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

Summary

In this talk, the speaker discusses the revolutionary technology of base editing, a tool that can correct genetic mutations at the DNA level. They explain how point mutations can lead to genetic diseases and how CRISPR, originally a bacterial defense mechanism, has been repurposed to develop base editors. These molecular machines can change specific DNA bases without cutting the DNA, offering a potential cure for diseases like sickle cell anemia and progeria. The speaker also touches on the ethical considerations and future applications of this groundbreaking technology.

Takeaways

• 🧬 The human genome consists of two sets of three billion DNA letters, which are susceptible to changes due to various factors like sunlight, smoking, and unhealthy eating.
• 🔄 Point mutations, which are single-letter swaps in DNA, occur frequently and can sometimes lead to genetic diseases.
• 🌟 Most point mutations are harmless, but a few can disrupt cellular functions and lead to serious genetic diseases like sickle cell anemia and progeria.
• 🔬 Scientists have developed a technology called 'base editing' that can correct point mutations in the genome, potentially curing genetic diseases.
• 🛡️ Base editors use the programmable CRISPR system to target specific DNA sequences and convert one base to another without cutting the DNA.
• ✂️ CRISPR, originally a bacterial defense mechanism against viruses, has been repurposed for gene editing in eukaryotic organisms.
• 🧬 The first base editor developed converts cytosine (C) to thymine (T) and guanine (G) to adenine (A), addressing about 14% of known disease-associated point mutations.
• 🌱 Base editing has been applied in various organisms, including plants, to improve crop quality and in animals to correct genetic diseases.
• 🏥 While base editing shows promise, challenges remain in delivering these molecular machines into human cells and ensuring precise editing without off-target effects.
• 🌐 The development and application of base editing require collaboration among scientists, doctors, ethicists, and governments to ensure safe and ethical use.

Q & A

What is the most important gift parents give to their children according to the script?

The most important gift parents give to their children is the two sets of three billion letters of DNA that make up their genome.

What can cause changes to the human genome?

Changes to the human genome can be caused by sunlight, smoking, unhealthy eating, and spontaneous mistakes made by cells.

What are point mutations and how do they occur?

Point mutations are simple swaps of one DNA base, such as C, with a different base like T, G, or A. They occur when cells in the body accumulate these single-letter swaps.

Why are some point mutations harmful?

Some point mutations are harmful because they can disrupt an important capability in a cell or cause a cell to misbehave in harmful ways.

What is the significance of knowing the exact single-letter change that causes a genetic disease?

Knowing the exact single-letter change that causes a genetic disease is significant because it allows for the theoretical possibility of curing the disease by correcting that specific mutation.

How does CRISPR technology relate to the development of base editing?

CRISPR technology, originally a bacterial defense mechanism against viral infections, has been repurposed to develop base editing. CRISPR's programmable molecular scissors can be directed to cut specific DNA sequences, which base editors use to target and correct mutations.

What are base editors and how do they differ from CRISPR scissors?

Base editors are molecular machines that use CRISPR's programmable targeting mechanism but instead of cutting DNA, they directly convert one base to another without disrupting the rest of the gene. Unlike CRISPR scissors that cut DNA, base editors act more like pencils, rewriting one DNA letter into another.

How were the first base editors engineered?

The first base editors were engineered by disabling the CRISPR scissors' ability to cut DNA while retaining its targeting mechanism, attaching a protein that converts DNA base C into a base that behaves like T, and a third protein to protect the edited base from being removed by the cell.

What is the potential application of base editing in treating genetic diseases?

Base editing has the potential to treat genetic diseases by directly correcting the point mutations that cause them, such as sickle cell anemia, progeria, and others, without causing further disruption to the gene.

How have base editors been utilized in research and what are some of the milestones achieved?

Base editors have been used in research to correct point mutations causing diseases in various organisms, including bacteria, plants, mice, and primates. Milestones include reversing the consequences of diseases like progeria and beta thalassemia in animal models.

What are the challenges and future directions for base editing?

Challenges for base editing include efficient delivery into human cells, developing new molecular machines for additional base pair conversions, and minimizing off-target effects. Future directions involve collaboration with various stakeholders to ensure thoughtful, safe, and ethical application of base editing.