• “Our newfound ability to make edits to our genes raises some fascinating questions. Should we edit our species to make us less susceptible to deadly viruses? What a wonderful boon that would be! Right? Should we use gene editing to eliminate dreaded disorders, such as Huntington's, sickle-cell anemia, and cystic fibrosis? That sounds good, too. And what about deafness or blindness? Or being short? Or depressed? Hmmm. How should we think about that? A few decades from now, if it becomes possible and safe, should we allow parents to enhance the IQ and muscles of their kids? Should we let them decide eye color? Skin color? Height?” These are the types of slippery slope questions we’ll face with the advent of CRISPR gene editing technology - intro

The Double Helix

• We begin in the small town of Hilo, on Hawaii’s Big Island, where Jennifer Doudna grew up feeling out of place and isolated at school - she wasn’t one of the native Hawaiians, so she’d often immerse herself more in books or try to fit in
• “Doudna's father was a voracious reader… Often he would bring home a book, either from the library or the local secondhand bookstore, for her to read. And that is how a used paperback copy of James Watson's The Double Helix ended up on her bed one day when she was in sixth grade, waiting for her when she got home from school.” → The book merges the world of science and discovering DNA with gossip and flirting flare, sparking Doudna’s early interest in science and helping her believe women could become scientists!
• “It sparked the realization that it was possible to peel back the layers of nature's beauty and discover, as she says, "how and why things worked at the most fundamental and inner level." Life was made up of molecules. The chemical components and structure of these molecules governed what they would do.”
• Before we get into Doudna’s work in genetics, let’s run through a quick refresher course on the history of genes and dna

The Evolution of Genes & DNA

• “The realization that species evolve through mutations and natural selection left a big question to be answered: What was the mechanism? How could a beneficial variation in the beak of a finch or the neck of a giraffe occur, and then how could it get passed along to future generations? Darvin thought that organisms might have tiny particles that contained hereditary information, and he speculated that the information from a male and female blended together in an embryo. But he soon realized, as did others, that this would mean that any new beneficial trait would be diluted over generations rather than be passed along intact.” → Gregor Mendel, in his breeding studies with peas, discovered that certain hereditary traits could be more dominant or recessive, and that unit of heredity was the gene with DNA showing what makes you unique
• James Watson & Francis Crick discovered DNA in the early 50s, using work by Rosaline Franklin to fully understand the role they play in our genetic makeup → Doudna was inspired by Rosalind Franklin and although she constantly received resistance to her dream of being a scientist, she continued to pursue it nonetheless by attending Pomona College for chemistry
• The Human Genome Project taught us how to read thousands of disease-causing DNA mutations, but $3B later and it didn’t have a cure for any of them… that is what Doudna was attempting to solve → “Accomplishing the goal of being able to write as well as to read human genes required a shift in focus from DNA to its less famous sibling that actually carries out its coded instructions.” (The focus would be RNA, the molecule that actually does real work like creating proteins or fighting Covid)

Never Do Something That a Thousand Other People Are Doing

• Doudna decided to focus her doctoral research on the question of catalyst enzymes sparking chemical reactions and RNA → “For both Szostak, who was well established, and Doudna, who wasn't, switching to a focus on RNA was risky. "Instead of following the herd doing DNA," Szostak recalled, "we felt we were pioneering something new, exploring a frontier that was a little bit neglected but we all thought was exciting." This was long before RNA was being considered as a technology to interfere with gene expression or deliver edits to human genes. Szostak and Doudna pursued the subject out of pure curiosity about how nature works. Szostak had a guiding principle: Never do something that a thousand other people are doing. That appealed to Doudna” (amazing advice that applies to both entrepreneurship and investing, where we’ve seen companies like HBO and Trader Joe’s and LEGO lean into their uniqueness to win and value investors like Buffett buy companies when public enthusiasm was at all time lows)
• They were trying to understand how RNA ribozymes self replicate, and decided to do so they’d need to run towards the hardest problems: “She realized that in order to understand the workings of a self-splicing piece of RNA, she would have to fully discern its structure, atom by atom. "At that time, RNA structure was viewed as so difficult that it was maybe impossible to figure out," Szostak recalled. "Hardly anyone was trying anymore." → She kept asking herself: how did life begin? Could it have been from one of these self-splicing RNA molecules??

Taking After Her Role Model

• Sadly her father passed away just as she made a key discovery in the scientific world, uncovering the structure of RNA: “Just as the double-helix structure of DNA revealed how it could store and transmit genetic information, the structure discovered by Doudna and her team explained how the RNA could be an enzyme and was able to slice, splice, and replicate itself.” - why is this important?? - "One possibility is that we might be able to cure or treat people who have genetic defects."
• Doudna next started to study RNA interference, which is a process where small molecules go searching around for messenger RNA and slice them up, effectively silencing their instructions