8 March 2018

The dread and the awe: Crispr’s inventor assesses her creation

Sonia Ben Ouagrham-GormleySaskia Popescu

Sonia Ben Ouagrham-Gormley

Sonia Ben Ouagrham-Gormley is an associate professor in the Schar School of Policy and Government’s biodefense program, at George Mason University, and the author of Barriers to Bioweapons:...

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Saskia Popescu

Saskia Popescu is a doctoral candidate in biodefense at George Mason University and an infectious disease epidemiologist with a focus on hospital infection prevention. She has previously written...

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A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, by Jennifer Doudna and Samuel H. Sternberg, Houghton Mifflin Harcourt, New York, 2017, 304 pp., $28.00, ISBN 978-0-54471-694-0

Modern Prometheus: Editing the Human Genome with Crispr-Cas9, by James Kozubek, Cambridge University Press, Cambridge, United Kingdom, 2016, 440 pp., $26.99, ISBN 978-1-107-17216-6

A Crack in Creation is a book about awe—the awe an inventor feels when she surveys the new possibilities that her invention has enabled. It is also a book about dread—the dread the inventor feels when she contemplates potential misuse and abuse of her invention. It is partly a memoir. It is partly an appeal for public engagement in the debate over the revolutionary gene-editing technology known as Crispr-Cas9.

The Berkeley biochemist Jennifer Doudna is best known for having transformed Crispr-Cas9—a bacterial curiosity when it was discovered in the late 1980s—into a tool that can edit genes in any organism. Doudna’s discovery, achieved with the help of French colleague Emmanuelle Charpentier, has propelled her to prominence. It has created a world of potential new advances in medicine, agriculture, science, technology, and environmental stewardship. Yet these potential advances are sometimes overshadowed by the multitude of security, safety, and ethical risks that Crispr-Cas9 poses.

Doudna became aware of this paradox soon after publishing the seminal 2012 article that announced her discovery. She was surprised and delighted by the technology’s rapid spread and its use in a variety of fields, yet some applications—such as the use of Crispr to edit human embryos, as performed for the first time by Chinese scientists in 2015—made her uneasy about the future of the technology. Unscrupulous individuals’ interest in using Crispr for pure profit made her uneasy as well.

Doudna recounts the story of a female entrepreneur who attempted to enroll Sam Sternberg— Doudna’s former doctoral student, and co-author of the book—in a business venture to produce “Crispr babies” with “customized DNA mutations.” This served as a wake-up call for Doudna. She felt the need to bring risks such as these to public attention so that decision making about Crispr’s future applications would not remain the sole privilege of scientists and regulators. An open and public debate about Crispr, Doudna argues, is the only way to prevent the “lack of information or the spread of misinformation about germline editing” from getting in the way of beneficial Crispr applications.

Although A Crack in Creation is a personal history of Crispr, it also ably describes the key stages of Crispr’s development: its pre-history (Crispr was first observed in 1987), its modern history (starting with an article, published by Rodolphe Barrangou in 2007, which demonstrated experimentally that Crispr was indeed part of the bacterial immune system), and its current era (the discovery of multiple Crispr systems, organized into five groups, and their applications in a dizzying set of projects ranging from plant and animal engineering to the study of disease processes to the development of therapies for scourges such as cancer or HIV).

Doudna emphasizes an important theme that often gets lost in media coverage of gene-editing technology: Scientific knowledge is the result of a cumulative and collaborative process in which one scientist’s work builds on the findings of those who came before, as well as on contemporary findings. Discoveries therefore have their roots in work produced by a community of scientists—a community that feeds an eventual discoverer’s ideas and nurtures them to maturity. Doudna, to her credit, emphasizes that her own work was built on the scaffolding of important earlier studies. She conscientiously recognizes the work of her doctoral students and post-docs, who did much of the laboratory footwork that led to the development of the Crispr-Cas9 tool. Deserving particular credit is Martin Jinek, a Czech post-doc who had the idea of fusing the two RNA that compose the Crispr-Cas9 system into a single guide RNA. This technique transformed Crispr-Cas9 into a simpler gene-editing system and contributed to its rapid democratization.

Doudna feels a responsibility to alert the public about Crispr’s furious developments because her laboratory provided practicing and amateur scientists a powerful tool with which they can experiment—and do so in environments where few (or no) regulatory or safety rules protect the public. In Chapter 5 of her book, Doudna reviews the Pandora’s box of research that Cripsr-Cas9 has unleashed—and attempts to provide a framework for thinking about which kinds of work are beneficial and which are potentially harmful. “Essential” applications would include work poised to benefit health and advance medical research; improve food production; and help the environment. “Non-essential” applications would include apparently frivolous endeavors such as creating pet pigs and performing genetic enhancements. The proposed framework, however, quickly falls apart—as Doudna acknowledges—when confronted with potential tensions between scientific research and cultural and societal preferences.

For example, thanks to Crispr, behavioral and cognitive impairment can now be more easily studied using primates as human models. But does experimentation with primates cross an ethical line or (as in the view of these reviewers) create a security problem if it results in modeling that can support bioweapons development? Similarly, while Crispr could potentially relieve food shortages by improving plant resistance to diseases, will the public view resulting foods as genetically modified organisms and reject them in spite of their apparent value? These are questions with no obvious answers; hence, the importance of an informed and engaged public. Doudna has her own preferences. For example, she hopes that gene-edited livestock can make agriculture not just more profitable but more humane and environmentally friendly. But Crispr scientists should be prepared for the possibility that what they view as beneficial might be viewed as harmful by the public, and thus rejected.

Tough to use. Another important theme in Doudna’s book is that Crispr is still under development—and though the technology carries substantial promise, numerous limitations and challenges mean that clinical use is still far away. To begin with, Crispr cannot easily be used to treat any disease. It has potential as a good treatment solution for monogenetic diseases—that is, diseases such as sickle cell disease or cystic fibrosis, which are caused by a single gene mutation. Still, the challenge is to deliver the Crispr system to the affected organ. For blood disorders such as sickle cell, the disease-causing gene can be edited ex vivo (outside the body) and re-injected in the patient; healthy cells will proliferate and (hopefully) come to outnumber sickled cells. In 2016, US researchers showed that this could be achieved in the laboratory, and they are now planning to start clinical trials with actual patients. But for mutations that affect tissue, not blood—cystic fibrosis is an example—the editing must be performed in vivo (directly in the patient’s body) because organ tissue cannot be safely extracted and returned to a patient. Researchers are currently exploring various delivery mechanisms, but they haven’t yet found a safe way to ferry the Crispr system into affected tissue without causing immune reactions or unwanted mutations.

Diseases caused by multiple mutations present an even greater challenge for Crispr. This is because researchers must first figure out which of the gene mutation(s) is essential to causing the disease. For these diseases, which include cancer, Crispr can still be useful in understanding the disease process, and via multiplex studies that edit several genes at once, researchers could someday pinpoint the essential disease-causing mutation(s) and find therapies. Chinese scientists are already testing some of their ideas in trials involving human cancer patients.

In an otherwise interesting book, Doudna goes wrong in a couple of regards. First, when she discusses off-target effects—that is, unwanted mutations that can cause harm and potentially death—she commits a sin of omission. The message one takes from her book is that off-target effects are indeed a nuisance, but that they can be predicted using various algorithms developed for that purpose. The scientific literature on off-target effects, however, paints a different picture. Multiple unwanted mutations, together with insertions and deletions of genes, have been observed in laboratory studies involving Crispr, and much current research aims to explain the sources of and find solutions for these off-target effects. For example, in May 2017, a group of US researchers found that Crispr corrected a gene that causes blindness in mice—but it also generated over 1,000 unwanted mutations. Current algorithms used to predict the location of such off-target effects are not very accurate and miss many mutations. Typically, off-target effects can be more accurately detected if whole genomes are sequenced. But scientists usually limit their sequencing to sites predicted by algorithms, and thereby miss many unwanted alterations.

Doudna, like other Crispr scientists, notes that many drugs also cause off-target effects—commonly known in that context as side effects—and argues, therefore, that off-target effects should not disqualify Crispr’s use in the clinical field. But there’s a distinction: Side effects usually subside when the drug causing them is discontinued, while unwanted mutations caused by Crispr are permanent. To be sure, Crispr scientists including Doudna are aware of the importance of off-target effects, and are working toward gaining some level of control over them. But because Doudna’s book aims to engage and inform the public, a more candid discussion of this major challenge would have been helpful.

Second, Doudna at times uses unfortunate language when describing Crispr, often referring to it as a “weapons system.” Amid concerns over the technology’s potential for harm, descriptions of this sort do not help Crispr’s cause.

That said, A Crack in Creation is a book that will appeal to and usefully inform the general public. While better editing (no pun intended) might have eliminated the occasional repetition, the language is approachable, and Doudna has a knack for finding the right analogies to describe in simple terms the complex machinery and operation of Crispr. Academics and researchers interested in science and technology will also find in this book a good illustration of current debates about scientists and their responsibility for their discoveries.

Tangents and insights. In contrast, Jim Kozubek’s Modern Prometheus takes a more technical approach to understanding Crispr and assessing what the technology means for the future of genome editing and humanity as a whole. Kozubek, a computational biologist and freelance writer, provides a holistic history of the discovery of Crispr-Cas9—necessary if one is to understand the well-publicized patent dispute involving Doudna’s laboratory at Berkeley and Feng Zhang’s Broad Institute laboratory. Kozubek has held an affiliation with the Broad Institute—and though he takes care to include comments from major players in the Crispr-Cas9 community and communicate their stances on the future of the technology itself, germline editing, and the patent war, readers might find that his account seems at times to favor the Broad Institute, particularly in the section that discusses the patent battle.

That said, the book covers a lot of ground. Kozubek discusses the capabilities and limitations of Crispr-Cas9 and identifies a spectrum of pros and cons for its use. He addresses the broad questions about science and human well-being that advances such as Crispr pose. He ponders the power of genetic manipulation as a gateway to the dehumanization of medicine and the objectification of human beings. Kozubek draws comparisons with “Jurassic Park” and Mary Shelley’s Frankenstein to pose larger questions about genetic engineering—and also to point out that, though people are fascinated with technological advances, they often neglect to consider technologies’ implications, notably on people themselves. Indeed, humanity sometimes seems emotionally and ethically unable to keep up with technological progress.

One of the strengths of Modern Prometheus is its emphasis on the challenges that Crsipr-Cas9 faces: the unpredictability of biology and the limitations of Crispr-Cas9 itself. Kozubek points out that while Crispr-Cas9 makes genome editing easier and more accessible, the complexities of genetic changes and relationships make achieving desired outcomes an unpredictable and elusive pursuit. Ultimately, because genetic changes occur so frequently even without editing, introducing an edited gene into the human body might have effects that can’t be predicted.

Two aspects of the book are unexpectedly honest and therefore to be appreciated: a discussion of the business side of science and another of the sexist environment within both STEM research and academia. Kozubek points to the patent battle over Crispr-Cas9, and to conversations about marketing this new technology, as a recent example of how businesslike the world of science has become. Kozubek also discusses published accounts of Crispr’s development in which Doudna and Charpentier are treated like secondary characters—despite their centrality to the field. With greater attention now being brought to the poor treatment of women in the STEM fields and academia, this discussion is increasingly relevant.

Modern Prometheus is, to use a term Kozubek favors, a leviathan of a book. It bounces from the development of genome editing to the technology’s implications and back to its true limitations. Meanwhile, the author often dives so far into the technical aspects of gene editing that it is easy to feel disconnected. For readers to survive this text, it is critical that they possess some knowledge of biology and genetics. They must also be prepared for tangents and rabbit holes.

Kozubek devotes significant attention to the ethical debates surrounding Crispr-Cas9, but he mostly presents the views of major figures in the development of the technology and in the industry that surrounds it; he writes little about individuals in the biosecurity world who, increasingly, are part of such debates. And though Kozubek discusses Crispr-related controversies throughout the book, he concentrates the debate on oversight, regulation, and proposed moratoriums in a single chapter at the end. Genome editing’s prohibitive cost as a medical treatment is another issue that deserves more attention than it receives in Modern Prometheus. Overall, the book could have benefited from more intensive editing and better organization. The author’s propensity to go off on tangents, and his habit of comparing the gene-editing debate to episodes in the literary classics, feel forced and disjointed—making an already technical book that much harder to enjoy.

This is a book best reserved for academics and for policy makers who focus on science and technology. Its technical nature, along with the author’s Jackson Pollock–like approach to discussing the debate over genome editing, will inhibit the general public from enjoying it. Despite these shortcomings, Kozubek’s book provides a timely overview of the latest discussions around Crispr-Cas9 and includes insights from individuals working in the genome “trenches.” Kozubek’s clear dedication to the field, and his engagement with the ethical complexities of the Crispr-Cas9 debate, make Modern Prometheus a must-read for science and technology experts who wish to strengthen their understanding of a fascinating technology and the lively debate surrounding it.