Nanomedicine A New Frontier for Physics

1
NanomedicineA New Frontier for Physics

• Jens-Christian D. Meiners
• University of Michigan
• Dept. of Physics and Biophysics Research Division

2
The Nano-Gap Therapeutics
Surgery down to 100 µm Example Ophthalmologic
Microsurgery
Drugs up to 10 nm Example Insulin
Advanced Visual Instruments Inc.
http//www.med.unibs.it/marchesi/pps97/course/sec
tion11/insulin.html









3
The Nano-Gap Diagnostics
Molecular assays up to 10 nm Example Western
Blot for HIV testing
Histology down to 1 µm Example Esophageal
mucosa
20 µm
Wang et. al., Opt. Lett. 28, 414 (2003)
Commercial Methods in Clinical Microbiology. ASM
Press









4
Subcellular Structures
Moran, L.A. and Scrimgeour K.G. (1994)
"Biochemistry"
Cells are full of structures on the nanometer
scale!
5
Nanostructures and Diseases
Example Malfunctioning immotile cilia are
implicated in numerous diseases, ranging from
polycystic kidney disease to sensory dysfunction.
200 nm
From Somlo et al. 2002
From F. Hildebrandt
6
Bridging the Nano-Gap
Hollywood Miniaturize submarines (Fantastic
Voyage, Inner Space)
Physics Understand the physical laws for
nanoscale biological systems first!
7
Newtons Laws?
Inertia dominates
Friction dominates
forcemassacceleration
forcefrictionvelocity
Scaling Laws
massradius3
frictionradius
Nanoscale biological systems are dominated by
friction, not inertia!
8
Oscillations in Biological Systems
Mechanical Oscillators Strongly overdamped
not oscillating at all!
Chemical Oscillators Better, but high
consumption of reagents and / or energy
Biological Oscillators Complex
mechano-biochemical systems
9
Biological Oscillators
Minimal Clock in E. Coli
Alex Ninfa, U of M
10
Protein-mediated DNA Loops
Protein-mediated DNA Loops are at the heart of
these biological clocks and many other essential
biological functions. They can activate or
repress gene expression.
Prokaryotic activator loop
Repressor loop
Multiple loops Logic Functions!
We need to understand the physics behindDNA
bending and stretching to understandthese
mechano-biochemical systems.
11
Entropic Forces
Example from classical thermodynamics
Gas molecules distribute evenly in the available
volume (likely distribution)It is highly
unlikely that all gas molecules are found in one
half of the volumeIt takes an external force to
create such an unlikely distribution
12
Entropic Forces in Polymers
Polymers are long chain molecules Chemical bonds
are hard to stretch, but can often rotate freely
Likeliest conformation Random walk
Unlikely conformation Stretched or bent
A force is required to stretch a polymer!
13
Stretching DNA
We can attach magnetic microspheres to
surface-immobilized DNA molecules and stretch the
DNA withmagnets to measure its elasticity
14
Stretching DNA
Measuring the elasticity of a single DNA
moleculewith optical tweezers
Measurements fit the wormlike-chain (Marko
Siggia) model.
15
Tying a Knot into DNA
16
Observing Protein-Mediated DNA Loop Formation
and Breakdown

• A fluorescently labeled microsphere is tethered
  to a glass surface via a short DNA construct
• Evanescent wave excites fluorophores
• Tracking the image location and intensity of the
  fluorescent emission provides three-dimensional
  position information, yielding information about
  the tehter length

17
Observing Protein-Mediated DNA Loop Formation and
Breakdown

• Loop formation is seen as a decrease of the
  motion of the microsphere, as well as a reduced
  average distance from the cover glass.
• Can measure loop formation and breakdown rates.
• Can vary parameters such as loop size, mechanical
  tension, sequence-dependent curvature etc.

Motion
AveragePosition
18
Transport on the Nanoscale
Macroscopically We shake or stir to mix liquids
by inducing turbulence
Microscopically All flow is laminar,
turbulence cannot develop
19
Life at Low Reynolds Numbers
Reynolds number Dimensionless parameter that
determines whether turbulence can develop on a
length scale d.
Rdvelocitydensity / viscosity
On the cellular scale, all flow is
laminar Diffusion is slow, in particular in a
crowded environment gt Mixing is extremely
difficult
20
Active Transport through Molecular Motors
Molecular motors can carry cargo to specific
locations inside the cell. Example Kinesin moves
along microtubules
From the Hunt Lab
From Somlo et al. 2002
21
Active Transport through Molecular Motors
Kinesin moving on amicrotubule
Microtubules sliding onkinesin
From Ronald D. Vale, UCSFhttp//valelab.ucsf.edu/
images/mov-procmotconvkinrev5.mov
From Ronald D. Vale, UCSFhttp//valelab.ucsf.edu/
images/mov-invitmtglid.mov
22
Nano-Therapeutics
From Brad Orr, U of M
Synthesis of dendritic polymers
Michigan Nanotechnology Institute for Medicine
and Biological Science
23
Nano-Therapeutics
Functionalization with groups that recognize and
kill cancer cells
Michigan Nanotechnology Institute for Medicine
and Biological Science
More complex architecturesDNA-linked dendrimers
Michigan Nanotechnology Institute for Medicine
and Biological Science
Hope for multifunctional smart therapeutics
24
Conclusions

• There are important biological and medical
  problems on the nanometer scale.
• Understanding the relevant physical laws is
  necessary to make progress in this area.
• Ultimately, this will lead to novel therapeutic
  approaches in medicine.

Acknowledgments

• The Physics Demolab staff
• My research group
• NIH Institute for General Medical Sciences