How has DNA sequencing technology evolved since the Human Genome Project began?

Since Dr. Church pioneered direct DNA sequencing in 1984, sequencing has become over 10 million-fold cheaper. This exponential reduction in cost has made personal genome sequencing widely accessible and has advanced the field significantly.

Why is comparing different species' genomes important for tool discovery?

Comparing genomes across species is almost as effective as an experiment and provides richer data for exploration. This comparison helps in discovering new biological tools, creating a positive feedback loop: sequence genomes, find tools, use tools to read and write genomes, and find more tools.

What are the advantages of using biology for manufacturing compared to traditional methods?

Biology offers atomic precision in manufacturing, allowing for reproducibly made molecules with exact atomic configurations. Additionally, biological systems can replicate themselves, a capability currently ludicrous for non-biological machines, offering exponential scalability.

Can genetic engineering make cells resistant to all viruses?

Yes, Dr. Church's lab has successfully demonstrated changing the genetic code in industrial organisms like E. coli to make them resistant to all known viruses. This involves making many thousands of changes that viruses cannot easily mutate around, potentially applicable to plants, animals, and human stem cells.

How does AI, like AlphaFold, contribute to genome engineering?

While AlphaFold primarily predicts protein 3D structures, computer-aided design, especially with machine learning and large synthetic molecule libraries, helps explore the 'landscape of functionality.' This allows for rapid testing of millions or billions of subtle genetic variations to understand their functional consequences.

Is CRISPR the only gene-editing tool, and is it overhyped?

CRISPR is a revolutionary tool but not the only one. Older, precise methods like homologous recombination and SSAPs (Lambda red) exist and are still in use. Dr. Church suggests that reading genomes and considering wider integrated approaches, including delivery and testing, are equally vital, and that public focus on CRISPR might be an oversimplification.

What are the core ideas behind efforts to mitigate or reverse aging?

One school of thought, favored by Church, views aging as a programmed process, possibly modifiable by addressing a 'small core set of systems biology systems medicine.' Strategies include rejuvenating environments (like eggs in cloning), transcription factors (Yamanaka factors), and blood-borne factors that reset the age clock.

Why are dogs considered a good model for human aging and gene therapy research?

Dogs are large mammals with closer similarities to humans than rodents, living in similar environments, eating similar food, and exhibiting similar emotions. Their owners can also detect subtle positive and negative consequences of treatments earlier, making them a particularly good conduit for translating therapies to humans.

What is the ethical debate around 'enhancement' versus 'therapy' in genetic engineering?

The distinction between enhancement and therapy is often fluid, as many common technologies (smartphones, cars) are already enhancements. Dr. Church argues that biotechnologies like vaccines are enhancements that protect us, making the obsession with defining a 'perfect human' or avoiding enhancement seem odd and inconsistent with other accepted technologies.

What is Dr. George Church's stance on germline editing moratoriums?

Dr. Church opposes explicit moratoriums on germline editing, arguing that existing regulatory bodies like the FDA already provide caution and oversight for new drugs. He believes preventing careful data accumulation through bans is counterproductive and that a compelling medical need would eventually lead to public acceptance, similar to IVF.

How can society foster a well-reasoned public understanding of complex genetic technologies?

Promoting conversation through common media like books, movies, and television can help frame complex science in an entertaining and educational way, allowing for exploration of both positive and negative scenarios without avoiding concerns. This helps make scientific advancements more accessible and understandable to the broader public.

What is the 'double standard' in public perception of genetic modification?

There's often a double standard where random, uncontrolled mutations (e.g., from UV radiation in plants) are accepted, but precise, controlled genetic edits are viewed with suspicion. This is akin to accepting IVF but rejecting germline editing, or chemotherapy but not gene therapy for germline concerns.

How does Dr. Church's narcolepsy impact his creative process?

Dr. Church describes finding himself in a 'limbo between dreaming and awakeness' when super bored, excited, or facing difficult problems. He often falls asleep and wakes up seconds later with solutions to abstract or practical problems, experiencing a heightened state of awareness, which he attributes to aiding his creativity.

What is the backstory behind Dr. Church's book 'Regenesis' being encoded in DNA?

After reviewing a paper where authors encoded their names in a tiny genome, Dr. Church decided to encode his entire book, 'Regenesis,' into DNA. He used a generalized binary code that could encode text and later images, creating 70 billion copies and inadvertently launching an industry for digital encoding in DNA that can record vast amounts of data in living organisms.

George Church, PhD: Rewriting Genomes to Eradicate Disease and Aging

FoundMyFitness

Science & Technology3 min read123 min video

Aug 24, 2022|97,413 views|1,399|52

synthetic biology aging CRISPR/Cas9 base editing Dr. George Church PCSK9 inhibitors Human Genome Project AlphaFold Vertebrate Genomes Project Genome Project-Write Neurodivergence Regenesis

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Key Moments

TL;DR

George Church discusses gene editing, synthetic biology, and rewriting genomes for health and longevity.

Key Insights

The Human Genome Project, initially costly, has led to exponentially cheaper DNA sequencing, enabling new possibilities in biology.

Writing and editing genomes (synthetic biology) is crucial for understanding biological functions and developing transformative technologies.

Biology offers unique advantages in manufacturing due to its atomic precision and scalability, surpassing traditional manufacturing in many aspects.

Advanced gene editing tools, including CRISPR and others, are essential for complex tasks like rewriting entire genomes and creating virus-resistant cells.

Understanding and potentially mitigating aging involves targeting core biological processes, with potential for rejuvenation and treating age-related diseases.

Gene drives offer a powerful tool for eradicating disease-carrying insects, but careful consideration of ecological impacts and public dialogue is necessary.

THE EVOLUTION OF GENOME SEQUENCING AND WRITING

The conversation begins by tracing the journey from the Human Genome Project to the current era of genome writing. Initially a $3 billion endeavor, DNA sequencing is now vastly cheaper and more accessible. George Church highlights that understanding biology requires the ability to not only read but also write and edit its code, akin to reverse-engineering electronics or software. This ability drives the development of radical, transformative technologies in synthetic biology. The exponential decrease in sequencing costs, driven by technological advancement, has opened doors to more complex genetic manipulations and discoveries.

SYNTHETIC BIOLOGY: BIOLOGY AS A MANUFACTURING PLATFORM

Church emphasizes the potential of synthetic biology to revolutionize manufacturing. He posits that essentially everything currently manufactured can eventually be produced using biological systems, offering advantages like atomic precision and unparalleled scalability, even on a global scale. Biology's capacity for replication far exceeds current technological capabilities, suggesting a future of hybrid systems inspired by both biological and electronic principles. While not yet utilizing the entire periodic table, biology's intrinsic precision and self-replication capabilities set it apart from conventional manufacturing.

DELVING INTO GENOME EDITING TOOLS AND APPLICATIONS

The discussion explores various gene editing tools, including CRISPR-Cas9, while highlighting that CRISPR is not the only or always the best tool for the job. Older methods like homologous recombination and ssaps (single-strand annealing proteins) offer precision, especially for larger edits or complex genetic rewrites. Multiplex editing, capable of making thousands or even millions of edits in a single cell, is key for ambitious projects like creating cells resistant to all viruses or rewriting entire genomes. These technologies are crucial for applications ranging from industrial microorganisms to potential human therapies.

TARGETING AGING AND AGE-RELATED DISEASES

A significant portion of the conversation focuses on aging, viewed as a programmable process that may be reversible or manageable. Church describes two main schools of thought: damage repair and epigenetic reprogramming. He explains that factors like Yamanaka factors, soluble proteins, and even blood composition can influence cellular age. The goal is not to eliminate aging entirely but to mitigate age-related diseases, restoring youthfulness and healthspan by addressing the core 'hallmarks of aging'. This research has progressed from rodent models to dogs, with aspirations for human clinical trials.

GENE DRIVES AND ECOSYSTEM MANAGEMENT

Gene drives, a technology that can rapidly spread a genetic trait through a population, are discussed as a tool for ecological benefit, such as eradicating disease-carrying insects like mosquitoes or ticks. While the primary goal is often to confer resistance to diseases affecting other species (e.g., mosquitoes to malaria), the potential for unintended species extinction is a significant concern. Church stresses the importance of extensive testing in contained environments, public dialogue, and exploring alternatives like genetically engineered rodent populations to manage diseases like Lyme, emphasizing a cautious, step-by-step approach.

ETHICAL CONSIDERATIONS AND THE FUTURE OF GERMLINE EDITING

The ethical landscape of germline editing is complex, marked by a tension between the desire for progress and the need for caution. Church argues against strict moratoria, emphasizing existing regulatory frameworks like the FDA's. He advocates for a balanced approach, focusing on outcomes rather than just the technology itself. The conversation touches upon the public's evolving perception of new technologies, comparing the initial controversy around IVF-'test-tube babies' to germline editing. While acknowledging potential risks, Church highlights the importance of informed dialogue, robust testing, and exploring compelling use cases for technologies like germline editing.

Mentioned in This Episode

●Products

●Software & Apps

●Tools

●Companies

●Organizations

●Books

●Concepts

●People Referenced

Common Questions

The main goal is to understand how biological systems work and to develop new technologies, similar to reverse engineering software. By modifying genetic code, scientists can discern function and create useful synthetic biology applications for societal and ecological benefit.

Topics

Genome Sequencing Rejuvenation DNA Writing Virus Resistance Genetically Modified Organisms Bioethics Heritable Traits Disease Eradication

Mentioned in this video

companyeGenesis

A company co-founded by Luhan Yang that focuses on cell and organ therapies, including developing pigs for xenotransplantation.

conceptHomologous recombination

An older, powerful, and precise gene-editing method that predates CRISPR and can be used over large distances, for which Smithies and Capecchi received the Nobel Prize.

personKevin Esvelt

A former postdoc and colleague of Dr. Church at MIT, known for his work on gene drives, particularly engaging communities like Nantucket regarding Lyme disease interventions.

personAndrew Wakefield

The scientist who faked data linking vaccines to autism, which had a negative impact on public trust in vaccines, including the Lyme disease vaccine.

personEd Regis

Co-author of Dr. Church's book 'Regenesis,' and an experienced popular science writer.

personLuhan Yang

Former graduate student and postdoctoral fellow in Dr. Church's lab, co-founded eGenesis and Qihan, and co-authored a paper on using CRISPR to eliminate African swine fever virus.

conceptAfrican swine fever virus

A mammalian virus that Dr. Church's lab, with Luhan Yang's team, used CRISPR to attack, marking a practical application of CRISPR against mammalian viruses.

bookRegenesis: How Synthetic Biology Will Reinvent Nature and Ourselves

A book co-authored by Dr. George Church and Ed Regis, published in 2014, discussing the future of synthetic biology. It was famously encoded into DNA.

organizationPersonal Genome Project

An initiative launched in 2005 by Dr. Church to promote personal genome sequencing and public sharing of genomic data.

productGolden Rice

A genetically modified rice variety designed to produce beta-carotene, a precursor to vitamin A, to combat vitamin A deficiency in developing nations.

personNoah Davidson

A former postdoc in Dr. Church's lab who founded Rejuvenate Bio, working on gene therapies for rejuvenation in dogs and potentially humans.

toolSSAPs (Lambda red)

A precise editing method that dates back two decades before CRISPR, used by Dr. Church's lab around 2009 to create libraries of billions of edited cells.

companyQihan

A company co-founded by Luhan Yang that focuses on cell and organ therapies.

organizationHuman Genome Project

A $3 billion moonshot project initiated in 1984, co-founded by Dr. George Church, with the goal of sequencing a single reference human genome. It laid the foundation for modern genomics, drastically reducing sequencing costs.

personFred Sanger

Published an independent DNA sequencing paper in the same year as Wally Gilbert's team (1977), known for the 'Sanger method'.

personMario Capecchi

Awarded the Nobel Prize for his work on homologous recombination gene editing.

personOliver Smithies

Awarded the Nobel Prize for his work on homologous recombination gene editing.

toolBase editing

A gene-editing technology that doesn't involve double-stranded DNA breaks, currently in Phase 1B trials for targeting PCSK9 as a treatment for hypercholesterolemia.

companyRejuvenate Bio

A company founded by Noah Davidson, focusing on gene therapies for aging and age-related diseases in pets, with potential human applications.

conceptPCSK9

A gene target in base editing trials for hypercholesterolemia. Humans with natural null mutations for PCSK9 are healthy, indicating its safety and effectiveness as a therapeutic target.

organismE. coli

toolCCR5