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Fundamental Medical Science I

Coordinator: Prof. Susan Tai

Oct 11 – Dec 3, 2010

Please refrain from instant messaging, e-mailing, surfing the Internet, playing games, writing papers, doing homework, etc. during class time

Please refrain from using cell phones and other electronic gadgets while attending class

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the study of basic concepts and understanding of cellular and molecular biology, genetics and fundamental basic principles of cellular function.

Fundamental Medical Science I

Topics which will be covered in the lectures

1.  the structure and function of the cell 2.  the intracellular activities and pathways 3.  different regulatory mechanisms 4.  gene expression 5.  mutation and repairing 6.  cause and inheritance of genetic disorders 7.  protein synthesis and function 8.  protein related diseases 9.  stem cells and stem cell therapy 10. cancer and carcinogenesis

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2009,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Elizabeth  H.  Blackburn,  Carol  W.  Greider,  Jack  W.  Szostak    "for  the  discovery  of  how  chromosomes  are  protected  by  telomeres  and  the  enzyme  telomerase"  

2008,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Harald  zur  Hausen,  Françoise  Barré-­‐Sinoussi,  Luc  Montagnier    "for  his  discovery  of  human  papilloma  viruses  causing  cervical  cancer"  

2007,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Mario  R.  Capecchi,  Sir  MarRn  J.  Evans,  Oliver  Smithies    "for  their  discoveries  of  principles  for  introducing  specific  gene  modifica;ons  in  mice  by  the  use  of  embryonic  stem  cells"  

2006,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Andrew  Z.  Fire,  Craig  C.  Mello    "for  their  discovery  of  RNA  interference  -­‐  gene  silencing  by  double-­‐stranded  RNA"  

2005,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Barry  J.  Marshall,  J.  Robin  Warren    "for  their  discovery  of  the  bacterium  Helicobacter  pylori  and  its  role  in  gastri;s  and  pep;c  ulcer  disease"  

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2004,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Richard  Axel,  Linda  B.  Buck    "for  their  discoveries  of  odorant  receptors  and  the  organiza;on  of  the  olfactory  system"  

2003,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Paul  C.  Lauterbur,  Sir  Peter  Mansfield    "for  their  discoveries  concerning  magne;c  resonance  imaging"  

2002,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Sydney  Brenner,  H.  Robert  Horvitz,  John  E.  Sulston    "for  their  discoveries  concerning  'gene;c  regula;on  of  organ  development  and  programmed  cell  death'  

2001,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Leland  H.  Hartwell,  Tim  Hunt,  Sir  Paul  M.  Nurse    "for  their  discoveries  of  key  regulators  of  the  cell  cycle"  

2000,  THE  NOBEL  PRIZE  IN  PHYSIOLOGY  OR  MEDICINE  Arvid  Carlsson,  Paul  Greengard,  Eric  R.  Kandel    "for  their  discoveries  concerning  signal  transduc;on  in  the  nervous  system"  

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Teaching and Learning Method

•  Lecture              :  6  hours/week.  •  Tutorial  and  Plenary      :  7  hours/week.  

•  Laboratory  prac;ce      :  4  hours/week.  

•  Self  directed  learning    :  12  hours/week  

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1.  Cell  Structure  and  Func;on                                  Prof.  Susan  Tai  

2.  Human  Gene;cs                  Dr.  Andi  Utama  3.  Gene;cs  in  Medicine                    Dr.  Ivet  Suriapranata  

4.  Biochemistry  and  Human  Health              Dr.  Indra  Bach;ar  5.  Signal  Transduc;on  and  Regula;on            Dr  Sigit  Purwantomo  

6.  Cell  metabolism                        Dr.  Ivet  Suriapranata  

7.  Cancer  and  Carcinogenesis            Dr.  Andi  Utama  8.  Stem  Cell                          Dr.  Agus  Se;yono  

Weekly Lectures Lecturers

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Structure and function of cells in the human body

Weekly Objective

1. Plasma membrane 2. Cytoplasm and organelles 3. Cell skeleton 4. Nucleus and chromosome 5. Cell Cycles

a. Cell growth and apoptosis b. Cell division – mitosis and meiosis

6. Cell injury and regeneration Describe how abnormal intracellular collections can interfere with function Appreciate how mutations in a single gene may dramatically effect cell organization, organ development and function.

Topics which will be covered in week 1

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FUNDAMENTAL MEDICAL SCIENCE 1

Cytology

Ivet Suriapranata October 2010

The  Cell:    

•  the  minimal  self-­‐reproducing  unit  •  the  vehicle  for  transmission  of  the  gene;c  informa;on  in  all  living  species  

Alberts et al. Molecular Biology of the Cell

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The word CELL comes from a Latin word: CELLULA (small room)

Robert Hooke/ cork tree

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The Cell Theory

1839 by Matthias Jakob Schleiden and Theodor Schwann;

All organisms are composed of one or more cells.

All cells come from preexisting cells.

Vital functions of an organism occur within cells

All cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.

red: keratin green: DNA

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unicellular organism : bacteria, yeast

multicellular organism : animal, human

If a typical cell size is 10 µm, and a typical cell mass is 10 ng

How many cells are there in humans?

•  self-contained and self-maintaining

•  takes in nutrients

•  converts these nutrients into energy

•  carries out specialized function

•  reproduces as necessary

•  stores its own set of instructions for carrying out each of these activities.

Characteristics of each cell

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components of DNA:

four nucleotides: A, T, C, G

joined together by sugar-phosphate linkages

double strand DNA -> double helix structure

All cells store their hereditary information in the same linear chemical code (DNA)

All cells replicate their hereditary information by templated polymerization

The sequence of nucleotides in an existing DNA strand, controls the sequence in which nucleotides are joined together in a new DNA strand

Base pairing: A<->T; C<->G

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All cells transcribe portions of their hereditary information into the same intermediary form (RNA)

All cells translate RNA into Protein in the same way

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monomers of protein: amino acids

protein molecules are created by joining amino acids in particular sequence fold

each amino acid has a distinctive chemical character

proteins/ polypeptides bind with high specificity to other molecules and act as enzymes

All cells use protein as catalysts

Plasma membrane: selective barrier

separate and protect a cell from its surrounding environment and is made mostly from a double layer of lipids

All cells are enclosed in a plasma membrane across which nutrients and waste materials must pass

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cytoplasm

Plasma membrance

DNA in nucleoid

Ribosomes

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Flagella a long, slender projection from the cell body, composed of microtubules and surrounded by the plasma membrane. In small, single-cell organisms they may function to propel the cell by beating in a whip-like motion;

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Cell Wall a fairly rigid layer surrounding a cell, "located external to the cell membrane, "that provides the cell with structural support, protection, "and a filtering mechanism"

The cell wall is constructed from different materials dependent upon the species. "

Bacterial cell walls are made of peptidoglycan (also called murein), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids

Bacterial cell walls are different from the cell walls of plants and fungi which are made of cellulose and chitin

The cell wall is essential to the survival of many bacteria and the antibiotic penicillin is able to kill bacteria by inhibiting a step in the synthesis of peptidoglycan

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Two different types of cell wall in bacteria Gram-positive and Gram-negative.

The names originate from the reaction of cells to the Gram stain, a test for the classification of bacterial species

Gram-positive bacteria possess a thick cell wall containing many layers of peptidoglycan and teichoic acids.

In contrast, Gram-negative bacteria have a relatively thin cell wall consisting of a few layers of peptidoglycan surrounded by a second lipid membrane containing lipopolysaccharides and lipoproteins.

Most pathogenic bacteria have the Gram-negative cell wall

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Gram positive bacteria: Bacillus anthracis

Gram negative bacteria: Pseudomonas aeruginosa

Cell capsule (or glycocalyx): Layer outside bacterial cell wall well organized and not easily washed off. composed of polysaccharides helps to protect bacteria against phagocytosis, considered a virulence factor

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Functions of the prokaryotic plasma membrane: 1. Osmotic or permeability barrier 2. Location of transport systems for specific solutes (nutrients and ions) 3. Energy generating functions (respiratory and photosynthetic electron transport systems, establishment of proton motive force, and transmembranous, ATP-synthesizing ATPase) 4. Synthesis of membrane lipids (including lipopolysaccharide in Gram-negative cells) 5. Synthesis of murein (cell wall peptidoglycan) 6. Assembly and secretion of extracytoplasmic proteins 7. Coordination of DNA replication and segregation with septum formation and cell division 8. Chemotaxis (both motility per se and sensing functions) 9. Location of specialized enzyme system

Plasma membrane: Phospholipid bilayer

The yellow polar head groups separate the grey hydrophobic tails from the aqueous cytosolic and extracellular environments.

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Mesosome: invagination of plasma membrane

Ribosome for Protein translation

DNA in prokaryotes is condensed in nucleoid

Table 1. Summary: Characteristics of typical bacterial cell structures.

Structure Flagella

Function(s) Swimming movement

Predominant chemical composition Protein

Pili

Sex pilus Mediates DNA transfer during conjugation Protein

Capsules (includes "slime layers" and glycocalyx)

Attachment to surfaces; protection against phagocytic engulfment, occasionally killing or digestion; reserve of nutrients or protection against desiccation

Usually polysaccharide; occasionally polypeptide

Cell wall

Gram-positive bacteria

Prevents osmotic lysis of cell protoplast and confers rigidity and shape on cells

Peptidoglycan (murein) complexed with teichoic acids

Gram-negative bacteria

Peptidoglycan prevents osmotic lysis and confers rigidity and shape; outer membrane is permeability barrier; associated LPS and proteins have various functions

Peptidoglycan (murein) surrounded by phospholipid protein-lipopolysaccharide "outer membrane"

Plasma membrane

Permeability barrier; transport of solutes; energy generation; location of numerous enzyme systems Phospholipid and protein

Ribosomes Sites of translation (protein synthesis) RNA and protein

Inclusions Often reserves of nutrients; additional specialized functions Highly variable; carbohydrate, lipid, protein or inorganic

Chromosome Genetic material of cell DNA

Plasmid Extrachromosomal genetic material DNA

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Bacterial disease:

Mycobacterium tuberculosis

Escherichia coli

Salmonella typhi

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Multidrug resistance bacteria:

Bacteria have been able to adapt so that antibiotics are no longer effective.

They have done this via several mechanisms:

No longer relying on a glycoprotein cell wall.

Enzymatic deactivation of antibiotics

Decreased cell wall permeability to antibiotics

Altered target sites of antibiotic

Efflux mechanisms to remove antibiotics

Increased mutation rate as a stress response

Many different bacteria now exhibit multidrug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, Mycobacterium tuberculosis

To limit the development of antibiotic resistance:

Only use antibiotics for bacterial infections Identify the causative organism if possible Use the right antibiotic; don't rely on broad range antibiotics Don't stop antibiotics as soon as symptoms improve; finish the full course Most colds, coughs, bronchitis, sinus infections, and eye infections are viral; do not use antibiotics

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Eukaryo(c  Cell  Structure  

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•  Ribosomes      150,000g  for  90  min  

•  Mitochondria      15,000g  for  20  min  •  Endoplasmic  Re(culum  60,000g  for  30  min  

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Exocytosis

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Proteins mediate and regulate the transport of metabolites, macromolecules and ions

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The mitochondrion is shaped perfectly to maximize its efforts.

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•  creates  energy  for  the  cell.  The  process  of  crea5ng  cell  energy  is  known  as  cellular  respira(on.    

•  very  small  organelles.  You  might  find  cells  with  several  thousand  mitochondria.  The  number  depends  on  what  the  cell  needs  to  do.  If  the  purpose  of  the  cell  is  to  transmit  nerve  impulses,  there  will  be  fewer  mitochondria  than  in  a  muscle  cell  that  needs  loads  of  energy.  If  the  cell  feels  it  is  not  ge@ng  enough  energy  to  survive,  more  mitochondria  can  be  created.  Some5mes  they  can  even  grow,  move,  and  combine  with  other  mitochondria,  depending  on  the  cell's  needs.    

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Mitochondrial Diseases

Mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria-small, energy-producing structures that serve as the cells' "power plants."

Nerve cells in the brain and muscles require a great deal of energy, and thus appear to be particularly damaged when mitochondrial dysfunction occurs.

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 The  nucleus  is  the  largest  cellular  organelle  in  animals.  In  mammalian  cells,  the  average  diameter  of  the  nucleus  is  approximately  6  micrometers  (μm),  which  occupies  about  10%  of  the  total  cell  volume.  The  viscous  liquid  within  it  is  called  nucleoplasm.  

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