Can we cure genetic diseases by rewriting DNA? | David R. Liu

The Fragility of Our DNA

The Gift of DNA

• The most significant gift from parents is the two sets of three billion letters of DNA that constitute an individual's genome, highlighting its complexity and fragility.

• Various factors such as sunlight, smoking, unhealthy eating, and spontaneous cellular mistakes can lead to changes in the genome.

Point Mutations and Their Impact

• Cells accumulate billions of single-letter swaps known as "point mutations" daily; most are harmless but some can disrupt cell functions.

• Harmful point mutations can lead to genetic diseases like sickle cell anemia or progeria if inherited or developed early in life.

Genetic Diseases Caused by Point Mutations

• Specific point mutations are linked to severe genetic diseases; for instance, sickle cell anemia results from a single A to T mutation in hemoglobin genes.

• Progeria is caused by a T instead of a C at a specific genomic position, leading to rapid aging and early death around age 14.

Advancements in Gene Editing

Introduction to CRISPR

• Bacteria evolved CRISPR as a defense mechanism against viral infections approximately three billion years ago.

• CRISPR utilizes a protein that acts like molecular scissors to cut DNA, essential for distinguishing between bacterial and viral DNA.

Functionality of CRISPR

• The unique feature of CRISPR allows it to be programmed to target specific DNA sequences for cutting during future infections.

• Researchers have adapted CRISPR technology for gene editing in humans, allowing targeted cuts within our genomes.

Limitations and Innovations in Gene Editing

Challenges with Traditional Gene Editing

• While disrupting genes can be useful, simply cutting mutated genes does not restore their function; this is crucial for treating genetic diseases.

• Introducing new DNA sequences post-cutting often fails across various cell types due to predominant disrupted gene outcomes.

Development of Base Editing

• To address these challenges, researchers developed "base editors," which modify individual DNA bases without causing disruptions.

• Base editors utilize the programmable nature of CRISPR but convert one base directly into another rather than cutting the DNA strand.

Engineering Base Editors

Construction Process

• The first base editor was engineered from three distinct proteins that do not originate from the same organism; it combines elements from disabled CRISPR scissors with additional proteins for chemical reactions on specific bases.

Base Editing: A Revolutionary Approach to Genetic Modification

Mechanism of Base Editing

• The process begins with the pairing of DNA bases, where T pairs with A. Changing a C to a T on one strand creates a mismatch that the cell must resolve by replacing one strand.

• A three-part protein was engineered to flag the nonedited strand for replacement by nicking it, tricking the cell into converting G to A during repair, thus changing C-G pairs into stable T-A pairs.

• This first class of base editor can convert Cs into Ts and Gs into As at targeted positions, addressing about 14% (5,000 mutations) of known disease-associated point mutations.

Development of Second Class Base Editor

• To correct more mutations (up to half), including those causing progeria, a second class of base editor was developed under Nicole Gaudelli's leadership.

• The challenge arose from the absence of proteins that convert A into G or T into C in DNA; however, Nicole chose to pursue an ambitious plan despite this obstacle.

• Researchers evolved their own protein in the lab using a selection system that allowed only successful variants capable of performing necessary chemistry to survive.

Achievements and Applications

• The newly developed protein was attached to disabled CRISPR scissors, creating a second base editor that converts As into Gs using similar strategies as the first editor.

• In just three years since development, base editing has gained significant traction in biomedical research with over 6,000 requests from more than 1,000 researchers globally.

Clinical Milestones and Future Directions

• Although too new for human clinical trials yet, animal studies have shown success in correcting genetic diseases like progeria through viral delivery methods.

• Collaborative efforts have demonstrated effective use in reversing conditions such as tyrosinemia and muscular dystrophy by directly correcting point mutations responsible for these diseases.

Broader Implications and Challenges Ahead

• Base editors are also being utilized in agriculture for crop improvement and understanding gene roles related to diseases like cancer.

• Companies like Beam Therapeutics and Pairwise Plants are leveraging base editing technology for treating genetic diseases and enhancing agricultural practices within just three years since inception.

What is the Future of Genetic Engineering?

The Role of Base Editing in Genetic Transformation

• The speaker poses a question about reading science-fiction novels, setting a thematic tone for discussing futuristic concepts.

• Acknowledges the contributions of dedicated students who creatively engineered solutions to advance genetic editing technologies.

• Highlights base editing as a transformative tool that turns science-fiction aspirations into reality, emphasizing its potential impact on genetics.

• Suggests that the most significant legacy we can offer our children may not just be their DNA but also methods to protect and repair it.