Human Genome Editing (5-6)

CRISPR/Cas9

• The Cas9 nuclease creates a double strand break at a (hopefully) unique site in the genome

• The sequence specificity is determined by the synthetic guide RNA (sgRNA)

• The host cell repairs the break

• If a repair template is provided, the break is frequently repaired by HDR, allowing for gene replacement

Metachromatic Leukodystrophy

MLD is caused by a faulty gene which means children affected cannot produce an important enzyme called ARSA - a protein that helps the body’s metabolism work. As a result, fatty chemicals called sulfatides build up. These gradually destroy the protective layer around cells in the brain and nervous system, leading to a devestating deterioration. Children lose the ability to walk, talk or eat - and eventually to see or hear

Teddi Shaw

The first indavidual to recieve gene therapy on the NHS

• Her older sister was too old to treat and is terminally ill

• It cost £2.875m (most expensive medicine approved by NHS), called Libmeldy

How did He Jiankui edit the human genome?

He jiankui used CRISPR-Cas9 gene-editing technology to modify the CCR5 gene in human embryos. The goal was to make the babies resistant to HIV by disabling CCR5, a gene that codes for a protein HIV uses to enter cells. The edited embryos were implanted into a woman, leading to the birth of twin grils in 2018

What were the consequences of He Jiankui’s gene-editing experiment?

The experiment faced global ethical backlash due to concerns over safety, lack of transparency, and potential unintended mutations. In 2019, He Jiankui was sentenced to three years in prison for violating medical regulations. The scientific community condemned his work, leading to stricter regulations on human genome editing worldwide. The long-term health efects on the children remain unknown

Potential Applications of Heritable Genome Editing (A-C)

• Category A, Cases of serious monogenic diseases which ALL children would inherit the disease genotype (e.g. Huntington’s disease (v rare))

• Caregory B, Serious monogenic diseases whith some not all of a couple’s children would inherit the disease-causing genotype (e.g. cyctsic fibrosis)

• Category C, Other diseases with less serious impact that those in A or B (familial hypercholesterolemia)

Potential Applications of Heritable Genome Editing (D-F)

• Category D, Polygenic diseases (Type 2 diabetes/ Schizophrenia/ some cancers)

• Category E, Other applications (not heritable diseases)(e.g. EPO gene for endurance sports, thousands of genes linked to intelligence)

• Category F, Gentic conditions that result in infertility

What counts as a rare disease?

• European union classes as, less than 1 in 2,000 citizens

• As of now there are around 6,000 clinically defined rare diseases

• Currently 72% of these are caused by a simple genetic mutation inherited from one or both parents

Applications of genome editing - human health

• Health reasearch using genome edited animals to study disease

• Treating disease, cell-based therapies

• Avoiding the inheritance of single gene conditions

• Introducing gene variants that confer ‘desirable’ phenotypic traits

Ethical concerns of Genome Editing - Human Health

• Risk of unintended effects due to off-target DNA alterations

• Making changes that will be passed on to future generations, regulations and governance

• Concerns that widespread of genome editing may amount to ‘liberal’ eugenics driven primarily by the choices of parents

• Concerns about how to deliniate morally acceptable and unacceptable uses of genome editing for governance purposes

Germline Genome Ediditng

• Heritable (edit will be passed on)

  • e.g. allele swap of CCR5 gene to make offspring (hopefully) resistant to aquiring HIV from HIV-positive father

  • No one knows the details as it was never peer-reviewed

  • Widely criticised by international community

  • Put in prison lol