Ep156: David Liu on New Tools and Techniques for Biology

Episode Summary

Executive Summary: David Liu traces how a childhood shaped by immigrant parents, public schools, and fascination with nature led him to chemical biology and a career centered on technology development. He explains how DNA-templated synthesis, CRISPR, base editing, and prime editing emerged from a consistent focus on powerful tools, problem selection, and turning discovery into therapies—especially for genetic disease.

Main Topics: Immigrant family, childhood, and formative influences (Priority: 5/5): Liu describes growing up in Riverside, California, with immigrant parents in science and engineering, a hardworking household, and early exposure to curiosity, resilience, and academic excellence. Early fascination with science and the natural world (Priority: 4/5): He recalls space imagery, backyard experiments, insects, and plants as the roots of his awe for biology and his drive to understand how nature works. Harvard, chemistry, and the importance of teachers (Priority: 5/5): Liu explains why Harvard appealed to him, how great teaching shaped him, and how an undergraduate experience in EJ Corey’s lab tied chemistry to biology and technology. Technology development as a career theme (Priority: 5/5): From DNA-templated synthesis to phage-assisted continuous evolution, Liu argues that new tools amplify scientific discovery and make previously impossible questions answerable. CRISPR, Editas, and gene disruption therapeutics (Priority: 5/5): He recounts the rise of CRISPR and how first-generation gene editing focused mainly on gene disruption, with sickle cell disease as a leading therapeutic use case. Base editing and prime editing as precise correction tools (Priority: 5/5): Liu contrasts scissors-based nucleases with deterministic correction platforms that can rewrite DNA without double-strand breaks, enabling true gene repair. Academic entrepreneurship and company-building (Priority: 4/5): He discusses founding or co-founding companies, how venture investors pushed for dedicated platforms, and how he balanced academic independence with translational impact.

Key Arguments: Problem selection matters more than trying to solve easy problems; the best projects are those that, if successful, would matter broadly and have real downstream impact. New scientific tools transform what questions can be asked and what therapies can be built; technology development is a multiplier for the whole field. CRISPR nucleases are powerful but inherently produce uncontrolled mixtures of DNA repair outcomes, making them best suited for gene disruption rather than precise correction. Base editing and prime editing address a major unmet need by enabling targeted gene correction without relying on double-strand breaks and homology-directed repair. Sickle cell and beta thalassemia were ideal first-generation CRISPR targets because disrupting fetal hemoglobin silencing can therapeutically reawaken a naturally protective pathway. The strongest biotech companies should be dedicated to a single platform so the science is not a side project competing with other priorities. Phage-assisted continuous evolution (PACE) is a general engine for optimizing biomolecules when rational design alone is insufficient. Academic founders can and should engage with industry when it accelerates translation, as long as the science remains rigorous and the commitments are managed responsibly.

Data Points: Father’s commute: ~4 hours per day - Liu says his father commuted about two hours each way to an aerospace job for decades. Harvard chemistry tenure context: Very few assistant professors were tenured at the time - He cites the department’s culture when discussing Joe Grabowski’s advice to join another lab. Nobel prize attendance: 1990 - He attended the Nobel ceremony in Stockholm at age 17 after winning a junior science competition. Age at Nobel ceremony: 17 - His high school science prize allowed attendance the following year. First company timing: Around 2003-2004 - VCs approached him about DNA-encoded libraries and he later founded Ensemble Therapeutics. NIH grant attempts for DNA-encoded libraries: 3 attempts - He says the idea took three tries to get funded. Base editing paper: 2016 - He notes the first base editing paper was published in 2016. Prime editing paper: Late 2019 - He notes the first prime editing paper was published in late 2019. Base editing clinical trials: 8 - Liu says base editing is already in eight clinical trials. Gene-editing clinical trials using nucleases for disruption: Roughly 50+ - He contrasts this with the small number that attempted precise correction. Clinical trials using precise correction with nucleases: 1 - He says only one trial really tried DNA-cutting scissors for precise correction. Known disease-causing genetic misspellings: More than 100,000 - He uses this to highlight the scale of the correction challenge. Share of genetic misspellings addressable by base editing: About one-third - He says the four base-editing substitutions cover roughly a third of known disease-causing mutations. Potential coverage by prime editing: More than 90% - He says prime editing could theoretically correct over 90% of the mutation pie chart. On-target double-strand break reduction with base/prime editors: Orders of magnitude lower; about 1% to 0.1% - He contrasts this with nuclease-based editing, which is effectively 100% double-strand breaks. Naturally occurring nicks in DNA: ~10,000 per day per cell - He cites this as part of the rationale for prime editing’s nick-based mechanism. Employees across Beam and Prime: 700+ - He says the two companies collectively employ more than 700 people.

Pivotal Quotes: "I think the most important aspect of research is problem selection." — David Liu: He is explaining how he chooses scientific problems that can have large downstream impact if solved. "Base editors, I've likened to pencils... and prime editors are more like molecular word processors, if you will, in that they do search and replace gene editing." — David Liu: He summarizes the conceptual difference between scissors-based nucleases and precise rewriting systems. "If I can contribute in some small way to those grandiose sounding aspirations, then I think that will, you know, I'll die with a smile on my face." — David Liu: He reflects on the long-term goal of freeing humans from harmful DNA misspellings and enabling genetic futures to be changed.

Implications: The interview shows how platform innovation, not just single drug programs, can reshape biotech. Liu’s work suggests precision gene correction is moving from concept to clinic, expanding treatment possibilities for many genetic diseases.