Nanotechnology:The ultimate tools for medicine ?
PD Dr.med Patrick [email protected]
Div. of Intensive Care Medicine & Cardiology Physics in Medicine Research Group
University Hospital Basel
What happened to the Bayer shares ?
The promise of Nano-Medicine
Eric Drexler, 1986
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 !
List of all original papersclinical application of nanotechnology in medicine :
body
dimensions of life - dimensions of medicine
organs
blood vesselsneuron
smostcells
nucleuscell
organelles supramol.assemblies
proteinssmall molecules
mdmcmmm
m
nm
mdmcmmm
m
nm
body components
atoms
in vivo diagnosis
human eyestethoscopeX-ray
ultrasoundcathetersMRI
( only blood cells:microscopes )
biochemical tests
artificial hips
scalpelcatheters
therapeutic radiation
treatment
drugs
“there is plenty of room at the bottom”
Medical treatment today: a fundamental size mismatch...
bodyorgans
blood vesselsneuron
smostcells
nucleuscell
organelles supramol.assemblies
proteinssmall molecules
mdmcmmm
m
nm
mdmcmmm
m
nm
body components
atoms
disease disease starts herestarts here
artificial hips
scalpelcatheters
therapeutic radiation
your doctor’s watchmaker toolyour doctor’s watchmaker tool
drugs
your doctor is watering flowers..your doctor is watering flowers..
Where all the action is: the cell !
nucleus: genome,gene expression
cytoplasm: metabolism
mitochondria mRNA
ribosomes
proteins
fibrils
vesicles
endoplasmaticreticulum
membrane proteins
receptors
channels
Nanotechnology in medicine: What are the targets ?
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
some lipid lowering drugs:
effects on plaquescan save lifes
effects on immune system
effects on liver
muscles:can lead to cell death
can endanger human life
can endanger large companies
The bulldozer approach to atherosclerosis
Using a bulldozer for watchmaking ?the example of coronary artery disease
Cells begin to accumulate cholesterol
altered micromechanics
inflammation of the arteriosclerotic plaque
reactive molecules
altered membrane protein expression
cytokines
heat vessel narrowing
plaque rupture
myocardial infarctionstroke
angina
Watering flowers or flooding the neighburhood ?Treatment of cancer
anti-cancer drugs: typically kill rapidly growing cells
kill rapidly growing cancer cells
may save human lifes
may not kill slowly growing cancer cells
cancer may recur
kill normal, rapidly growing cells -intestine -> vomiting -blood cells -> anemia -immune system ->infections
may endanger life
cancer: - starts as a single cell
-is a focal disease
Medical diagnosis & treatment tomorrow: improve current technology
bodyorgans
blood vesselsneuron
smostcells
nucleuscell
organelles supramol.assemblies
proteinssmall molecules
mdmcmmm
m
nmatoms
Better materials for prostheses, stents etc:strenght, durability, biocompatibility
Enlarge catheter-based measurement toolbox
Biochemical tests: more sensitive/specificfasterbedside/point of carearray of parametersless expensive
Medical diagnosis tomorrow: break completely new ground !
bodyorgans
blood vesselsneuron
smostcells
nucleuscell
organelles supramol.assemblies
proteinssmall molecules
mdmcmmm
m
nmatoms
in vivo small scale disease characterisationin vivo single cell probes
in vivo cell nucleus probesin vivo probes for cell organelles
in vivo probing of fibrous structuresin vivo membrane protein monitoring
in vivo biochemical monitoring
Medical treatment tomorrow: break completely new ground !
bodyorgans
blood vesselsneuron
smostcells
nucleuscell
organelles supramol.assemblies
proteinssmall molecules
mdmcmmm
m
nmatoms
-targeted drug delivery -nanomechanical interventions
- to specific locations- to specific tissues- to specific cells- based on sensor information
e.g. - kill cancer cells directly- repair cellular substrate of
atherosclerosis early- find/treat infections locally- directed somatic gene therapy- attack Alzheimer’s disease
Point of care diagnosis:immunological array testing
Bernard, Michel & al, IBM Rüschlikon 8/01
micromosaic immunoassays applied to clinical inflammation markers
M.Wolf, Kantonsspital Basel/IBM Rüschlikon8/01
10m
Point of care diagnosis:nanomechanical olfactory sensors
Baller, Lang, Gerber & al, IBM /Uni Basel Arntz, IBM /Uni Basel /Kantonsspital Basel
Erased due to publication restrictions of novel technology
Erased due to publication restrictions of novel technology
Nanotechnology in action: observing disease processes involving fibrils
C. Goldsbury, J. Kistler, U. Aebi et al, J. Mol. Biol. 285, 33 (1999)
growth of beta-amyloid (->Alzheimer !) visualized by AFM
Gene chips: a promizing target for nanotech
www.clontech.coma gene microarray featuring8000 individual human cDNAs
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
Drug delivery devicesSensor driven drug application
- e.g. insulin treatment in diabetics
site-specific drug application- e.g. selectively targeting cancer cells with anticancer drugs
Single cell needles/syringes
nondestructive monitoringof cell metabolism
drug delivery device
“closed loop therapy”
cell gene therapybased on sensor info
Nanotubes in Medicine
Erased due to publication restrictions of novel technology
Topics for nanomaterials in medicine
BiocompatibilityFundamentals of self-assembly
Improved mechanical characteristics
Drug releasing materials
Biodegradable materials
cell specific surface molecules
The single cell as treatment target: Learn from creation !
virus specific protein
TLymphocyte
nucleus
“lethal kiss”
Steps toward single cell treatment
cell specific surface molecules
virus specific protein
nucleus
sensorunit wiring
catheter
effectorunit
Steps toward single cell treatment
cell specific surface molecules
virus specific protein
nucleus
sensorunit
effectorunit
power,logic
Nano-Robot
Heat production
anaerobic metabolismlactate productionpH decrease
Biologic examples for simple autonomous units
key capability not capable ofenergy production
red blood cells:gas transportpH buffer
glycolysisself replicationmobilityprotein synthesis
blood platelet:shape change,degranulateaggregateupon signal
glycolysis self replicationprotein synthesis
virus: none“cristal” with softwarecan dock to/invade cells.
metabolismmobilityself replication
neurons: electrical response to electrical/chemical stimuli
complex
Lymphocytes: recognize self and non-selfspecific response
complex
Wishlist for single cell sensorsin the nanoscale
presence/concentration of proteins
presence of mRNA
Receptor binding phenomena
tip-based spectroscopy (optical, NMR)
electric potentialheat productionpHRedox potentialgas pressures
NO concentrationconcentration of small biomolecules (lactate, cations, cAMP..)
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 ?
Nanoviruses
“A synthetic nanovirus is 5 years away”
C.Hutchinson, AAAS 2001
BBC News
Foresight Guidelines on Molecular Nanotechnology
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.
Version 3.7: June 4, 2000
Ecophagy
Some Limits to Global Ecophagyby Biovorous Nanoreplicators,
with Public Policy Recommendations
Robert A. Freitas Jr.
http://www.foresight.org/NanoRev/
“Replication time of biovorous nanoreplicators is limited by substrate availability: t >12’000 sec.”
“Early detection is key to effective defense”
Nanotech in Medicine:Ethical Questions
Breaking new ground:Creation of autonomous (“living”) agentsBlurring of frontiers between “beings” and “things” -> “allowed to mankind” ? -> “acceptable to society” ? -> controllable at long term ? -> potential for infectious spread of self-replicating machines ?
Gradual improvement of current tools/techniques-> probably acceptable to everybody-> which parts of mankind will profit ?
Nanotech in Medicine:Outlook
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
1) Nanotechnology will -revolutionize medical laboratory diagnosis within a few years
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
Thanks toThe physicists for inventing nanotech
Prof. Pfisterer and Prof. Marsch for encouragement & support
Everybody in the Nano NCCR, esp Prof. Guentherodt for their great collaboration with that strange species
of “medical doctor interested in physics”
My wife and children for the lonely hours due to nanomedicine