CRISPR takes the chemistry prize

For much of recorded human history, the origin and distinctions found in animal and plant species has been perplexing. Why are characteristics inheritable? How come some animals can cross-breed while others can’t? How do we improve our livestock or make hardier plants?

For thousands of years, farmers and herders improved their stock through the slow process of selectively breeding the best from one generation to produce the next. Cows got bigger. Horses got faster. Cobs of corn were grown from teosinte. Husbandry and botany were the tools for improving species. But why did this work?

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It took until the mid-1800s before a mechanism was finally proposed. Working for nearly a decade and growing over 5,000 pea plants the Augustinian friar Gregor Mendel was able to come up with a basic understanding of heredity: characteristics are unitary. They are discrete (i.e. purple vs white; tall vs dwarf) with nothing in between. Further, genetic characteristics have alternate forms with each inherited from one of the two parents. We now call these alleles, with one dominant which is reflected in the characteristics of the plant. And different characteristics or traits occur independently.

Mendel’s work was published in an obscure journal and remained relatively unknown until it was rediscovered in 1900. By 1925, scientists working on fruit flies had developed a model for genetics and the basic patterns of genetic inheritance were established. But what was the unit of heredity?

With a basic understanding of genetic inheritance, biologists turned to investigating the nature of the gene – the simplest unit of inheritability. Although it was originally thought the blueprints for life must be written in proteins, by the late 1940s and early 1950s scientists became convinced DNA was coded with the genes. Then, in 1953, Francis Crick and James Watson discovered the double helix. Over the next decade chemists subsequently cracked DNA’s code and biochemistry was born. The central dogma of biology emerged – from DNA we get RNA and from RNA we get protein.

By 1972, biochemists were able to map the complete genetic code of simple organisms and by the turn of the 20th century they had done the same for humans. With the advent of modern technology, we have a much more detailed and complete picture of the evolution of life and interconnectedness of all living creatures.

In 2002, Emmanuelle Charpentier started working at the University of Vienna where her research group focused on a bacteria, Streptococcus pyogenes, which infects millions of people every year. While it usually manifests as easily treatable infections such as tonsillitis and impetigo, it can also turn into flesh eating bacteria under the right circumstances. Charpentier was interested in how its genes were regulated as a way to deal with the organism.

In the meantime, Jennifer Doudna was leading a research group at the University of California-Berkeley, studying RNA and specifically RNA interference. For many years, researchers believed they understood the functional role of RNA but in 2006 they discovered small RNA molecules that help regulate gene activity in cells.

And around the same time, microbiologists had discovered repetitive DNA sequences in the genetic material of bacteria and archaea which are remarkably well conserved. The sequences appear over and over again between stretches of unique DNA – like sliding a piece of paper or multiple pieces of paper between the pages of a book.

They called these repeating sequences "clustered regularly interspaced short palindromic repeats" or CRISPR, for short. And the interesting thing is the non-repeating unique sequences – the pages – seem to match the genetic code of various viruses. They hypothesized these unique sequences represented the bacterial immune system where small strands of viral DNA encoded into the genome as a memory device. And the mechanism involved appeared to be similar to RNA interference.

When Charpentier’s research group mapped the CRISPR system in S. pyogenes, they already knew it required a single protein Cas9 to cleave viral DNA but they discovered an additional factor called trans-activating crispr RNA. And this lead to a meeting with Doudna in which the two research groups began collaborating. With a little effort, they were able to show CRISPR/Cas9 worked in a test tube by slicing up DNA very precisely. And with a little more tweaking, they had come up with a pair of molecular scissors which would allow them to cut out and replace any piece of DNA.

Essentially, CRISPR/Cas9 allows scientists to remove specific portions of a genome with atomic precision. It takes advantage of the mechanism already found in bacteria but modified into a powerful tool for genetic research. And possibly for medicine as it could be used to eliminate faulty genes and genetic damage thereby curing genetic-based diseases.

For their groundbreaking research and vision, Charpentier and Doudna were awarded the 2020 Nobel Prize in Chemistry for the development of a method for genome editing.

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