To find the origin of life, Szostak and Doudna began studying RNA and how it could replicate itself.
RNA, not DNA:
When Doudna’s lab rotation ended in the spring of 1986, she asked Jack Szostak if she could continue doing doctoral research under his direction.
Szostak agrees, but adds a word of caution. He will no longer focus on DNA in yeast. While other biochemists were excited about DNA sequencing for the Human Genome Project, he decided to turn his lab’s attention to RNA, which he believed could reveal the secret to human health. The greatest of all biological mysteries: the origin of life.
He told Doudna he was intrigued by the discoveries Cech and Altman had made about how certain RNAs had the catalytic power of enzymes. His goal was to determine whether these ribozymes could use this power to reproduce.
“Does this piece of RNA have the chemical parts to replicate itself?” he asked. He thought that should be the focus of her doctoral thesis.
She was infected by Szostak’s enthusiasm and signed up to become the first graduate student in his lab to study RNA. “When we were taught biology, we learned about the structure and code of DNA, and we learned about how proteins do all the heavy work in cells, and RNA is considered the dull middleman, like a middle manager.
I was quite surprised to learn that there was a young genius, Jack Szostak, at Harvard, who wanted to focus 100% on RNA because he thought it was the key to understanding the origin of life.”
For both Szostak, who was already established, and Doudna, who had not yet shifted her focus to RNA, it was a risk. “Instead of following the herd in DNA research,” Szostak recalls, “we felt we were pioneering something new, exploring a frontier that people had somewhat ignored, but all of us Everyone thought it was very interesting.” This was long before RNA was considered a technology that interfered with gene expression or made edits to human genes. Szostak and Doudna pursued this topic simply out of curiosity about how nature works.
Szostak has one consistent rule: Never do what thousands of others are doing. That appealed to Doudna. She said:
“It’s like when I’m on the football field and want to play a position that other kids don’t play. I learned from Jack that there is more risk but also more reward if you venture into a new field.”
By this time, she knew that the most important clue to understanding natural phenomena was to find out the structure of the molecules involved. That required her to learn some of the techniques that Watson, Crick and Franklin used to elucidate the structure of DNA. If she and Szostak succeed, it could be an important step in answering one of the biggest of all biological questions, perhaps the biggest: How did life begin?
Origin of life
Szostak’s excitement about understanding how life began taught Doudna a second big lesson, beyond taking risks by moving into new fields: Ask big questions. Although Szostak liked to delve into the details of his experiments, he was also a great thinker, one who relentlessly pursued truly profound insights.
He asked Doudna: “What other reason is there to do science?” That was the question that became one of her own guiding principles.
There are some truly great questions that our mortal minds may never be able to answer: How did the universe begin? Why is there something rather than nothing? What is consciousness? Some other questions that could be conquered by the end of this century: Is the universe deterministic? Do we have free will? Among the really big problems, the question we are closest to solving is probably how life began.
The central tenets of biology require the presence of DNA, RNA, and proteins. Because it is unlikely that all three emerged from the primordial stew at the same time, a hypothesis arose in the early 1960s – independently elaborated by the renowned Francis Crick and others – that there was a simpler predecessor system.
Crick’s hypothesis is that very early in Earth’s history, RNA was able to replicate itself. That raises the question of where the first RNA came from. Some speculate it came from outer space. But the simpler answer might be that the early Earth contained the chemical building blocks of RNA, and it didn’t require anything other than randomly mixing them together. The year Doudna joined Szostak’s lab, biochemist Walter Gilbert called this hypothesis “the RNA world.”
An essential characteristic of living things is that they have a method for creating more organisms similar to themselves: reproduction. Therefore, if you want to make the argument that RNA could have been the precursor molecule to the origin of life, it would be useful to show how it can replicate itself. This is the project that Szostak and Doudna embarked on.
Doudna used a variety of strategies to create an RNA enzyme, or ribozyme, that could splice small pieces of RNA together. Ultimately, she and Szostak were able to create a ribozyme that could splice a copy of itself. She and Szostak talked about this in a 1998 article in Nature. Biochemist Richard Lifton later called the paper a “technical tour de force.”
Doudna has become a rising star in the rare field of RNA research. That remained somewhat of a backwater in the biological world, but over the next two decades, an understanding of how small strands of RNA worked became increasingly important, even for the field of gene editing. and the fight against coronavirus.