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Possible Future Treatments

Possible Future Treatments

 

Gene therapy:

  • The genotype (therefore the phenotype of target cells) is altered:
  1. Normal alleles of the gene are inserted into the target cells using a genetically modified virus or using liposomes (spherical phospholipid bilayers)
  2. The normal form of the gene is transcribed and translated
  3. A functioning protein is produced in the target cells

 

Virsuses:

  • Virus; DNA sequence that allows it to replicate is removed and replaced with the normal allele of the desired gene (and a promoter sequence which initiates tanscription and translation)
  • When infected with some viruses; the viral DNA becomes incorporated into our cells’ own DNA
  • Others the viral DNA remains independent within the nucleus of our cells (this is used into the CFTR trials)
  • Potentially efficient form of gene transfer however it produces an inflammatory response (symptoms – headache, fatigue, fever, raised heart rate)

 

 

Liposomes:

  • A copy of the normal allele is inserted into a loop of DNA (plasmid)
  • The plasmid is then combined with liposomes (spherical phospholipid bilayers)
  • Positively charged head groups of the phospholipids combine with the DNA to form a liposome-DNA complex
  • CF patient breathes in an aerosol containing these complexes using a nebuliser; the liposomes fuse with epithelial cell membranes and carry the DNA into the cells

 

Progress:

  • CFTR protein allele has been successfully transferred to lung epithelial cells of CF patients
  • Presence of functionaing ion channels indicated by reduction in potential difference across the membranes in the nose and lungs and increased chloride secretions
  • Temporary fixture; longest trial lasted 15 days

 

  • First condition sucessfully treated using gene therapy was rare disorder severe combined immunodeficiency (SCID)
  • Could not make enzyme needed for immune system to wor
  • Ashanti DeSilva; white blood cells removed, alleles for functioning gene inserted into white blood cells using a virus
  • Cells replaced; now has regular transfusions

 

  • These treatments all work to alter specific somatic (body) cells and are permitted under UK legislation
  • Alternatively germ line therapy could be used, on egg and sperm cells, is not permitted (every cell in the body contains the new gene) ethical issues

 

 

 

 

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Treatment of Cystic Fibrosis

Treatment of Cystic Fibrosis

 

MedicationDietDigestive Enzyme supplementsPhysiotherapyHeart and lung transplant
·         Bronchodilators

·         Antibiotics

·         DNAease enzymes

·         Steroids

·         High energy foods

·         Salt supplements

·         Double protein intake

·         Help with digestion process·         Percussion therapy 

 

  • Bronchodilators – drugs that are inhaled using a nebuliser, the drugs relax the muscles in the airways, opening them up and reliving the tightness of the chest
  • Antibiotics – to kill or prevent the growth of bacteria in the lungs
  • DNAase enzymes – infection in the lungs leads to the accumulation of white blood cells in the mucus, when broken down they release DNA which makes the mucus more viscious. DNAase enzymes can be inhaled using a nebuliser, they break down the DNA
  • Steroids – reduce inflammation of the lungs
  • Percussion therapy – rhythmic tapping of the walls of the chest to loosen mucus and improve air flow.
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Cystic Fibrosis Inheritance

Cystic Fibrosis Inheritance

 

Genes and chromosome pairs:

  • Gene; a length of DNA that codes for a protein
  • Every cell (except sex cells) contain two copies of each gene, one from each parent
  • Both copies have the same locus on each of the paired chromosomes
  • 23 pairs of chromosomes; the chromosomes in each pair are called homologous chromosomes
  • Cystic fibrosis is caused by a gene mutation that is passed from parent to offspring

Genotypes, Phenotypes and alleles:

  • Mutation in the CF gene (the length of DNA that codes for the CFTR protein)
  • CF gene occurs in two alternative forms or alleles
  • Healthy gene = F / Non-functional protein = f

 

  1. FF – a person with two identical copies of the normal allele does have cystic fibrosis
  2. ff – a person with two copies of the mutated allele has cystic fibrosis
  3. Ff – A person with one normal allele and one mutated allele does not have cystic fibrosis but is a carrier and coud pass on the disease

 

  • The alleles that a person has make up their genotype
  • Homozygous genotype; both the same (ff/FF)
  • Heterozygous genotype; different alleles (Ff)
  • Characteristic caused by the genotype is the phenotype

 

Predicting the genotype of offspring:

  • When gametes are produced, each egg or sperm has only one allele, f or F
  • Punnett square; illustrates all the possible ways in which the two types of allele can combine, showing the possible genotypes of children
  • Carriers (Ff) have some protection against typhoid

 

Inheritance of genetic diseases:

  • Cystic fibrosis is a monohybrid inheritance; characteristics controlled by one gene

 

  • Thalassemia; genetic disease cause by recessive alleles of a gene on chromosome 11
  • Gene is involved in the manufacture of haemoglobin which carries oxygen round body
  • Someone who is homozygous makes no haemoglobin, or non-functional haemoglobin – homozygous condition is often lethal
  • Heterozygous conditions (advance) – have no symptoms but have protection against malaria

 

  • Albinism, phenylketonuria and sickle cell anaemia are also called by single recessive alleles

 

  • Achondroplasia is caused by a dominant allele
  • A homozygote always dies
  • Heterozygote – restricted growth

 

  • Huntington’s diseae and the ability to taset PTC are also caused by dominant alleles

 

The work of Mendel:

  • Carried out breeding experiments
  • He established that a number of characteristics of the garden pea were determined by separate genes
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What goes wrong with DNA?

What goes wrong with DNA?

  • A mistake in translation can produce mRNA with one or more incorrect codons
  • Error in cystic fibrosis sufferers is in the DNA as the problems are in every epithelial cell
  • Mistakes arise when DNA copies itself curing the process of DNA replication

 

DNA replication:

  • When a cell divides an exact copy of the DNA must be produced so that each daughter cell receives a copy – replication
  • DNA double helix unwinds from one end, the two strands split apart as the hydrogen bonds between bases break
  • Free DNA nucleotides line up alongside each DNA strand and hydrogen bonds form between the complimentary bases
  • The enzyme DNA polymerase links the adjacent nucleotides to form a complimentary strand
  • Each strand of DNA acts as a template on which a new strand is built; two complete DNA molecules are formed
  • Each of the two new DNA molecules contains one old strand and one new strand – semi-conservative replication

 

 

Semi-conservative replication:

  • Meselson and Stahl did experiments to show how DNA replicated
  • Three possible ways to replicate; fragmentary, conservative, semi-conservative

 

  • Uses light and heavy strands of DNA; achieved by using bacteria that had been grown in a medium containing only the heavy isotope nitrogen, 15
  • All the nucleotides in bacteria started out with heavy nitrogen, making the DNA denser than usual (yellow strand)
  • Then moved bacteria to a medium containing only normal 14N, meaning all new nucleotides introduced into the replicated DNA were light
  • Original; heavy / new; light
  • Bacteria was allowed to divide and replicated before being extracted and centrifuged
  • When centrifuged the heavy DNA sinks to the bottom while light DNA collects near the top, medium in the middle
  • The result: one medium band density (no heavy density left – excluding the conservative model)
  • After the DNA was extracted and centrifuged after two rounds of replication gave two bands (one medium, and one light)
  • Confirmed semi-conservative model and ruled out fragmentary (that would only be light and heavy)

 

Mistakes in replication:

  • As the new strand is being built an incorrect base may slip into place – mutation
  • Sometimes mutations occur in the DNA of an ovary or testis cell that is dividing to form an egg or sperm. This may be passed onto future generations
  • Some mutations have no effect
  • Genetic disorder; mutation within the gene, and a new base triplet is created that codes for a stop or different amino acid

 

Sickle Cell Anaemia:

  • Mutation in the gene that codes for one of the polypeptide chains in haemoglobin (the pigment in red blood cells which carries oxygen around the body)
  • Adenine replaces thymine along the chain
  • Protein produced contains the non-polar amino acid valine rather than polar glutamic acid
  • Haemoglobin made less soluble
  • Distorted shape; oxygen levels are low, molecules form long fibres that stick together inside the cell
  • The sickle shaped cells carry less oxygen and can block blood vessels

 

Mutations and Cystic Fibrosis:

  • Hundreds of mutations; affect the CFTR protein in different ways
  • Sometimes ATP is unable to bind and open the ion channel
  • In other cases the channel is open but changes in the protein structure lead to reduced movement in chloride ions through the channel
  • Most common mutation; deletion of three nucleotides (loss of phenylalanine – causing misfolding of protein)

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CFTR Protein

CFTR Protein

  • Cystic fibrosis is caused by a mutation in the DNA that carries the instructions for making the CFTR protein

 

Structure of DNA:

  • James Watson and Francis Crick proposed model for DNA based on X-ray diffraction patterns
  • DNA is found in every cell nucleus
  • Contains the genetic code which dictates all inherited characteristics of an organism
  • Controls manufacture of proteins; this makes you unique

 

Gene and Genome:

  • Gene; a sequence of bases on a DNA molecule coding for a sequence of amino acids in a polypeptide chains
  • Each chromosome in the cell nucleus contains DNA and carries genes
  • The genes make up a fraction of the total DNA in the chromosomes
  • All the genes in an individual (or species) are known as the genome

 

Nucleotides:

  • DNA is one type of nucleic acid called deoxyribonucleic acid (long chain molecule made of many unites called nucleotides or mononucleotides)
  • Mononucleotide; three molecules joined together by condensation reactions
  • Deoxyribose – 5 carbon sugar; phosphate group; an organic base (contains nitrogen)

 

  • Link together by condensation reactions between the sugar of one nucleotide and the phosphate of the next
  • Long chain of mononucleotides = polynucleotide
  • The nitrogen containing base (organic base) is variable (adenine, cytosine, guanine, thymine)
  • In DNA two long strands of nucleotides twist around each other to form a double helix

 

 

 

  • The two strands which run in opposite directions are known as the antiparallel strands (held together by hydrogen bonds between base pairs)

 

Pairing up of bases:

  • Adenine pairs with thymine
  • (one ring structure – T & C)
  • Cytosine pairs with guanine
  • (two ring structure – A & G)
  • Creates a three ring structure which makes the molecule a uniform width along its length
  • Shape and chemical structure of the bases determines how many hydrogen bonds each has and which base they pair with (A and T = 2) (C and G = 3)

 

DNA coding for proteins:

  • CF gene is on chromosome seven (instructs the cell to make the CFTR protein that forms the transmembrane chloride channel)
  • However the sequence of bases in the DNA tells the cell which amino acids to link together to make the CFTR protein
  • Each gene is a sequence of bases on a DNA molecule coding for a sequence of amino acids in a polypeptide chain

 

 

 

 

The triplet code:

  • One base does not code for one amino acid
  • The code carried by the DNA is a three-base, triplet code
  • Several triplets code for the same amino acid; others can be start or stop signals (chain terminators)

 

DNA to proteins:

  • DNA in our chromosomes carries the genetic information from one generation to the next
  • DNA carries codes which determine the structure and function of cells by telling the cells which proteins to make
  • DNA in the nucleus; proteins made in the cytoplasm
  • In order for the DNA to reach the cytoplasm, a copy is made
  • The copy is made from RNA instead of DNA, this can leave the nucleus

 

Difference between DNA and RNA:

 

DNARNA
·         Two polynucleotide strands

·         Deoxyribose

·         Thymine

·         One polynucleotide strand

·         Ribose sugar not deoxyribose

·         Uracil

 

 

Three types of RNA:

  • messenger RNA
  • transfer RNA
  • ribosomal RNA

 

Protein Synthesis:

  • two stages; one in the nucleus and the second in the cytoplasm
  • transcription and translation

 

Transcription:

  • takes place in the nucleus
  • DNA double helix unwinds and the hydrogen bonds between bases break
  • Sequence of one strand, template strand (antisense strand), is used in the production of a messenger RNA molecule
  • mRNA is built from free RNA nucleotides which line up alongside the DNA template strand
  • every triplet code on DNA creates a complimentary codon on the messenger RNA
  • template is also known as the antisense strand because once transcribed it makes an mRNA molecule with the same base sequence as the DNA coding strand
  • the coding strand is known as the sense strand
  • involves the enzyme RNA polymerase
  • the mRNA molecule leaves the nucleus through a pore in the nuclear envelope and enters the cytoplasm

 

Translation:

  • takes place on the ribosomes (small organelles made of ribosomal RNA and protein)
  • ribosomes are found free in the cytoplasm or attached to endoplasmic reticulum
  • transfer RNA molecule, carrying an amino acid molecule, has three bases called an anticodon and these pair with complimentary bases on the mRNA codon
  • the amino acids that the tRNA carry join by means of peptide bonds

 

 

 

  • Sequence of amino acids, primary structure, determines its 3-D structure and properties of the protein. When even slightly altered it may substantially alter the proteins structure and properties

 

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Reproductive System

Reproductive System

  • Females have reduced chance of pregnancy; mucus plug develops in the cervix
  • Men usually lack the sperm duct on both sides which means sperm cannot leave the testes
  • If the sperm duct is present, it is usually blocked by sticky mucus
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Enzyme Function

Enzyme Function

  • Globular proteins that act as biological catalysts
  • Speed up chemical reactions that would normally be slow at cell temperature
  • Precise 3-D shape includes a depression surface; active site
  • Amino acids involved on active site whilst other remain 3-D shape

 

Lock and Key theory:

  • The molecule (substrate) must have a specific, complimentary shape, to fit into the active site.
  • Substrate forms temporary bonds with amino acids of the active site to create an enzyme-substrate complex
  • Enzyme holds the substrate so that they react more quickly
  • When reaction has finished, the products are released, leaving the enzyme unchanged

 

Induced Fit theory:

  • Active site is flexible
  • When the substrate (s) enter the active site the enzyme changes shape slightly
  • When reaction finishes and the enzyme returns to its normal shape
  • Only a specific substrate will induce the change in shape of an enzyme’s active site

 

Activation Energy:

  • To convert substances into products bonds must change (within and between molecules)
  • Breaking chemical bonds requires energy to start the reaction – activation energy
  • Heating a substrate or using an enzyme would give this energy
  • Heat agitates atoms that become unstable and start the reaction
  • Enzymes reduce the time this process takes

How?

  • The specific shape of the enzyme and the substrate is such that electrically charged groups on their surfaces interact
  • Attraction of oppositely charged groups may distort the shape of the substrate and assist in breaking/making bonds
  • Sometimes the amino acids contain acidic side chains which may provide conditions favourable for the reaction
  • Substrate molecules are sometimes altered, not added to or broken down, these are isomerase enzymes

 

IntracellularInside the cells
ExtracellularOutside the cells
CatabolicBreaking down reactions
AnabolicBuilding up reactions

 

 

Finding rates of enzyme-controlled reactions:

  • Rate of reaction measured by: the quantity of substrate used or the quantity of product formed in a given time
  • The reaction will firstly occur quickly however as the substrate is used up there are fewer substrate molecules to bind with the enzyme and the reaction slows down
  • The rapid slope is the initial rate of reaction

 

Enzyme and Substrate concentration; rate of reaction:

  • Initial rate of reaction is directly proportional to the enzyme concentration because the more enzyme that is present the greater the number of active sites
  • It will continue in this linear fashion if there is an excess of substrate
  • Reaction can be limited by the enzyme if there is increased substrate concentrations but not enough active sites
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Digestive System

Digestive System

  • People with CF have a high basal metabolic rate
  • Pancreatic duct becomes blocked with sticky mucus, stop the release of digestive enzymes
  • Lower concentration of enzymes in the small intestine reduces the rate of digestion
  • Food is not fully digested so less nutrients are absorbed
  • Energy loss in faeces; process called malabsorption syndrome

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Water Regulation; unaffected lungs

Water Regulation; unaffected lungs

  • Cells that line the airways produce mucus
  • Water in the mucus is continuously regulated to maintain a constant viscosity
  • Must be runny enough to be moved by beating cilia
  • However it cannot be so runny that the fluid floods the airway
  • Regulation of water content is achieved by transport of sodium ions and chloride ions across epithelial cells
  • Water then follows the ions due to osmosis

Excess water:

  • Too much water; detected by epithelial cells
  • Carrier proteins in the basal membranes on the epithelial cells actively pump sodium ions out of the cells
  • The concentration of sodium ions in the cell falls
  • Creating a concentration gradient across the apical membrane
  • Sodium ions diffuse down this concentration gradient
  • They then enter to cell by facilitated diffusion through sodium channels in the apical membrane
  • The raised concentration of sodium ions creates a potential difference between the tissue fluid and the mucus on the apical membrane side
  • Electrical gradient created – causes negative charged chloride ions to diffuse out the mucus into the tissue fluid
  • Elevated Na+ and Clconcentrations draw water out of the cell by osmosis across the basal membrane in tissue fluid
  • Water loss increases overall solute concentration within cell; higher in cell
  • Causing water to be drawn out the mucus by osmosis across the apical membrane into the cell

Too little water:

  • Chloride ions are transported across the basal membrane into epithelial cells
  • Creates a concentration gradient across the apical membrane
  • At same time, the CFTR protein channels open
  • Chloride ions diffuse out of the cell through the CFTR channels down this concentration gradient into the mucus
  • When open, the CFTR channels block the sodium ion channels
  • Build-up of negative charge chloride ions in mucus creates an electrical gradient between mucus and tissue fluid
  • Sodium ions diffuse out of the tissue fluid and move down the gradient, passing between cells into mucus
  • Movement of ions into mucus draws water out of the cells by osmosis until solutions outside cell are isotonic (same concentration of water molecules)

People with CF:

  • CFTR protein may be missing or not functioning properly
  • When there is too little water; Clcannot be secreted across the membrane
  • No blockage of sodium ions, sodium is continuously absorbed by the cells
  • This draws chloride ions and water out the mucus into the cells making it more viscous

 

 

 

 

 

 

 

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Transport of Substances through Cell Membrane

Transport of Substances through Cell Membrane

 

 

 Type of moleculeExamplesThrough which part of the membraneActive or passiveWith or against the concentration gradient
DiffusionSmall, uncharged moleculesCarbon dioxide and oxygenPhospholipid bilayerPassiveWith (high to low)
Facilitated DiffusionHydrophilic moleculesglucoseThrough channel proteins/via carrier proteinspassiveWith (high to low)
OsmosisWater molecules·Phospholipid bilayerpassiveWith (high to low)
Active TransportSubstancesIons into root hairs, muscles and nerve cellsThrough carrier proteins that change shapeactiveAgainst (low to high)
ExocytosisVery large molecules/particlesProteins (insulin/

polysaccharides)

Not through membraneactiveeither
EndocytosisVery large molecules/particlescholesterolNot through membraneactiveeither

 

Diffusion:

  • Net movement of molecules/ions from an area of high concentration to an area of lower concentration
  • Continues until equilibrium
  • Small uncharged molecules
  • Pass between the lipid molecules
  • No energy needed

 

Facilitated Diffusion:

  • Hydrophilic molecules
  • Insoluble in lipids
  • Cross the membrane by either diffusing through water-filled pores within channel proteins that than span the membrane
  • Different channel proteins for transporting different molecules (each has a specific shape for a specific ion/molecule)
  • Some may be opened or closed depending on a signal (hormone or change in voltage across the membrane) these are GATED CHANNELS
  • No energy needed

 

  • Carrier proteins; ion/molecule binds onto a specific site on the protein which then changes shape
  • Movement can occur in either direction; net movement dependent on the concentration across the membrane
  • Molecules move from high to low
  • No energy needed

 

Osmosis:

  • Net movement of water molecules from a solution with lower concentration to a solution with a higher concentration of solute.
  • Partially permeable membrane

 

Active Transport:

  • Transports substances against a concentration gradient (low to high)
  • Energy required; comes from respiration and the energy transfer molecule ATP
  • Specific carrier proteins are also needed; substance binds to carrier proteins
  • Energy from ATP changes the shape of the carrier protein, causing the substance to be released on the other side of the membrane
  • Occurs in every cell
  • Transports ions across epithelial cells

 

Exocytosis:

  • Very large molecules or particles transported across cell surface membranes
  • Relies on fluid nature of the membrane
  • Release of substances from the cell as vesicles fuse with the cell membrane (usually proteins or polysaccharides)

 

Endocytosis:

  • Substances taken into the cell by the formation of vesicles
  • Part of cell surface membrane engulfs the material to be transported
  • Substance can also be absorbed by attaching to a receptor in the membrane then endocytosis
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