Medicine of the Future—The Transformation from Reactive to Proactive (P4) Medicine as presented at the Ohio State University Medical Center Personalized Health Care National Conference. Leroy Hood, MD, PhD, is the president and founder of the Institute of Systems Biology. Dr. Hood is a member of the National Academy of Sciences, the American Philosophical Society, the American Academy of Arts and Sciences, the Institute of Medicine and the National Academy of Engineering. His professional career began at Caltech where he and his colleagues pioneered four instruments — the DNA gene sequencer and synthesizer and the protein synthesizer and sequencer — which comprise the technological foundation for contemporary molecular biology. In particular, the DNA sequencer played a crucial role in contributing to the successful mapping of the human genome during the 1990s. http://www.systemsbiology.org/Scientists_and_Research

1. Medicine of the Future—The Transformation from Reactive to Proactive (P4) Medicine Predictive, Personalized, Preventive and Participatory Lee Hood Institute for Systems Biology, Seattle

3. Contemporary Systems Biology is Predicated on Viewing Biology is an Informational Science

6. Most Sophisticated Integrated Biological Network Defined to Date

8. A Systems Approach to Prion Disease in Mice

9. Prion disease example: Prion Protein Exists in Two Forms Cellular PrP C PrP Genetic Mutations PrPSc Infections Spontaneous conversion Infectious PrP Sc

11. Multiple groups: five inbred strains, two transgenic strains and one knockout strain Differentially Expressed Genes--DEGs--7400 to 333

13. Neuropathological Features PrP accumulation Microglia / Astrocyte activation Synaptic Degeneration Normal Infected Nerve cell death

15. PrP accumulation network

21. A Systems Approach to Blood Diagnostics

22. Dynamics of a Prion Perturbed Network in Mice Nerve cell death

24. Organ-Specific Blood Fingerprints Making Blood A Window Distinguishing Health and Disease Blood Vessel

25. Presymptomatic Diagnosis of Murine Prion Disease with Organ-Specific Protein in Blood Samples 15/45 brain-specific blood proteins enabled early detection Clinical Signs at 18 wk Presymptomatic Diagnosis at 10 wk

27. Technologies Will Create New Patient Data Spaces to be Explored and Will Greatly Expand the Old Patient Data Spaces

29. Genome Sequencing of Individuals

30. Study Families to Suppress Noise and Carry out Powerful New Genetic Analyses Unaffected parents Children with craniofacial malformation and lung disease Lynn Jorde and Michael Bamshad: family DNA—Sequencing by Complete Genomics, Inc

32. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X 65 crossovers in (2) male meioses (left) 104 crossovers in (2) female meioses (right) Recominational Genome Map from Miller’s Syndrome Children 0 50 100 150 200 250 x x x Both children inherited the same allele from both parents Each child inherited a different allele from each parent Children inherited the same allele from dad, different alleles from mom Children inherited the same allele from mom, different alleles from dad

33. Microfluidic Protein Chip

34. DEAL for In vitro molecular diagnostics : Integrated nanotech/microfluidics platform Jim Heath, et al Organ 1 Organ 2 Tox response inflammation cells out 300 nanoliters of plasma Assay region Dynamic range--10 8 Sensitivity--high atmole 5 minute measurement

35. New Approach to Protein-Capture Agents

37. Single-Cell Analyses

38. Multiplexed ELISA for secreted proteins Single Cell Analyses Adrian Ozinsky

39. Routine Analyses on Individual Patients with 10 years

41. Organ-Specific Blood Protein Fingerprint Analyses Will Transform Biology and Medicine

52. ISB Strategic Partnerships to Hasten the Realization of P4 Medicine

56. Two Luxemboug Research Projects

58. ISB’s Approach to P4 Medicine: Genetics and Environment integration is key to future medicine Tissue, Blood protein And stem cell Read-out Predictive, Personalized Diagnostics Genome Environment Disease & Health Complex biological Networks Systems Genetics

60. A Second Strategic ISB Partnership—the P4 Medical Institute—ISB/OSU

65. P4 MI Core Competencies Translational Science Social Sciences & Ethics Policy & Regulation Technology Higher Education Commercial Analysis P4MI Charter Members Healthcare Delivery Legal Consumer Behavior

70. The P4 Medical Institute Through the ISB/OSU Strategic Partnership Could Play a Key Role in Accelerating the Emergence of P4 Medicine

71. Acknowledgements Prion--Institute for Systems Biology Daehee Hwang Inyoul Lee Hyuntae Yoo Eugene Yi (proteomics core facility) Bruz Ma r zolf (Affymetrix core facility) Nanotechnology-- J Heath, Caltech Luxembourg projects-- David Galas, ISB P4 Medical Institute —Fred Lee, David Galas, Diane Isonaka Prion--McLaughlin Research Institute Great Falls, Montana Ranjit Giri Douglas Spicer Rajeev Kumar Rose Pitstick Rebecca Young George A. Carlson