Podcast Summary: "Making Sense with Sam Harris" Episode #394 — Bringing Back the Mammoth

Introduction

In episode #394 of Making Sense with Sam Harris, host Sam Harris engages in a compelling conversation with Ben Lamb, the co-founder and CEO of Colossal Biosciences. The episode, released on December 3, 2024, delves into the ambitious mission of Colossal Biosciences: resurrecting extinct species such as the woolly mammoth, the Tasmanian tiger, and the dodo. The discussion navigates through the technical, ethical, and environmental facets of de-extinction, highlighting the company's innovative approaches and the potential implications for biodiversity and human health.

Guest Background: Ben Lamb

Ben Lamb introduces himself as an insatiably curious individual with a diverse career spanning mobile gaming, conversational operating systems, and satellite software for defense applications. His journey took a pivotal turn when he met Dr. George Church, a renowned biologist at Harvard, leading to the inception of Colossal Biosciences. Lamb emphasizes his role as a systems designer rather than a traditional technologist or engineer, bringing a holistic perspective to the company’s groundbreaking work.

Ben Lamb [02:32]: "I'm definitely insatiably curious and so I'm always looking at things from a systems design perspective... I got massively excited about the opportunities [in synthetic biology and AI]."

Colossal Biosciences: Mission and Vision

Colossal Biosciences positions itself as the world's first de-extinction and species preservation company. The primary goal is to combat the alarming loss of biodiversity, which recent data indicates could see a 50% reduction by 2050, a significant increase from earlier estimates of 15%. By resurrecting extinct species, Colossal aims to restore ecological balance and enhance biodiversity, with secondary benefits including advancements in genetic engineering technologies applicable to human healthcare.

Ben Lamb [06:06]: "We decided that we wanted to build the world's first de-extinction and species preservation company... we can inspire people, create true impact, but also create massive value creation around the way."

Choosing the Target Species

Colossal has announced three primary species for resurrection:

1. Woolly Mammoth: The flagship project, initially championed by George Church, aims to reintroduce these majestic creatures to restore tundra ecosystems.
2. Tasmanian Tiger (Thylacine): Extinct since 1936 due to human activities and government bounties, its revival could help re-establish ecological niches in Australia.
3. Dodo: Symbolizing de-extinction, the dodo's resurrection serves as a powerful statement about biodiversity preservation.

Ben Lamb [06:10]: "We've announced three species to date: the woolly mammoth, the Tasmanian tiger, and the dodo... the dodo symbolizes de-extinction."

De-Extinction vs. Jurassic Park: A Comparative Analysis

A significant portion of the conversation addresses the pervasive association of Colossal's work with the fictional narrative of Jurassic Park. Lamb clarifies the fundamental differences between their scientific endeavors and the dramatized resurrection depicted in the film. Unlike Jurassic Park, which relies on improbable DNA retrieval from amber-encased mosquitoes and assumes the repair of millions of years-old DNA, Colossal employs a more scientifically grounded approach.

Key distinctions include:

• DNA Source and Integrity: Colossal recognizes that amber preserves only minimal DNA fragments, unsuitable for complete genome reconstruction. Instead, they focus on high-quality ancient DNA from cold, dry environments, ensuring better preservation.
• Genomic Engineering Approach: Rather than attempting to fill gaps in ancient DNA with surrogate species like frogs, Colossal leverages comparative genomics. By thoroughly understanding the genetic differences between Asian elephants (the closest living relatives to mammoths) and mammoths, they can selectively edit elephant genomes to incorporate mammoth traits.

Ben Lamb [07:24]: "We're trying to truly understand the genomes so that we could selectively choose the genes that we then want to engineer into that of a living species. So it's almost like reverse Jurassic Park."

Technical Approach: Paleogenomics and Genetic Engineering

The discussion delves deep into the technicalities of resurrecting extinct species, particularly the woolly mammoth. Colossal's methodology involves:

1. Genome Sequencing: Colossal has sequenced approximately 65 mammoth genomes, primarily from Siberian and Russian samples, and is expanding to Alaskan specimens. This extensive genomic data allows them to identify essential mammoth genes responsible for traits like cold tolerance, fat storage, and curved tusks.

2. Comparative Genomics: By comparing the sequenced mammoth genomes with those of Asian elephants, Colossal identifies the genetic variations necessary to confer mammoth characteristics to elephant cells.

3. Genetic Editing: Utilizing advanced tools beyond traditional CRISPR, Colossal employs a combination of nucleotide changes, gene knockouts, and large DNA block syntheses. Their focus on "multiplex editing" enables simultaneous modifications across the genome, enhancing efficiency and reducing the likelihood of off-target effects.

4. Artificial Intelligence Integration: AI plays a crucial role in optimizing the genetic editing process. Colossal has developed proprietary models that accurately recommend the most effective editing tools for specific genetic modifications, streamlining experimental workflows and minimizing costly errors.

Ben Lamb [10:39]: "We do it almost exactly in reverse... identify the core areas around cold tolerance, fat hair, curved tusk. So we actually have enough to do our work."

Ben Lamb [20:38]: "AI is a necessary component... we're using AI not just for comparative genomics, but even in what selection of what editing tool we should use for the editing job that we're trying to pursue."

Overcoming Biological Challenges

One significant hurdle in genetic engineering of large mammals like elephants is their natural resistance to cancer, primarily due to the overexpression of the p53 protein. Colossal has had to innovate in:

• Cell Culture Techniques: Developing immortalized cell lines to maintain healthy cell cultures during genetic modifications.
• Regulating p53 Expression: Temporarily reducing p53 levels to allow genetic editing without triggering cellular senescence, then restoring its expression to prevent oncogenesis.

Ben Lamb [17:00]: "We had to figure out how we can, quote, unquote, turn down P53 so that we could edit the cells and then be able to turn it back up. Because you don't want to produce, you know, cancer in elephants."

Progress and Current Status

As of the podcast's release, Colossal Biosciences has not yet achieved the creation of a living extinct species. All projects remain in the laboratory phase, focusing on in vitro developments and genetic validations.

Ben Lamb [22:20]: "There is no secret pregnant Asian elephant, mammoth, unfortunately, I would be the first. I couldn't be more excited to share it with you if there was."

The team continues to advance their genomic editing techniques, optimize AI-driven tools for genetic modifications, and collaborate with leading universities to enhance the completeness and accuracy of their genomic data. A forthcoming research paper promises to shed more light on their comparative genomics findings, expected mid-next year.

Ethical and Environmental Considerations

While the transcript provided does not delve deeply into ethical or environmental discussions, Colossal's mission inherently raises questions about the ecological impact of reintroducing extinct species, potential unintended consequences, and the moral implications of de-extinction. Future episodes and discussions may further explore these dimensions.

Conclusion

The episode offers a fascinating glimpse into the cutting-edge world of de-extinction, led by innovators like Ben Lamb and George Church. By leveraging advancements in genomics, AI, and genetic engineering, Colossal Biosciences aims to address critical environmental challenges and pioneer new frontiers in biological science. While the realization of resurrecting species like the woolly mammoth remains on the horizon, the conversation underscores the blend of scientific rigor, technological innovation, and visionary thinking driving this transformative endeavor.

Notable Quotes

• Ben Lamb [02:32]: "I'm definitely insatiably curious and so I'm always looking at things from a systems design perspective... I got massively excited about the opportunities [in synthetic biology and AI]."

• Ben Lamb [07:24]: "We're trying to truly understand the genomes so that we could selectively choose the genes that we then want to engineer into that of a living species. So it's almost like reverse Jurassic Park."

• Ben Lamb [20:38]: "AI is a necessary component... we're using AI not just for comparative genomics, but even in what selection of what editing tool we should use for the editing job that we're trying to pursue."

• Ben Lamb [22:20]: "There is no secret pregnant Asian elephant, mammoth, unfortunately, I would be the first. I couldn't be more excited to share it with you if there was."

Accessing the Full Episode

To listen to the complete conversation between Sam Harris and Ben Lamb, including in-depth discussions and additional insights, subscribe to the Making Sense podcast through samharris.org. Subscribers gain access to full-length episodes, bonus content, and the latest updates on Colossal Biosciences' pioneering work in de-extinction.