Genetic Diseases and their treatment A quick reminder DNA = deoxyribonucleic Acid, a double helix Strands linked via chemicals called nucleotide bases Thymine always links with Adenosine Guanine always links with Cytosine This is the genetic code CCGATTCGA CCGATTCGA There are FOUR such bases Thymine, Adenosine, Guanine and Cytosine Each set of 3 bases = codon
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Genetic Diseases and their treatment
A quick reminder
DNA = deoxyribonucleic Acid, a double helix
Strands linked via chemicals called nucleotide bases
Thymine always links with Adenosine
Guanine always links with Cytosine
This is the genetic code
CCGATTCGACCGATTCGA
There are FOUR such bases
Thymine, Adenosine, Guanine and Cytosine
Each set of 3 bases = codon
Thousands of genes are collected together on CHROMOSOMES
DNA strands in chromosome
Genes represented by
coloured bands in chromosome
Humans have 23 pairs of chromosomes – 22 pairs autosomal and one pair sex chromosomes (called “X” & “Y” because of shape)
1 - 3 4 - 5
6 - 12
13 - 15 16 - 18
19 - 20 21 - 22
23
1 - 3 4 - 5
6 - 12
13 - 15 16 - 18
19 - 20 21 - 22
23
GENES
GENES
...CCGATTCGA......CCGATTCGA...
Part of a gene sequence could be
Mary had a little limb
Mary hid a little lamb
Mary hid a little limb
Mary had a little lamb
This could mean...
A defect in the gene coding for the letter “a” (i.e. a POINT MUTATION)
could result in
Each human cell has > 3 billion base pairs
Although we have > 90 % genes in common with chimps and mice, a 1-2% difference = 10s millions combinations
Genes are not necessarily contiguous sections of a chromosome.
Coding bits (codons) are interspersed with “non-functional” DNA (so-called Junk DNA).
Might provide protection against harmful mutations – disputed.
MAJOR change in “output” from apparently
trivial error
(humans = 1% of genome code for proteins)
GENES and INHERITANCE
Single genes RARELY code for a single effect – but they are much easier to study
Between genes are codons that control “START” reading of a gene and “STOP” reading
Mutations (errors in replication ; UV radiation etc)
Gene for eye colour
Both copies code
for BROWN eyes (homozygous)
INHERITANCE - Dominant and Recessive Genes
BROWN eyes BLUE eyes
Both copies code
for BLUE eyes (homozygous)
BROWN eyes
BROWN eye colour is DOMINANT
One copy codes BROWN, other copy codes BLUE
(heterzygous)
Genetic Diseases
● AUTOSOMAL RECESSIVE ● AUTOSOMAL DOMINANT Only one mutated gene = HETEROZYGOUS
Autosomal recessive inheritance
Have to have TWO aberrant genes i.e. be HOMOZYGOUS
If only one mutated gene i.e. HETEROZYGOUS CARRIER
● X-LINKED RECESSIVE (Female is CARRIER but MALE
is affected)
Autosomal RECESSIVE - Cystic Fibrosis
● Signs &Symptoms➢ Mucous build up in LUNGS (pancreas, liver, kidney, intestines)
Most common in Northern Europeans (1 in 3000 births; 1 in 25 = carrier)Least common in African/Asians
Life Expectancy 40 – 50 yrs in developed world
Treatment
Usually due to DELETION of 3 bases on gene 7 – results in faulty protein. This results in secretions that should be thin being THICK (but ~ 300 mutations identified in CF)
Signs & Symptoms➢ NONE (apart from occasional mood swings/unsociability) in 1st 30-40yrs
– ie until AFTER had children (hence inheritance)➢ Twitches, jerks, spasms➢ Objects hard to grasp➢ Hands & legs uncontrollable writhing (“giant puppet show”)
➢ Finally deep cognitive decline with near complete loss motor function
➢ Malnourishment, dementia, infections - DEATH
TREATMENT
Neurological disease
Woody Guthrie
Autosomal DOMINANT – Marfan's Syndrome
● Can have norm life span● M and F equally affected● 1 in 5000 (¾ = inherited' ¼ = spontaneous
mutation)● No ethnicity
Connective Tissue disease
Signs & Symptoms➢ Defects in heart valves, lungs, eyes,
bones & meninges➢ People tend to be TALL, THIN with
disproportionally LONG LEGS, TOES, ARMS,FINGERS
TREATMENT
X-linked RECESSIVE - Haemophilia
● Signs & Symptoms➢ Minor injuries (bruise)
cause uncontrolled bleed under skin and into joint
➢ Pain➢ Distortion of joint➢ Death
Queen Victoria's family tree – inheritance of Haemophilia
Haemophilia (due to missing clotting factor) is (usually) due to faulty, recessive gene on X chromosome – so
very rare in women (women have TWO X chromosomes) but they can be carriers (men rarely carriers
● Signs & Symptoms➢ Progressive leg weakness, baby boy using parents' legs to pull self
up when learning to walk, not able to walk by 12 years➢ Eventually all voluntary muscles affected, then heart and
breathing later on➢ Paralysed from neck down by 21st year
Life Expectancy ~ 25 years
1 in 7000 live birthsTREATMENT
Progressive muscular weakness & wasting
ALSO● Higher risk ADHD● Learning Disorders (eg
dyslexia)● Short term memory impairment
Genetic therapies
● Deliver functioning genes to adult (ie already affected) cells● Deliver functioning genes to embryos – then implant● Delete aberrant genes from (preimplant) embryonic / foetal cells OR adult cells
AIM
PROBLEM➢ How to get editing system to target➢ How to change ALL affected cells➢ How to ensure correction is permanent (heritable) not just adding a functional gene
Genetic therapies
● MANIPULATION SYSTEMS➢ CRISPR cas9➢ Base editing➢ (older systems (eg zinc-finger
nucleases & TALENs, seem redundant now)
● DELIVERY SYSTEMS
Direct injection into organ (eg functioning
gene into lungs into CF patients) or into fertilised ovum (before 1st division)
Nanoparticles (ie 1-100nm) silica, gold (injected into muscle of mice with MD, only 5% muscles repaired but enough to improve muscle strength)
Fatty particles (used to treat hepatitis B in mice
VirusesBacteria
Own Cells white blood cells (leukaemia)
T- cells (cancer)
red blood cells (sickle cell anaemia)
Stem cells (vast potential applications)
Side Step.......
● Viruses ● “Average virus” is 1/100th size of “average”
bacteria ● Packet of DNA or RNA in protein coat =
VIRION● Invade cells ● Commandeer cell's chemical machinery to
keep virus going & replicate virus● Viruses readily mutate in host cells● Provide horizontal gene transfer – ie
movement of genetic material between unicellular and/or multicellular organisms (vertical is parent to offspring)
Capsid = protein coat, sometimes enveloped in lipid
VIRUS particle = virion
DNA or RNA strands in core
BacteriaOne celled organism lacking nucleus or membrane bound cellular organelles
Gene Editing
CRISPRPart of bacterial (Streptococcus
pyogenes) defence against viruses
Exposure to virus means bacterium copies a bit of viral DNA so it can recognise the virus in the future
A repeat exposure to the virus means the bacterium can use a special RNA molecule to guide a protein (Cas 9) to that part of the viral DNA, and disable it by cutting
For therapeutic use, guide RNA (gRNA) is created that matches the gene of interest.
gRNA plus Cas9 are put into a plasmid, and the plasmid put into target cell
gRNA locates target gene in the cell's DNA and Cas9 cuts both strands of DNA
Cell repairs break by joining the cleaved DNA strands thus disabling target gene (non homologous end joining NHEJ
After cleavage, a functional gene (=mutation)can be inserted (homology directed repair HMD
Guide RNA
Gene Editing
CRISPR vs previous gene editing techniques
● Easier● Cheaper ● Quicker (1-2 weeks vs 1-2 years)● More efficient
CRISPR good at disabling gene (65% of HD gene in key areas animal brain disabled)Less good at repairing genes (repair is more useful in embryos)
Mosaics : - embryos where only SOME of the cells are “fixed”. Adult MAY be Ok – but faulty gene still present – might become active; if in germ cells will pass to next generation Difficult to screen for in pre-implantation embryos (usual screen might not work)
How to switch off CRISPR after desired change made and before potentially deleterious change happens (already achieved, “kamikaze” CRISPR)
CRISPR targets a sequence of bases – not individual ones (cf base editing)
DNA repair mechanism not perfect – may incorporate wrong bits of DNA as part of the “patch”Some problems
Base Editing (modified version of CRISPR)
Has been used experimentally to correct blood disease fault in non-viable human embryos
DISEASE VS DISORDER
Bipolar disorder
Asperger's
Schizophrenia
Van Gogh
Elly Simmonds Steve Jobs
Philip K DickDwarfism
Criminal Behaviour
Bonnie & Clyde
SOME ETHICAL CONSIDERATIONS
● Would-be parents who want unaffected children can have IVF with donor egg / sperm OR select from pre-implantation embryos
● Are lives of people affected by genetic diseases “less”
● Are “healthy” “normal” people entitled to make decisions of behalf of those with life limiting diseases
● Should genetic manipulation be only targeted at the post-natal (curing existing condition) not the preimplantation
● Is this EUGENICS by another route?
Sources
● Biologist Magazine● The Gene (S. Mukherjee)● New Scientist● BBC.co.uk● BBC R4● Royal Soc Biology Blogs and News Items● Shutterstock● Wikipedia● Www.jax.org