Institute for Medical and Biological Engineering, and American Associate for the Advancement of Science. He is the president-elect of the IEEE Control Systems Society, and is the vice president and chair of the Technical Board for IFAC. His research interests are in systems biology, network science, modeling and analysis of circadian rhythms, drug delivery for diabetes, and model-based control.

Andrew Ewald, PhD

Johns Hopkins University

Dr. Andrew Ewald is an Associate Professor of Cell Biology, Oncology, and Biomedical Engineering at the Johns Hopkins University School of Medicine. His studies how cells build organs and how these same cellular processes can contribute to breast cancer metastasis. Dr. Ewald’s research lab recently identified a unique class of breast cancer cells that lead the process of invasion into surrounding tissues—a first step in cancer metastasis. Further research is planned to examine if these cells are viable targets for therapy.

Dr. Ewald received his undergraduate degree in physics with honors from Haverford College. He earned his PhD in biochemistry and molecular physics from the California Institute of Technology, studying with Scott Fraser. He completed postdoctoral work with Zena Werb in mammary biology and cancer at the University of California, San Francisco. Dr. Ewald joined the Johns Hopkins faculty in 2008.

He is a member of the American Association for Cancer Research, Society for Developmental Biology, and the American Society for Cell Biology. He is a fellow of the Keith R. Porter Endowment for Cell Biology and his work has been recognized with the American Association of Anatomists’s 2011 Morphological Sciences, the International Society for Optics and Photonics (SPIE)’s 2015 Systems Biology Pioneer Award, and the Metastatic Breast Cancer Network’s 2015 Metastatic Breast Cancer Research Leadership Award.

Scott E. Fraser, PhD

University of Southern California

Professor Fraser has a long-standing commitment to quantitative biology, applying the tools of chemistry, engineering, and physics to problems in biology and medicine. His personal research centers on imaging and molecular analyses of intact biological systems, with an emphasis on studies of early animal development, organogenesis, and medical diagnostics. After receiving training in physics (BS, Harvey Mudd College, 1976) and biophysics (PhD, Johns Hopkins University, 1979), Dr. Fraser joined the University of California, Irvine faculty, and rose through the ranks to become Chair of the Department of Physiology and Biophysics. In 1990 he moved to Caltech as the Anna L. Rosen Professor of Biology, and the Director of the Biological Imaging Center. He is deeply committed to interdisciplinary training and translational research, having helped to found the Caltech Brain Imaging Center, the Kavli Institute of Nanoscience, and the Director of the Rosen Center for Biological Engineering. In Fall 2012, Dr. Fraser moved to University of Southern California (USC) to take a Provost Professorship in the Dornsife College of Letters, Arts, and Sciences, the Children’s Hospital Los Angeles, Keck School of Medicine and the Viterbi School of Engineering. He remains active in interdisciplinary research and serves as the Director of Science Initiatives for the USC campuses.

Peter Kuhn, PhD

University of Southern California

Dr. Kuhn is a scientist and entrepreneur with a career long commitment in personalized medicine and individualized patient care. He is focused on the redesign of cancer care.

Dr. Kuhn is the Dean’s Professor of Biological Sciences and Professor of Medicine and Engineering at USC, a founding member of the Michelson Center for Convergent Biosciences, a co-founder of the BRIDGE @ USC and director of the Southern California Physics Oncology Center. Prof. Kuhn’s strategy is to advance our understanding of the human body to improve the human condition. His research is shedding new light at how cancer spreads through the body. This new science will lead to a personalized care strategy that is biologically informed and clinically actionable.

Dr. Kuhn is a physicist who trained initially at the Julius Maximilians Universität Würzburg, Germany, before receiving his Masters in Physics at the University of Albany, Albany, NY in 1993 and his PhD in 1995. He then moved to Stanford University where he later joined the faculties of Medicine and Accelerator Physics. From 2002 to 2014 he established a translational science program at the Scripps Research in La Jolla, CA that brought together over forty scientists from basic, engineering and medical sciences to work on understanding the spread of cancer in the human body. He has published over 200 peer scientific articles and patents as a result of his research. He founded Epic Sciences, Inc. in 2009 to develop cancer diagnostic products. Today Epic Sciences is a premier partner to most pharmaceutical and biotech companies in the development of precision companion diagnostics for cancer care.

The University of Southern California (USC) recruited Dr. Kuhn in 2014 to advance the next frontier of human scale science that can improve the human condition. At the convergence of biological, engineering and medical sciences will we learn how major diseases from cancer to neurodegenerative

Christopher E. Mason, PhD

Weill Cornell Medical College

Christopher E. Mason completed his dual BS in Genetics and Biochemistry from University of Wisconsin-Madison in 2001, his PhD in Genetics from Yale University in 2006, and his post-doctoral training at Yale Medical School, while also holding a fellowship at Yale Law School.

In 2009, Dr. Mason founded his laboratory at Weill Cornell Medical College in the Department of Physiology and Biophysics and at the Institute for Computational Biomedicine, as well as the Tri-Institutional Program on Computational Biology and Medicine, the Weill Cornell Cancer Center, and the Brain and Mind Research Institute.

He has won the Hirschl-Weill-Caulier Career Scientist Award, the Vallee Foundation Young Investigator Award, the Center for Disease Control and Prevention (CDC) Honor Award for Standardization of Clinical Testing, the WorldQuant Foundation Research Scholar Award, and he was named as one of the “Brilliant Ten” Scientists in the world by Popular Science magazine in 2014. His work has been featured on the covers of Nature Biotechnology, Nature Collections, Cell Systems, Neuron, Genome Biology and Evolution, and also on the cover of the Wall Street Journal and The New York Times, as well as over 300 other media outlets around the world.

Paul Newton, PhD

University of Southern California

Professor Newton received his BS in Applied Math/Physics at Harvard University and his PhD in Applied Mathematics from Brown University. After a post-doctoral fellowship at Stanford University, he was Assistant and Associate Professor in Mathematics and the Center for Complex Systems Research at the University of Illinois Champaign-Urbana. He has held visiting appointments at Caltech, Brown, Hokkaido University, The Kavli Institute for Theoretical Physics at University of California, Santa Barbara, and The Scripps Research Institute. He is currently Professor of Applied Math and Engineering in the Viterbi School of Engineering at the University of Southern California and where he also has appointments at the Norris Comprehensive Cancer Center at the Keck School of Medicine.

Amanda Randles, PhD

Harvard University; Lawrence Livermore National Laboratory

Amanda is a Lawrence Fellow at Lawrence Livermore National Laboratory. In general, her work focuses on the design of large-scale parallel applications targeting problems in physics. Her research goals are to both investigate fundamental questions related to fluid dynamics as well as extend the multiscale models developed in her thesis to study cancer metastasis. For this collaborative work, she continues as a Visiting Scientist at the Dana-Farber Cancer Institute working in Franziska Michor's lab.

She completed her PhD in Applied Physics at Harvard University with a secondary field in Computational Science. Her advisors were Efthimios Kaxiras and Hanspeter Pfister. She received her Bachelor's Degree in both Computer Science and Physics from Duke University, and her Master's Degree in Computer Science from Harvard University. Before graduate school, she worked for three years as a software developer at IBM on the Blue Gene Development Team. Her primary roles were in application development and performance.

Amanda is the recipient of the NIH Early Independence Award, Lawrence Livermore Lawrence Postdoctoral Fellowship, the DOE Computational Science Graduate Fellowship (CSGF) and the National Science Foundation Graduate Research Fellowship. Through CSGF, she completed a summer practicum at Lawrence Livermore National Laboratory in 2011. While in graduate school, she also spent several summers working on wireless network modeling at the Massachusetts Institute of Technology Lincoln Laboratory. She was awarded the 2009 Honorable Mention, and the 2010 and 2012 George Michael Memorial HPC PhD Fellowship, the Google Anita Borg Memorial Scholarship for Women in Computer Science and selected as a US Delegate for both the 62nd Nobel Laureate Meeting dedicated to Physics in Lindau, Germany and the Heidelberg Laureate Forum.

Chris Sander, PhD

Memorial Sloan Kettering Cancer Center

Chris Sander is acknowledged as an initiating leader in the field of computational biology, an interdisciplinary field that aims to solve important problems in biology using techniques of mathematics, physics, engineering, and computer science. Dr. Sander's current research interests are in computational genomics and systems biology, with a focus on network pharmacology and combinatorial therapy to block the emergence of resistance to otherwise successfully targeted cancer therapies. He is active in the National Institutes of Health Cancer Genome Atlas Project and a leader in the bioPAX and PathwayCommons community efforts to create an open-source information resource for biological pathways. With his group, Niki Schultz, and Ethan Cerami as key architects, Dr. Sander created the cBioPortal for Cancer Genomics that provides convenient access to The Cancer Genome Atlas for thousands of cancer researchers. He and his collaborators, especially Debora Marks at Harvard Medical School, apply maximum entropy methods and high-throughput sequencing to compute protein 3D structures from protein sequences. This effectively solves the long-standing challenge of the computational protein folding problem for proteins, as more and more evolutionary sequence information becomes available. Currently, Dr. Sander is Head of the Computational Biology Center at Memorial Sloan Kettering Cancer Center and Tri-Institutional Professor at Rockefeller and Cornell Universities. Earlier, he was Chief Information Science Officer at Millennium Predictive Medicine and Millennium Pharmaceuticals and founding chair of the department of Biocomputing at the European Molecular Biology Laboratory and co-founder of the research section of the European Bioinformatics Institute.

Abstracts

Time for Change: Circadian Rhythms in Health and Disease
Steve A. Kay, PhD, DSc, University of Southern California

Most life on our planet has evolved under conditions of day - night cycles, due to the rotation of the earth. Consequently, many organisms exhibit daily, or circadian, rhythms in behavior, physiology and metabolism. Research over the past 20 years has shown that internal clocks or oscillators, which generate 24 h timing information, generate these overt rhythms.  An obvious example of this is the daily sleep-wake cycle that exists in humans. We now know that these clocks are composed at the molecular level of complex feedback loops in transcription and posttranslational regulation, generating timing information at the cellular level. For example, more than 20% of the transcriptome in any cell type cycles on a 24 h basis.  More recently, it has become increasingly apparent that the control of many fundamental physiological processes is under the control of the circadian clock, ranging from neuronal activity in the brain to glucose homeostasis in the liver and cell division in epithelia. Furthermore, many studies are now demonstrate clear links between disruption of clocks that can occur through shift work and other stresses, and the development of diseases such as diabetes or breast cancer. We will present recent biomedical research on how we arrive at an understanding of clock function, and how we can use high throughput genomic and chemical biology approaches to develop novel therapies based on our molecular understanding of circadian clock mechanisms.
 

Networks and Control in Systems Biology
Francis J. Doyle, III, Department of Chemical Engineering, University of California Santa Barbara

Robustness, the ability to maintain performance in the face of perturbations and uncertainty, is a key property of living systems. While ‘homeostasis’ has long been recognized as an important phenomenon, the molecular and cellular bases of robustness have only recently begun to be understood. Biology and engineering employ a common set of basic ‘control’ mechanisms to achieve such robust regulation, namely redundancy, feedback control, modularity and hierarchies to ensure robust performance. New systems theoretical approaches to complex engineered systems are required that allow the reverse engineering of general design principles that can provide insights into cellular robustness. While preliminary results are available for simple (low-dimensional, deterministic) biological systems, general tools for analyzing these tradeoffs are the subject of active research.
 
In this talk, I will outline methods that are drawn from the field of control and network systems to generate insights into the functioning of these robust biophysical networks, as well as their failure under disease states. Examples will be used to motivate problems and methodologies, including Post-traumatic Stress Disorder, Diabetes, and Circadian Rhythms.
 

Clonal Evolution Models of Breast Tumor Growth, Resistance, and Migration
Paul K. Newton, PhD, Viterbi School of Engineering, University of Southern California

Cancer is an evolutionary process taking place within a genetically and functionally heterogeneous population of cells that traffic from one anatomical site to another via hematogenous and lymphatic routes. The population of cells associated with the primary and metastatic tumors evolve, adapt, proliferate, and disseminate in an environment in which a fitness landscape controls survival and replication. Our goal in this talk is to provide an increasingly complex and detailed hierarchy of mathematical models which can produce quantitative simulations of stochastically evolving populations of cancer cells competing with healthy cells in spatially structured environments (directed graphs). The cells have birth and death rates that are determined by a fitness function associated with a prisoner’s dilemma payoff matrix. Within the context of prisoner’s dilemma language, the healthy cells are the cooperators, and the cancer cells are the defectors. In an isolated tumor, the fitness of the cancer cells, hence their birth rate, surpasses that of the healthy cells, yet the overall fitness of the organ decreases as the cancer cells multiply. Each cell in the model system has a heritable numerical `genome’ (binary string) which has the ability to undergo point mutations. Permutations of the binary string determine fitness, and are course-grained into two basic cell types: healthy (low fitness) and cancerous (high fitness). Metastatic dissemination is simulated via Monte Carlo simulations on a Markov directed graph, where each anatomical site in the body is a node of the graph, and transition probabilities determine metastatic spread of the disease from node to node. The structure of the graph, the transition probabilities, the structure of the payoff matrices, and the mutational dynamics all contribute to aspects of simulated outcomes as well as likely responses to simulated therapies.
 

Human Scale Fluid Dynamics: How a Millisecond Can Help Us Understand a Lifetime
Amanda Randles, PhD, Harvard University; Lawrence Livermore National Laboratory

The potential impact of hemodynamic simulations on the diagnosis and treatment of patients suffering from vascular disease is tremendous. Empowering simulation of the full arterial tree can provide insight into diseases such as arterial hypertension and enables the study the impact of local factors on global hemodynamics. When combined with computational approaches that can extend the models to include physiologically accurate hematocrit levels in large regions of the circulatory system, these image-based models yield insight into the underlying mechanisms driving disease progression and inform surgical planning or the design of next generation drug delivery systems. I will present a computational model of three-dimensional hemodynamics on 1,572,864 cores of the Blue Gene/Q supercomputer, implemented within the HARVEY code. A new highly scalable implementation of the Lattice Boltzmann method is presented to address key challenges like multiscale coupling, limited memory capacity and bandwidth, and flexible load balancing. We demonstrate the first high-resolution simulation of blood flow in the systemic arterial tree as well as a 2x improvement in work-per-second. As minimizing the runtime for modeling hemodynamics in full arterial networks will enable unprecedented risk stratification on a per-patient basis, we introduce methods that reduce time-to-solution by 82%. Finally, I will present the expansion of the scope of projects to address not only vascular diseases, but also treatment planning and the movement of circulating tumor cells in the bloodstream.
 

Quantitative Real-Time Analysis of Collective Cancer Invasion and Dissemination
Andrew J. Ewald, PhD, Johns Hopkins University

Cancer most commonly arises in epithelial cells and mortality from epithelial cancers is chiefly attributable to their spread to distant sites, a process termed metastasis. Because it occurs deep inside the body and necessarily involves multiple organ systems, our cellular and molecular understanding of metastasis is limited. We have developed novel ex vivo assays to enable real-time analysis of specific stages in metastatic spread, focusing initially on invasion and dissemination into the surrounding stroma. Briefly, we isolate organoids from primary tumors through mechanical and enzymatic processing; each organoid consists of 200-300 cancer cells. We then tested a series of natural and synthetic 3D scaffolds and identified collagen I as a microenvironment that promotes in vivo-like invasion. Epithelial tumors contain cancer cells in different genetic and phenotypic states and we sought to identify the cells most responsible for metastatic spread. Within the group of 300 cancer cells, typically 5-15 cells would pioneer the invasion into collagen I and so we contrasted their molecular phenotype with cells that remained in the bulk. We discovered that the cells leading invasion shared a common molecular identity, including expression of both luminal and basal cytokeratins, across mouse models of breast cancer and in diverse human breast tumors. We further showed that this basal molecular phenotype was induced following contact with the extracellular matrix and that knockdown of keratin-14 was sufficient to abrogate invasion in 3D culture and in vivo. We are currently exploiting this system to isolate the molecular programs driving invasion and metastasis.
 

Integrative Genomics for Tumor Clonality, Entire Cities, and the International Space Station
Christopher E. Mason, PhD, Weill Cornell Medical College

The avalanche of easy-to-create genomics data has impacted almost all areas of medicine and science, and here we report the implementation of genomics technologies from the single-cell to an entire city, as well as integrative genomics approaches to space medicine.  Recent methods and algorithms enable single-cell and clonal resolution of phenotypes as they evolve, both in normal and diseased tissues.  Notably, some of these changes can be discovered by single-cell analysis and enable prognostic relevance.  We also show that the genome, epigenome, transcriptome, and epitranscriptome all harbor some evidence of tumor evolution.  Finally, we will discuss pilot data for creating enabling patients to become more involved in their ‘omics data, including to an integrative genomics view of an entire city (based on our Pathomap project) that leverages longitudinal genomics and microbiome profiles of the New York City subway system.   All of these pieces work together to guide the most comprehensive, longitudinal, mutli-omic view of human physiology with the National Aeronautics and Space Administration (NASA) Twins Study, which just launched to the International Space Station (ISS) and is enabling the most in-depth physiological and medical profile of a human being ever created.
 

Perturbation Science: From Physics to Molecular Biology to the Design of Combination Cancer Therapy
Chris Sander, PhD, Memorial Sloan Kettering Cancer Center

Cells and organisms have evolved as robust to external perturbations and adaptable to changing conditions. This capacity poses severe problems for cancer patients. Some targeted anti-cancer drugs work remarkably well, yet resistance is almost certain to emerge. Three particular scientific challenges arise: (1) discover the escape routes in response to drugs and how to block the exits by combinatorial intervention; (2) in The Cancer Genome Atlas, empirically describe the landscape of oncogenic alterations for improved therapeutic navigation; and (3) use experimental perturbation biology (systematic perturbation coupled with rich observation of response, such as changes in protein levels and protein modifications) to derive executable network models for cancer cells that guide the development of combination therapy. Work was done in collaboration with Sven Nelander, Anil Korkut, Evan Molinelli, Martin Miller, Wei Qing Wang, Xiaohong Jing, Andrea Pagnani, Riccardo Zecchina, Giovanni Ciriello, Nikolaus Schultz, Debora Marks et al.
 

Building and Breaking Hearts, and Other Organs
Scott E. Fraser, PhD, University of Southern California

The formation of organs like the vertebrate heart has long been known to result from the choreographed motion, patterning and differentiation of the multiple cell types that contribute to the heart. However, the exact details of the events, and the signals that pattern them, have yet to be fully defined. The heart is both the first organ to become functional, and even minor defects in the developmental program can have major consequences. To fully define the key events of heart development, which are well underway when the heart is no larger in diameter than a human hair, we perform quantitative imaging of the cells, their gene expression, and their interactions with the neighboring cells. This quantitative imaging permits us to draw on the fruits of the genomic revolution, and to determine which of the genes and proteins expressed in the heart are key to its development. Imaging the beating heart as it patterns has required us to construct faster and more efficient microscopes, resulting in a two-photon light-sheet microscope that combines the deep penetration of two-photon microscopy and the speed of light sheet microscopy. This generates images with more than ten-fold improved imaging speed and sensitivity. Imaging of the cells embedded in the beating heart reveals unexpected behaviors of the patterning cells, offering new insights into the origins of congenital heart malformations and suggesting novel means to diagnose and treat malformations.
 

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Wall Street Inn

212.747.1500

Ritz-Carlton New York, Battery Park

212.344.0800