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

Dr. George Church and the Human Genome Project

• Dr. George Church: key figure in the Human Genome Project 
  • Pioneered method of direct DNA sequencing in 1984
  • Contributed to exponential shifts in understanding, feasibility, and capability in biology
• Human Genome Project: $3 billion moonshot to sequence a single reference genome for humans 
  • Sequencing now over 10 million times cheaper
  • Most people can get their genome sequenced inexpensively

The Importance of More Genomes and Population Variation

• More genomes needed for better understanding 
  • Population variation as important as the reference genome
  • Helps ensure a good reference
• Genome comparisons can lead to new tool discovery 
  • Positive feedback loop: sequence genomes, find tools, use tools to read/​​write genomes, find more tools

Synthetic Biology and Manufacturing

• Biology is atomically precise and scalable 
  • Can potentially manufacture everything without biology
  • Can use a wide range of elements and chemical bonds
• Unique aspects of biology: 
  • Ability to replicate (e.g., a cell phone cannot make a copy of itself)
  • Hybrid systems using biological and electronic inspiration could lead to new innovations

Writing the Human Genome to Understand It

• Writing the human genome can help better understand it

  • Current human genome is a rough draft, not a full instruction book
  • Writing the genome can provide insights into its function and structure
  • Can lead to new discoveries and applications in medicine and other fields
    Reverse Engineering and Synthetic Biology

• Reverse engineering in biology involves making changes to understand the function of specific genes or code

• Synthetic biology often involves changing one or two genes, but more complex changes may require rewriting the entire genome

Changing the Genetic Code for Virus Resistance

• Project to change the genetic code to make cells resistant to all viruses
• Viruses depend on the host’s genetic code and translation ribosomal machinery
• Changing the code without hurting the host can make the host resistant to viruses
• This method has been tested in E. Coli and could potentially be applied to plants, animals, and humans

De-​​Extinction and Genome Editing

• De-​​extinction involves making changes to bring back certain traits or physiology of extinct species
• This process may require many changes throughout the genome, making it more like a complete rewrite than simple editing

Vertebrate Genomes Project

• Aims to sequence the whole biosphere, focusing on vertebrates as they often constitute keystone species in ecosystems
• Helps to document, freeze, and protect species, as well as understand the impact of human activity on ecosystems

Computer-​​Aided Design of Genomes and AI Advances

• Software like AlphaFold focuses on predicting protein structures, but other machine learning methods can be used to study the functional consequences of genetic changes
• Machine learning can be combined with multiplex libraries to study the landscape of functionality in proteins, RNAs, and DNAs

• Synthetic biology libraries can act as a “wetware computer” to generate data for machine learning algorithms
  Biology as Software

• Metaphors are imperfect, but useful

• Synthetic biology can involve both digital and analog circuits
• Biology allows for billions and trillions of prototypes and accelerated evolution

Synthetic Biology Advancements

• Excitement and concerns with new technologies
• Exponential growth, sometimes faster than Moore’s Law for electronics
• Importance of government agencies, equitable distribution, and accessibility

Gene Editing Tools

• CRISPR is revolutionary, but not the only method
• Importance of reading genomes and other editing methods
• Homologous recombination, SSAPs, and recombinases are other powerful methods

Gene Editing Therapy

• Most gene therapies involve adding genes, not editing
• Delivery is crucial for effective gene therapy
• Genetic counseling can be a low-​​cost preventative measure

Multiplex Editing

• Ability to perform thousands or millions of edits in human cells
• Impacts large genome creation, tissue engineering, and germline editing

• Expands the potential applications and precision of gene editing
  Gene Editing and Aging

• Gene editing pigs to enhance resistance to retroviruses 
  • Potential to eliminate viral spillover events from livestock to humans
  • CRISPR used to attack viral DNA, eliminating mammalian viruses from the environment
  • Goal to make plants, animals, and humans resistant to viruses
• Base editing as a potential treatment for hypercholesterolemia 
  • Phase 1B trial with PCSK9 target
  • Could be a one-​​time treatment, unlike expensive and frequent antibody treatments
• Aging as a fundamentally programmed process 
  • Aiming to treat serious diseases of aging
  • Possibility of changing the aging clock through rejuvenation processes 
    • Gametogenesis and fertilization
    • Cloning
    • Yamanaka factors (OSKM)
    • Bloodborne factors
  • Two schools of thought: damage school and epigenetic school 
    • Epigenetic school: convincing cells they are young so they fix themselves
  • FDA approval for specific indications, but could be applicable to almost all aging
• Previous publication on gene therapy and aging 
  • Added three soluble factors (TGF-​​beta receptor, FGF21, and alpha-​​clopo) to mice
  • Reversal of aging biomarkers observed
  • Separate experiment with three transcription factors (OS and K of OSKM)
    Gene Therapy and Aging
• Experiments with adeno-​​associated virus, fullestatin, and polymerase 
  • Affects ends of chromosomes (telomeres)
  • Impacts hallmarks of aging, biomarkers of aging, and diseases of aging
  • Affects multiple diseases in mice and dogs
• Three factors: FGF 21, TGF beta, and alpha Clotho 
  • Soluble and act like young blood in rejuvenating mice and dogs
  • Aim to affect the whole body through two tiers of delivery
• Dogs as a conduit to humans 
  • Large mammals with similar environments and emotions
  • Owners can sense subtle positive and negative consequences

Rodents in Aging Research

• Advantages of using rodents 
  • Short lifespan (2 years) makes it easy to see longevity effects
  • Can test multiple gene therapies before moving to larger animals and humans
• Limitations of rodent models 
  • Differences in treatment and environment compared to humans
  • Alternative animal models (e.g., pigs) and human organoids being developed

Germline Editing

• Controversy surrounding germline editing 
  • Concerns about ethics and potential harm to patients or society
  • Example: JK Hu in China and the CRISPR-​​edited babies
• Public response to new medical technologies 
  • Comparison between in vitro fertilization in 1978 and CRISPR-​​edited babies in 2018
  • Changing perceptions of what is “natural” and acceptable in medicine
    Germline Editing and Public Perception

• Germline editing is a controversial and complex issue

• Public understanding and acceptance may evolve over time, similar to in vitro fertilization (IVF)
• Education and conversation are key to addressing concerns and misconceptions

Eliminating Diseases of Poverty

• Reducing the medical load from infectious diseases can have a positive impact on poverty
• Improved agriculture and better medical care can contribute to poverty reduction
• HIV elimination could be achieved through a multipronged effort, including gene therapy

Next-​​Generation Embryo Selection vs. Germline Editing

• Embryo selection could achieve many of the same goals as germline editing, but with limitations
• Advances in sequencing and understanding of genetics could lead to practical editing through embryo selection

• Social norms and education play a role in the acceptance and implementation of these technologies
  Gene Drives and Disease Eradication

• Gene drives can be used to eradicate insect-​​borne human diseases like malaria and Lyme disease 
  • Example: making mosquitoes resistant to malaria, preventing transmission to humans
• Concerns about unintentional extinction of a species 
  • Limited number of mosquitoes carry malaria, so extinction risk may be acceptable
  • First priority is to try to eradicate disease without causing extinction
• Dialogue between scientists and communities 
  • Example: Nantucket and Martha’s Vineyard considering gene drive to wipe out Lyme disease
  • Alternative: genetically engineered rodent population resistant to Lyme disease without gene drive
  • Communication and understanding of science is crucial for public acceptance

Lyme Disease Vaccine

• A Lyme disease vaccine was previously available but was pulled from the market 
  • Timing coincided with the false data on vaccines causing autism
  • Lyme disease was less severe at the time
• New vaccines in development target multiple tick-​​borne diseases and strains of Lyme 
  • Public may be more accepting of a vaccine now, understanding the consequences of not having one
  • Lyme disease vaccine for dogs has been available and successful

Personal Experience with Narcolepsy

• Dr. Church discovered his narcolepsy in his late 30s, likely onset at age 13
• Open communication about the condition is important
• Creative ideas may come from the limbo between dreaming and wakefulness

• Personal anecdotes from scientists should not be taken as recommendations; clinical trials provide more reliable information
  Dealing with Narcolepsy

• Disclosure of the condition to others can be helpful

• Eating right before bedtime can help manage sleepiness during the day
• Standing or pacing during lectures or activities to stay awake
• Avoiding driving due to the risk of falling asleep

Falling Asleep and Problem Solving

• Tendency to fall asleep when bored or facing a difficult problem
• Solutions to problems often come upon waking up
• Waking up from a nap with heightened awareness

Salvador Dali and Sleep

• Allegedly used a spoon on his nose to induce sleep and gain inspiration for his paintings
• Harnessing the dream state for creativity

Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves

• Co-​​authored with Ed Regis
• Encoded the book into DNA
• 70 billion copies made
• Launched an industry for digital encoding in DNA
• Recording physiological data in living organisms

Future Projects

• Dr. Church is working on another book, not a direct sequel to Regenesis but related to the field of synthetic biology