Presentation on theme: "Nanomedicine A New Frontier for Physics Jens-Christian D. Meiners University of Michigan Dept. of Physics and Biophysics Research Division."— Presentation transcript:
Nanomedicine A New Frontier for Physics Jens-Christian D. Meiners University of Michigan Dept. of Physics and Biophysics Research Division
The Nano-Gap: Therapeutics Advanced Visual Instruments Inc.http://www.med.unibs.it/~marchesi/pps97/course/section11/insulin.html Drugs: up to ~10 nm Example: Insulin Surgery: down to ~100 µm Example: Ophthalmologic Microsurgery
The Nano-Gap: Diagnostics Wang et. al., Opt. Lett. 28, 414 (2003) Commercial Methods in Clinical Microbiology. ASM Press Molecular assays: up to ~10 nm Example: Western Blot for HIV testing Histology: down to ~1 µm Example: Esophageal mucosa 20 µm
Subcellular Structures Moran, L.A. and Scrimgeour K.G. (1994) "Biochemistry" Cells are full of structures on the nanometer scale!
Nanostructures and Diseases Example: Malfunctioning immotile cilia are implicated in numerous diseases, ranging from polycystic kidney disease to sensory dysfunction. From Somlo et al From F. Hildebrandt 200 nm
Bridging the Nano-Gap Hollywood: Miniaturize submarines (Fantastic Voyage, Inner Space) Physics: Understand the physical laws for nanoscale biological systems first!
Newton’s Laws? Inertia dominates:Friction dominates: force=mass×accelerationforce=friction×velocity Scaling Laws: mass~radius 3 friction~radius Nanoscale biological systems are dominated by friction, not inertia!
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
Biological Oscillators Minimal Clock in E. Coli: Alex Ninfa, U of M
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: We need to understand the physics behind DNA bending and stretching to understand these mechano-biochemical systems. Multiple loops: Logic Functions!
Entropic Forces 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 volume It takes an external force to create such an unlikely distribution Example from classical thermodynamics:
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!
Stretching DNA We can attach magnetic microspheres to surface- immobilized DNA molecules and stretch the DNA with magnets to measure its elasticity:
Stretching DNA Measuring the elasticity of a single DNA molecule with optical tweezers Measurements fit the wormlike- chain (Marko –Siggia) model.
Tying a Knot into DNA
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
Observing Protein-Mediated DNA Loop Formation and Breakdown Motion Average Position 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.
Transport on the Nanoscale Macroscopically: We shake or stir to mix liquids by inducing turbulence Microscopically: All flow is laminar, turbulence cannot develop
Life at Low Reynolds Numbers Reynolds number: Dimensionless parameter that determines whether turbulence can develop on a length scale d. R=d×velocity×density / viscosity On the cellular scale, all flow is laminar Diffusion is slow, in particular in a crowded environment => Mixing is extremely difficult
Active Transport through Molecular Motors Molecular motors can carry cargo to specific locations inside the cell. Example: Kinesin moves along microtubules From Somlo et al From the Hunt Lab
Active Transport through Molecular Motors From Ronald D. Vale, UCSF procmotconvkinrev5.mov Kinesin moving on a microtubule: Microtubules sliding on kinesin: From Ronald D. Vale, UCSF invitmtglid.mov
Nano-Therapeutics Michigan Nanotechnology Institute for Medicine and Biological Science Synthesis of dendritic polymers From Brad Orr, U of M
Nano-Therapeutics Functionalization with groups that recognize and kill cancer cells More complex architectures: DNA-linked dendrimers Hope for multifunctional “smart” therapeutics Michigan Nanotechnology Institute for Medicine and Biological Science
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