Chapter 1: The Evolution of Gene Editing Technologies

Recently, I discussed the groundbreaking human trial involving CRISPR/Cas9 technology aimed at rectifying the genetic anomalies responsible for sickle cell disease and beta-thalassemia. Introduced in 2012, CRISPR/Cas9 built upon earlier DNA modification techniques such as zinc-finger nucleases and TALE nucleases. All three methods function by severing both strands of the DNA double helix. During the repair process, the cell's inherent repair mechanisms can inadvertently introduce unwanted base pair insertions and deletions (often referred to as indels), along with the intended corrections. Each of these technologies possesses unique strengths and weaknesses, making them more suitable for specific scenarios.

A recent advancement in this field is base editing, developed by a team led by David Liu at the Broad Institute of MIT and Harvard. This technique distinguishes itself by not cutting both strands of the double helix, enhancing its precision. However, its operations are somewhat limited; it can only perform four out of twelve possible base substitutions. While this allows for the correction of certain disease-related mutations, it does not cover all potential alterations.

In October 2019, Liu and his team unveiled an even more advanced method known as prime editing. This innovative approach can execute all twelve base substitutions and allows for multiple base insertions or deletions without the need for a double-strand break. Prime editing employs a multi-step process: it starts by cutting one strand, then executes the necessary substitution, insertion, or deletion, and finally nicks the second strand to enable the complementary bases to be replaced. This process results in a modified DNA segment that remains intact, significantly minimizing the likelihood of unintended off-target effects.

This novel prime editing variation of CRISPR technology is capable of correcting the genetic defects associated with sickle cell disease and beta-thalassemia, similar to what standard CRISPR/Cas9 has achieved in human trials, but with a reduced risk of off-target modifications. Moreover, its range of potential applications is considerably broader. The ClinVar database identifies over 75,000 pathogenic mutations within the human genome, with more than 89% being potentially addressable through prime editing.

From zinc fingers to TALE nucleases, followed by CRISPR/Cas9, base editing, and now prime editing, the pace of progress in gene editing continues to accelerate. Current research efforts are being vigorously pursued in laboratories worldwide. While it may take several years before these innovative therapies are routinely used in clinical settings, the hope for effective treatments or even cures for previously untreatable conditions offers a promising outlook for those affected.

The promise of CRISPR-based gene editing therapy for hATTR amyloidosis explores the potential and impact of CRISPR technology on genetic disorders.

Chapter 2: Addressing Ethical Considerations in Gene Editing

As advancements in gene editing technologies unfold, the ethical implications and safety measures surrounding these innovations come into focus. The question arises: where are the safeguards in gene editing?

Beyond the Science: Where Are the Safeguards in Gene Editing? discusses the ethical considerations and necessary regulations in the field of gene editing technology.