#077 Rewriting genomes to eradicate disease and aging | Dr. George Church
Dr. George Church, a professor at Harvard Medical School and MIT, discusses revolutionary advances in synthetic biology, from gene editing for virus resistance and aging reversal to the ethical complexities of germline editing and de-extinction.
Deep Dive Analysis
22 Topic Outline
Introduction to Dr. George Church and Synthetic Biology
History and Evolution of the Human Genome Project
Advantages of Manufacturing with Biology
Why Writing Genomes is Key to Understanding Biology
Goals of Large-Scale Genome Writing: Virus Resistance and De-extinction
The Vertebrate Genomes Project and Ecosystem Restoration
Computer-Aided Genome Design and AI Tools like AlphaFold
Biology as Software: Metaphor, Advancements, and Concerns
CRISPR-Cas9 vs. Other Gene Editing Technologies
Multiplex Editing: Applications in Xenotransplantation and Molecular Flight Recorders
Preventing Viral Spillover from Livestock to Humans
Base Editing and PCSK9 Gene Therapy for Cholesterol
Aging as an Evolved Program and Strategies for Rejuvenation
Animal Research vs. Human Organoids for Aging and Disease Models
Engineering Enhanced Transplant Organs and Cells
Controversies and Public Acceptance of Germline Editing
Synthetic Biology for Space Travel and Alleviating Poverty
Embryo Selection vs. Germline Editing: Practical and Ethical Similarities
Understanding Neurodivergence and the Unknown in Genetics
Gene Drive Technology for Eradicating Diseases like Lyme
Dr. Church's Personal Experience with Narcolepsy and Creativity
The Story of Encoding a Book in DNA
6 Key Concepts
Genetic Recoding
This process involves changing the genetic code of a cell or organism to make it resistant to all viruses. It works by altering the ribosomal translation machinery, which viruses depend on, so they can no longer infect and utilize the host's cellular processes.
Multiplex Editing
Multiplex editing refers to the ability to perform tens or hundreds of thousands, or even millions, of precise genetic edits simultaneously across an entire genome. This capability enables large-scale changes like rewriting whole genomes or creating complex biological recording devices.
Base Editing
A gene editing tool that allows for precise, single-nucleotide changes in DNA without creating double-stranded breaks. It is considered a more refined and potentially safer approach than traditional CRISPR-Cas9, which often involves breaking both DNA strands.
Epigenetic School of Aging
This school of thought proposes that aging is largely a reversible process controlled by epigenetic factors. It suggests that if a cell can be 'convinced' it is young, it will largely repair itself, as evidenced by phenomena like gametogenesis, cloning, Yamanaka factors, and the effects of young blood.
Molecular Flight Recorder
Analogous to an airplane's black box, this is a biological device designed to be incorporated into living organisms. It compactly records vast amounts of physiological data from every cell, which can then be selectively read out to debug what went wrong or analyze biological states.
Gene Drive
A genetic engineering technique that biases the inheritance of a particular gene, causing it to spread through a population at a higher rate than Mendelian inheritance. This can be used to rapidly introduce or eradicate specific traits within a species, such as making mosquitoes resistant to malaria.
12 Questions Answered
Writing and editing genomes is crucial for truly understanding how biological systems work, similar to reverse engineering software or electronics, by observing the functional consequences of specific changes. It also drives the development of useful synthetic biology applications.
Biology offers atomic precision in manufacturing, allowing for molecules with thousands of atoms to be made reproducibly. It also has the unique ability to replicate, potentially enabling scalable and self-copying manufacturing systems.
By changing the genetic code of the host cell, specifically by altering codons in the ribosomal translation machinery, viruses can be prevented from utilizing the host's machinery, making them unable to mutate effectively and achieve a healthy state.
By sequencing the genomes of all known vertebrates, the project helps identify keystone species, protect and reintegrate lost genetic diversity, and potentially prevent or reverse extinction, aiding in the restoration of wilderness environments.
Synthetic biology is advancing at an exponential rate, with capabilities in reading and writing DNA doubling at least once a year, sometimes achieving a factor of 10 per year, potentially making it faster than Moore's Law.
While revolutionary, CRISPR tends to be imprecise or small in scope compared to methods like homologous recombination, which is precise over large distances, or SSAPs/Lambda Red, which can achieve precise editing for large libraries of cells.
Gene editing can target and eliminate endogenous retroviruses built into animal genomes (like pigs for xenotransplantation) or attack external viral DNA (like African swine fever virus) to prevent zoonotic transmission.
This school believes that if cells can be convinced they are young, they will largely fix themselves, as seen in rejuvenation processes during reproduction, cloning, or through factors like Yamanaka factors and young blood.
Organoids offer an alternative to animal models by providing increasingly accurate human-specific organ systems in a dish, allowing for ethical testing of therapies and even serving as the therapies themselves, potentially skipping developmental biology stages.
A moratorium is seen as unnecessary because existing regulatory mechanisms, like the FDA, already prevent new drugs and therapies from being used without rigorous testing, and preventing careful data accumulation could hinder life-saving advancements.
Acceptance may come as people see the benefits of germline-manipulated animals (e.g., for organ transplants), as somatic gene therapies become more common and proven safe, and if a compelling use case for a serious medical condition emerges that is difficult to fix in adults.
Gene drives can be engineered to spread traits through insect populations (e.g., ticks or mosquitoes) that make them unable to carry or transmit human diseases, potentially leading to the eradication of the disease.
37 Actionable Insights
1. Stay Informed on Scientific Advances
Actively seek knowledge about radical transformative technologies like gene editing and gene drive to be better prepared for productive public conversations and to intuitively grasp their potential impact.
2. Prioritize Technology Development for Cost Reduction
Advocate for and invest in technology development upfront in large scientific projects, as this approach can significantly reduce costs and expand the scope and accessibility of the research outcomes.
3. Focus on Societally Beneficial Projects
Prioritize scientific projects that are consciously aimed at generating positive societal consequences, as these are more inspiring, garner broader support, and drive creativity and technological advancement.
4. Ensure Equitable Tech Distribution and Education
Work towards equitable distribution of new technologies and provide education and dialogue opportunities so that everyone on the planet can understand, access, and evaluate these advancements for their own benefit.
5. Radically Reduce Synthetic Biology Costs
Aim to drastically reduce the cost of synthetic biology technologies, such as reading and writing DNA, by millions of fold to ensure universal accessibility and impact, similar to the eradication of smallpox.
6. Diversify Funding for Grand Scientific Challenges
Pursue funding for large-scale scientific projects, such as the Genome Project Write, through multiple channels including philanthropy, industry, and various government agencies (e.g., NIH, DOE, NSF, ARPA, DARPA, IARPA) to ensure robust support and diverse perspectives.
7. Protect Biodiversity & Reduce Agricultural Footprint
Document, freeze, and protect existing organisms and genetic diversity, while simultaneously working to shrink agricultural land and water use by 10 to 100 fold to preserve natural environments.
8. Support Regulatory Agencies Intellectually and Financially
Provide strong intellectual and financial support to government regulatory agencies like the FDA, EPA, and USDA, as they are essential for overseeing the safe and ethical development of new technologies.
9. Integrate Genome Reading into Gene Editing
Prioritize and utilize genome reading at all stages of gene editing, from discovering tools and defining goals to monitoring editing success and assessing physiological outcomes, as it is fundamental to the entire process.
10. Employ Diverse Gene Editing Tools
Broaden the approach to gene editing by utilizing a diverse set of tools beyond CRISPR, such as homologous recombination and SSAPs/Lambda Red, which offer advantages in precision and scope for various applications.
11. Embrace Full Spectrum of Genome Engineering
Understand and utilize the full range of genome engineering methods, including reading, precise editing, and de novo synthesis, to achieve more nuanced and visionary applications beyond the public’s focus on single technologies like CRISPR.
12. Optimize Gene Therapy Delivery Mechanisms
Focus on optimizing delivery mechanisms for gene therapies to ensure the genetic material reaches the correct target cells at the right dose and time, with minimal off-target effects, which is critical for safety and efficacy.
13. Develop Enhanced, Resilient Cell and Organ Therapies
Aim to develop cell and organ therapies that are not merely replacements but are enhanced with superior qualities, such as immunological superiority, resistance to pathogens, cancer, senescence, and suitability for cryopreservation.
14. Utilize Soluble Factors for Systemic Gene Therapy
Consider gene therapies that deliver genes for soluble factors (e.g., alpha-Klotho, FGF-21, soluble TGF-beta receptor) to a subset of cells, allowing these proteins to circulate and achieve whole-body effects, especially when direct delivery to all cells is challenging.
15. Engineer Cell Therapies for Virus Resistance
When developing cell therapies, consider engineering the blood cells to be resistant to all viruses, which could offer enhanced safety and efficacy for patients, pending regulatory approval.
16. Leverage Dogs as Translational Research Models
Utilize dogs as a valuable model for developing human therapeutics, as their similar physiology, environment, and owner observation allow for better translation of results and earlier detection of subtle effects compared to rodents.
17. Screen Longevity Interventions in Rodents
Employ rodent models for initial screening of longevity and age-related disease interventions due to their short lifespan, which allows for rapid observation of significant effects before progressing to larger animal or human studies.
18. Utilize Human Organoids for Research
Integrate human organoids into research as an alternative to traditional animal models, as they offer increasingly accurate and human-specific insights into organ function and disease, potentially streamlining therapeutic development.
19. Apply Nuanced Protein Engineering
When modifying proteins, aim for nuanced engineering that selectively removes undesirable functions, such as viral binding, while preserving essential beneficial functions, like immunological activity, to achieve multi-faceted resistance or enhancement.
20. Extensively Test Gene Drive Ecological Impacts
Before deploying gene drive technologies, conduct extensive studies of ecosystem interactions and rigorous testing in large, enclosed ecosystems to ensure they do not inadvertently cause species extinction or other undesirable ecological impacts.
21. Prioritize Gene Drive Targets with Minimal Ecological Risk
When considering gene drive technologies, prioritize targeting species whose extinction would have minimal ecological impact, such as specific disease-carrying mosquitoes that are not keystone species, after thorough study of ecosystem dependencies.
22. Engage Public, Offer Gene Drive Alternatives
Foster open public dialogue about new biotechnologies and offer non-gene drive alternatives for pest and disease control, even if they are more expensive or less certain, to build trust and address community concerns.
23. Embrace Preconception Genetic Counseling
Opt for preconception genetic counseling to understand carrier status for genetic diseases, enabling informed family planning choices that can prevent severe conditions in children, offering a low-cost preventative alternative to expensive reactive gene therapies.
24. Support and Utilize Effective Vaccines
Actively support and utilize effective vaccines, ensuring public understanding is based on accurate scientific data to prevent the spread of misinformation and leverage these powerful tools for public health, as seen with the Lyme disease vaccine’s history.
25. Adopt Cautious, Phased Approach to New Tech
When developing new medical technologies, acknowledge that zero risk is unattainable and inaction is also risky; instead, proceed cautiously with small animal or organoid studies, followed by small human clinical trials, gradually expanding as safety and efficacy are confirmed.
26. Evaluate Trade-offs and Context, Not Perfection
When considering new biotechnologies or enhancements, focus on evaluating trade-offs and specific contextual benefits rather than striving for an ill-defined “perfect” outcome, as all solutions have situational advantages and disadvantages.
27. Distinguish Anecdotes from Clinical Recommendations
Always differentiate between personal anecdotes, even from experts, and recommendations derived from rigorous clinical trials, as only the latter provides generalizable and evidence-based guidance for health and lifestyle choices.
28. Communicate Personal Health Conditions
Openly communicate personal health conditions, such as narcolepsy or diabetes, to those around you, as hiding them can be more dangerous than communicating them, especially in emergencies.
29. Adapt Lifestyle to Manage Sleepiness
If prone to sleepiness after meals or during passive activities, consider adapting eating patterns (e.g., eating before bed if it helps, though not generally recommended) and incorporating light physical activity like standing or pacing to maintain alertness.
30. Choose Career and Activities Compatible with Health
Select a career path and daily activities that are compatible with personal health limitations, such as avoiding driving if prone to falling asleep, to ensure safety and find a suitable and fulfilling professional fit.
31. Empower Choice Over Neuroatypical Traits
Explore and develop technologies that provide individuals with neuroatypical traits the choice and control to modulate these characteristics, allowing them to leverage potential advantages for specific tasks while also adapting to social or functional demands.
32. Leverage Sleep for Problem-Solving (If Applicable)
For individuals who find themselves falling asleep during difficult problem-solving, consider allowing for short naps, as some, particularly those with narcolepsy, report waking with solutions to abstract or practical problems.
33. Harness Hypnagogic State for Creativity
For creative individuals, consider experimenting with methods to capture ideas from the hypnagogic state (the transition between wakefulness and sleep), as it can be a source of unique inspiration, similar to Salvador Dali’s technique.
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6 Key Quotes
I have speculated that essentially everything that we can currently manufacture today without biology, we will be able to manufacture with biology and with potential advantages. Biology is intrinsically atomically precise, and it's scalable to cover the whole planet essentially for free.
Dr. George Church
The greatest danger we have as a public is not having knowledge that can help us be better prepared to have productive conversations as these advances develop.
Rhonda
The genome project wasn't as impressive to me as the reducing the cost project, a thousand dollar genome project, sort of the technology development.
Dr. George Church
CRISPR was basically a hatchet, and I sometimes call it genome vandalism.
Dr. George Church
Doing nothing is very risky. Status quo is very risky relative to the future.
Dr. George Church
The nice thing about germline is every subsequent generation gets it for free.
Dr. George Church
1 Protocols
Aging Reversal Combination Gene Treatment
Dr. George Church- Deliver genes for three soluble factors (FGF-21, alpha-clotho, and a soluble form of TGF-beta receptor) to a subset of cells in the body using adeno-associated virus.
- These subset cells then produce and broadly deliver the soluble proteins throughout the body.
- The soluble factors act like 'young blood' to rejuvenate mice and dogs, impacting multiple hallmarks and diseases of aging, with the goal of achieving youthfulness and lack of age-related diseases.