This sample is based on a Master’s-level Biology brief asking for more than an explanation of CRISPR. The student has to connect the HBB mutation to the sickle-cell phenotype, explain how gene editing work

MSc Biology Assignment Sample: CRISPR-Cas9 Gene Editing for Sickle Cell Disease

Level: Master’s / Level 7
Subject: Molecular Biology and Genetics
Assignment Type: Critical Scientific Review
Word Count: 3,500 words
Referencing: Harvard
Main Topic: CRISPR-Cas9, HBB, BCL11A and sickle cell disease

This sample is based on a Master’s-level Biology brief asking for more than an explanation of CRISPR. The student has to connect the HBB mutation to the sickle-cell phenotype, explain how gene editing works in haematopoietic stem cells, compare two different therapeutic strategies and then decide how convincing the experimental and clinical evidence actually is.

The difficult part of this assignment is not describing CRISPR-Cas9. It is keeping the discussion focused on sickle cell disease while moving between molecular biology, stem-cell biology and clinical evidence.

For example, simply stating that BCL11A editing increases fetal haemoglobin would not be enough at Level 7. A stronger answer has to explain why the erythroid enhancer is targeted instead of knocking out BCL11A completely, what type of DNA repair is being used, whether edited CD34+ cells retain engraftment capacity and whether the clinical follow-up is long enough to support claims about durability.

The sample below shows how those questions can be dealt with in one connected argument.

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What the Assignment Brief Actually Requires

This assignment contains several separate tasks that could easily be missed if it were treated as a general essay about gene editing.

Requirement in the Brief	What the Answer Needs to Do
Explain the molecular basis of SCD	Connect HBB p.Glu6Val to HbS polymerisation, erythrocyte damage, haemolysis and vaso-occlusion
Explain CRISPR-Cas9	Apply PAM recognition, Cas9 cleavage, NHEJ and HDR specifically to HSPCs
Compare two treatments	Directly compare HBB correction with BCL11A/HbF reactivation
Analyse primary studies	Examine experimental design, methods, findings and limitations rather than only quoting results
Discuss safety	Separate off-target cleavage from unintended changes occurring at the intended target
Explain ex vivo treatment	Follow the process from CD34+ collection through editing, conditioning, reinfusion and engraftment
Consider newer technologies	Evaluate base editing and prime editing specifically for SCD
Reach an overall judgement	Decide what the evidence currently establishes and what remains uncertain

This mapping matters because a technically accurate discussion could still perform poorly if one of these elements were left unanswered.

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The Scientific Question Behind the Assignment

The central question is not simply:

Can CRISPR treat sickle cell disease?

That has already become too broad to be useful.

A better question is:

Why has BCL11A enhancer editing reached clinical use before direct correction of the HBB mutation, even though HBB correction appears to be the more direct molecular solution?

The answer comes down to how the two approaches use DNA repair.

Direct HBB correction normally requires precise repair of the disease-causing sequence. Conventional approaches therefore depend heavily on homology-directed repair, which is more difficult to achieve efficiently in the long-term haematopoietic stem cells that need to survive transplantation.

BCL11A enhancer editing has a different objective. The aim is to damage a specific regulatory element rather than reconstruct it precisely. Insertions and deletions produced through non-homologous end joining can therefore contribute directly to the desired therapeutic effect.

This distinction explains an important point in the clinical evidence:

the approach that changes the disease indirectly can currently be easier to deliver efficiently than the approach that corrects the disease-causing nucleotide directly.

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Evidence Used in This Sample

The answer does not treat every published CRISPR study as equivalent. The studies represent different stages in the development of the treatment.

Study	Biological Question	Experimental System	What It Adds	Main Limitation
Canver et al. (2015)	Which part of the BCL11A enhancer controls HbF repression?	Human erythroid cells / CRISPR mutagenesis	Identified functional enhancer regions suitable for therapeutic targeting	Preclinical mechanistic evidence
Dever et al. (2016)	Can the HBB locus be corrected directly?	Human CD34+ HSPCs and transplantation models	Demonstrated targeted HBB repair in clinically relevant cells	Did not establish long-term human efficacy
Wu et al. (2019)	Can BCL11A enhancer editing work in transplantable HSPCs?	Human HSPCs and xenotransplantation	Linked editing to HbF induction, reduced sickling and engraftment	Mouse transplantation cannot reproduce decades of human haematopoiesis
Frangoul et al. (2021)	Can edited cells produce meaningful benefit in a human?	Early clinical treatment	Human proof of concept	Very limited initial SCD sample
Frangoul et al. (2024)	Does exa-cel control severe clinical disease?	Multicentre clinical study	Strong evidence of reduced severe vaso-occlusive crises	Small safety population and limited follow-up for a potentially lifelong therapy
Newby et al. (2021)	Can base editing avoid conventional Cas9 double-strand breaks?	Patient HSPCs and mouse transplantation	Produced a non-sickling β-globin variant	Preclinical evidence
Everette et al. (2023)	Can prime editing restore wild-type HBB?	Patient HSPCs and mouse transplantation	Demonstrated direct HBBS-to-HBBA correction	Clinical durability remains unknown

The value of these papers is not simply that they all concern CRISPR. Together they show the progression from identifying a biological target → editing human stem cells → demonstrating engraftment → showing a cellular phenotype → showing clinical benefit in patients.

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One Important Distinction Students Often Miss

Off-target editing and unsafe editing are not the same thing.

An edit can occur at exactly the intended DNA sequence and still produce an undesirable outcome.

Cas9 generates a double-strand break, and the cell determines how that break is repaired. Large deletions or genomic rearrangements can therefore occur around the intended cleavage site even when Cas9 has recognised the correct target.

For this reason:

correct target recognition ≠ guaranteed correct repair

This distinction becomes especially important in SCD because the edited cell population contains long-lived haematopoietic stem cells. A genomic alteration present in one persistent stem-cell clone could theoretically remain in the blood system for many years.

A strong Master’s answer therefore needs to examine both:

off-target specificity

and

on-target repair outcomes.

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How to Read the Sample Answer

The answer below follows one argument from beginning to end.

It first establishes why the HBB mutation causes disease. It then explains why HbF can suppress the sickling phenotype. Only after that biological foundation does it compare direct HBB repair with BCL11A enhancer editing.

The clinical studies are then judged against the biological claim being made.

This means that evidence of:

editing

is not treated as the same thing as evidence of:

engraftment

which is not treated as the same thing as evidence of:

clinical benefit

and none of these, on their own, proves:

lifelong genomic safety.