1. © 2006 STEP Consortium Toward the Virtual Physiological Human: a primer for Policy Makers STEP CONSORTIUM

2. © 2006 STEP Consortium The problems Genetic research is producing less clinical impact than expected because the increasing knowledge on the genome and the proteome is somehow disconnected with that of the physiome The specialisation of western medicine, based on the subdivision of the body in sub-systems, makes difficult to tackle all diseases with a strong systemic component The society a medicine based on quantitative evidences, where every clinical decision can be explained by clear and logical arguments

3. © 2006 STEP Consortium An example: osteoporosis OP is becoming a pandemic It has a genetic component but it is also strongly modulated by the hormonal balance, the dietary regime, and the type of daily physical activity The best method to monitor OP (DXA) can predict retrospectively only 65% of the OP spontaneous fractures (tossing a coin would give 50%) Preliminary studies suggest that the use of a predictive models that integrate the organ and the tissue scales with metabolic and lifestyle factors can increase accuracy up to 85-95%

4. © 2006 STEP Consortium The human Puzzle

5. © 2006 STEP Consortium The human Puzzle The human body is like a jigsaw puzzle made of a trillion pieces Currently we are trying to understand the whole picture by looking at a single piece, or at a few closely interconnected pieces We do need a frame, within which we can finally start to place the pieces all together, and the glue that connect them The frame is not the whole picture, but is the only way we might hope to see it one day

6. © 2006 STEP Consortium Paradigmatic Shift in Biomedical Research Complement Reductionism With Integrationism

7. © 2006 STEP Consortium The name of the Rose Integrative Biology Integrative Physiology Integrative Medicine System Biology Multiscale Bioengineering Physiome Integrative Research

8. © 2006 STEP Consortium Integration across …. Across sub-systems

9. © 2006 STEP Consortium Integration across …. Across dimensional scales Organism (7) OrganSystem(6 ) Organ (5) Tissue (4) Cell (3) Molecule (2) Atom (1) Across Temporal scales

10. © 2006 STEP Consortium Integration across …. Across Disciplines Medicine BioEngineering Biology

11. © 2006 STEP Consortium Paradigmatic Shift in Biomedical Research laboratory and clinical observation are cumulated and made accessible by all those who can use them to develop or to validate new hypotheses knowledge we have on a sub-system, a certain dimensional scale, a certain biophysical aspect can be formalised and interconnected to those other are developing on contiguous sub-systems, scales, domains We call this new approach Integrative Research

12. © 2006 STEP Consortium Integrative Research The Integrative Research approach requires a radical transformation on the way biomedical research is conducted It is necessary to create a framework made of technology and methods We call this framework Virtual Physiological Human

13. © 2006 STEP Consortium Virtual Physiological Human Descriptive –a framework within which observations made in the laboratories, in the hospitals, and in the field all over the world can be collected, catalogued, organised, shared and combined in any possible way

14. © 2006 STEP Consortium Virtual Physiological Human Integrative –a framework that allows experts to collaboratively analyse this observations and develop systemic hypotheses that involve the knowledge of multiple scientific disciplines

15. © 2006 STEP Consortium Virtual Physiological Human Predictive –a framework that makes possible to interconnect predictive models defined at different scale, with different methods, and with different levels of detail, into systemic networks that provide concretisation to those systemic hypotheses, and make possible to verify their validity by comparison with other clinical or laboratory observations

16. © 2006 STEP Consortium EuroPhysiome: Scope The scope of the EuroPhysiome Initiative is to promote the development of the Virtual Physiological Human, a methodological and technological framework that will enable the investigation of the human body as a single complex system We claim that, given sufficient resources, the European Research System can develop in the next 10 years the Virtual Physiological Human

17. © 2006 STEP Consortium Seeding the EuroPhysiome: a roadmap to the Virtual Physiological Human STEP is developing this roadmap through a consensus process involving hundreds of experts and the representatives of clinical, industrial and societal stakeholders The RoadMap is a document that describes the research and technological development that Europe should follow to achieve the realisation of the Virtual Physiological Human

18. © 2006 STEP Consortium Toward the VPH: Phase #1 VPH-related research projects in IST: –AneurIST (neurovascular pathology) –ImmunoGrid (immune system physiology) –LHDL (musculoskeletal system physiology) 2005 - 2010

19. © 2006 STEP Consortium Toward the VPH: Phase #2 Building the EuroPhysiome –STEP Action: consensus process to write the VPH research roadmap http://www.europhysiome.org –Biomed Town:Internet community reserved to the biomedical researchers http://www.biomedtown.org 2006 - 2007

20. © 2006 STEP Consortium Toward the VPH: Phase #3 VPH research in multiple FP7 programs –QoL (DGRes): System Biology: linking genome, proteome and physiome Predictive multiscale models of human pathophysiology Clinical applications of VPH models –IST (DGInfso): VPH Technology development Large scale infrastructures VPH Knowledge management Simulation and visualisation 2007 - 2016

21. © 2006 STEP Consortium VPH: Economic Impact Strong impact on Body Industry: all industries developing products exchange forces with the human body –Automotive industry (vehicle safety and comfort) –Tools and workplace industry (ergonomics and safety) –Aerospace industry (effects of weightlessness on humans, extra-vehicle activity suites) –Defence industry (evaluation of biological damage of conventional weapons, armours and shields) –Sport and Leisure industry (equipment for leisure and for competition) –Medical industry (design of drugs, prostheses, artificial organs) –Entertainment industry (creation of digital characters)

22. © 2006 STEP Consortium VPH: Health Impact Rare diseases Systemic diseases (cancer, osteoporosis, cardiovascular, obesity, diabetes, etc.) Preventive medicine, nutrition and lifestyle Disabling diseases (whiplash, back pain, repeated injury syndromes, etc) Reduced risk in clinical trials

23. © 2006 STEP Consortium VPH: Policies Impact Toward a quantitative evidence-based medicine Personalised Healthcare (gender, age, etc.) Easier production of public health epidemiology studies Reduce animal experimentation Fight the “re-invent the wheel” syndrome in research Increase the public visibility of research investments

24. © 2006 STEP Consortium Yearly check-up: 15-05-2017 Today I went to see the doctor for my yearly check-up. A friend of mine suggested a new clinical department where they use a special diagnostic system called "Virtual Physiological Human" or VPH in short. When I arrived the nurse led me into a room stuffed with strange equipment and a huge wall-size holo-screen on one side. Dr. Smith, my physician, came in and started to interact with the computer using the natural gesture-eye interface. Big deal! Even my game box has this type of interface, nowadays. The holo-screen projected a 3D model of the human body; with a few gestures, the doctor made evident a number of physiological signals that I understood were coming from the model. Ok, this is the VPH. After scrutinizing it some more, I realised that this computer body was breathing, moving its eyes, etc. In response to a vocal command by the Doctor, it started to walk around, and I could see with perfect accuracy the muscle contracting under the skin. The VPH started to jog, and after a short while I noticed small drops of sweat forming on its brows. The doctor made the skin on the chest transparent, and suddenly I could see the heart beating, the blood flowing in the vessels and changing colour when passing through the lungs.

25. © 2006 STEP Consortium Yearly check-up: 15-05-2017 A quick zoom exposed the tissue of a muscle in the arm; the doctor showed me the nutrients arriving at the muscle fibres, the nervous signals sent from the brain to the motor axons, and the electrochemical process that made the muscle contract and exert force. Well, this was impressive! But still I did not understand what this had to do with my yearly check-up. The doctor asked me to undress and to stand on a small platform. A laser scan quickly passed over my whole body; suddenly the generic model on the screen changed and it was me! It was my size and my shape. It even had my face. With a simple voice command by the doctor, the VPH automatically marked all the blemishes on the skin. The doctor quickly took a look at a few of those that the computer had marked in red; he clicked on two of them and suddenly a small robotic arm came out the wall, and pointed to these two small moles. On the screen a highly enlarged picture of each mole appeared. Meanwhile I realised that my digital counterpart was starting to emit a number of signals. The doctor gave a command and the system zoomed in at the feet, where a small dot was plotting a very complex line; after a little while I understood that dot was my centre of gravity, and if I moved, it followed my motion. The doctor asked me to close my eyes, raise my arms, stand on one foot, and a lot of all those nonsense things doctors ask you to do on these occasions. But the amazing thing was that while this was happening I could see how the internal organs of my body worked. Dr. Smith applied to my skin a number of small sensors; he explained to me that they would wirelessly transmit many physiological signals to the computer. At that point I realised that the VPH started to breath with me; I held my breath, and the VPH stopped as well! I touched my wrist, and I could feel the beat of my heart fully synchronised with that of the VPH. Weird!

26. © 2006 STEP Consortium Yearly check-up: 15-05-2017 The doctor asked me to mount an exercise bike and start pedalling. I could see my muscles contracting, my joints articulating, my heart beating! The doctor zoomed into the heart region, and the VPH showed some coloured dots that the doctor told me represented the various molecules and electrical signals that are exchanged to keep the heart beating. The doctor told me something required further attention: I started to get nervous. They took me into another room and put me inside a big machine (they called it a high resolution MRI) that made a pulsing noise for a few seconds. Back to the holo-screen where my heart model was now huge, full of details, and with a number of graphs with strange numbers around it. The doctor studied it for a while and then told me everything was fine for now, but that I could have problems in the future. He showed me a thickening in a vessel near the heart, and told me that if this thickening increased, it could disturb the flow of the blood to the heart. The VPH gave the chemical composition of this stuff, and the doctor suggested it might have something to do with my cholesterol levels. Maybe I did not look sufficiently impressed, because he opened a new view over a very complex VR representation (he told me it was a world-wide database of cardiovascular diseases), searched for a short while, and then showed me another heart with a thickening like mine, but much more pronounced. The blood flow was much reduced in this case, and the heart was beating in a very strange way. Although most of numbers on the screen did not make any sense to me, it was clear something was seriously wrong. OK, I told him, I got the message. He gave me a memory stick, which he said contained all my data, some dietary recommendations, and a cardiovascular training program to load onto my home computer. I left the hospital with a clear sense of understanding of my health. No more bacon for breakfast!

27. © 2006 STEP Consortium Yearly check-up: 15-05-2017 Today I went to see the doctor for my yearly check-up. A friend of mine suggested a new clinical department where they use a special diagnostic system called "Virtual Physiological Human" or VPH in short. When I arrived the nurse led me into a room stuffed with strange equipment and a huge wall-size holo-screen on one side. Dr. Smith, my physician, came in and started to interact with the computer using the natural gesture-eye interface. Big deal! Even my game box has this type of interface, nowadays. The holo-screen projected a 3D model of the human body; with a few gestures, the doctor made evident a number of physiological signals that I understood were coming from the model. Ok, this is the VPH. After scrutinizing it some more, I realised that this computer body was breathing, moving its eyes, etc. In response to a vocal command by the Doctor, it started to walk around, and I could see with perfect accuracy the muscle contracting under the skin. The VPH started to jog, and after a short while I noticed small drops of sweat forming on its brows. The doctor made the skin on the chest transparent, and suddenly I could see the heart beating, the blood flowing in the vessels and changing colour when passing through the lungs. A quick zoom exposed the tissue of a muscle in the arm; the doctor showed me the nutrients arriving at the muscle fibres, the nervous signals sent from the brain to the motor axons, and the electrochemical process that made the muscle contract and exert force. Well, this was impressive! But still I did not understand what this had to do with my yearly check-up. The doctor asked me to undress and to stand on a small platform. A laser scan quickly passed over my whole body; suddenly the generic model on the screen changed and it was me! It was my size and my shape. It even had my face. With a simple voice command by the doctor, the VPH automatically marked all the blemishes on the skin. The doctor quickly took a look at a few of those that the computer had marked in red; he clicked on two of them and suddenly a small robotic arm came out the wall, and pointed to these two small moles. On the screen a highly enlarged picture of each mole appeared. Meanwhile I realised that my digital counterpart was starting to emit a number of signals. The doctor gave a command and the system zoomed in at the feet, where a small dot was plotting a very complex line; after a little while I understood that dot was my centre of gravity, and if I moved, it followed my motion. The doctor asked me to close my eyes, raise my arms, stand on one foot, and a lot of all those nonsense things doctors ask you to do on these occasions. But the amazing thing was that while this was happening I could see how the internal organs of my body worked. Dr. Smith applied to my skin a number of small sensors; he explained to me that they would wirelessly transmit many physiological signals to the computer. At that point I realised that the VPH started to breath with me; I held my breath, and the VPH stopped as well! I touched my wrist, and I could feel the beat of my heart fully synchronised with that of the VPH. Weird! The doctor asked me to mount an exercise bike and start pedalling. I could see my muscles contracting, my joints articulating, my heart beating! The doctor zoomed into the heart region, and the VPH showed some coloured dots that the doctor told me represented the various molecules and electrical signals that are exchanged to keep the heart beating. The doctor told me something required further attention: I started to get nervous. They took me into another room and put me inside a big machine (they called it a high resolution MRI) that made a pulsing noise for a few seconds. Back to the holo-screen where my heart model was now huge, full of details, and with a number of graphs with strange numbers around it. The doctor studied it for a while and then told me everything was fine for now, but that I could have problems in the future. He showed me a thickening in a vessel near the heart, and told me that if this thickening increased, it could disturb the flow of the blood to the heart. The VPH gave the chemical composition of this stuff, and the doctor suggested it might have something to do with my cholesterol levels. Maybe I did not look sufficiently impressed, because he opened a new view over a very complex VR representation (he told me it was a world-wide database of cardiovascular diseases), searched for a short while, and then showed me another heart with a thickening like mine, but much more pronounced. The blood flow was much reduced in this case, and the heart was beating in a very strange way. Although most of numbers on the screen did not make any sense to me, it was clear something was seriously wrong. OK, I told him, I got the message. He gave me a memory stick, which he said contained all my data, some dietary recommendations, and a cardiovascular training program to load onto my home computer. I left the hospital with a clear sense of understanding of my health. No more bacon for breakfast!