Podcast Summary: 3 Takeaways – "Editing Life Itself: A Conversation with David Liu, the Scientist Who’s Rewriting DNA and the Future" (#253)
Release Date: June 10, 2025
Host: Lynne Thoman

Introduction

In episode #253 of 3 Takeaways, host Lynne Thoman engages in a profound conversation with Dr. David Liu, a pioneering scientist in the field of gene editing. Dr. Liu, Vice Chair of the Faculty at the Broad Institute of MIT and Harvard, a Harvard professor, and founder of multiple biotech companies, shares his groundbreaking work on base editing and prime editing—techniques revolutionizing how we approach genetic diseases.

Understanding DNA Mutations

The discussion begins with an exploration of DNA mutations and their origins. Dr. Liu explains the inherent instability of DNA's chemical structure, leading to spontaneous mutations:

Dr. Liu (02:36):
"Each of your cells has roughly 1 1/2 billion Cs, the letter C in DNA. About 300 of them every day will spontaneously change into a U, which... can cause mutations. In fact, that's the most common single letter mutation that causes genetic disease."

He elaborates on external factors contributing to DNA damage, such as smoking, carcinogen exposure, and excessive sunlight, emphasizing the constant mutational challenges our genomes face.

Case Study: Treating KJ Muldoon

A significant portion of the episode delves into the landmark case of KJ Muldoon, the first baby treated with Dr. Liu's gene editing tools. Dr. Liu outlines the collaborative effort behind this treatment:

Dr. Liu (04:04):
"This is the definition of a village effort... our lab developed the base editing technology that was used to correct KJ's mutation."

The treatment involved correcting a single-letter mutation in the CPS1 gene, which regulates ammonia levels in the body. Elevated ammonia can be fatal and cause severe brain damage. Remarkably, the entire process—from genetic diagnosis to dosing—was completed in seven months, a timeline that traditionally spans seven years. The successful reduction of KJ's blood ammonia levels and his ability to tolerate protein in his diet mark a triumph in gene editing therapies.

Expanding Applications: Beyond KJ

Dr. Liu discusses other genetic diseases currently being targeted with base and prime editing technologies:

Dr. Liu (09:00):
"Sickle cell disease has been treated in multiple clinical trials by base editing, installing mutations in fetal hemoglobin genes to reawaken them to compensate for mutated adult hemoglobin genes."

He highlights the versatility of these technologies in treating a wide array of conditions, including liver disorders like alpha-1 antitrypsin deficiency and blood diseases.

Deep Dive: Base Editing vs. Prime Editing

To elucidate the mechanics behind his inventions, Dr. Liu breaks down base editing and prime editing in layman's terms:

Dr. Liu (11:24):
"Base editors are machines that use the targeting mechanism of CRISPR... but instead of cutting the DNA, they rearrange the atoms in one DNA letter to become a different DNA letter."

Prime editors, on the other hand, introduce a new DNA sequence:

"They guide the cell through a process where a newly synthesized flap of DNA replaces the original DNA on both strands. This allows for search and replace gene editing, enabling the insertion or deletion of letters with extreme precision."

These advancements allow for direct chemical modifications of the genome, addressing mutations at their foundational level.

Ethical Considerations in Gene Editing

Addressing the moral landscape, Dr. Liu shares insights from his experience teaching gene editing ethics:

Dr. Liu (15:12):
"It's a very interesting and complicated debate that ultimately will boil down to how people feel about what it is to be human... whether humans should hold some level of sacredness about the 'original state' of their genome."

He emphasizes the balance between ethical caution and the profound benefits of correcting genetic diseases, advocating for thoughtful consideration informed by patient communities.

Beyond Humans: Gene Editing in Agriculture and Animals

Expanding the conversation, Dr. Liu touches on the applications of gene editing beyond human health:

Dr. Liu (17:27):
"You can use base editing and prime editing and the CRISPR scissors to make crops that are more nutritious, disease-resistant, or able to grow in challenging climates."

He notes that while agricultural applications face fewer regulatory hurdles compared to human therapies, they hold immense potential for societal benefit.

Risks Associated with Gene Editing

No discussion on gene editing is complete without addressing potential risks. Dr. Liu outlines the primary concerns:

Dr. Liu (18:22):
"We have a responsibility to minimize the likelihood that gene editing would initiate cancer... so far, there hasn't been evidence that editing has initiated a serious side effect in a patient."

He acknowledges the importance of rigorous testing and monitoring as clinical trials expand, ensuring that unintended consequences are swiftly identified and mitigated.

Three Key Takeaways

Concluding the episode, Dr. Liu distills his insights into three essential takeaways for the audience:

1. Scientific Reality Over Fiction:

   "Humans now have the ability... to correct misspellings in our DNA that cause terrible disease. The science isn't science fiction anymore, it's science reality."

2. Economic Viability and Investment:

   "Even though there's enormous benefit... that does not guarantee that there's an economically viable path to bring these new medicines to patients... we need to decide how to invest as a society."

3. Value of Public Investment in Basic Science:

   "No one could have guessed that studying repetitive DNA sequences in bacteria could eventually lead to... rescuing a baby from that disease. We have to be doubling down on US support of basic science."

These takeaways underscore the transformative potential of gene editing, the necessity for strategic investment, and the fundamental importance of supporting basic scientific research.

Conclusion

Dr. David Liu's contributions are reshaping the landscape of genetic medicine, offering hope for curing previously intractable diseases. His insights on the technological, ethical, and societal dimensions of gene editing provide a comprehensive understanding of its current state and future trajectory. This episode of 3 Takeaways not only highlights the marvels of scientific innovation but also calls for informed dialogue and investment to fully realize its benefits.

Listen to the full episode here to dive deeper into the fascinating world of gene editing with Dr. David Liu.