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Creation Story

By: Michael M. Rosen
November 27, 2017

ne small step for humans, one giant leap for humankind.” Thus did University of California biochemist Jennifer Doudna assess the revolutionary gene editing technique she helped invent: CRISPR—“clustered regularly interspaced short palindromic repeats.” By using CRISPR to correct a gene abnormality in a fertilized embryo, researchers edged closer to curing hypertrophic cardiomyopathy, which can trigger sudden death in young athletes.

In A Crack in Creation, Doudna and her laboratory collaborator Samuel Sternberg tell CRISPR’s genesis and evolution story, which promises to fundamentally reshape the way we think about disease and genetic enhancement, while raising profound ethical issues along the way. Scientists are now able to use biotechnology tools to tinker with and manipulate the DNA inside living cells. With CRISPR, the genome—an organism’s entire DNA content, including all its genes—has become “almost as editable as a simple piece of text…This process is far simpler and more effective than any other gene-manipulation technology in existence.”

In their generously-illustrated retelling of CRISPR’s creation story, Doudna and Sternberg provide a helpfully-explained but never condescending lesson in genetic engineering’s evolution. Beginning in the 1960s, researchers focused on introducing viruses carrying genes that conferred certain benefits into human hosts. But this gene therapy, as it came to be called, encountered implementation difficulties and sometimes-fatal side-effects. Others employed “gene targeting,” which involved mixing DNA solutions in the laboratory and physically squirting them onto cells.

CRISPR, however, works differently. Unique genetic sequences inside bacterial cells—the palindromic repeats—match similar sequences in aggressive viruses and therefore serve as the bacteria’s natural defense against such viral invasions. Doudna and her team discovered a CRISPR-associated sequence—known as Cas9—adjacent to the repeats that includes RNA (the messenger-and-transcription equivalent of DNA) molecules, which in turn locate specific DNA targets within virtually any cell. Once the CRISPR-Cas9 combination finds a particular DNA location—say, a dangerously mutated section—it can cut the helix in the appropriate spot and fill the gap with a “corrected” version of the relevant gene. Unlike earlier gene therapies, CRISPR doesn’t involve the introduction of any foreign DNA, so the potential side-effects are substantially diminished.

Scientific discovery often results as much from happy circumstance as from laboratory diligence, and Doudna’s serendipitous encounters with key scholars like Berkeley professor Jillian Banfield and Emmanuelle Charpentier, a French scholar with her own lab in Sweden, stoked her interest in CRISPR and triggered her key breakthrough, respectively.

Her dramatic “aha!” moment arrived in June 2012, when, while preparing dinner, with “visions of this tiny machine danc[ing] in my head,” she felt “pure joy, the joy of discovery” and marveled at “how incredible [it is] that bacteria had found a way to program a warrior protein to seek and destroy viral DNA…and how miraculous, how fortunate, that we could repurpose this fundamental property for an entirely different use.”

CRISPR’s power is immense. “Armed with the complete CRISPR toolkit,” Doudna and Sternberg observe breathlessly, “scientists can now exert nearly complete control over both the composition of the genome and its output…[T]he pace of further tool development isn’t slowing down…It often feels like the genome-engineering applications made possible by CRISPR are limited only by our collective imagination.”

The authors explore both the technology’s boundless potential and concomitant ethical challenges. CRISPR has the power to reshape cancer and genetic disease treatments, and improve food production, eradicate certain pathogens, and even resurrect extinct species through animal and plant genome manipulation. If misinformed GMO opponents can be held at bay, the prospects for tastier, hardier, longer-lasting produce, not to mention farming livestock and fish with a smaller environmental footprint, are nearly limitless. The authors remain hopeful that CRISPR-engineered food organisms may not even be considered “genetically modified” because they don’t require the introduction of any foreign DNA.

Other promising CRISPR applications include genetically enhancing laboratory animals, “xenotransplantation,” or organ farming in animals for transplanting into humans, and bygone species like the auroch, the saddleback tortoise, the great auk, the Pyrenean ibex, and even the woolly mammoth’s reintroduction. The extermination of destructive species, like malaria-transmitting mosquitoes, is also possible.

Perhaps most importantly, CRISPR has sharply elevated the prospects for curing cancer, HIV, and other genetic diseases. But with the Promethean power to eradicate pests and disease, to resurrect bygone species, and to enhance existing ones, comes the weighty burden of using this groundbreaking technology responsibly. Here, one must consider the lengthy history of regulatory and ethical arguments over genetic engineering, including gender-selection in embryonic pre-implantation genetic diagnosis, mitochondrial replacement therapy, and so-called “savior siblings.”

The dilemma is especially pronounced in CRISPR precisely because the technology is so much simpler and more accessible than its predecessors. And Doudna is ecumenical in identifying those she believes should contribute to the broader discussion about how to use these tools ethically. “I wanted to ensure that the discussion involved not only researchers and bioethicists,” she writes, “but also a great range of stakeholders, including social scientists, policy-makers, faith leaders, regulators, and members of the public.”

Initially, she came down on the side of temporarily “refrain[ing] from attempting to make heritable changes to the human genome.” It’s one thing to relieve human suffering by curing disease, but it’s quite another to experiment with eradicating it entirely from our genetic material, at least in part because thence lies the path to eugenics.

Using CRISPR to eliminate genetic diseases is less ethically troubling than using it to enhance the genome through fostering genetic mutations that confer athletic endurance, leaner muscles, and reduced sleeping requirements, for example. And while the line between the two can occasionally blur, it still represents a helpful ethical demarcation.

 

Doudna plainly has deeply internalized these dilemmas—she recounts a disturbing dream in which Hitler himself seeks her input on potential CRISPR applications—and she’s unafraid to reveal her inner turmoil. She has helped convene symposia populated by diverse participants dedicated to developing a coherent response to these challenges. And while laying down appropriate ethical and technological boundaries will always remain controversial, Doudna and company have begun to draw the map.

One key legal issue is soft-pedaled in the book, perhaps understandably: Doudna and Steinberg allude briefly to “a dispute over CRISPR patent rights” involving professors Feng Zhang and George Church of the Broad Institute (a joint venture between MIT and Harvard), whom she characterizes as “innovators of gene-editing technology.” In fact, Berkeley and Broad have waged a battle royale over competing inventive rights to CRISPR and its applications, with Zhang and Church claiming to have beat Doudna and Charpentier to the punch in successfully using CRISPR on human cells. What may result is the requirement that companies license both technologies, which may complicate their commercialization. “They have a patent on green tennis balls. We [likely] will have a patent on all tennis balls,” Doudna told the media following a February 2017 patent court ruling. “I don’t think it really makes sense.” (Elsewhere in the book, Doudna is characteristically gracious to both Church and Zhang, praising their original research.)

In addition, the book’s unusual collaborative style can sometimes be jarring: the cover bears two authors’ names, but the story is written in the first-person singular, tracing the trajectory of Doudna’s discoveries. Sternberg plays an important role in an interesting side story about CRISPR’s potential human-embryo-engineering outgrowth, but otherwise appears to be a glorified ghost writer; his prominent place as a co-author seems out of place.

And at times, their ethical analysis lapses into platitudes, like when they muse that “weighing the dangers inherent in a technology like CRISPR against the responsibility to use its power for the benefit of humanity and our planet will be a test like no other. Yet it’s one that we must pass.” The reader, unfortunately, is occasionally left wondering how exactly we may pass this test. While the authors offer a thoughtful analysis of the trade-offs involved in human genetic engineering, the arguments they advance regarding plant and animal species lack the same rigor, often boiling down to the rhetorical question: Can we honestly afford not to do this?

But these superficial flaws hardly mar the stunning tableau the authors have painted, let alone the staggering research they illustrate. Doudna’s pioneering work already appears to be changing the world, with the pace of discovery only accelerating. The CRISPR creation story she and Sternberg have written is an engrossing preview of what’s to come.