The Code Breaker: Jennifer Doudna and the Race to Understand Our Genetic Code by Walter Isaacson with Sarah Durand

Jennifer Doudna was born on February 19, 1964 in Washington, D.C., the oldest of three girls. Her father dreamed of becoming a professor of American literature. To achieve this dream, he earned a Ph.D. and eventually was offered a job at the University of Hawai'i at Hilo. Doudna's family moved to the islands in 1971 when she was seven-years-old.

Doudna, who was often called a "haole", a derogatory term for non-Native Hawaiians, felt lonely and uncomfortable in her new home. But things changed for the better when her family moved out of Hilo and into a new development on the slopes of the Mauna Loa volcano. In the smaller school, Doudna felt less like an outsider and began to thrive. She skipped grade 5 and made a new friend in Lisa Hinkley whose boldness to be herself, encouraged Doudna.

As Doudna and Hinkley explored the sugar cane fields, the meadows, and lava-flow caves, she became intrigued by the many wonders of nature she discovered: a spider with no eyes, a thorny vine called hilahila or "sleeping grass". Two important people fostered Doudna's curiosity: a family friend and biology professor named Don Hemmes, and her father. Hemmes showed Doudna the different fungi he was studying, while her father, an avid reader gave Doudna a copy of The Double Helix by James D. Watson. This book, which explained how Watson and Frances Crick discovered the double helix structure of DNA, was inspiring to Doudna. Their story made Doudna realize that science could be fun and be used to uncover the secrets of the natural world. But the treatment of Rosalind Franklin, a  woman structural biologist whose significant contribution to Watson and Crick's work went unrecognized, made her aware that although women could become great scientists, they might not see their contributions acknowledged in the same way as male scientists.

In 1981, Doudna attended Pomona College in Claremont, California, studying chemistry and went on to do graduate work at Harvard in 1985. As part of her lab rotation, Doudna studied with Roberto Kolter, head of the graduate studies program, and with Jack Szostak, a molecular biologist studying yeast DNA.  As a Ph.D. student, Doudna worked on the structure of  RNA. In 1991, Doudna and her husband Tom Griffin moved to Boulder, Colorado where she did her postdoctoral work with structural biologist Thomas Cech. It was Cech who shared the Nobel Prize for discovering ribozymes. Griffin and Doudna eventually divorced. 

At this time, Doudna was determined to uncover the three-dimensional structure of RNA, hoping to uncover how "...its twists and folds bring atoms together and cause reactions that allow the RNA to replicate." In 1993, Doudna accepted a job at Yale as a professor where she continued her research on determining the structure of RNA. Accompanying her to Yale, was Jamie Cate, with whom she would eventually marry in 2000 and have a son Andrew in 2002. In the fall of 1995, while visiting her terminally ill father, Doudna received a map that revealed the structure of of a specific RNA molecule's three-dimensional shape. "The structure Doudna and her team had discovered explained how RNA could be an enzyme and be able to slice, connect, and copy itself." Doudna and Cate published their discovery: this was Doudna's first major scientific success.

It would be a chance discovery by a Spanish graduate student, Francisco Mojica at the University of Alicante that would change everything. In an organism called archaea that are similar to bacteria, Mojica discovered fourteen identical DNA sequences that were repeated at regular intervals. Other researchers also made similar discoveries in other bacteria. Mojica coined the term CRISPR - "clustered regularly interspersed short palindromic repeats" for this sequence. He soon discovered "...that CRISPR was a type of immune system" that bacteria had evolved in their battle against bacteriophages or viruses that attack them. They could also pass this immunity onto their offspring by incorporating some of the virus's genetic material. Soon researchers discovered specific CRISPR associated enzymes - called Cas which were able to insert bits of the virus's DNA into the bacteria's DNA. 

Doudna became involved in this research because she was an expert in RNA interference - at this time the mechanism believed to be at work here. Doudna wanted to find out what CRISPR was made of and try to understand how it worked. It was this path that would uncover the most amazing discoveries and lead to a future not only with the potential to heal but also the potential for abuse. But for Doudna personally, it would snag her science's most coveted prize - the Nobel Prize!

Discussion

The Code Breaker is a biography of Nobel-prizing winning structural biologist, Jennifer Doudna. Her journey from an insecure young girl who saw herself as an outsider to a world expert on the structure of RNA molecules and the gene-editing tool CRISPR and ultimately a Nobel Prize winner is inspiring. Isaacson focuses on the people and events in Doudna's early life that helped her transition from loner to team player, from a child curious about the natural world to accomplished scientist. Like so many women scientists before her, it was the influence of her father that set Doudna on the path to becoming a scientist.

But The Code Breaker is also the story of scientists in a race to decode RNA molecular structure and in the process discovering a powerful tool that may allow us to change our genetic makeup in ways we cannot yet comprehend.

The Code Breaker is divided into seven parts with the first four parts focused on Doudna's education as well as explaining the detailed science of the molecular research Doudna and other scientists were involved in during the 1990's and 2000's, including the discovery of CRISPR. Parts Five and Six deal with CRISPR babies and the events surrounding Chinese biologist He Jiankui who created three CRISPR babies in defiance of international protocols against editing genes in human embryos. Part Six explores the moral questions a new technology like gene-editing pose, especially since there is the potential for these tools to be used in very questionable ways. Part Seven explores the efforts Doudna and other scientists made during the Covid-19 pandemic in using CRISPR to create fast, efficient testing.

It is Isaacson's discussion of the ethical questions that gene-editing poses that is probably the most interesting aspect of this biography. Almost immediately after Doudna-Charpentier published their groundbreaking paper on the structure and working of CRISPR-Cas9 in June of 2012,  Doudna began to have serious reservations about its potential for misuse. As it turned out, she was right to be worried. In 2018, a young, ambitious Chinese scientist, He Jiankui, used CRISPR-Cas9 to edit the CCR5 gene in three viable human embryos, which were then brought to term. This was done in defiance of agreed but unenforceable international protocols against germline editing of human embryos. The moral and ethical dilemmas were now real.

Isaacson spends considerable effort discussing Jiankui's research, the moral and bioethical questions gene-editing raises, as well as Doudna's efforts to determine where and when CRISPR ought to be used. However, Isaacson, at times uses euphemistic terms that frequently bog down modern bioethical discussions, preventing a discussion of the real issues. 

At times the ethical issues are framed from a perspective that tends to ignore the ongoing serious, moral and ethical questions that continue to be unresolved for technologies that have been used for decades. For example, Isaacson relates that Doudna's teenage son seemed unconcerned about the moral issues regarding gene-editing. Isaacson writes that Doudna, wondered "if history will treat germline editing like IVF, which was very controversial when it first happened." However, there are many, many ongoing bioethical and moral issues, decades on, regarding the use of  IVF, despite the large number of people using the procedure. For example, there are over one million frozen IVF embryos in the United States alone and there is no consensus as to what to do with them. The IVF industry is largely unregulated and there are countless stories about the mix-ups in labs of embryos, of questionable parentage and botched creation of embryos. IVF is also not without serious risks to women, to the children born using this procedure and has a success rate of  only thirty percent. There is also considerable evidence that an immoral IVF-surrogacy industry in poorer nations, exploiting poor women, has developed. There are also increasing issues with donor semen being used in IVF procedures, creating large numbers of half-siblings and the risk of possible inter-marriage. To compare future gene-editing to the way IVF has developed, is to realize that there will likely be many unforeseen problems and abuses. In fact, IVF proceeded without the resolution of many of these issues, and it's likely gene-editing will too.

In another example, Isaacson uses the phrase "fertilized eggs", an inaccurate term since these are not "eggs" but now human blastocysts or zygotes. They are not simply biological cells but nascent human beings.  In his discussion of preimplantation genetic diagnosis Isaacson writes, "A couple who knows they carry the gene (for Huntington's) could decide to have a baby through IVF in order to screen their embryos for the disease. If the parents can produce enough fertilized eggs, the ones with Huntington's can be eliminated." The term "eliminated" is a euphemism for allowing a very young human embryo to die simply because it has a disease. PGD is a process of creating large numbers of human embryos (a problem previously mentioned) in order to find the ones that are perfect (i.e. do not have Huntington's disease.) This "solution" is a form of eugenics, in which weaker/sicker humans are murdered to "improve" the human race.  Accurate terminology is essential when having these serious ethical discussions, so there is clarity and honesty about what is being proposed and what the issues truly are. 

Isaacson goes on to state that "In making a gene edit to eliminate Huntington's, nothing is changed except the bad mutation. You won't change the gene for eye color, for example." He goes on to question where a gene edit like this should be allowed because it is so targeted. Yet in an earlier chapter  about the events surrounding He Jiankui's attempt to edit the CCR5 protein responsible in HIV in twin embryos, Isaacson mentions that Jiankui's paper revealed that in the twin named Lulu, "only one of the two relevant chromosomes had been properly modified" and that "....there was evidence that some unwanted edits had been made in the embryos." It would seem that in undertaking gene-editing, much is unknown, and that CRISPR-Cas9 may cause unwanted edits or additions that are unknown. There is also the ethics of doing what is largely experimentation on human beings who are not able to give their consent. To this date, not much is known about the twins Lulu and Nana, their health or what exactly those edits are.

In the chapter, Regulating Gene Editing, the author works through a number of interesting scenarios, posing questions and leaving the reader to consider these situations, as well as suggesting when gene-editing might be permissible. The following chapter also explores Doudna's own personal journey as she struggles to determine under what conditions gene-editing should be allowed. 

In the Epilogue, the authors include black and white photographs of some of the important scientists in this story, and a visual of how CRISPR works. There is a detailed Glossary of terms as well as a large Notes section for sources from each chapter.

The Code Breaker is definitely a book for older readers, mainly because of the complex science described in the book and the ethical questions that need to be considered and answered before scientists move forward with CRISPR. It is adapted from the nonfiction book of the same title, written for adult readers. In The Code Breaker, Isaacson and Durand have crafted an engaging account of cutting-edge molecular biology research that has the potential to impact the future of humanity. It is told from a very personal perspective - that of Jennifer Doudna, a remarkable and brilliant woman scientist. It also demonstrates that a career in science not only possible for women, but personally fulfilling with the possibility now of actually having one's accomplishments recognized.

Book Details:

The Code Breaker: Jennifer Doudna and the Race to Understand Our Genetic Code by Walter Isaacson with Sarah Durand
New York: Simon and Schuster Books for Young Readers      2021

320 pp.