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 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 Environment Pre-cancer Cancer Symptoms 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 in Biomedical Science
Convergence July 2011
“merging of distinct technologies, processing disciplines, or devices into a unified whole that creates a host of new pathways and opportunities”
“blueprint for innovation” Convergence timeline
Timeline: The three revolutions
Genomics Revolution
1950 1960 1970 1980 1990 2000 2010
2001: Human Genome Project, Celera publish working draft of human genome
Image and info credits (clockwise from top-left): DNAmazing.com, Gene.com, BioX.stanford.edu, qb3.org, mit.edu/ki, nap.edu, sciencemag.org, nature.com, nlm.nih.gov Biotech cluster at Kendall Square (MIT)
Courtesy of Phil Sharp Learn More about NCI PS-OC Program
http://physics.cancer.gov Additional Slides Total NIH Projects for South Africa over Past 10 Years
Total: 302 Total Funds: $333,176,492 Sub-Projects: 34 Sub-Projects Funds: $18,803,545
http://report.nih.gov/index.aspx Cancer Statistics between South Africa and Africa (All)
South Africa Africa (All) APHELION - Distinguished Panelists and Advisors
Expert panel: Chair: Paul Janmey, UPenn Dan Fletcher, UCB Sharon Gerecht, JHU Paul Dan Sharon Ross Ross Levine, MSKCC Parag Mallick, Stanford Owen McCarty, OHSU Lance Munn, Harvard Cindy Reinhart-King, Cornell Parag Owen Lance Cindy
Advisors: Tito Fojo, NCI Denis Wirtz, JHU
Tito Denis http://www.wtec.org/aphelion APHELION – A Global Study by the World Technology Evaluation Center (WTEC)
APHELION: Assessment of Physical Sciences and Engineering Advances in Life Sciences and Oncology Goal: To determine the status and trends of global research and development whereby physical sciences and engineering principles are being applied to cancer research, oncology, and other biomedical research areas in leading laboratories and organizations via an on-site peer review process.
http://www.wtec.org/aphelion NCI-OPSO/NSF-ENG & MPS Joint Collaborations:
Physical and LIfe Sciences Early Research (PLIER) Awards
Semahat Clark David Demir Cooper Brandt
(ENG) Theresa Kaiming Good Ye
(MPS) 2011: 6 Awards
Office of Physical Sciences-Oncology (OPSO) 2012: 6 Awards NSF-MPS Led Workshops
November 1-2 November 13-14 November 5-6 2010 2012 2013
Physics of Theoretical Foundations of Drug Physics of Cancer Metastasis and Immune Resistance in Cancer Cancer Krastan Imaging Blagoev Physical Sciences/Engineering & Oncology http://physics.cancer.gov
August 18, 2011 November 22, 2012 An Indirect Way to Tame Cancer: Biomechanical Perspective
Rakesh Hydrostatic Jain Pressure Solid Stress Biomechanical Perspective
Pre-losartan
Collagen Breast Breast Pancreatic Perfused Vessels Pre-losartan