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Convergence of Physical Sciences for Biomedical Applications Larry A. Nagahara Associate Director Physical Sciences in Oncology Initiative Division of Cancer Biology (DCB) National Cancer Institute (NCI) National Institutes of Health (NIH) U.S. Joint Services & OSD Africa Technical Exchange Meeting, May 5-9, 2014 National Institutes of Health (NIH): 27 Institutes and Centers NHGRI NIA NIDA NINDS NIDCD NIMH NEI NIAAA CIT NINR NLM NIDDK NIH Campus – Bethesda, Maryland FIC CSR NIBIB NIMHD NIDCR NIEHS NIGMS NICHD CC NIAMS NCATS NCCAM NIAID NCI NHLBI NIH Budget ~ $30.8 Billion (FY12) NCI Budget ~ $ 5.07 Billion (FY12) ~82% for extramural support ~ 76% for extramural support ~63,000 grants and contracts ~7,800 grants and contracts National Cancer Institute Organization National Cancer Institute $5.07B Director (FY12) Office of the Deputy Director Harold Varmus, MD Director Douglas Lowy, MD Nobel Prize (1989) CSSI OPSO Center for Strategic (2013) ~$132 M (~4%) Scientific Initiatives Division of Division of Division of Center for Cancer Division of Cancer Division of Division of Cancer Cancer Treatment Cancer Control and Cancer Extramural Epidemiology Research and Population Prevention Activities and Genetics Biology Diagnosis Sciences ~$858M (~17%) ~$919M (~29%) ~$779M (~25%) ~$441M (~14%) ~$264M (~8%) ~$21M (~0.4%) Conducting – Intramural Funding – Extramural Red numbers: FY12 grants data only from http://fundedresearch.cancer.gov/nciportfolio; Black numbers: from FY12 http://obf.cancer.gov/financial/factbook.htm Cancer Global Effect – Incidence/Mortality 7.6 million people died of cancer in 2005 (out of 58 millions deaths) >70% in low and medium income countries New cancer cases in the US will approach 2 million by 2025 Source: International Agency for Research on Cancer: GLOBOCAN 2008 Database Cancer Statistics between South Africa and US South Africa US What is It? Tumor, Cancer, and Metastasis “…>90% of deaths is caused by disseminated disease or metastasis…” Gupta et. al., Cell, 2006 and Siegel et. al. CA Cancer J Clin, Feb 2014 In the US, Cancer Continues to be Represent an Enormous Burden 577,190 Americans died of cancer in 2012 (projection) 1,638,910 Americans will be diagnosed with cancer this year $263.8 billion in 2010 for cancer healthcare costs & lost productivity Unlike Other Major Disease Killers, Cancer Continues to Take Nearly the Same Toll as it did in 1950 586.8 600 1950 500 2010 400 Δ 228% Δ 362% Δ 219% Δ 12% 300 179.1 193.9 200 180.7 172.8 Death Rates Per Rates Death 100,000 Americans 100,000 100 39.1 48.1 15.1 0 Heart Cerebrovascular Pneumonia/ Cancer Diseases Diseases Influenza Source for 2012 deaths and diagnoses: American Cancer Society (ACS) 2012 Cancer Facts & Figures; Atlanta, Georgia Source for 2010 age-adjusted death rate: National Center for Health Statistics, NCHS Public-use file for 2010 deaths. OPSO Petri Dish: Proper “Culture” Office of Physical Sciences – Oncology (OPSO) History Think Tanks (2008) Feb’08 PS-OC Scientific Network Outreach Jul’08 John Anna Neiderhuber Barker Oct’08 Prospective Infrastructure ~300 RFA Announced (2008) Evaluation Support extramural participants 12 Awarded (2009) Ask Investigators To Bring: The OPSO activities contains multiple “active” ingredients to promote and catalyze collaboration between investigators that bridge physical sciences and oncology Marchperspectives. 28, 2014 Different Perspective Historical Perspective: Galvani and Volta 1781-1791: Luigi Galvani, professor of medicine, discovered “animal electricity” Carried out a wide ranging series of experiments which found convulsive movements of the frog occurred when two metals were made to touch each other while one metal was in contact with a nerve and the other was in contact with a muscle of the frog Believed that the “animal electricity” came from the muscle and did not perceive electricity as separable from biology 1791-1800: Alessandro Volta, professor of physics, invented the battery Repeated Galvani’s experiment and initially embraced his work. However soon reached a different conclusion and reasoned that “animal electricity” was a physical phenomenon Invention of “voltaic pile” (a.k.a., battery) inspired by (disprove) Galvani’s work to show that a steady electric current could be generated by two dissimilar metals between an electrolyte What if Galvani and Volta had worked together? George Gamow, Francis Crick, & RNA Tie Club Member Training RNA Tie Club Member Training RNA Tie Club Designation Designation George Gamow Physicist ALA Edward Teller Physicist LEU Alexander Rich Biochemist ARG Erwin Chargaff Biochemist LYS Robert Ledley Mathematical Biophysicist ASN Nicholas Metropolis Physicist, Mathematician MET Paul Doty* Physical Chemist ASP Gunther Stent Physical Chemist PHE Martynas Ycas Biochemist CYS James Watson** Biologist PRO Alexander Dounce Biochemist GLN Harold Gordon Biologist SER Robley Williams Electron Microscopist GLU Leslie Orgel Theoretical Chemist THR Richard Feynman** Theoretical Physicist GLY Max Delbrück** Theoretical Physicist TRY Melvin Calvin** Chemist HIS Francis Crick** Physicist TYR Norman Simmons Biochemist ISO Sydney Brenner** Biologist VAL RNA Tie Club: “Solve the riddle of the RNA structure and to understand how it built proteins” Gamow postulated that a nucleotide code consisting of three letters would be enough to define all 20 amino acids (i.e., the concept of the “codon” ). Sydney Brenner provided experimental evidence for the codon Francis Crick proposed the “adaptor hypothesis” involving a molecule ferrying the amino acids around, and putting them in the correct order corresponding to the nucleic acid sequence. These “ferrying” molecules were later found by Robert Holley and named it transfer RNAs. PS-OC Network (circa 2014): Physical scientists & cancer researchers integrated at the start PI + SI Liphardt Weaver O’Halloran Licht Shuler Hempstead Manalis Jacks Stanford Northwestern Cornell MIT 12 “Virtual” Centers Over 110 Institutions: 83 Domestic Hillis Agus Michor Holland 32 Foreign USC DFCI corresponding to: PS-OC Network 700+ investigators, Scripps Princeton collaborators, & Kuhn Bethel Austin Tlsty advisors 550+ trainees (post-docs, graduate, & ASU TMHRI Moffitt Johns Hopkins undergraduate) Davies Grady Ferrari Curley Gatenby Gillies Wirtz Semenza participating in the PS-OC Network Emergent Properties – Physics of Flocking “Collective Behavior” Hard Substrates Promote Acinar Disorganization Increasing Matrix Stiffness Phase Contrast α6β4 integrin β-catenin DAPI 150 Pa 400 Pa 675 Pa 1050 Pa >5000 Pa Elastic Modulus (Pa) Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, (2005). Emergent Long Range Mechanical Cooperation among Disorganizing Mammary Acini UC Berkeley PS-OC Jan Valerie Liphardt Weaver Hundreds of acini ~1 million cells red dots = acini green = collagen PNAS 111, 658 (2014) What if substrate is modifiable, like it is in a real tissue? Emergent Long Range Mechanical Cooperation among Disorganizing Mammary Acini Emergent Long Range Mechanical Cooperation among Disorganizing Mammary Acini Solitary Acini FractionOrganized Interacting Acini PNAS 111, 658 (2014) UC Berkeley PS-OC Outreach Pilot Project Issue: The Triangle Region of North Carolina has one of the highest rates of breast cancers death for young African American women. 47.2 deaths AA vs. 26.5 deaths Caucasian /100,000 women Victoria Seewaldt, MD 0 mos 36 mos 48 mos ER/PR+ Duke University T1N0 Hypothesis: Is there a threshold effect that drives Focal Pre-cancer Cancer Symptoms rapidly progressing breast Age shifted 30 40 50 cancer? Access 0 mos 6 mos 12 mos ER/PR- Her2- Biology T1N0 Obesity/early pregnancy Pre-cancer Cancer Symptoms Environment Non-focal Physical-Based Accelerated 30 32 33 Cancer Problem: Many Cancer Patients Develop Resistance to Therapy Galapagos Islands Spin Glass Analogy: “Weakling Interacting Systems” Sewall Wright (1932) Landscape Theory Robert Austin Princeton PS-OC Cancer Problem: Many Cancer Patients Develop Resistance to Therapy What are the fundamental bases of rapid development of resistance? “Death Galaxy” in Action Cancer Problem: Many Cancer Patients Develop Resistance to Therapy 10mg/ml, ~200x MIC 10µg/ml, ~200x MIC Science 333, 1764 (2011) Evolution of Resistance in Multiple Myeloma in the Microhabitat with Drug Gradients Flow Direction 10mg/ml, ~200x MIC (200 nM DOX) 150 μm 100 μm Time Physical Sciences-Oncology Network (PS-ON) (PS-OC) Program: PAR-14-169 (PS-OP) Program: NOT-CA-14-039 FY09 FY14 FY16 PS-ON: PS-OC PAR-14-169/ Pre-Award RFA-CA09-009 PS-OP NOT-CA-14-039 Future Current PS-OC Program: Re-issuances of Physical Sciences-Oncology Initiative: 12 U54 PS-OCs Physical Sciences-Oncology Network (PS-ON) ~$30M/year 100+ institutions and Two Programs (PAR): 600+ investigators Physical Sciences Oncology Centers (PS-OCs): PAR-14-169 worldwide Physical Sciences Oncology Projects (PS-OPs): NOT-CA-14-039 4 Themes: Physics (Physical Laws and 2 Themes (suggested): Principles) of Cancer The Physical Dynamics of Cancer Evolution and Evolutionary Theory of Spatial Organization and Cancer Cancer Competition under Type 1 (New) Information Coding, Decoding, Transfer, and Funding Mechanism: Translation in Cancer PS-OCs – U54 – up to $1.5M (DC)/year (5 years max.) De-convoluting Cancer’s Complexity PS-OPs – U01 – up to $0.5M (DC)/year (5 years max.) (Foreign Institutions are also welcome to apply) New Frontiers in Cancer Research Hepatology 53, 604 (2011) 1662 (2010) 1662 328 Science Science Tissue Eng. 19, 730 (2013) Convergence
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