January 28, 2016 — Very few technologies truly merit the epithet “game changer” — but a new genetic engineering tool known as CRISPR-Cas9 is one of them. Since we first developed the ability to alter the genetic material inside a plant or animal in the 1970s, efforts to do so have required weeks, months or even years of molecular tinkering. With CRISPR (the technology’s shorthand name), precision and speed have soared.
“In the past, it was a student’s entire Ph.D. thesis to change one gene,” Bruce Conklin, a geneticist at the Gladstone Institutes in San Francisco, recently told The New York Times. “CRISPR just knocked that out of the park.”
The tool is also extremely versatile and seems to work in nearly every creature and cell type in which it has been tried. In the words of Jill Wildonger of the University of Wisconsin–Madison, “It really opens up the genome of virtually every organism that’s been sequenced to be edited and engineered.”
And that, when it comes to agriculture and the environment, is both its promise and its peril. CRISPR opens the door to all kinds of potential food production improvements. But improvements for whom? Farmers? Consumers? Agribusiness? Sustainable farming systems? Industrial agriculture? And who will decide?
If we want to make sure this powerful technology promotes just and sustainable food, we’ll need to accompany its development with a policy framework that reflects the nuances of its biology and its diverse applications — and that responds to the concerns of people who are affected when technologies migrate from lab to land.
CRISPR as a gene-editing tool has a complex origin story, with researchers in California and Massachusetts waging a patent war over its innovation, while recent stories tell of independent discoveries at Vilnius University in Lithuania. For our purposes, I’ll focus on what happened here at the University of California, Berkeley where in 2011, Jennifer Doudna, a biochemist and molecular biologist, and Emmanuelle Charpentier, a microbiologist now at the Max Planck Institute for Infection Biology in Germany, grew intrigued by the way many bacteria respond to viral invasions. The microbes, it turns out, have an uncanny ability: They store DNA from invading viruses in a sort of genetic library called CRISPR. If the same virus should attack again, the bacteria can use CRISPR to mobilize an enzyme called Cas9 to cut up the intruder’s corresponding DNA.
In 2012 Doudna and colleagues realized it would be at least theoretically possible to adapt the CRISPR-Cas9 complex so it could function not just in microbes, but in other organisms too — from fungi to plants to people. And by providing their own “guide,” they could effectively steer Cas9 to cut those organisms’ DNA in any spot they wished (see illustrated sidebar: “How CRISPR works”).
They soon succeeded in developing a programmable version of CRISPR. And reporting in a 2014 Science paper, Doudna and Charpentier sketched the contours of its transformative potential: “These results highlight a new era in which genomic manipulation is no longer a bottleneck to experiments, paving the way toward fundamental discoveries in biology, with applications in all branches of biotechnology, as well as strategies for human therapeutics.”
CRISPR can also be used to introduce new genetic material, providing a big boost to an emerging technology known as “gene drive.”These diverse applications are made possible by the many types of editing CRISPR enables. CRISPR can make precise mutations by substituting existing DNA sequences with desired ones. It can disable whole genes by snipping them out or via imprecise repairs that knock out gene function. The Cas9 enzyme itself can be manipulated to enhance or suppress gene expression — a powerful way of controlling genes without any editing, per se.
CRISPR can also be used to introduce new genetic material, providing a big boost to an emerging technology known as “gene drive.” Gene drives work by “selfishly” promoting the likelihood of their inheritance, accelerating the spread of a modified gene throughout an entire population (a great graphic here). Theorized since the 1940s as a technique that might offer unprecedented control over insectborne diseases, gene drives didn’t become viable until CRISPR came along. In late 2015, biologists at the University of California, Irvine and the University of California, San Diego reported the first working version in lab mosquitoes. If released into the wild, such CRISPR-edited insects could offer a way to tackle pernicious global health problems including malaria, dengue fever, sleeping sickness, yellow fever, West Nile virus and Lyme disease. Crop diseases and pests are also now in gene drives’ crosshairs.
In sum, shifting CRISPR from its native bacteria into a widely applicable programmable tool was more than a technical coup. As Doudna told The New York Times, it was at this moment that “the project went from being ‘This is cool, this is wonky’ to ‘Whoa, this could be transformative.’”
CRISPR on the Farm
Few will argue against using CRISPR in controlled laboratory environments to induce cancer in T-cell lines for drug development, to build better mouse models, to study what goes on inside plant cells as they fight invasions from bacteria or fungi. But pure science can’t be smoothly carved away from real-world applications. How will we deal with prospects for editing the genes of organisms in living environments?
In the realm of agriculture, that’s no longer hypothetical.
Since its 2013 demonstration as a genome editing tool in Arabidopsis and tobacco — two widely used laboratory plants — CRISPR has been road-tested in crops, including wheat, rice, soybeans, potatoes, sorghum, oranges and tomatoes. By the end of 2014, a flood of research into agricultural uses for CRISPR included a spectrum of applications, from boosting crop resistance to pests to reducing the toll of livestock disease.
Reports suggest that an entire barnyard of edited animals destined for industrial agriculture is rapidly filling the R&D pipeline.Chinese scientists, for example, reported creating a strain of wheat that is resistant to powdery mildew, a destructive fungal disease. DuPont is currently collaborating with Doudna’s company, Caribou Biosciences, to grow corn and wheat strains edited for drought resistance, with market prospects slated for 5 to 10 years and field trials set to begin in spring 2016.
Meanwhile, the first commercially available gene edited crop — produced using not CRISPR but another form of gene editing known as RTDS — has already appeared: an oilseed rape created by Cibus, a San Diego–based company. The rape has been altered for herbicide resistance, enabling farmers to spray their crop with weed killer. According to Nature, Cibus is marketing the product as non–genetically modified, since only a few snippets of the plant’s existing genes have been changed and “no gene has been inserted from a different kind of organism, nor even from another plant.” Even though RTDS is a different system than CRISPR, the similarities are sufficient enough that identical policy and regulatory questions apply to both.
At the Roslin Institute in Scotland, a unique CRISPR experiment is underway in pigs. In sub-Saharan Africa and Eastern Europe, a hemorrhagic virus that causes African swine fever sweeps through pig populations, devastating small farms. Some warthogs, however, seem mostly unaffected by the illness, and a research team led by biotechnologist Bruce Whitelaw believes that a gene called RELA, which varies slightly between wild and domesticated pigs, might account for the immunity difference. Using CRISPR, the researchers have recently tweaked domesticated pig genes to achieve the exact warthog RELA sequence. Trials began last summer exposing modified piglets to the virus to test if they are indeed immune.
Reports suggest that an entire barnyard of edited animals destined for industrial agriculture is rapidly filling the R&D pipeline. Recombinetics, a start-up firm, made headlines with hornless dairy cattle carrying a smidgen of genes from naturally smooth-headed beef cows. The company is now working on Brazilian beef cattle with larger muscles (for more meat, which may be more tender), while other firms are developing chickens that only produce female offspring (for egg-laying) and beef cattle that only produce males (for more efficient feed-to-meat conversion).
With respect to gene drives, while agriculture remains at the periphery thus far, researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering have outlined heady prospects. Gene drives could “pave the way toward sustainable agriculture,” they suggest, by reversing pesticide resistance in insects and herbicide resistance in weeds. Drive systems could also destroy or modify pesky plant pests and squelch populations of invasive species, such as rats and kudzu.
Improvement — With Concerns
Both journalists and the scientists they interview have largely framed agricultural uses of CRISPR as an improvement over conventional breeding and conventional genetic engineering alike, because it offers subtlety, speed and a high degree of control over the outcome.
A CRISPR-tweaked farm system could have a smaller environmental footprint and even humanitarian benefits, if it means farmers don’t have to dehorn cattle or cull their male bulls.“It’s like a find-replace function in the genome of these animals,” Scott Fahrenkrug, CEO of Recombinetics, told The New York Times. “You can change even a single base pair, or you can delete a gene very precisely,” Pamela Ronald, a geneticist at the University of California, Davis explained in Nature. The resulting animals and plants could potentially yield more food with less pressure on inputs such as water and land. A CRISPR-tweaked farm system could have a smaller environmental footprint and even humanitarian benefits, if it means farmers don’t have to dehorn cattle or cull their male bulls.
But others have questioned the “precision” part of precision breeding. Charles Benbrook of the Center for Sustaining Agriculture and Natural Resources at Washington State University points to the unexpected effects when new genes are added or existing ones are silenced. CRISPR is also known for making unintended edits, though the frequency of such “off-target effects” is falling.
And even with the increased precision, there’s no guarantee of the desirable outcome. Traits such as drought tolerance not only are associated with many genes, but also are subject to complex environmental interactions: How much the gene functions will depend on precipitation, heat, the nature and depth of soils, and so forth. Moreover, the genetic background of each individual species or crop will also influence the behavior of genes.
“So in many cases,” says Doug Gurian-Sherman, a plant pathologist and director of sustainable agriculture at the Center for Food Safety, “the particular genes used will only work well in certain genetic backgrounds and environments.” If we want to design agriculture for local ecosystems, suited to the specific soils, climates and cultivation practices of local people, editing is at best a partial solution.
Whose benefits are being considered when we dream of what CRISPR can do?A separate concern — already visible with the pigs snuffling around the Roslin Institute — is lack of an overarching sustainability or justice directive for genomic agricultural science. As Nature aptly noted, while Whitelaw’s pig project will largely benefit poor farmers, this is “a rarity for editing research.” A much more common goal in livestock editing has been to generate higher-profit cattle, pigs and sheep — the familiar trappings of industrial food with its concomitant implications for small, sustainable farmers. Whose benefits are being considered when we dream of what CRISPR can do?
Not those of complex ecological systems, it appears. As mentioned above, among the agricultural applications of CRISPR in the research pipeline are those that would alter the biology of insects and weeds — in some cases, editing genes to overcome resistance to pesticides and herbicides. CRISPR-assisted gene drive technology could propel such mutations through populations in the wild, creating the potential to modify entire plant or animal communities over just a few years.
It’s a curious vision of sustainable agriculture, though, that sees overcoming resistance to agrochemicals as progress. Should we really be enabling farmers to spray more glyphosate into their fields when the World Health Organization has found the chemical to be a “probable” carcinogen and when it’s been associated with collapsing populations of monarch butterflies? And using gene drives to snuff out wild organisms because they carry diseases or nibble on crops could have serious unintended consequences, such as destabilizing food webs and facilitating invasions by other species.
When it comes to animal engineering, we can appreciate the greenhouse gas–reduction benefits of better feed-to-meat conversion ratios. But is this just making something less bad, rather than good? And is scaled-up livestock production what society should now be chasing at all, given the environmental and public health upshots of intensive animal farming — not to mention mounting medical evidence that people should eat less meat?
Consider the Mutation, Consider the Application
With Big Food rapidly moving to take advantage of this new tool, the persistent questions that surround genetically modified organisms are cropping up in new contexts and with new complexities. How will we handle the technology? How should we regulate it? Can CRISPR foster advances for the common good?
Key to making good decisions, first of all, is to understand that not all applications of CRISPR are created equal — or have equal implications for the sustainability of agriculture. I’d argue “yes” — but to ensure benefits outweigh downsides will require a change more revolutionary than any tech breakthrough: an inclusive process for deliberating on and providing adequate societal oversight of risks, trade-offs and opportunity costs of CRISPR engineering. It will hinge on the involvement of everyday people — not just scientists or companies — in decisions about the food system.
Key to making good decisions, first of all, is to understand that not all applications of CRISPR are created equal — or have equal implications for the sustainability of agriculture. Like all breeding and biotech, genomic editing will bring positive and negative consequences, and should be evaluated on a full range of social and environmental effects. Our policies need to treat CRISPR not as a single technology, but as a toolbox full of technologies, each of which is specific to the mutation, organism and ecosystems in question.
In an article in the New York Times, for example, journalist Jennifer Kahn, like many others, is careful to point out that several companies are using CRISPR to create crops without using genes spliced in from other species, “like a flounder gene inside a tomato.” Here, public perception of CRISPR’s relative safety as compared to other genetic engineering methods has important policy implications. Flounder inside a tomato screams “GMO,” while genomic editing that does not introduce foreign genes is supposedly very different.
However, for all the attention to precise edits that do not introduce foreign genes, it’s important to understand that CRISPR is highly adept at that kind of modification too. Using CRISPR, wheat, corn, pigs, bananas — any agricultural organism, really — could be engineered to include gene sequences from a range of donors: microbes or fungi or fish. “You can easily use CRISPR-Cas9 to edit virtually any genome with your desired donor DNA,” explains Fuguo Jiang, a postdoctoral fellow in Doudna’s lab. “That is the power of gene editing.”
Meanwhile, even many CRISPR edits that don’t intentionally involve genes from other organisms are turning out to include exactly that. The way researchers usually get CRISPR technology working in a plant cell is to use a pest bacterium (Agrobacterium tumefaciens) to shuttle in the genes that code for Cas9. As result, bacterial DNA can wind up in the plant genome. Even when A. tumefaciens is not used, according to Nature, “fragments of the Cas9 gene may themselves be incorporated into the plant’s genome” — moving it into the touchy category of organisms whose genetic material contains foreign DNA.
Of course, scientists are rapidly trying to innovate around that unintended foreign introduction in order to strengthen the claim that CRISPR should not be regulated in the same way as conventional genetic modification. As Huw Jones, a senior research scientist at Rothamsted Research, a U.K. agricultural experiment station, told Nature, “If Europe regulates genome-edited organisms in the same way it does GM organisms, it will kill the technology here for all except the biotech companies working with profitable traits in the major crops.”
We will need a more inclusive process of deliberative governance, including the many people, in many environments, who’ll be affected by CRISPR, just as we need such a process for other biotechnologies. Scientists have persuasively argued, too, that CRISPR offers routes around some of the main causes of GMO concern, including random integration of transgenes — and resulting unintended effects such as disrupted host metabolism, or producing allergenic or toxic compounds.
These arguments do have their merits, yet they are also coming from scientists whose passions and careers are staked in biotechnology and molecular editing. We will need a more inclusive process of deliberative governance, including the many people, in many environments, who’ll be affected by CRISPR, just as we need such a process for other biotechnologies. For example, what are the ecologists saying? What do indigenous peoples want?
To U.S. regulators, most organisms currently under development — Cibus’ oilseed rape, Recombinetics’ hornless cows and Caribou Biosciences’ corn and wheat — may not be considered genetic modification. This is because U.S. policy is product-based, and with many types of CRISPR edits, the product will not include foreign genetic material. In cases where editing introduces sequences from close crop wild relatives, the product might even be genetically indistinguishable from the results of conventional crossbreeding — and, say researchers, could even qualify as organic. But the rules are different in Europe, where the term “GMO” is defined not by verifiable characteristics of a product but by the process used to create it. As long as methods of genetic engineering are used somewhere in the production process, then the label would apply.
If anything, CRISPR helps us see that GMO/non-GMO binaries are overly simplistic.The European Commission has not yet decided, however, how it will treat genomic editing, including CRISPR. Nor has the U.S. Food and Drug Administration confirmed whether CRISPR animals will be regulated in the future.
If anything, CRISPR helps us see that GMO/non-GMO binaries are overly simplistic. This one tool can perform many DNA nips and tucks and can up-regulate or down-regulate genes in ways that are not transgenic — yet are by no means inconsequential. Many CRISPR edits, I can’t overemphasize, won’t involve any questions about foreign DNA, but will be equally dramatic in their effects. In crops and animals, “gene knockouts” can eliminate genes that affect food quality, divert energy away from valuable end products, and confer susceptibility to crop diseases. Using the Cas9 enzyme’s powerful ability to enhance or suppress gene activity could touch on many important processes of crop and livestock metabolism, resistance and yield.
Many researchers and companies are vying to call all of the above non-transgenic. Some folks have recently gone so far as to say that GMO is a “metaphor,” a cultural construct that doesn’t map onto anything in the real world, and therefore can’t be regulated in any meaningful way. I agree that reaching a single, comprehensive definition of GMOs is elusive. But trying to argue that there are no boundaries hopelessly mingles all sort of genetic modification and processes together so they are all acceptable.
What I hope CRISPR offers instead is an opportunity to better incorporate the full range of biological, cultural and political meanings into our discussions of genetic engineering, and to mark out certain things for closer scrutiny and control — as should be the case in democratic societies, rather than freewheeling markets.
We might envision something modeled on the IAASTD process, which between 2005 and 2007 gathered 900 participants from governments, scientific institutions, the private sector and civil society to deliberate the same big questions facing CRISPR today: “How can we reduce hunger and poverty, improve rural livelihoods, and facilitate equitable, environmentally, socially and economically sustainable development through the generation, access to, and use of agricultural knowledge, science and technology?”
What we learned from IAASTD (read the synthesis report here), is that small farmers, fishers, pastoralists and indigenous communities around the world aren’t afraid of biotechnologies. But neither do they see much use for them, given many lower-hanging fruit — such as agroecology — for improving the productivity and resilience of farming systems. And when there is fear, it is not the Frankenfood flavor, but the apprehension, as Pope Francis recently expressed, that “following the introduction of these crops, productive land is concentrated in the hands of a few owners due to ‘the progressive disappearance of small producers, who, as a consequence of the loss of the exploited lands, are obliged to withdraw from direct production [Episcopal Commission for Pastoral Concerns in Argentina, 2005].’” The most vulnerable of these, Francis continues, “become temporary labourers, and many rural workers end up moving to poverty-stricken urban areas. The expansion of these crops has the effect of destroying the complex network of ecosystems, diminishing the diversity of production and affecting regional economies, now and in the future.”
CRISPR is giving us a rare opportunity to escape GMO definitions stuck in the 1980s and begin treating agriculture and food as the complex systems they are. Thirty years ago, we didn’t understand what the then-new genetics was, or what it might yield. In what scholar Donna Haraway calls the “god-trick,” we thought of genetics as the key to scientific mastery of nature, as if there was no context, no agency in the object, no imperfection in human knowledge. Molecular science somehow licensed us to treat genes as separate from ecology and bodies. Now we are fathoming intricate interactions between genes and environments, and ecosystems whose changes aren’t smooth or predictable, but that bristle with threshold effects and emergent properties. We’ve come to appreciate the inseparability of nature and culture in complex systems.
CRISPR is giving us a rare opportunity, then, to escape GMO definitions stuck in the 1980s and begin treating agriculture and food as the complex systems they are. It invites us to update biotech governance to include expertise from a wider public and range of sciences. We’ll need to consult not just geneticists but also ecologists. Not just natural scientists but social scientists. Not just scientists, but farmers, consumers, seed producers and workers across the food chain.
In the process, as journalist Brooke Borel persuasively argues, we should be alert for conflicts of interest, scrutinizing power structures and considering “who is included in the work and who is excluded or marginalized, whether because of gender or race or any other identity.” These factors matter because they shape who has access to the making of science, and who has influence over its aims.
Will we take up the CRISPR challenge? Early developments in applications for agriculture suggest that we could miss this rare chance to foreground sustainability and public deliberation, rather than re-entrenching an industrial status quo. But if we raise our voices now, early developments could force disruptive, democratic thinking instead.
Author’s note: A special thanks to Dr. Fuguo Jiang for answering my many CRISPR questions. Any errors in the piece are my own, not those of the reporters and researchers whose work I have learned from.
CORRECTION 02.19.16: The article originally stated that the herbicide-resistant oilseed rape created by Cibus was a “‘CRISPRed’ crop.” However, Cibus’ gene editing technology is RTDS (Rapid Trait Development System), a mutagenesis technology distinct from CRISPR and other systems which use enzymes to cut DNA. The article has been updated accordingly.Photo:Dean Calma / IAEA