A New Generation of GMOs

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Courtesy of Courtesy of Ensia

Is synthetic biology on its way to our farms, markets and tables?

Thousands of researchers will descend on Boston this fall for an event billed as the world’s largest gathering of synthetic biologists. The field is evolving so rapidly that even scientists working in it don’t agree on a definition, but at its core synthetic biology involves bringing engineering principles to biotechnology. It’s an approach meant, ultimately, to make it easier for scientists to design, test and build living parts and systems — even entire genomes.

If genetic sequencing is about reading DNA, and genetic engineering as we know it is about copying, cutting and pasting it, synthetic biology is about writing and programming new DNA, with two main goals: create genetic machines from scratch and gain new insights about how life works.

In Boston, scientists and students will showcase synbio projects developed over the summer, including systems ranging from new takes on natural wonders, such as the conversion of atmospheric nitrogen to a useful form (nitrogen fixation), to newly imagined functions, such as an odorless E. coli cell meant to crank out a lemony, edible “wonder protein” containing essential amino acids.

Now in its 11th year, the iGEM (International Genetically Engineered Machine) competition has grown up alongside synthetic biology itself. Organized by a nonprofit foundation spun out of MIT, the event has acquired a mix of public and private partners, including the FBI, the National Science Foundation, Monsanto and Autodesk. And no wonder. Synbio could produce both transformative science and big business. By some estimates, the global market for synthetic biology is projected to grow to $16 billion by 2018. Much of the anticipated activity centers on pharmaceuticals, diagnostic tools, chemicals and energy products such as biofuels. But in the face of energy and water constraints, a squeeze on cultivable land, and an imperative to limit greenhouse gas emissions, synbio could also transform the way we farm and eat.

Whereas many genetically modified crops today contain a single engineered gene, synthetic biology makes it easier to generate larger clusters of genes and gene parts. These synthetic clusters can then be engineered by more conventional methods into plants or microbes. As a result, today’s iGEM competitors may be tomorrow’s developers of a new generation of genetically modified organisms. By assembling biological systems from genetic code catalogued in online databases and fine-tuned through computer modeling, they could deliver more nutritious crops that thrive with less water, land and energy and fewer chemical inputs, in more variable climates and on lands that otherwise would not support intensive farming.

Synthesized DNA can be harnessed for food production in a few ways. Foods and flavorings created through fermentation with engineered yeast are one option. A startup called Muufri, for example, is working on an animal-free milk product; a crowd-funded group of “biohackers” collaborating in community labs in the Bay Area aims to create a vegan cheese; and the Swiss company Evolva is using synthetic biology to develop saffron, vanillin and stevia. Other companies, such as Solazyme, are engineering microalgae to produce algal “butter,” protein-rich flour, and a vegan protein. And in academia, research is under way for clusters of synthesized genes to eventually be inserted directly into plants or into microbes in soil and roots that affect plant growth.

To some, it is a frightening future that has synthesized DNA coming to the farm, market and dinner table. Environmental news site Grist has called synthetic biology “the next front in the GMO war.” Friends of the Earth, an environmental organization that views genetically modified crops as “a direct extension of chemical agriculture,” calls synbio an “extreme form” of genetic engineering.

According to Dana Perls, food and technology campaigner for Friends of the Earth, the group is not opposed to the technology, but rather for its responsible use. “We’re at this crossroad,” she says. “We have the opportunity to look back at history and learn from our mistakes.” Transparency is key. “Before synthetic biology gets rubber-stamped as sustainable or natural or a technology which could help mitigate climate change, we need international and national regulations specific to these technologies,” she says. “We need to make sure it’s not going to do more harm than good.”

Indeed, we’re only beginning to unravel the ecological implications of the technology. Experts consulted for a recent report from the Woodrow Wilson Center’s Synthetic Biology Project say potential risks demanding more research range from the creation of “new or more vigorous pests and pathogens” to “causing irreparable loss or changes in species diversity or genetic diversity within species.”

Assessing these risks in the real world is complex. While some engineered traits “will clearly have great benefit to the environment with little risk,” says plant geneticist Pamela Ronald, who directs the Laboratory for Crop Genetics Innovation at the University of California, Davis, “each gene or trait must be assessed on a case-by-case basis.” Experimental organisms would typically be tested in a lab or confined field trials, which may be inadequate to foretell the co-evolution and interplay of a full ecosystem. According to the Wilson Center report, some of the most advanced models in use today for eco-evolutionary dynamics falter beyond a 10-year time frame.

“We don’t know how these organisms [developed through synthetic biology] will interact with pollinators, soil systems, other organisms,” Perls says. And a self-replicating organism with synthetic DNA, released into an ecosystem, could swap genes with wild counterparts. “We need to expect escape; and when that happens, we need to be prepared to deal with it,” she says.

While many people involved with synthetic biology say existing regulation of engineered plants — generally split in the United States among the Environmental Protection Agency, Food and Drug Administration and Department of Agriculture — will extend adequately to synbio, others see a need to shore up oversight. Policy analysts with the J. Craig Venter Institute, the European Molecular Biology Organization, and the University of Virginia, for example, concluded earlier this year that the shift to synthetic biology could leave “many engineered plants without any premarket regulatory review” because the USDA’s authority depends on a technique that’s outdated for many applications. And the increasing number and diversity of microbes expected to be engineered for commercial use, the authors warned, will challenge the “EPA’s resources, expertise and perhaps authority to regulate them.”

That report came on the heels of a Kickstarter project called Glowing Plants aimed at producing “sustainable natural lighting” through synthetic biology, which exposed some possible loopholes. The company laid out a plan to derive DNA from fireflies, modify it to work in a flowering plant related to mustard, order the reprogrammed sequence from a company that laser-prints DNA, coat it onto metal particles, and inject it into seeds using a device called a gene gun. And they promised to distribute some 600,000 of these seeds to supporters.

“Is it legal? Yes it is!” the Glowing Plants team wrote. FDA regulation is out because the plant is not meant to be eaten, and EPA says the project would be a matter for the USDA. But because the genes are transferred via gene gun (a technique developed after guidelines were established in the late 1980s), the plant falls outside the USDA’s purview. As a spokesperson for the agency later told the journal Nature, “Regarding synthetic biologics, if they do not pose a plant risk, APHIS [the Animal and Plant Health Inspection Service] does not regulate it.” The landscape is different overseas. “Regrettably,” the Glowing Plants team wrote, “the European Union has tighter restrictions in place so we can’t send seeds there as a reward.”

Hungry, Hungry Planet

To be sure, the global food system is ripe for redesign. “Agriculture is the biggest driver of environmental impacts on the planet,” says Paul West, co-director and lead scientist for the Global Landscapes Initiative at the University of Minnesota. Agriculture occupies about 40 percent of Earth’s ice-free land and accounts for some 70 percent of water use. “And because of all the fertilizer that’s used, it’s the main source of water quality problems,” West says. By 2050, we can expect at least 2 billion additional eaters, as well as heightened demand for feed crops to support growing appetites for meat and dairy.

At the same time, climate models point to a future of tightening constraints on food systems around the globe. Although warmer temperatures could increase yields in some regions, West says, temperature and rainfall changes alone could slash overall crop yields by an estimated 10 to 40 percent. Expected changes in the frequency of drought, flooding and extreme weather events could drive those losses even higher, he says.

A variety of reforms can help to address these challenges. Reducing waste, tweaking the location and timing of fertilizer applications, stopping irrigation leaks, and diversifying crop production would offer a good start. Synthetic biology could become part of a solution at some point, West says. But because “what we eat is so heavily influenced by culture, taste, preference and cost,” he says, “even if something works really well on paper, it doesn’t mean that it’s accepted.”

“A Special Lightning Rod”

Genetically engineered foods, “ignite a special lightning rod,” University of California, Berkeley, bioethicist David Winickoff observes. Unlike drugs produced through biotechnology, such as insulin, we “still have a substitute product that’s quote, ‘pure,’” when it comes to food, says Winickoff, who directs the Berkeley Science, Technology, and Society Center.

Yet, with few exceptions, “almost everything we eat is produced on farms, which is an artificial environment,” says Ronald. What’s more, in an era of climate change and ecosystem-scale restoration, Winickoff says, “it’s harder to maintain an idea of ‘pure’ nature.” If our species has already shaped the state of our planet, might that compel further intervention, he asks, to right past wrongs — or at least adapt to their consequences?

“There have been all kinds of examples of technocratic interventions that have gone wrong, or at least have [had] large social consequences — some good and some bad,” Winickoff says.

“With large interventions, there are winners and losers,” he adds. “It doesn’t just have to do with aggregate risk and benefit, but thinking about how risk and benefits are allocated.”

The New “Natural”

“What synthetic biology should be able to do is improve the efficiency with which we’re converting, ultimately, sunlight into proteins and carbohydrates,” says Neil Goldsmith, CEO of Evolva. The company has generated and screened billions of variations on a genetic theme to arrive at the design for a system that runs on sugar, electricity, water (a reminder that even microbial factories require inputs) and yeast cells containing synthesized DNA. The yeast cells are removed during production, and at a molecular level, the result is identical to the chemical that gives vanilla orchid seeds their distinctive flavor.

According to Evolva, its living vanillin factory mirrors the fermentation process used to make beer. And compared to existing vanilla flavorings derived from petroleum, the company claims to offer “greater naturalness.” In Goldsmith’s view, there’s no such thing as an artificial gene. “DNA is DNA,” he says. In terms of function, “what matters to a gene is sequence, not how you made it.”

Friends of the Earth has launched a campaign to stop “synbio vanilla” from making its way into ice cream, warning that the product “could set a dangerous precedent for synthetic genetically engineered ingredients to sneak into our food supply and be labeled as ‘natural.’” In response, Häagen-Dazs and a handful of other ice cream makers that use vanilla extract from actual vanilla beans have said they will not use vanilla flavor produced through synthetic biology.

For groups like Friends of the Earth, part of the concern is that synthesized DNA is developed “outside of nature, outside of the process of natural selection.” It is a startlingly far cry, Perls says, from crossbreeding crops over decades and centuries, and “ultimately letting nature figure out how those crops are going to survive.”

Out of the Freezer, Into the Field

While synthesized DNA in food is running its first public-opinion gantlet en route to the frozen desserts aisle, synbio approaches in time could reprogram the most basic interactions between plants and their environment.

The ability to synthesize DNA has “completely transformed” much of the Ronald Lab’s work at UC Davis because researchers no longer need to isolate a DNA sequence to study it. About 25 years ago, Ronald began searching for genes in rice that allow the plant to resist disease or tolerate stress. In 1995, her team isolated a gene that confers disease resistance. In 2006, the researchers were finally able to isolate a group of genes that could bestow flood tolerance on rice varieties that would otherwise die after a few days underwater. And by 2013, more than 4 million farmers in the Philippines, Bangladesh and India had planted rice engineered (through a process known as precision breeding) to have that genetic marker.

“Synthesis would not have sped things up much,” Ronald says, because the slow-going work in this case had to do with identifying genes of interest and introducing them into plants. What has changed is that researchers can now scan for candidates among the growing number of DNA sequences documented in government databases, and once candidates are identified, it’s easier to start studying and prioritizing them. “You can synthesize a lot of constructs and test them very rapidly,” she says.

“We need to reduce carbon emissions and toxic inputs, use less land and water, combat pests, and increase soil fertility,” Ronald says. While it’s too early to predict which tool will be most efficient in achieving the goals of safety and sustainability over the long term, she says, “For a farmer or a geneticist, we use whatever tool will work.”

The accelerating pace of this work opens a door for new risks. According to Pamela Silver, professor of biochemistry and systems biology at Harvard Medical School, however, synthetic biology is like many other technologies in the realm of dual-use research. “There’s the good side and the potential dark side.”

Synthetic biology builds on decades of advances in molecular biology, systems biology and biotechnology. In the 1980s, polymerase chain reaction technology made it possible to zoom in on a segment of DNA and make billions of copies, Silver explains. In time, scientists could take genes and make specific mutations, but it was still nature’s foundation. Today, “you are no longer stuck with what nature has on offer. You can start to create things,” Silver says. “You could do it in the PCR days, but now, as the cost of making DNA gets ever cheaper, then it’s really only your imagination that’s the limit.”

Automatic Shutdown

Some synthetic biologists are imagining an “off” switch for engineered traits. Crops today that have been engineered to tolerate pests, herbicides, disease or drought express that tolerance all the time. With the tools of synbio, biophysicist and synthetic biologist Christopher Voigt explains, an organism could be programmed to have a genetic trait “deal with the problem and then go away.”

As the tools to design entire genomes catch up to the ability to construct them, Voigt expects to see cereal crops programmed to sense and respond to environmental information, like dryness. In the coming years, Voigt says, “You’ll think about the organism you want and then be systematic about building that organism up from scratch.”

As a demonstration, Voigt’s team at MIT has inserted a cluster of 16 delicately tuned genes into a bacterium to give it nitrogen-fixing abilities. If successfully applied to plants, this approach could potentially reduce applications of nitrogen fertilizers, which contribute to emissions of nitrous oxide — a powerful greenhouse gas. There are implications for energy, too. According to a recent paper on emerging synbio policy issues from the Organisation for Economic Co-operation and Development, the impact of creating self-fertilizing plants through synthetic biology “could revolutionize agriculture and would significantly decouple agriculture from the oil industry.”

“Nitrogen fixation is very sensitive,” Voigt says. “If you change any of the levels, it stops working altogether.” Part of the challenge is that oxygen produced by plants during photosynthesis is “supertoxic” for a key enzyme called nitrogenase, explains Himadri Pakrasi, director of the International Center for Advanced Renewable Energy and Sustainability at Washington University in St. Louis and leader of the school’s iGEM team. “This is probably why most plants have not figured out how to fix nitrogen for themselves,” he says.

A special class of cyanobacteria, however, manages to accomplish both photosynthesis and nitrogen fixation. The key is having a genetic switch to run photosynthesis during the day and nitrogen fixation at night. Pakrasi’s team is working to “import” the switch and parts for nitrogen fixation — about three dozen genes — from this cyanobacterium into a different cyanobacterium that also performs photosynthesis but lacks the genetic parts to fix nitrogen.

In the original organism, the genes involved in nitrogen fixation are scattered “all over the genome,” which is inconvenient for transplanting. Synthesizing these genes into a neat package, or plasmid, is now relatively simple, and it’s getting cheaper, Pakrasi says. His lab can purchase a gene from one of a growing number of DNA makers for as little as $300, less than half of the price they paid for the same product even a few months ago.

“The next phase of the challenge is much bigger: how to connect the operation of this made-up plasmid to the genetic program that’s existing in the cyanobacteria,” he says. Synthetic biology approaches offer a way to tinker with those connections so the custom-built gene cluster can function in the new cell. “If we solve this, which we haven’t yet, then the same principles can be applied to chloroplasts in crop plants,” Pakrasi says. He envisions the scheme helping to boost yields of corn, rice, wheat and other crops in places where fertilizers today are expensive for many farmers. “And if that can be done, it can solve the world’s food problem in a very big way.”

Farming techniques have changed for 10,000 years, and they’re on the cusp of major changes now. But it’s still early days for synthetic biology. “Hopefully,” Ronald says, “those changes will allow us to preserve our Earth in good shape for another 10,000 years.”

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