Cellular biophysics презентация

What is Biophysics?
It is neither “physics for biologists”, nor “physical methods applied to biology”
It is a modern, interdisciplinary field of science leading to new approaches for our understanding of biological functions.
Paradigm: “Biological system is not simply the sum of its molecular components but is rather their functional integration” –example biological membrane.
Mathematics +Physics +Biology + Chemistry

Intersection (not union) of Biology, Physics and:
Computer-Science
& Math
Genomics
& Systems
Biology, Ecology, Society, & Evolution
Chemistry &
Technology

The purpose of the course:
A concise review of MAJOR CONCEPTS OF SELECTED TOPICS in BIOPHYSICS, describing cellular function with the focus on unifying principles and mechanisms, with links to the physico-chemical properties of the components; a consideration of the energetic and kinetic aspects of the processes; and the strategies and KEY TECHNIQUES used in performing the studies.
Two exams: mid-term exam (20% of the total points)
And the final (30% of the grade)
Attendance -15%;
Work in the Class/mini-qizzes/ project-35%

Biological Membrane
Highly organized anisotropic structure
Relationship STRUCTURE-FUNCTION are central to biophysics

William Thomson (Lord Kelvin)
”I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science, whatever the matter may be”.
1883, “Electrical units of measurements”

Charles Darwin
“I have deeply regretted that I did not proceed far enough at least to understand something of the great leading principles of mathematics, for men thus endowed seem to have an extra sense.”
Autobiography, 1997

Why we should care about the numbers in biology?
The importance of biological numeracy centers on the way in which a quantitative formulation of a given biological phenomenon allows us to build models in order to understand HOW it works.

Examples of problems to solve:
How brain processes and stores information?
How the heart pumps blood?
How muscles contract?
How plants use light for grow in photosynthesis?
How genes are switched on and off?

What is the goal of biophysics?
(1) create simplified models
(2) make quantitative predictions
(3) Experimentally test quantitative predictions

.
Most of what we know in Physics has been derived from experience with the inanimate world. It is a challenge to transfer these concepts to living objects such as cells, tissues, and entire organisms, where it is not certain if they are appropriate or even relevant.

Why Model?
To understand biological/chemical data.
(& design useful modifications)
To share data we need to be able to
search, merge, & check data via models.
Integrating diverse data types can reduce random & systematic errors.

What are biophysicts study? (Heidelberg)
Collective cell migration (Spatz)- is the process of several cells migrating as a cohesive group, in which each individual actively coordinates its own movement with that of its neighbors
Engineering of synthetic cells (Platzman)-The major aim of our interdisciplinary research is the bottom-up assembly of synthetic cells which can adhere, migrate and divide.
Biophysics of cell interactions (Boehm)-Many mammalian cells are enveloped by a sugar-protein coat. This coat mainly consists of hyaluronan (HA) and plays a major role in all interactions of the cell with its environment. Thus our main research interest is the analysis of cellular interactions in response to HA.
Spectroscopy technologies (Zamir and Majer)-Reconceptualizing fluorescence correlation spectroscopy for monitoring and analyzing of periodically passing objects.
Super-resolution microscopy technology- (S.Hell)-Current efforts of this interdisciplinary group of physicists, chemists and biologists aim to improve resolution, contrast, speed and versatility of optical nanoscopy.

The primary objective of the program is to educate and train individuals with this background to apply the concepts and methods of the quantitative sciences to the solution of biological problems.

Divisions of Biophysics:
Molecular biophysics
Biomechanics
Membrane Biophysics
Bio-electrochemistry
Environmental Biophysics
Theoretical Biophysics
Biophysical Techniques (general, imaging, medical)
Impact on biotechnology and medicine

HOW: Biophysical techniques and applications

Engine of discovery:Biophysical techniques and applications

Biophysical techniques and applications

History: First “Biophysicists”
Heraclitus 5th century B.C. – earliest mechanistic theories of life processes, insight into dynamic.
“Change is central to Universe”.
“Logos is the fundamental order of all “on Nature” changes of objects with the flow of time”
“You can not step twice into the same river”

Epicurus 3rd century B.C. – atom. Living organisms follow the same laws as non-living objects.
Galen 2th century AD – physician, most accomplished medical researcher of the Roman period. His theories dominated Western medicine for over millennium.
Better anatomy only by Vesalius in 1543
Better understanding of blood and heart in 1628
Leonardo da Vinci 16th century – mechanical principles of bird flight (to use for engineering design) - BIONICS
First “Biophysicists”

Giovanni Alfonso Borelli 17th century- related animals to machines and utilized mathematics to prove his theories.
De Motu Animalium – comprehensive biomechanical description of limb’s mobility, bird’s flight, swimming movement, heart function.
Borelli farther of biomechanics

Luigi Galvani / Alessandro Volta
Bio-electrochemistry
18th (1771) Galvani touched frog nerve with charged scalpel.
Signal transduction in neurons and communication between neurons and muscle has electrical nature.

Electric circuit = two different metals + sciatic nerve of the frog
Nerve of the frog's leg = electrolyte and sensor
Metals = electrodes
If close the circuit dead leg will twitch.
Volta created first battery by substituting frog leg with electrolyte.
From frog leg to first battery.
Luigi Galvani / Alessandro Volta
With two different metals
effect is stronger.
Contact potential !!

OFFICIAL BIRTH OF BIOPHYSICS

Optical aspects of the human eye
Theory of hearing
Brown’s motion
Osmotic process
Nonequilibrium thermodynamics
Discovery of X-rays – emergence of radiation biophysics
Discovery of DNA structure
Information theory
Statistical physics of biopolymers
…
History of discoveries in Biophysics:

The major advance in understanding the nature of gene mutation and gene structure. The work was a keystone in the formation of molecular genetics.
Transmission of order from one organism to it’s descendants

.
Quantitative definition of life?
Probability of replication … simple in, complex out
(in a specific environment)
Robustness/Evolvability
(in a variety of environments)
Challenging cases:
Physics: nucleate-crystals, mold-replica, geological layers, fires
Biology: pollinated flowers, viruses, predators, sterile mules,
Engineering: self-assembling machines.
Structure, function, replication, growth, origin, evolution…

Schroedinger cat

In order to function:
All groups of living organisms on Earth share several key characteristics:
Order; Sensitivity or response to stimuli; Reproduction; Growth and Development; Homeostasis; Energy processing
All living things detect changes in their environment and respond to them. All living things are capable of reproduction, the process by which living things give rise to offspring. All living things are able to maintain a constant internal environment through homeostasis. All forms of life are built of CELLS.
.

Are viruses alive??
(computer & biological viral codes)
Computer viruses & hacks :
over $3 trillion/year (Most costly
virus MyDoom-$38 billions in damages
AIDS - HIV-1
36.9 mln dead (worse than black plague & 1918 Flu)
Polymerase drug resistance mutations
M41L, D67N, T69D, L210W, T215Y, H208Y
PISPIETVPVKLKPGMDGPK VKQWPLTEEK
IKALIEICAE LEKDGKISKI
GPVNPYDTPV FAIKKKNSDK
WRKLVDFREL NKRTQDFCEV

Concept Computers Organisms
Instructions Program Genome
Bits 0,1 a,c,g,t
Stable memory Disk,tape DNA
Active memory RAM RNA
Environment Sockets,people Water,salts
I/O AD/DA proteins
Monomer Minerals Nucleotide
Polymer chip DNA,RNA,protein
Replication Factories 1e-15 liter cell sap
Sensor/In Keys,scanner Chem/photo receptor
Actuator/Out Printer,motor Actomyosin
Communicate Internet,IR Pheromones, song
Conceptual connections

Self-compiling & self-assembling
Complementary surfaces
Watson-Crick base pair
(Nature April 25, 1953)
MC. Escher

.
Minimal Life:
Self-assembly, Catalysis, Replication, Mutation, Selection
Cell boundary

/
Replicator diversity
DNA
Protein
Growth rate
Polymers: Initiate, Elongate, Terminate, Fold, Modify, Localize, Degrade
Self-assembly, Catalysis, Replication, Mutation, Selection Polymerization & folding (Revised Central Dogma)

.
Maximal Life:
DNA
Protein
Growth rate
Expression
Interactions
Polymers: Initiate, Elongate, Terminate, Fold, Modify, Localize, Degrade
Self-assembly, Catalysis, Replication, Mutation, Selection Regulatory & Metabolic Networks

Types of Systems Interaction Models
Quantum Electrodynamics subatomic
Quantum mechanics electron clouds
Molecular mechanics spherical atoms nm-fs
Master equations stochastic single molecules
Fokker-Planck approx. stochastic
Macroscopic rates ODE Concentration & time (C,t)
Flux Balance Optima dCik/dt optimal steady state
Thermodynamic models dCik/dt = 0 k reversible reactions
Steady State ΣdCik/dt = 0 (sum k reactions)
Metabolic Control Analysis d(dCik/dt)/dCj (i = chem.species) Spatially inhomogenous dCi/dx
Population dynamics as above km-yr
Increasing scope, decreasing resolution

.
Integrate : Optimal BioSystems
Elements of Life-Molecules & Purification
Systems Biology & Applications of Models
Life Components & Interconnections
Continuity of Life & Central Dogma
Qualitative Models & Evidence
Synthetic Life

From atoms to (bio)molecules
H2O H2 , O2 H+ , OH-
CH4 C60 CO3-
NH3 N2 NO3-
H2S Sn SO4-- Mg++
PH3 K+PO4-- Na+
Gas Elemental Salt

STEP 1: Purify
Elements, molecules, assemblies, organelles,
cells,
organisms
chromatography
Clonal growth

.
Pre 1970s: Column/gel purification revolution
Mid-1970s: Recombinant DNA brings
clonal (single-step) purity.
1984-Now: Sequencing genomes & automation
aids return to whole systems.
Whole genome sequencing.
Purified history

.
Integrate : Optimal BioSystems
Elements of Life-Molecules & Purification
---Systems Biology & Applications of Models
Life Components & Interconnections
Continuity of Life & Central Dogma
Qualitative Models & Evidence
Synthetic Life

.
Why Genomes & Systems?
#0. Why sequence the genome(s)? To allow #1,2,3 below.
#1. Why map variation?
#2. Why obtain a complete set of human RNAs, proteins
& regulatory elements?
#3. Why understand comparative genomics and how genomes evolved? To allow #4 below.
#4. Why quantitative biosystem models of molecular interactions with multiple levels (atoms to cells to organisms & populations)?
To share information. CONSTRUCTION is a test of understanding & to make useful products.

.
Number of component types (estimate)
M.gen Worm Human
Bases .58M >97M 3000M
DNAs 1 7 25
Genes .48k 19k 21k
RNAs .4k >30k .2-3M
Proteins .6k >50k .3-10M
Cells 1 959 1014

.
Glycine
Gly
G
The simplest amino acid
component of proteins
config(glycine,[
substituent(aminoacid_L_backbone),
substituent(hyd),
linkage(from(aminoacid_L_backbone,car(1)),
to(hyd,hyd(1)),
nil,single)]).

.
20 Amino acids of 280
T

.
Some Grand (& useful) Challenges
A) From atoms to evolving minigenome-cells.
Improve in vitro macromolecular synthesis.
Conceptually link atomic (mutational) changes to population evolution
(via molecular & systems modeling).
Novel polymers for smart-materials, mirror-enzymes & drug selection.
B) From cells to tissues.
Model combinations of external signals & genome-programming on expression.
Manipulate stem-cell fate & stability.
Engineer reduction of mutation & cancerous proliferation.
Programmed cells to replace or augment (low toxicity) drugs.
C) From tissues to physiological & eco- systems
Programming of cell and tissue morphology.
Quantitate robustness & evolvability.
Engineer sensor-effector feedback networks where macro-morphologies
determine the functions; past (Darwinian) or future (prosthetic).

.
Continuity of Life & Central Dogma
DNA
Protein
Growth rate
Expression
Interactions
Polymers: Initiate, Elongate, Terminate, Fold, Modify, Localize, Degrade
Self-assembly, Catalysis, Replication, Mutation, Selection Regulatory & Metabolic Networks

.
"The" Genetic Code
M
Adjacent mRNA codons
F
3’ uac
5'... aug
3’aag
uuu ...
‘Silent’ codon changes

.
Translation
t-,m-,r-RNA
Ban N, et al. 1999 Nature. 400:841-7.
Large macromolecular complexes:
Ribosome: 3 RNAs (over 3 kbp plus
over 50 different proteins)
Science (2000) 289: 878, 905, Science (2000) 289: 878, 905, 920, 3D coordinates.

.
How many living species?
5000 bacterial species per gram of soil (<70% DNA bp identity)
Currently: 8,7 million species on Earth (eukaryotic); bacterial and
archea (from 100,000 to 10 millions)
During last 250 years, 1.2 million eukaryotic species have been
identified and taxonomically classified
1st sequenced – Haemophylus influenzae, 1995
Whole genomes: 17,420 bacteria; 362 Archea; 98 insects; 150 plants;
235 terrestrial vertebrates (80 mammalians)
(Data from 2014, “Scientist”)
& Why study more than one species?
Comparisons allow discrimination of
subtle functional constraints.

.
Continuity & Diversity of life

2nd law of thermodynamic - in isolated system molecular disorder never decreases spontaneously.
Question: why Earth is full of life which is highly organized?
Vitalism?
How life generates order?
Question biophysicists ask: