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> The Big Read

The Code Breaker

Walter Isaacson's book is heavy on the science as he chronicles Jennifer Doudna's Nobel Prize-winning discovery of the gene-editing tool CRISPR / BY Carolyn Abraham / March 16th, 2021


Ever since early humans discovered rocks as a bashing device, new tools have fueled the progress of our species – hammers, knives, fishhooks, the compass, the harness, duct tape.

These days, high-tech tools propel civilization. Computing power allows us to do almost anything from anywhere and, in the life sciences, it has revolutionized biology, allowing us to quickly crack and decipher the genetic code of virtually any organism, from the novel coronavirus to the three billion units of our own DNA.

In 2012, an astonishing new tool emerged that allowed us to go beyond reading genetic code to writing it with unprecedented ease, speed and precision. CRISPR, as it’s known for short, is like a pair of biochemical scissors that not only give humankind the capacity to redesign the world around us, but to redesign us.

Work is underway to use the gene-editing tool to delete genes from our DNA that cause disease, enhance those that might improve our health or extend life spans, and, for better or worse, create designer babies. Should the efforts bear fruit – and a few already have – CRISPR could enable us to genetically modify people and change the fate of our species forever.

Book cover, black and white photo of Jennifer Doudna

 

In his fascinating new book, The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, American author Walter Isaacson tackles this prospect head on in his exhaustive chronicle of how CRISPR came to be. On one hand, it’s a delightful story of pure curiosity. On the other, it’s a gripping account of the nasty scientific rivalries that fueled the race to develop it, and the battles that surround it still – patent disputes, debates about equitable access, and moral controversies that may never be resolved.

Most people, for instance, might agree that deleting genes for fatal conditions such as Huntington’s or sickle cell disease is a grand idea, but what about genes for deafness, blindness, or depression? Should tinkering with genes involved in intelligence, athleticism, height or weight stay on the table? And how much freedom should parents have in selecting the traits of their unborn children?

“Figuring out if and when to edit our genes will be one of the most consequential questions of the twenty-first century, so I thought it would be useful to understand how it’s done,” writes Isaacson, a professor of history at Tulane University and former chair of CNN and editor of Time magazine.

Women in the Lab

 

Isaacson tells the story through the life and work of Jennifer Doudna, the biochemist at the University of California, Berkeley who, together with French biologist Emmanuelle Charpentier, was awarded the 2020 Nobel Prize in Chemistry for their CRISPR discovery in 2012. Announced last October, the win made Doudna and Charpentier two of only seven women – out of 184 recipients – to receive a Nobel for chemistry since the prize was created in 1901.

Science has a long history of undervaluing and overlooking the achievements of women, an unfortunate tradition Isaacson explores in recounting the experience of British chemist Rosalind Franklin, who died at 37 without an aliquot of recognition for her key contribution to genetics.

Doudna, who grew up in Hilo, Hawaii, read all about Franklin when she was in sixth grade. Her father, a university professor, had given her a copy of The Double Helix, James Watson’s memoir about the 1953 discovery of the structure of DNA. In it, the notoriously indelicate Watson criticizes Franklin’s lack of lipstick and “dresses that showed all the imagination of English blue-stocking adolescents.” At the same time, he acknowledges the value of Franklin’s expertise in x-ray crystallography and the photographs it produced. One in particular, used without Franklin’s knowledge or permission, helped to unravel the mystery of DNA’s form, although Franklin received no credit. Watson, along with British biologist Francis Crick and Franklin’s boss Maurice Wilkins, shared the 1962 Nobel Prize in Physiology or Medicine.

To Doudna, Watson’s memoir read like a detective novel and inspired her to be that kind of detective. According to Isaacson, while she realized Watson’s treatment of Franklin had been condescending, it was an “eye-opener” that women could be scientists – in fact, great scientists.

After earning her doctorate at Harvard Medical School in 1989, Doudna focused her research on the chemistry and structural biology of molecules. Like Franklin, she sometimes used x-ray crystallography, where diffracted x-rays can reveal the shape of a protein or molecule in crystalized form. Doudna was specifically interested in RNA – ribonucleic acid – the molecular messenger that carries out the instructions encoded in DNA. At the time, it was a deliberate break from the DNA-focused herd. But she was determined to understand RNA as the molecule that orchestrates when, how and what proteins and enzymes a cell will make. It turned out to be just the kind of unusual expertise that would bring the CRISPR mystery to her lab door.

Decoding CRISPR

For several years, CRISPR had been a puzzling observation made by researchers who studied microbes, and Isaacson details the marvelous story of how it was first fully characterized by the Spanish microbiologist Francisco Mojica in 1993. While working on his thesis at the University of Alicante, Mojica liked to collect one-celled organisms from saltwater ponds while his family frolicked at the beach. In the genomes of archaea, which are similar to bacteria, Mojica spotted a series of identical DNA sequences repeated at regular intervals that read the same backwards and forwards. Since one-celled life forms don’t have code to waste, he assumed it must be important. Eventually, several bacterial species were found with these repeated stretches, which Mojica named “clustered regularly interspaced short palindromic repeats,” or CRISPR for short. But his eureka moment came with the realization that between these repeated sequences were stretches of genetic code that matched those belonging to viruses that attack the bacteria. It was like a catalog of mug shots. Mojica had stumbled on the fact that bacteria had an immune system, and that somehow CRISPR enabled them to ward off a viral invader.

In 2007, Mojica’s observation was confirmed by two researchers who worked for Danisco, a Danish food company that makes starter cultures for the fermentation of dairy products. Starter cultures for yogurts and cheese are big business, and the company invested heavily to find out how CRISPR might protect its bacterial assets from viral threats. With a historical record of bacterial strains dating back decades, Danisco’s researchers not only showed that CRISPR repels a virus, but that they could vaccinate bacteria against new infections by adding the genetic codes of novel viruses between the repeated sequences.

Even before the Danisco paper appeared in Science, Doudna was trying to figure out how CRISPR worked. A Berkeley colleague had called out of the blue in 2006 believing that the function of CRISPR involved RNA, Doudna’s specialty, so she and her team were investigating the enzymes CRISPR uses to cut up viruses. Then in 2011, Doudna met Charpentier at a conference in Puerto Rico, where the stylish Parisienne scientist, then working on CRISPR at Umea University in Sweden, suggested they collaborate to nail down the essential components of this uncanny bacterial immune system.

Together, the lab teams of Doudna and Charpentier eventually showed that, with the help of RNA and enzymes, how CRISPR acted like pre-programmed scissors, primed to track down and cut out the genetic code of whatever lay between the clustered repeats of DNA sequence. In their historic 2012 Science paper, they also identified the essential ingredients needed to adapt CRISPR for use as a tool to edit the genes of any life form. Over the next six months, five different labs demonstrated that it could indeed be done.

As Isaacson succinctly described it: “By studying a phenomenon that took a billion years of evolution to perfect in bacteria, they were able to turn nature’s miracle into a tool for humans.”

Taking Credit

The subjects of Isaacson’s earlier biographies, which include Albert Einstein, Steve Jobs, Henry Kissinger, and Leonardo DaVinci, are household names nearly as well known for their eccentricities or public personas as for their accomplishments. Doudna does not fit that prototype. But Isaacson’s portrayal makes it clear that the 57-year-old wife and mother of an 18-year-old son shares several traits in common with other notable achievers – curiosity, ambition, ingenuity, hyper focus, and an unabashed competitive streak.

 

Author Walter Isaacson, a history
Tulane University history professor Walter Isaacson has written biographies of Albert Einstein, Steve Jobs, Henry Kissinger and Leonardo DaVinci. Photo: Courtesy of Walter Isaacson

 

Isaacson writes that women in science tend to be shy about promoting themselves. He cites a 2019 study that examined six million articles in which women were listed as the principal authors and found they are less likely to use self-promotional terms such as “novel,” “unique,” or “unprecedented” to describe their findings. This trend was especially pronounced in the most prestigious journals, where women were 21 per cent less likely than men to use positive terms, and as a result, their work was cited 10 per cent less of than men. But, says Isaacson, Doudna does not fall into this trap, and works tenaciously to get her lab’s work published. Though it’s “not necessarily my nature,” Doudna says, “I’ve discovered that the journal editors favor people who are aggressive or pushy…” It’s an edge that served her well in the fierce race to turn CRISPR into a gene-editing tool.

In Isaacson’s even hands, the clash between the CRISPR scientists unfolds with more drama and suspense than one might expect of a science book. But The Code Breaker is at its thumping heart a book about science, often diving as deeply into the technical side as the human egos that make it go.

The competition centres around who deserves the most credit, by way of what are expected to be incredibly lucrative patents and prizes, for adapting CRISPR as a tool to edit human DNA. The main rivalry involves Doudna at Berkeley and Feng Zhang, a gene-editing researcher at the Massachusetts Institute of Technology’s Broad Institute, along with its influential founding director, geneticist Eric Lander, now science adviser to U.S. President Joe Biden.

Under Lander, Zhang published a paper proving CRISPR could be used in human cells before Doudna did. Yet Zhang and Lander’s application for a patent to lay claim to the gene-editing system in human cells was filed well after Doudna and Charpentier’s patent application was submitted. But MIT paid the U.S. Patent and Trademark Office an extra fee to fast track its review and in 2014, MIT was awarded the CRISPR patent. Berkeley went on to file an appeal that its researchers were in fact the first to invent CRISPR as an editing system – and the case has yet to be decided.

In the meantime, in 2016, Lander authored an 8,000-word article in the journal Cell, entitled, “The Heroes of CRISPR” that focused on Zhang and the contributions of others to the gene-editing field that belittled and downplayed the work of Doudna and Charpentier. Its publication provoked a firestorm of outrage among the world’s lab coats, including one Doudna ally who likened the piece to the work of “an evil genius.” Isaacson describes it as “history weaponized.” In the shadow of the injustice done to Rosalind Franklin, Isaacson notes that Lander’s narrative also read to some as yet another instance of a powerful man trying to write a woman out of scientific history.

A Pandemic Pause

If there’s a weakness in the book, it may be the length, specifically the final chapters on the potential applications of CRISPR in the global pandemic. Of course, there’s no questioning Isaacson’s inclination to do so. In 2020, COVID-19 brought a hard stop to most life science projects, including trials suggesting CRISPR may indeed be a cure for sickle cell disease and hereditary blindness. But the pandemic also heralded a pause in the raging patent battles over CRISPR, prompting Doudna and Zhang both to figure out how to use the editing tool to fight COVID.

In his epilogue, Isaacson touts the benefit of that pause, and the wisdom of moving slowly where CRISPR is concerned. Yet there will always be those in a rush to use the newfound power the technology provides. In 2018, the Chinese researcher He Jiankui announced he had gone rogue and created the world’s first gene-edited babies, two girls whose DNA he had tried to make resistant to the AIDS virus. In 2020 he was sentenced to three years in prison after Chinese officials deemed the scientific feat illegal.

In spite of the rebels to come, and regardless of what the patent courts decide or how the profits are divided up, at the end of the day a new era of questions loom now that we have in hand a tool enabling us to hijack our own evolution.

Carolyn Abraham is an award-winning science journalist and author of two books, Possessing Genius: The True Account of the Bizarre Odyssey of Einstein’s Brain and The Juggler’s Children: A Journey into Family, Legend and the Genes that Bind Us. 

The Code Breaker by Walter Isaacson was published March 9 by Simon & Schuster.

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