The reader who follows recent developments in genetics may often experience a feeling of vertigo. Consider as just one example the intellectually dizzying prospect on evolution opened by recent work in epigenetics—revealing among other things that some major steps in evolutionary history such as the evolution of placental mammals were not the result of cumulative random variations but, rather, were triggered suddenly by infectious viral DNA inserting itself into chromosomes.
Sam Sternberg and Jennifer Doudna’s new book on the sudden development of the CRISPRcas9 gene editing system renders the view more dizzying still, reflecting on “the maelstrom of naturally churning genomes”—from viral infections, mutations induced by radiation or chemicals, simple copying errors, and the thousand other insults the living genome is heir to. Given the potential for incredibly powerful, inexpensive gene editing using CRISPR, this prospect could become far more dizzying still in a very short time, from our own manipulation and alteration of genes’ contents—including human genes. It has already been used to edit specific, targeted genes in plants and animals, e.g., to produce meat animals with a lot of extra muscle development. Experiments on human embryos were already begun in China in 2015. Every citizen should read this book as soon as possible.
The authors reassure us that the effects of this new technology would be just adding “a droplet” to that already “churning maelstrom.” Yet the book also expresses some deep misgivings, particularly if CRISPR is used for human germline editing, creating heritable alterations that will be passed down to all subsequent generations of progeny. An alarming prospect and a mixed message, to be sure. And the book is clearly written to help a broad popular audience understand how CRISPR developed, as well as what ethical challenges it poses. So let’s step back and try to get an overview of the book and its contribution to public discussion of this new technology.
The CRISPRcas9 system is part of bacterial immune responses to protect themselves against attack by bacterial viruses. How it works only came to be well understood between 2007-2012 and Doudna’s lab at the University of California at Berkeley (where co-author Sam Sternberg was a grad student at that time) was one of fewer than a dozen centers in which most of the work to understand that system was done. A seminal paper published 28 June 2012—first pointing out that the system could be programmed for gene editing in any species—was co-authored by Doudna and by Emmanuelle Charpentier at Umeå University in Sweden. Since then, the field of using CRISPR to edit genes has exploded.
One thing we get from the CRISPR story is (e.g., pp. 60-61) an inspiring portrayal of how many dozens of researchers in many labs all over the world contributed pieces to solving the puzzle over a period of 25 years. Science as a vast collaborative enterprise comes through clearly—as does the potential for basic research on a topic as obscure as bacterial immune responses to suddenly, unexpectedly open the door to an applied technology with potential applications in everything from agriculture and meat production to medicine—gene editing might well cure genetic illnesses, or even prevent them via editing the genes in a human embryo before implantation via IVF.
In places the story of the discovery reminds us of how the entire history of modern microbiology, biochemistry and molecular biology (p. 54) has been bound up with industrial processes—biotechnologies—ever since Liebig and Pasteur, from the 1840s onward. Also of the astonishing range and interconnectivity of the modern global scientific enterprise—a salutary reminder at a time when President Trump, EPA Director Scott Pruitt and others misguidedly want to muzzle that enterprise or hamstring it, in a short-sighted view that doing so would be better for industry—especially the fossil fuel industries.
Not that the story is one of pure, pristine scientific curiosity, untainted by large amounts of money to be made. When the medical potential of the technique became clear, Doudna and others set up a biotech company to develop the potential applications. And within seven months of the publication of their paper first acknowledging CRISPR’s potential for gene editing, even in humans, a patent dispute arose between Douda/U.C. Berkeley and Feng Zhang at the Broad Institute/M.I.T. Zhang’s group had published in January 2013, and quickly filed for a patent, on application of the CRISPR technique specifically to eukaryotic cells. A Nobel Prize is certainly at stake here as well; those can be awarded to a maximum of three investigators, while at least four top players have been important.
In 2016, famous molecular biologist Eric Lander, affiliated with The Broad Institute, published a piece in the journal Cell (v. 164: 18-28) titled “The Heroes of CRISPR.” The article was a subtle, masterly narrative that appeared to give generous credit to Doudna and Charpentier, among a long list of others—thus subtly diluting the apparent importance of their contribution. While appearing “even-handed,” Lander’s piece unmistakably slanted the narrative, to make it appear that Zhang’s group had made the final, key contribution to turn CRISPR into a truly useable tool. However, an equally compelling argument can be made for Doudna and Charpentier. Indeed, the US Patent Office took quite awhile to resolve the dispute, only in Feb. 2016 finally ruling that Zhang’s patent would be granted and did not infringe on the broader patent on genetic engineering the Berkeley group was awarded. Lander’s influence and behind the scenes lobbying were seen by many—including most historians of science like myself—as unfairly putting a thumb on the scale. Lander was lambasted far and wide as “the villain of CRISPR” for his oh-so-clever attempt to slant the writing of the history, with both Nobel prize medals and patents worth many millions of dollars at stake.
This book was widely expected to be Doudna’s side of the story. Yet because she chose to address it first and foremost to educate a broad public audience about CRISPR and to get them to think hard about all the ethically murky possibilities it has suddenly thrust upon us as a society, Doudna’s story is not especially effective as a detailed contribution to the history. It serves the public education purpose very well indeed. As I stated earlier, every citizen should read it and think hard about what germline gene editing in human embryos may portend.
Sternberg and Doudna lay out ethical challenges of biotechnology that are relevant to evaluating the new CRISPR challenges. They discuss GMO food organisms, for example, chastising a segment of the public for failing to accept the scientific evidence that these do not harm human health. She gives short shrift here to ecological arguments: that the pollen from GMOs drifting on the wind and cross-pollinating other crops is an ecological experiment on a large scale whose impact has been far too little studied. Similarly, this problem causes economic chaos for organic farms near fields planted with GMO crops. These authors are deeply troubled by human hubris when it comes to germline editing. Used to thinking inside test tubes or individual organisms, they do not seem to fully appreciate the havoc on a much larger, ecological scale that we might be toying with in our supreme techno-optimism.
In early sections of the book, they address ethical problems in a vague, journalistic style: (e.g., p, xvi) “Should we begin editing genes in unborn children to lower their lifetime risk of heart disease, Alzheimer’s, diabetes, or cancer?” Many books and articles on such topics pose questions this way but then offer no guidelines or evidence to help answer the question. Such a writing style is pretty unhelpful. Fortunately, by pp. 222-240, this book finally moves beyond this style and begins to lay out relevant ethical differences between different kinds of gene editing experiments and to make a clear argument: Given certain safeguards, use of gene editing for existing humans with genetic diseases will certainly meet or surpass the ethical standards that have guided most of medicine. About germline editing, the situation is more complicated. The authors show clearly that the “it’s not natural” argument is bogus. But they do not in the end convince this reviewer the risks of human hubris are not greater than evolution’s own tinkering power. Their discussion is quite helpful in teasing out many ethically meaningful distinctions; however, their reasoning doesn’t always persuade. On p. 234, for example, they state “Governments are not simply going to begin forcing parents to edit their children’s genes….Unless we’re talking about coercive governments controlling their citizens’ procreative liberty, germline editing would remain a private decision for individual parents to make for their own children, not a decision for bureaucrats to make for the population at large.” They are naively underestimating the strength, even today, of e.g., the anti-abortion movement, which is daily helping bureaucrats in a majority of U.S. states deprive women and couples of reproductive choices. If Supreme Court Justices are counted among such bureaucrats, the degree of potential government intrusion into reproductive freedoms is higher still. Mandatory motherhood is an urgent goal for a large part of the U.S. population.
Then there is the health insurance industry and its ability to affect people’s choices about reproductive matters based on prices. Precisely because CRISPR is so potent a tool, we need to think very carefully about “upside risks”: unintentional changes to our society that may be harmful, resulting from the fact that human gene editing, even germline editing in embryos, is now very close to reality. As a society we might not be happy if this leads to increased pressures to alter babies, in order to keep down insurance premiums for all. We almost certainly would feel it was a massive price to pay, if the use of CRISPR widens the gap between rich and poor—a trend already accelerating in our society in many other ways in the past 30 years. It is hard to imagine in the current widening gap, the feasibility of the requirements they think essential: “so long as the methods are safe and offered in an equitable manner.” A final problem their analysis needs to consider: We are beset by pressing preventable health crises like the opioid epidemic, diet- and exercise-related obesity (and the attendant high blood pressure, diabetes, etc.), under-treated chronic diseases– rheumatoid arthritis, kidney disease, cardiovascular disease. Given this, how can a rational allocation of limited medical resources possibly conclude that more lives would be saved, more quality of life maintained, and more lost worktime and productivity prevented by investing resources in high-tech gene editing rather than using those same limited resources to address these less sexy, but much more urgent problems?
My disagreements with some of the authors’ conclusions do not change the fact that this book is a desperately needed, effective attempt by scientists to help educate the broad public about an urgent new technology, while there’s still time for a public discussion to help shape the uses to which it is about to be put.
A Crack in Creation: The New Power to Control Evolution is published by The Bodley Head. The book is available in the U.S. with the title A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, published by Houghton Mifflin Harcourt. Visit the book’s website for more information.