Nanotechnology:The ultimate tools for medicine ?

PD Dr.med Patrick HunzikerPatrick.Hunziker@unibas.ch

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