lecture 19 - editing genetic disorders

Gene therapy

adding a working copy of a gene into a cell using a virus; does not fix the original mutation but adds a new working gene somewhere in the genome

Genome editing

directly fixing, destroying, or replacing a mutated gene at a specific location in the genome using tools like CRISPR

CRISPR

stands for Clustered Regularly Interspaced Short Palindromic Repeats; a system used to find and cut specific DNA sequences in the genome

Cas9

the enzyme in the CRISPR system that acts as the cutter; guided to the correct DNA sequence by guide RNA

Guide RNA

a short RNA sequence that directs Cas9 to the correct location in the genome to be cut

Why gene therapy is hard in adults

all cells contain the mutated DNA, there are trillions of cells to fix, foreign DNA triggers immune response, and insertion location is random and could cause new mutations

Why gene therapy is not heritable

it is done on body cells not on eggs or sperm, so the original mutation can still be passed on to children

Chaperone medication

a drug that helps a misfolded protein fold correctly so it can be shipped out of the rough ER; example is treatment for some CFTR mutations in cystic fibrosis

Why not all CFTR mutations respond to chaperone medication

chaperone medications only work if the protein is actually made but just misfolded; if the mutation prevents the protein from being made at all, there is nothing to fix

Enzyme replacement therapy

replacing a missing or broken protein by giving the patient a working version; only works for proteins that act outside of cells, in the blood, gut, or lysosomes because proteins cannot cross cell membranes

Why proteins cannot replace all genetic disorders

proteins cannot cross cell membranes, so replacement only works for proteins that act in the blood, stomach or gut, or lysosomes

Organ transplant as treatment

replacing a diseased organ with healthy donor tissue; cures the affected tissue but not the underlying genetic disorder, and requires lifelong immune suppressing drugs to prevent rejection

Cell therapy

removing a patient's own cells, editing them in a lab, and putting them back; avoids rejection because the cells belong to the patient

Why cell therapy avoids rejection

the edited cells come from the patient themselves so the immune system recognizes them as self

Junctional epidermolysis bullosa

a skin disorder treated with cell therapy; skin cells were removed, a virus inserted a working gene, and corrected cells were grown into sheets of skin and grafted back onto the patient

Casgevy

the first FDA approved treatment for sickle cell anemia using CRISPR; costs around 2 million dollars, is a permanent cure, but works by turning on a different gene rather than fixing the original mutation

How Casgevy works

stem cells are removed from bone marrow, the gene BCA11A that turns off fetal hemoglobin production is destroyed, chemotherapy destroys old bone marrow, and edited cells are reinjected to create new healthy bone marrow

CCR5

a receptor on helper T cells that HIV uses to enter the cell; removing this gene makes cells resistant to HIV infection

First human gene editing experiment

CCR5 was removed from a patient's own T cells to protect them from HIV; this was the first use of gene editing on human cells

2018 CRISPR controversy

a scientist used CRISPR to remove CCR5 from three human embryos at the single cell stage, making heritable edits without the knowledge of the parents or doctors; he was jailed for three years

Why editing at the single cell stage is different

modifications made to a zygote are passed on to every cell in the body and can be inherited by children, which is why it is currently considered unethical

Gene therapy vs genome editing comparison

gene therapy randomly inserts a working gene but leaves the mutation in place; genome editing targets the exact mutation to destroy or replace it; both use viruses to deliver material into cells and both make permanent changes that are not passed to children

Why editing complex traits like intelligence or height is not feasible

these traits are polygenic meaning they are controlled by thousands of genes each with tiny effects, so there is no single gene to edit

Why genome editing in adults only affects some cells

it is impossible to reach every single cell in the body, so some cells are missed and still carry the original mutation

Pros of gene therapy and genome editing

permanent cure for the affected tissue, cells pass the fix on when they divide, can be targeted to the exact mutation

Cons of gene therapy and genome editing

small risk of creating new unwanted mutations, not all cells are reached, currently unethical to edit germ cells or zygotes to make it heritable