Growing Better Food with GMOs, Germs, and Gigabytes
For the 55% of humans who live in cities, it can be easy to forget just how much of our planet is dedicated to agriculture. More than one-third of all the land on Earth is used to raise the food we eat, and of that, an area nearly the size of Australia is dedicated to growing cereal crops alone. As a species, we are nearly completely dependent on plants for our survival, which are in turn at the mercy of their environment — too much rain, too little sun, too many insects, or the arrival of a new virus can wipe out an entire harvest.
While plants have evolved strategies to cope with those threats (waxy leaves, sticky sap, commensal relationships with fungi, etc.), humanity, for millennia, has also been coaxing them to develop traits that are more appealing to its needs. Selectively breeding plants with desirable qualities together gave us the starchy, calorie-rich staple crops we eat today. The birth of the field of genetics in the mid-20th century allowed scientists to transfer genes from one organism into another, leading to the creation of the first genetically modified organisms (GMOs) in the 1980s. “Transgenic” GMO plants have since flourished in the face of challenges like pests, weeds, and environmental stressors, and have become the backbone of the modern agriculture industry. Today, the next generation of plant scientists is using new gene editing technologies like CRISPR to modify the genes of food crops directly, allowing them to enhance plants’ innate abilities with even greater precision.
Some say that CRISPR crops have arrived just in time, as decreasing yields, a changing climate, declining soil quality, environmental degradation, and growing resistance to pesticides and herbicides are all straining the agricul-ture industry’s ability to meet the global demand for food, not only now, but for the future. Our food production needs to double by 2050 to accommodate
a projected global population of 10 billion. Editing the genomes of plants so that they can grow taller, produce more food, use less water, and resist pathogens, while reducing the impact of agriculture on the environment, could be the answer to preventing widespread human suffering and starvation.
The wide-scale adoption of genetically modified crops needed to achieve that vision is not without its challenges, however. GMO plants are currently subject to a patchwork of regulations that differ from country to country, and the rigorous process of getting a new GMO crop approved can last over a decade and cost tens of millions of dollars. Public opinion of GMOs is also not as positive as the industry would like, and consumer preference for non-GMO options is growing.
Despite these challenges, a new crop of agriculture technology companies and research efforts, encouraged by a newly relaxed US ruling on the regulation of CRISPR-edited plants, has sprung up in the last decade. Armed with gene editing, biological-based technologies, and digital tools, they aim to bring the ancient science of agriculture into the twenty-first century, saving our species and our planet in the process.
A Tale of Transgenics
The vast majority of the seeds planted on commercial farms today are GMOs. More than 90% of the corn, soybeans, cotton, sugar beets, and canola grown in the US has been genetically modified in some way, and the worldwide market for GMOs is estimated to surpass $36 billion by 2022. Even if you don’t eat corn or beets regularly, it’s likely that nearly everything you’ve consumed today was produced, in some form, from GMOs. The corn syrup that sweetened your muffin or cereal was likely made from Roundup Ready corn, which contains a gene isolated from a bacterium that allows it to survive if sprayed with the herbicide Roundup. The soy lecithin that kept the oils in your afternoon chocolate bar from separating and made your pizza dough fluffy was probably produced from Bt soybeans, which have been engineered to produce a protein that is toxic to certain kinds of insect pests. And GMO corn and soybeans make up the majority of grains that are refined into cooking oils and fed to chickens, cows, and pigs.
In addition to the beneficial traits that allow them to survive better and produce more food, GMO crops have effectively become the industry standard because it takes only about ten years to develop a new GMO plant — compare that to the thousands of years of trial-and-error our ancestors needed to convert an ancient tall grass with small, hard, black seeds into the sweet, starchy, kernel-packed plant we know today as corn. Each of the countless iterations of breeding plants with slightly more edible seeds together was effectively a roll of Nature’s dice, with the hope that it would produce offspring with the desired traits.
This slow and inefficient “selective breeding” process remained our only way of changing our foods to better serve us through the turn of the 20th century, when it was discovered that radiation caused spontaneous, unexpected changes in living organisms. Starting in the 1920s, scientists bombarded thousands of different plants with x-rays to see what kinds of new traits arose, and many of the resulting mutant varieties are still grown today, like the Rio Red grapefruit, which remains one of the most popular versions of the fruit. But plant breeders still had no way to predict or control what the results of radiation would be — whether a mutation made a plant more appealing or killed it was still up to Nature’s dice, albeit they were now rolling faster.
Advances in breeding multiple varieties of plants together led to the creation of hardier and more productive “hybrid” crops in the 1960s, which are credited with enabling the Green Revolution that allowed the planet to more than triple its grain production in just two decades. The process of creating these hybrids, however, was still labor-intensive and subject to the whims of genetics.
In the early 1980s, it was discovered that the microbe Agrobacterium tumefaciens could inject a small portion of its own DNA through plants’ thick and highly impermeable cell walls and integrate into its host’s genome. Scientists could thus use Agrobacterium as a kind of delivery service to introduce a gene for a desired trait into a plant, whose offspring could also inherit the gene. The first “transgenic” plant was created this way in 1983, when an embryonic tobacco plant was infected with Agrobacterium carrying an antibiotic resistance gene originally found in bacteria. Later tests confirmed that the adult plant was antibiotic-resistant. The age of GMO crops had begun.
GMOs: Friends or Foes?
The first genetically modified food crop was introduced to the market in 1994, and over the following two decades the global acreage of GMO crops jumped from 27.5 million acres to an astonishing 448 million as farmers eagerly bought and planted transgenic crops with traits like pesticide and herbicide resistance, improved nutritional value, and tolerance to environmental stressors like drought, frost, and high soil salinity. Beyond their dominance of agriculture in the US, GMOs now account for 95% of the cotton grown in India, over 90% of the soybeans in Brazil and Argentina, and 95% of the canola produced in Canada. These crops are attractive to growers because they help both increase the amount of food they can produce and lower production costs.
Roundup Ready crops, produced by Bayer Crop Science (formerly Monsanto), are one of the most wide-spread GMOs grown on the planet. Their genetically induced immunity to Roundup allows farmers to simply spray their fields with the herbicide to kill any unwanted weeds rather than tilling the soil to control weed growth. No-till farming also reduces soil erosion and chemical run-off from fields, helping to reduce environmental impact. Another popular GMO variety, Bt crops’ endogenous production of bacterial Bt toxin protects plants from insect damage and reduces the use of pesticides, which also lowers cost.
In addition to providing protection against external threats, GMOs can also enhance the quality of crops themselves. GRAINZYME Phytase, a type of GMO corn made by Boston-based Agrivida, has been engineered to produce the enzyme phytase within its kernels. Phytase is usually added to animal feed to help pigs, chickens, and cows break down the phytic acid present in grains to extract phosphate and maximize their nutrition. “Phytic acid is actually an ‘anti-nutrient,’ in that it binds to other things in the grain and makes them less available to the animals. With our GRAINZYME system, we see that animal performance improves beyond what we would expect if we simply gave them phosphate,” says Michael Raab, Agrivida’s president.
All existing GMOs are created through the insertion of a “foreign” gene from one type of organism into another. Because such an organism could not have arisen naturally, governments around the world require that any new GMOs be put through a regulatory process to demonstrate that the new gene does not have any deleterious effects on the plant or on humans before they can be put on the market.
Different countries have different levels of stringency for GMOs. India has only approved GMO cotton, while Australia permits GMO cotton, canola, and safflower to be grown, but no food crops. The EU has had a de facto ban on the sale of foods produced from GMOs since 2001, but has left it up to its member states to decide whether to plant GMOs on their land (though the EU imports millions of tons of GMO crops every year for livestock feed and other uses). Even in the US, which has one of the most lenient GMO policies, the process to develop a new GMO can take up to twelve years and cost upwards of $130 million. That expense means that only a few companies — namely Bayer, DowDuPont (to become Corteva Agriscience), and Syngenta (owned by ChemChina) — have the means to create new GMOs on a global scale. Some argue that as a result, the agriculture industry has essentially become an oligopoly in which competition is stifled and farmers are locked into buying more expensive GMO seeds to keep up with the demands of a commodity market, which puts small growers and would-be innovators out of business.
As well as these regulatory challenges, GMOs have a notoriously bad reputation among the public and in the media. In an era when consumers are increasingly demanding products that are “natural,” many people see plants that are developed in a lab as inherently artificial and possibly even dangerous. 39% of Americans believe that GMOs are worse for their health than non-GMOs (though there is no scientific evidence of any difference), and this large minority is fueling a growing market for non-GMO products. Global sales of more than 50,000 products verified as “Non-GMO” by the advocacy group The Non GMO Project jumped from $348.8 million in 2010 to $10 billion in 2015. Even GMOs that are developed for humanitarian reasons have endured a backlash: Golden Rice, a strain of rice that produces vitamin A as a way to combat childhood blindness in resource-poor countries, has been stuck in regulatory limbo for nearly two decades, and in 2013 a group of angry protesters stormed a test field where the crop was growing in the Philippines and ripped the plants out of the ground.
Plants produced through selective breeding are considered “natural” varietals and skip the GMO regulatory pathway in most countries, so many companies are eschewing GMOs in favor of optimizing selective breeding to produce better plants. Bayer, for example, has an active “marker-assisted breeding” program, which takes DNA samples of thousands of different strains of plants to analyze their genetics as well as their physical traits, which it then uses to select the best candidates for cross-breeding.
Proponents of genetic modification have continued to improve upon the Agrobacterium gene-transfer method. In the ’90s and early ’00s, technologies to edit organisms’ genomes were developed, including zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), but these technologies could not meet the throughput demands for commercial-scale agriculture. Then, in 2012, the now-famous CRISPR (short for “clustered regularly interspaced short palindromic repeats”) gene editing technology was announced, which provides a much easier and cheaper way to make precise genetic changes. As a result, editing crops’ genes suddenly became feasible. And, unlike earlier genetic modification methods used in crops, CRISPR can edit the genome of any plant to a high degree of accuracy without introducing foreign DNA.
The concept of CRISPR has often been compared to a molecular pair of scissors that cuts DNA at a very specific place. The enzyme Cas9, first isolated from bacteria, is the cutting portion of the scissors, which can be “loaded” with a molecule of RNA that is engineered to match a known sequence of DNA in a given organism. When the loaded enzyme is introduced into a host cell, the RNA molecule then guides it to that genetic sequence, and Cas9 cuts both DNA strands. The cell’s natural genetic repair mechanism recognizes the cut and joins the strands back together. This process is error-prone and often introduces a mutation that can change or disable a gene located at the target sequence. If scientists want to introduce a new, heavily modified version of the native genetic sequence, they can include a template strand of DNA along with the Cas9-RNA complex, which the cell can incorporate into the genome at the cut point.
CRISPR offers another significant advantage over existing GMOs — the US Department of Agriculture (USDA) announced in early 2018 that it would not regulate any plants modified with gene editing technologies as GMOs, because the genetic changes produced by those methods could conceivably have arisen through traditional breeding or random mutation. This means that, ironically, plants whose genomes are edited using CRISPR can be labeled as non-GMO, and can thus be sold at a higher price to consumers who are willing to pay for that designation. The decision also releases crop developers from the lengthy and expensive GMO regulatory process, which some think has the potential to “democratize” the agriculture industry, as smaller companies and startups without the infrastructure of a Bayer or DuPont can much more readily afford to develop gene-edited plants.
“CRISPR is going to be a huge key player in…pretty much any biological science where your goal is to edit DNA,” says Markita Landry, an Assistant Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley. Her lab is working on ways to enable CRISPR and other gene editing technologies to reach their full potential by helping them get past the problem of the plant cell wall — only some species are susceptible to infection by Agrobacterium, and getting DNA into other plants requires the use of a gene gun, which is imprecise and damages plant tissues. Landry sees the most promise from carbon nanotubes, which can be loaded with a variety of cargoes (DNA, RNA, or proteins) and diffuse easily into plant cells. “With this technology, all we really need to do is mix two tubes together — DNA with carbon nanotubes and a plant sample — and we have a genetically transformed plant at the end. So, I’m hoping that this would be useful in expediting the way that we do molecular biology in plants,” Landry says.
Though Landry’s technology is still in development, varieties of CRISPR-edited mushrooms whose flesh does not turn brown when exposed to air and corn that is “waxier” for optimal use in products like glue sticks have received the green light from the USDA (though, as of May 2019, they have yet to hit the market), and a growing number of companies are investing in gene-edited crops.
Cambridge, MA-based startup Inari Agriculture is using CRISPR as part of its breeding program to create seeds that can be personalized for an individual farm’s specific conditions like climate and soil quality. Benson Hill Biosystems, founded in St. Louis, MO in 2012, aims to put gene editing in the hands of food producers through their CropOS software system, which allows growers to predict which breeds will work best for their fields, identify potentially helpful genes from other organisms, and create customized gene-edited varieties.
And existing industrial agriculture leaders are getting into the CRISPR game as well. “If you imagine any trait that might be beneficial for crops — anything from drought tolerance to disease resistance — variation in that trait exists in nature already. What’s really exciting about gene editing technology and CRISPR technology is not only can it recreate some of that same variation in plants, but it can also create a new variation that can then be selected for,” says Scott Knight, Head of Genome Editing and Yield at Bayer Crop Science. “We imagine that gene editing is going to work side by side with all of the previous work that we’ve done in breeding and traditional biotechnology over the last several decades.”
Not everyone is as open to CRISPR-edited crops as the USDA and the American agriculture industry, however. The EU recently declared that all CRISPR-edited plants would fall under its GMO regulatory framework, which effectively puts an indefinite moratorium on any significant gene editing research and development on the European continent.
The anti-GMO movement sees the USDA’s decision not to regulate gene edited crops as a shortsighted move that favors industry at the expense of consumers, who will be at risk of exposure to potentially harmful products without their knowledge or consent. The Non-GMO Project’s website states that, “All genetic engineering is inherently reductionist and relies on unproven and unreliable assumptions about the predictability of a given gene’s function in isolation from its original DNA sequence.” Dana Perls, the Senior Food and Agriculture Campaigner for environmental advocacy group Friends of the Earth, wrote in an opinion article for STAT News, “We need more science, assessment, answers, and regulations before we can decide whether these new biotech products should be in our stores — and on our plates.
Improving biology with biology
Some scientists and companies have decided to steer clear of any genetic modification in plants, whether performed by traditional GMO techniques or CRISPR, in their quest to improve crop yields. One of those scientists is Neena Mitter, a Professor at The Queensland Alliance for Agriculture and Food Innovation in Brisbane, Australia. She first worked on developing vegetable crops that were genetically resistant to viruses and other pathogens using the technique of RNA interference (RNAi), in which segments of DNA are inserted “backwards” into the genome so that they are transcribed into molecules of RNA that bind to and “silence” a complementary target RNA sequence. “It worked beautifully well, but very soon I realized it was not going to reach anywhere because industry [in Australia] was not going to fund research on genetic modification of vegetable crops,” Mitter says. “I started asking myself, ‘RNAi is such a wonderful tool, is there a way I can deliver it to plants while bypassing genetic modification? Can I just spray it on a plant and make it resistant?’” It turned out that a plant cell’s natural RNAi machinery can be jumpstarted by the introduction of a targeted, double-stranded version of RNA (dsRNA) that is common in viruses, without requiring genome editing. The idea of spraying dsRNA onto plants to control viruses had been proposed before, but the molecule degrades within a few days of application, which would require farmers to spray their fields almost constantly to maintain protection.
Mitter partnered with nanoengineers at the Australian Institute of Nanoengineering and Nanotechnology to develop a new technology called BioClay that packages dsRNA into nanoparticles made of a type of clay called layered double hydroxide. The nanoparticles protect the dsRNA and allow it to be released slowly onto the plant, where some of it is taken up into the plant’s cells and, if a virus or other pathogen infects the cell, triggers the cell to destroy the invader’s RNA. BioClay particles sprayed onto plants can stay in place for up to a month, even through heavy rain, and leave no residue. “The beauty of this approach is that it works just like any other crop protection scenario, and it’s recognized as a non-GM approach,” says Mitter. “We need to understand that integrated pest management is the key for the future. There is no chemical available now that can kill a virus in a plant system — current treatments target the insects that transmit those viruses. BioClay provides a unique solution that can target the virus itself.”
Other scientists think that focusing on molecules, whether DNA or RNA, is an oversimplified approach to a complex biological problem. Just as there is growing acceptance that the “microbiome” that inhabits our guts has significant effects on our health, there is increasing interest in studying and understanding the communities of microbes that live within plants. “Any plant, if cut open, has microbes living on the inside of its tissues — every blade of grass in your lawn, every leaf of every tree on the Boston Common, every rainforest in the world,” says Geoff von Maltzahn, co-founder and Chief Innovation Officer of Boston-based Indigo Ag. “Anything that compromises the health of the plant compromises the microbes’ health, so it would be in their best interest to evolve protections against that. We thought that maybe the internal plant microbiome could be a home for solutions to every challenge that farmers face in agriculture.”
Indigo Ag analyzes the microbes naturally found inside healthy plants, identifies those that confer certain advantages, and sells seeds pre-coated with microbes to farmers. As the seeds germinate, the microbes incorporate into the seedlings’ tissues and provide support throughout the plants’ lifetimes. “We could never have designed an intervention as powerful as what we’ve discovered in ‘Nature’s lab,’ because every time we isolate microbes from a plant, we’re benefitting from millions of years of Nature’s R&D,” says von Maltzahn. “GMO interventions are like transistors compared to the supercomputer that is a microbe that has evolved to live in and support a plant.”
Other companies are also using microbes to deliver benefits to plants. Growcentia, based in Fort Collins, CO, focuses on bacteria found in the soil, and has developed a blend of four species that have been proven to “liberate” phosphorous from the soil so that plants can better absorb it and use it to grow. Bayer has teamed up with Ginkgo Bioworks to form a new company called Joyn Bio, which is combining gene editing and microbe science by identifying the genes that give microbes their plant-supporting characteristics, then boosting them. “At Joyn, we’re focusing on microbes that already have these pathways present and enhancing their ability to carry out natural processes that are beneficial for agriculture,” says Brynne Stanton, Joyn’s Head of Metabolic Engineering. The first of those processes the company is targeting is microbes’ ability to “fix” nitrogen from the soil and make it available to plants, thus reducing farmers’ dependence on nitrogen fertilizers and the fossil fuels used to produce them.
The final digital frontier
A crucial component of the “Second Green Revolution,” as some are calling today’s agricultural innovations, is digital tools to help farmers catalog and analyze the large number of variables they encounter every day.
One such system is Bayer’s Field View, which allows farmers to build digital maps of their fields to track which crops are planted where and monitor their performance, and includes an Alexa-like device that plugs into their harvesting equipment and links that data with information from their machines. “It’s often said that agriculture is the last industry to be digitized, and we’re living that right now,” says Knight. “Growers want this technology. They’re very tech-savvy, they’re out there now in their fields with their iPads gathering information in real-time, and they strive to make those data-driven decisions.”
Digital tools are the glue that will help hold future agriculture together, linking soil and seed to algorithms and artificial intelligence, and many agricultural companies are diversifying to provide that value to farmers. “Growers can make up to millions of individual decisions every year, and many of them are based on intuition and experience without a lot of sophisticated data to guide those,” says Indigo Ag’s von Maltzahn.
If the Green Revolution was built on the four pillars of hybrid seeds, irrigation, mechanization, and chemicals, the current revolution in agriculture is being driven by the triumvirate of gene editing, biological-based interventions, and digital technology. While those fields may be new to agriculture, they’re commonplace in established tech clusters like those found in Cambridge, MA. Bayer set up shop in the area’s biotech-heavy Kendall Square when it opened its “LifeHub Boston” space in 2017, which serves as a way to monitor the pulse of the local tech community and encourage the development of novel solutions to the looming food scarcity problem. “What many people don’t realize is that agriculture innovations are just as difficult and expensive to bring to market [as pharmaceutical innovations],” says Jon Giebel, Program Lead of LifeHub Boston. “We’re here [in Cambridge] to help these entrepreneurs and university groups who are doing great science for human health applications, and show them opportunities to translate those into the plant health, food production, and crop yield spaces.”
The excitement around agriculture technology is palpable, especially because it has the potential for such broad-reaching impact. “In many ways, agriculture is the most important life science in the world,” says von Maltzahn. Just as successfully growing a plant requires the perfect combination of soil, sun, water, nutrients, and time, finding new ways to feed the world is an all-hands-on-deck effort between corporations, tech companies, scientists, and farmers. As Bayer’s Scott Knight notes, “Being able to provide tailored solutions that really put the right seeds at the right time in the ground, perhaps with the right microbe, is going to be critical to provide a sustainable and safe food supply for the future.”