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#077 Rewriting Genomes To Eradicate Disease & Aging With Dr. George Church | Found My Fitness

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Key Takeaways

  • CRISPR is a subset of editing; editing is a subset of genome engineering; genome engineering is gene therapy
  • “Shrinking our agricultural use, possibly by 10 or 100 fold is feasible to do with synthetic biology and other new tools.” – Dr. George Church
  • Advances in reading and writing DNA double at least once per year; most of the exponential increase has occurred in the last 10-20 years
  • Cons of synthetic biology: lack of equity in access to technology and treatments; head in the sand approach to new technologies – FDA does not review; ethical considerations
  • Preventive medicine in genetics: genetic counseling preconception would be helpful to understand the future of offspring (as opposed to spending millions over a lifetime in gene therapy if disease is present)
  • Aging studies in dogs (as opposed to rodents) are good parallel to outcomes in humans because they’re large, live in human environments, have similar emotions, and bonding
  • “What’s natural is a moving target – a lot of things that were demonized or villainized in the past are now taken for granted, for example, some of us might remember how cell phones with were demonized as melting your brain or getting radiation to your brain.” – Dr. George Church
  • Gene editing therapy has the potential to reduce medical load, improve agriculture, alleviate some poverty burden (if there’s less disease), eliminate disease animal-human transmission, eliminate or reduce germline disease
  • There is no way to have zero risk – status quo is risky, but we should start small in animal studies and then progress to human studies

Introduction

George Church, Ph.D. (@geochurch) is a professor of genetics at Harvard Medical School and of health sciences and technology at both Harvard and the Massachusetts Institute of Technology. Dr. Church played an instrumental role in the Human Genome Project and is widely recognized as one of the premier scientists in the fields of gene editing technology and synthetic biology. 

In this episode of Found My Fitness, Rhonda Patrick and George Church discuss the history of the Human Genome Project, the potential of genome editing to eradicate disease and aging, and ethical considerations.

Host: Dr. Rhonda Patrick (@foundmyfitness)

Background On Genome & Biology

  • Genome sequencing under NIH started in 1990 with a 15-year goal of technology development and full DNA sequencing
  • We need more reference genomes and population variation
  • Genome comparisons support completeness and new tool discovery
  • Shortcomings of biology tools: they doesn’t eloquently use periodic table or chemistry; doesn’t thoroughly utilize physics
  • Biology’s successes: anatomically precise; can reproducibly make molecules with extreme precision; replicate with high fidelity
  • The genome is often described as a human instruction manual
  • No full human genome has been sequenced – 92% is the closest we’ve gotten of a haploid cell
  • Why bother writing the genome: to understand how something works and create new technology, we need to understand how to write and edit
  • The goal of writing genome or chromosome: (1) there are advantages to changing so many genes(as opposed to one offs), you might as well write the whole thing (for example, change genetic code to become resistant to all viruses); (2) bring back physiology and formerly extinct traits; (3) being able to make human stem cells (for therapeutic purpose); (4) creating industrial microorganisms, plants and animals that are important to ecosystems and agriculture

Vertebrate Genome Project

  • The vertebrate genome project is the wish to sequence the entire biosphere
  • Vertebrates are usually keystone species in environments
  • Ripple effect of rewilding projects (like restoring wolves to Yellowstone): reintroducing animals to wild settings for restoration of the ecosystem – in Yellowstone the abundance of herbivores changed which changed the abundance of willows and trees, then beavers who built lakes, and so on
  • We’re causing the extinction of many species but also the creation of new species
  • We need to document, freeze, and protect what’s already there

Computer-Aided Design Of Genomes

  • Biology as software allows for accelerated evolution because you can make billions or trillions of sequences to see which works best
  • The genome consists of 1% of codes for proteins; alpha fold is focused mostly on proteins
  • Folding or proteins can be predicted or measured – synthetic biology allows you to explore the effects of changing the shape in addition to the structure to see what function is affected
  • Alpha fold: machine learning system that predicts protein’s 3D structure from amino acid sequence  
  • It’s more practical to study the functional consequences of substituting proteins

Gene Editing Tools

  • CRISPR is a subset of editing; editing is a subset of genome engineering; genome engineering is gene therapy
  • The use of gene therapy and editing is very expensive – millions of dollars per person over a lifetime 
  • Preventive medicine in genetics: genetic counseling preconception would be helpful to understand the future of offspring
  • Revolutionary impact of CRISPR: brought public awareness to reading and writing genome and synthetic biology
  • Nuance of CRISPR: you can’t edit if you can’t read – the big revolution is reading the genome
  • Editing methods like homologous recombination predate CRISPR
  • CRISPR was originally designed to eliminate bacterial viruses
  • Limitations of CRISPR: tends to be imprecise and small in scope; must get the right dose to the right person at the right time
  • The first completely recoded genome was done in a combination of sequence-specific amplified polymorphisms (SSAPs) and recombinases
  • New technology: deaminases can be don’t with or without CRISPR

Gene Editing To Eliminate Disease Transmission From Animals To Humans

  • Many viruses originate from raising livestock in captivity
  • Endogenous retroviruses have been eliminated from the pig genome
  • FDA is supportive of eliminating viruses from animal germline
  • If editing genetic code can make plants, animals, and humans resistant to present and future zoonotic diseases, that would handle all natural viruses  

Gene Editing & New Technology For Aging

  • Hypothesis: if you can target the core of genes of aging, you can reset the age clock
  • Yamanaka factor: take old cells and turn them into cells with characteristics of young cells
  • Blood studies in animals: old blood makes young animals old; young blood makes old animals young
  • Schools of thought: (1) fix damage; (2) epigenetic: if you can convince the cell it’s young, it’ll fix itself
  • We probably need to set all marks of aging, in all tissue types (or stem cells), in the whole body to have a shot at youthfulness and absence of age-related disease
  • Aging studies in dogs (as opposed to rodents) are good parallel to outcomes in humans because they’re large, live in human environments, have similar emotions, and bonding
  • Rodent studies have their place – because lifespan is shorter, you can easily see longevity effects and reversal of age-related diseases quicker
  • Gene editing studies are ongoing to make cells more resistant (relative to the norm) to Alzheimer’s disease
  • PCSK9 therapy provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream – an example of a widespread gene editing medication used at the population level

Addressing Germline Mutations

  • There’s a major double standard with germline engineering – you can radically change in one setting but not another
  • “What’s natural is a moving target – a lot of things that were demonized or villainized in the past are now taken for granted, for example, some of us might remember how cell phones with were demonized as melting your brain or getting radiation to your brain.” – Dr. George Church
  • Because of a 2016 ruling, FDA doesn’t review most germline synthetic biology studies  
  • Books, movies, and television could be helpful in opening a public dialogue
  • Multiplex editing could become inherited instead of passing mutation In-vitro fertilization (IVF)was demonized and now is mainstream
  • If it was needed, the number of embryos from IVF could jump because of the ability to epigenetically reprogram cell lines to become pluripotent stem cells which can become eggs

Understanding Unknown

  • Synthetic biology is not unique – there’s social hesitancy for new things (e.g., cell phones frying the brain)
  • There is no way to have zero risk – the status quo is risky, but we should start small in animal studies and then progress to human studies
  • There’s no such thing as “perfect” no matter what you’re talking about; trade-offs depend on the environment
  • The best science can do is give people a choice
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Notes By Maryann

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