Nanotechnology: The ultimate tools for medicine ?

1. Nanotechnology:The ultimate tools for medicine ? PD Dr.med Patrick Hunziker Patrick.Hunziker@unibas.ch Div. of Intensive Care Medicine & Cardiology Physics in Medicine Research Group University Hospital Basel

2. What happened to the Bayer shares ?

3. Eric Drexler, 1986 The promise of Nano-Medicine

4. Current impact of nanotech on medicine: Medline impact: 117 / 11’000’000 citations with “nanotechnology” (mostly “science fiction” articles) compare: 120’000 citations with “catheter” => in medicine, nanotechnology is in its infancy !

5. List of all original papersclinical application of nanotechnology in medicine :

6. treatment in vivo diagnosis body human eye stethoscope artificial hips organs X-ray therapeutic radiation MRI scalpel ultrasound blood vessels catheters catheters neurons most cells nucleus cell organelles supramol. assemblies proteins small molecules atoms dimensions of life - dimensions of medicine body components m m dm dm cm cm mm mm ( only blood cells:microscopes ) mm mm biochemical tests nm nm drugs “there is plenty of room at the bottom”

7. body artificial hips organs therapeutic radiation scalpel blood vessels catheters neurons most cells disease starts here your doctor’s watchmaker tool nucleus cell organelles supramol. assemblies your doctor is watering flowers.. proteins small molecules atoms Medical treatment today: a fundamental size mismatch... body components m m dm dm cm cm mm mm mm mm nm nm drugs

8. vesicles nucleus: genome, gene expression channels endoplasmatic reticulum fibrils receptors mRNA mitochondria ribosomes membrane proteins proteins Where all the action is: the cell ! cytoplasm: metabolism

9. Nanotechnology in medicine: What are the targets ?

10. some lipid lowering drugs: effects on plaques can save lifes effects on liver muscles: can lead to cell death can endanger human life can endanger large companies effects on immune system Watering flowers or flooding the neighburhood ?treating atherosclerosis with lipid lowering drugs arteriosclerosis: - begins at the cell -> focal lesions in the arteries - leads to myocardial infarction and stroke arterial plaque

11. The bulldozer approach to atherosclerosis

12. Cells begin to accumulate cholesterol altered micromechanics inflammation of the arteriosclerotic plaque vessel narrowing heat reactive molecules cytokines altered membrane protein expression plaque rupture angina stroke myocardial infarction Using a bulldozer for watchmaking ?the example of coronary artery disease

13. anti-cancer drugs: typically kill rapidly growing cells kill rapidly growing cancer cells may save human lifes kill normal, rapidly growing cells -intestine -> vomiting -blood cells -> anemia -immune system ->infections may endanger life may not kill slowly growing cancer cells cancer may recur Watering flowers or flooding the neighburhood ?Treatment of cancer cancer: - starts as a single cell -is a focal disease

14. body m Better materials for prostheses, stents etc: strenght, durability, biocompatibility organs dm cm blood vessels Enlarge catheter-based measurement toolbox mm neurons most cells nucleus cell organelles mm supramol. assemblies Biochemical tests: more sensitive/specific faster bedside/point of care array of parameters less expensive proteins small molecules nm atoms Medical diagnosis & treatment tomorrow: improve current technology

15. body m organs dm cm blood vessels mm in vivo small scale disease characterisation neurons most cells in vivo single cell probes nucleus in vivo cell nucleus probes cell organelles mm in vivo probes for cell organelles supramol. assemblies in vivo probing of fibrous structures in vivo membrane protein monitoring proteins in vivo biochemical monitoring small molecules nm atoms Medical diagnosis tomorrow:break completely new ground !

16. body m organs dm - to specific locations - to specific tissues - to specific cells - based on sensor information cm blood vessels mm neurons most cells nucleus cell organelles mm supramol. assemblies proteins small molecules nm atoms Medical treatment tomorrow:break completely new ground ! -targeted drug delivery -nanomechanical interventions e.g. - kill cancer cells directly - repair cellular substrate of atherosclerosis early - find/treat infections locally - directed somatic gene therapy - attack Alzheimer’s disease

17. Point of care diagnosis:immunological array testing micromosaic immunoassays applied to clinical inflammation markers 10mm M.Wolf, Kantonsspital Basel/IBM Rüschlikon8/01 Bernard, Michel & al, IBM Rüschlikon 8/01

18. Point of care diagnosis:nanomechanical olfactory sensors Baller, Lang, Gerber & al, IBM /Uni Basel Arntz, IBM /Uni Basel /Kantonsspital Basel

19. Erased due to publication restrictions of novel technology

20. Erased due to publication restrictions of novel technology

21. Nanotechnology in action: observing disease processes involving fibrils growth of beta-amyloid (->Alzheimer !) visualized by AFM C. Goldsbury, J. Kistler, U. Aebi et al, J. Mol. Biol.285, 33 (1999)

22. Gene chips: a promizing target for nanotech The human genome project: man>: ~ 40’000 genes -> measure activation of each (mRNA) -> no more than 40’000 enzymes -> all biologically relevant substance are substrates of these enzymes measurable www.clontech.com a gene microarray featuring 8000 individual human cDNAs

24. site-specific drug application - e.g. selectively targeting cancer cells with anticancer drugs Drug delivery devices Sensor driven drug application - e.g. insulin treatment in diabetics

25. drug delivery device “closed loop therapy” nondestructive monitoring of cell metabolism cell gene therapy based on sensor info Single cell needles/syringes

26. Nanotubes in Medicine Erased due to publication restrictions of novel technology

27. Topics for nanomaterials in medicine Biocompatibility Fundamentals of self-assembly Improved mechanical characteristics Drug releasing materials Biodegradable materials

28. virus specific protein T Lymphocyte cell specific surface molecules “lethal kiss” The single cell as treatment target:Learn from creation ! nucleus

29. nucleus virus specific protein catheter sensor unit cell specific surface molecules wiring effector unit Steps toward single cell treatment

30. Heat production nucleus virus specific protein anaerobic metabolism lactate production pH decrease sensor unit cell specific surface molecules power, logic effector unit Steps toward single cell treatment Nano-Robot

31. self replication mobility protein synthesis gas transport pH buffer glycolysis red blood cells: shape change, degranulate aggregate upon signal blood platelet: self replication protein synthesis glycolysis metabolism mobility self replication virus: “cristal” with software can dock to/invade cells. none neurons: electrical response to electrical/chemical stimuli complex Lymphocytes: recognize self and non-self specific response complex Biologic examples for simple autonomous units key capability energy production not capable of

32. Wishlist for single cell sensorsin the nanoscale electric potential heat production pH Redox potential gas pressures NO concentration concentration of small biomolecules (lactate, cations, cAMP..) presence/concentration of proteins presence of mRNA Receptor binding phenomena tip-based spectroscopy (optical, NMR)

33. potential problems of nanotechnology in medicine Number of cells in the body ~1012 -> for biological impact: treat >108 cells => new manufacturing methods needed Will the immune system recognize and eliminate nanoparticles ? (immune response, biocompatibility, nano-mimickry) Influenza viruses kills 10 Mio people during world war I Computer virus shoots down millions of PC’s worldwide in y 2000 -> Autonomous, self-replicating nano-agents: a danger for the future ?

34. Nanoviruses “A synthetic nanovirus is 5 years away” C.Hutchinson, AAAS 2001 BBC News

35. Foresight Guidelines on Molecular Nanotechnology Version 3.7: June 4, 2000 MNT (molecular nanotechnology) device designs should incorporate provisions for built-in safety mechanisms, such as: 1) absolute dependence on a single artificial fuel source or artificial "vitamins" that don't exist in any natural environment; 2) making devices that are dependent on broadcast transmissions for replication or in some cases operation; 3) routing control signal paths throughout a device, so that subassemblies do not function independently; 4) programming termination dates into devices, and 5) other innovations in laboratory or device safety technology developed specifically to address the potential dangers of MNT. Further research is needed on MNT risk management, as well as the theory, mechanisms, and experimental designs for built-in safeguard systems.

36. Ecophagy Some Limits to Global Ecophagyby Biovorous Nanoreplicators,with Public Policy Recommendations Robert A. Freitas Jr. http://www.foresight.org/NanoRev/ “Replication time t of biovorous nanoreplicators is limited by substrate availability: t >12’000 sec.” “Early detection is key to effective defense”

37. Nanotech in Medicine:Ethical Questions Gradual improvement of current tools/techniques -> probably acceptable to everybody -> which parts of mankind will profit ? Breaking new ground: Creation of autonomous (“living”) agents Blurring of frontiers between “beings” and “things” -> “allowed to mankind” ? -> “acceptable to society” ? -> controllable at long term ? -> potential for infectious spread of self-replicating machines ?

38. Nanotech in Medicine:Outlook 1) Nanotechnology will -revolutionize medical laboratory diagnosis within a few years 2) Nanotechnology will break new ground in - monitoring technology in critically ill patients - in vivo diagnosis within the body - allowing single cell diagnostics, monitoring & treatment in the body - will outperform the impact of gene therapy 3) Nanotechnology will - produce simple prototypes of nanorobots within a decade, thus - blur the frontier between “beings” and “things” -> an array of ethical question will be raised -> to be addressed early

39. Thanks to The physicists for inventing nanotech Everybody in the Nano NCCR, esp Prof. Guentherodt for their great collaboration with that strange species of “medical doctor interested in physics” Prof. Pfisterer and Prof. Marsch for encouragement & support My wife and children for the lonely hours due to nanomedicine