As the managing editor of The CRISPR Journal, I consider myself to be a science communicator. When not wrapping up my PhD in Rodolphe Barrangou’s lab, I work to promote science education in hopes of furthering the dialogue on genome editing. However, none of my efforts come close to achieving what filmmaker Adam Bolt has done with his documentary, Human Nature.
Recently our lab was treated to a screening of the film at the Annual Full Frame Documentary Film Festival in Durham, NC. The crowd was visibly excited for the sold-out screening. The movie features some of the biggest names in the CRISPR community, including Jennifer Doudna, Feng Zhang, and George Church: pioneers in the field, experts in the technology, and just downright interesting people. But what makes this film truly compelling is its balance. All of the narratives from these scientific heavy hitters were coupled with engaging, relatable accounts and stories from bioethicists, a genetic counselor, and most importantly, the patients and their families.
The case for Cas9
At Stanford University’s Lucile Packard Children’s Hospital, we are introduced to David Sanchez. David is a plucky teenager who likes to play basketball with his friends. David also has sickle cell disease (SCD), meaning he possesses an A-to-T point mutation in the b-globin gene, which causes his red blood cells to collapse, requiring frequent hospital visits, blood transfusions, and probably a reduced lifespan. The audience cared for David immediately. He is not a statistic, or a datapoint: He is a sick child and you want nothing more than to help him. For a long time, we did not have the tools to fix that single base, explains Matthew Porteus, a physician-scientist at Stanford; in fact, that single letter is what makes SCD especially challenging. Conventional gene therapies are a bit of a crapshoot. Gene insertions are random and can even be dangerous if the gene inserts into the wrong location.
This all changed with the “immortal” 2012 Doudna-Charpentier Science paper,1 as genome editing pioneer Fyodor Urnov describes it. As a biochemist, Jennifer Doudna says she only intended to develop a tool for the lab but is acutely aware that what her group helped create is something that “fundamentally allows us to change our relationship with nature.” Suddenly a CRISPR-based clinical trial for SCD—something that could help David—is a real possibility.
A cluster of scientists
More than two decades ago, the unusual repetitive sequences of CRISPR were first observed in archaea by Spanish microbiologist Francisco Mojica.2 It’s ironic that CRISPR is named for its repeats, considering it’s the intervening spacer sequences that are truly fascinating. Mojica jokingly exclaims, “Where the hell did these sequences come from?” That knowledge would not become apparent for a decade—when the yogurt company, Danisco, took interest. Rodolphe Barrangou recounted his time in industry, where he and colleagues demonstrated the function of these spacer sequences in bacterial adaptive immunity,3 and began exploiting them to create phage-resistant yogurt starter cultures.
But what really changed the game was when Jill Banfield, a microbial researcher at University of California Berkeley, informed her colleague, Jennifer Doudna, of these unique gene features—a fact she hopes will one day be emblazoned on her gravestone. Today, CRISPR genome editing is virtually ubiquitous in research laboratories around the globe. Stanford University Law professor, Hank Greely, compares CRISPR-based genome editing to the Model T—although there were predecessors, Ford made the car both cheap and reliable so that suddenly everyone could own one. CRISPR is the new PCR, and companies such as California-based Synthego are helping to enable broader access to this technology. However, on camera, Synthego made sure to emphasize that they “don’t ship to just anyone.” Evidently, biohackers and rogue scientists (the He Jiankui controversy broke too recently to be included in the film) are a growing concern.
As the genome editing field advances, Urnov cautions, people will be able to change their genetic makeup. The film explores two extremes of this issue: curing the human race of genetic disease and building a Hitleresque master race. We already know genes that can increase muscle mass, decrease the need for sleep, and even eliminate pain. Urnov foresees the usage of gene editing to eliminate pain associated with late-stage cancer, but what about enhancing special forces soldiers to make them immune to torture? This fine line is poised to be one of the major ethical debates of our generation. It’s hard not to be enthusiastic about the prospect of guaranteeing your child good health, but where do we stop? Of course we want to eradicate diseases, but what about hair or eye color? Height? Intelligence? And something that’s on all scientists’ minds right now: editing out the diseases of future generations. In 2015, a commentary aptly titled, “Don’t edit the human germ line,” was published in Nature.4 The authors, including Urnov and former Sangamo CEO, Ed Lanphier, stated that “genome editing in human embryos using current technologies could have unpredictable effects on future generations.” Because of this, its usage on sperm or eggs is “dangerous and ethically unacceptable.”
Although we are not in a place to manipulate future generations given our lack of knowledge of so many things, at the current rate of scientific progress it’s probably only a matter of when, not if. One of my favorite scenes in the film was when David, the SCD patient, is presented with this conundrum. Considering how young he is, and also how sick, his response is very thought-provoking. David believes it should be the choice of the child. In fact, he states, “I don’t think I’d be me if I didn’t have sickle cell.”
What makes the cut?
In addition to the human genome, the film also explores CRISPR applications in plants and animals (though to a much lesser degree). A biotech startup co-founded by George Church, eGenesis Bio, is using CRISPR to create humanized pigs to minimize organ transplant rejections. Despite being a vegan, Church says he supports this new venture in pig breeding because he understands just how many lives this technology could save—and it’s a “drop in the bucket compared to bacon.” Another media-friendly Church undertaking, the Woolly Mammoth project, seeks to create a woolly mammoth population with the ultimate goal of ecosystem restoration. This was of course coupled with the classic Jurassic Park quote from fictional mathematician Ian Malcom: “Your scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.” The film underscores that, unlike Jurassic Park, this project is motivated by environmental restoration, not profit. Similarly, the agriculture company Syngenta is trying to combat climate change and feed the growing human population by engineering drought-resistant crops. The scenes filmed in their greenhouses were both unbelievably futuristic and strikingly beautiful. Overall, I was disappointed by the lack of coverage on the benefits of genome editing in agriculture, although considering the title of the film, it might have been slightly out of scope—something to consider for the sequel, perhaps?
After the screening at the Full Frame festival, director Adam Bolt, Barrangou, and Syngenta executive, Ian Jepson, answered questions from the audience. Bolt had a reasonable response when asked why he chose not to discuss the pivotal CRISPR patent battle:5 “Right now we are talking about the patent, but in 10 to 15 years we will talk about what the technology has done.” That really is the underlying theme of his film: How can we take a tool and repurpose it to help people? That said, Urnov takes solace in the fact that the things that make us most human are also the most complex. We are nowhere near a point of engineering traits such as love or creativity. We may be able to change our genomes, but perhaps not so much our human nature.
1. Jinek M, Chylinski K, Fonfara I, et al. A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science 2012;337:816–821. DOI: 10.1126/science.1225829. Crossref, Medline, Google Scholar
2. Mojica FJM, Juez G, Rodriguez-Valera F. Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites. Mol Microbiol 1993;9:613–621. DOI: 10.1111/j.1365-2958.1993.tb01721.x. Crossref, Medline, Google Scholar
3. Barrangou R, Fremaux C, Deveau H, et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 2007;315:1709–1712. DOI: 10.1126/science.1138140. Crossref, Medline, Google Scholar
4. Lanphier E, Urnov F, Haecker SE, et al. Don’t edit the human germ line. Nature 2015;519:410–411. DOI: 10.1038/519410a. Crossref, Medline, Google Scholar
5. Sherkow JS. The CRISPR patent landscape: Past, present, and future. CRISPR J 2018;1:5–9. DOI: 10.1089/crispr.2017.0013. Link, Google Scholar
6. Hajian R. et al. Detection of unamplified target genes via CRISPR–Cas9 immobilized on a graphene field-effect transistor. Nat. Biomed. Eng. 2019; (Published online March 25, 2019. DOI: 10.1038/s41551-019-0371-x
Courtney Klotz is the managing editor of The CRISPR Journal and a newly minted PhD in the Barrangou lab at North Carolina State University.
*Human Nature is a documentary from director Adam Bolt and executive producers Dan Rather and Elliot Kirchner that explores CRISPR’s far-reaching implications in science, medicine, and agriculture—our entire relationship with nature This article is reprinted with permission of The CRISPR Journal, published by Mary Ann Liebert, Inc., Volume 2, Issue 2, April 2019.