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Researchers are considering ways to use synthetic biology for such conservation goals as eradicating invasive species or strengthening endangered coral. But environmentalists are worried about the ethical questions and unwanted consequences of this new gene-altering technology.

By RichardConniff July20,2017

The worldwide effort to return islands to their original wildlife, by eradicating rats, pigs, and other invasive species, has been one of the great environmental success stories of our time. Rewilding has succeeded on hundreds of islands, with beleaguered species surging back from imminent extinction, and dwindling bird colonies suddenly blossoming across old nesting grounds.

But these restoration campaigns are often massively expensive and emotionally fraught, with conservationists fearful of accidentally poisoning native wildlife, and animal rights activists having at times fiercely opposed the whole idea. So what if it were possible to rid islands of invasive species without killing a single animal? And at a fraction of the cost of current methods?

Thats the tantalizing but also worrisome promise of synthetic biology, aBrave New Worldsort of technology that applies engineering principles to species and to biological systems. Its genetic engineering, but made easier and more precise by the new gene editing technology called CRISPR, which ecologists could use to splice in a DNA sequence designed to handicap an invasive species, or to help a native species adapt to a changing climate. Gene drive, another new tool, could then spread an introduced trait through a population far more rapidly than conventional Mendelian genetics would predict.

Synthetic biology, also called synbio, is already a multi-billion dollar market, for manufacturing processes in pharmaceuticals, chemicals, biofuels, and agriculture. But many conservationists consider the prospect of using synbio methods as a tool for protecting the natural world deeply alarming. Jane Goodall, David Suzuki, and others havesigned a letterwarning that use of gene drives gives technicians the ability to intervene in evolution, to engineer the fate of an entire species, to dramatically modify ecosystems, and to unleash large-scale environmental changes, in ways never thought possible before. The signers of the letter argue that such a powerful and potentially dangerous technology should not be promoted as a conservation tool.

On the other hand, a team of conservation biologists writing early this year in the journal Trends in Ecology and Evolution ran off a list of promising applications for synbio in the natural world, in addition to island rewilding:

Kent Redford, a conservation consultant and co-author of that article, argues that conservationists and synbio engineers alike need to overcome what now amounts to mutual ignorance. Conservationists tend to have limited and often outdated knowledge of genetics and molecular biology, he says. In a 2014 article in Oryx, he quoted one conservationist flatly declaring, Those were the courses we flunked. Stanford Universitys Drew Endy, one of the founders of synbio, volunteers in turn that 18 months ago he had never heard of the IUCNthe International Union for Conservation of Natureor its Red List of endangered species. In engineering school, the ignorance gap is terrific, he adds. But its symmetric ignorance.

At a major synbio conference he organized last month in Singapore, Endy invited Redford and eight other conservationists to lead a session on biodiversity, with the aim, he says, of getting engineers building the bioeconomy to think about the natural world ahead of time My hope is that people are no longer merely nave in terms of their industrial disposition.

Likewise, Redford and the co-authors of the article in Trends in Ecology and Evolution, assert that it would be a disservice to the goal of protecting biodiversity if conservationists do not participate in applying the best science and thinkers to these issues. They argue that it is necessary to adapt the culture of conservation biologists to a rapidly-changing realityincluding the effects of climate change and emerging diseases. Twenty-first century conservation philosophy, the co-authors conclude, should embrace concepts of synthetic biology, and both seek and guide appropriate synthetic solutions to aid biodiversity.

The debate over synthetic biodiversity conservation, as theTrends in Ecology and Evolutionauthors term it, had its origins in a2003 paperby Austin Burt, an evolutionary geneticist at Imperial College London. He proposed a dramatically new tool for genetic engineering, based on certain naturally occurring selfish genetic elements, which manage to propagate themselves in as much as 99 percent of the next generation, rather than the usual 50 percent. Burt thought that it might be possible to use these super-Mendelian genes as a Trojan horse, to rapidly distribute altered DNA, and thus to genetically engineer natural populations. It was impractical at the time. Butdevelopmentof CRISPR technology soon brought the idea close to reality, and researchers have since demonstrated the effectiveness of gene drive, as the technique became known, in laboratory experiments on malaria mosquitoes, fruit flies, yeast, and human embryos.

Burt proposed one particularly ominous-sounding application for this new technology: It might be possible under certain conditions, he thought, that a genetic load sufficient to eradicate a population can be imposed in fewer than 20 generations. And this is, in fact, likely to be the first practical application of synthetic biodiversity conservation in the field. Eradicating invasive populationsis of coursethe inevitable first step in island rewilding projects.

The proposed eradication technique is to use the gene drive to deliver DNA that determines the gender of offspring. Because the gene drive propagates itself so thoroughly through subsequent generations, it can quickly cause a population to become almost all male and soon collapse. The result, at least in theory, is the elimination of mice, rats, or other invasive species from an island without anyone having killed anything.

Research to test the practicality of the methodincluding moral, ethical, and legal considerationsis already under way through a research consortium ofnonprofitgroups, universities, and government agencies in Australia, New Zealand, and the United States. At North Carolina State University, for instance, researchers have begun working with a laboratory population of invasive mice taken from a coastal island. They need to determine how well a wild population will accept mice that have been altered in the laboratory.

The success of this idea depends heavily,according togene drive researcher Megan Serr, on the genetically modified male mice being studs with the island lady mice Will she want a hybrid male that is part wild, part lab? Beyond that, the research program needs to figure out how many modified mice to introduce to eradicate an invasive population in a habitat of a particular size. Other significant practical challenges will also undoubtedly arise. For instance,a study early this yearin the journalGeneticsconcluded that resistance to CRISPR-modified gene drives should evolve almost inevitably in most natural populations.

Political and environmental resistance is also likely to develop. In an email, MIT evolutionary biologist Kevin Esvelt asserted that CRISPR-based gene drives are not suited for conservation due to the very high risk of spreading beyond the target species orenvironment. Even a gene drive systemintroduced toquickly eradicate an introduced population from an island, he added, still is likely to have over a year to escape or be deliberately transported off-island. If it is capable of spreading elsewhere, that is a major problem.

Even a highly contained field trial on a remote island is probably a decade or so away, said Heath Packard, of Island Conservation, a nonprofit that has been involved in numerous island rewilding projects and is now part of the research consortium. We are committed to a precautionary step-wise approach, with plenty of off-ramps, if it turns out to be too risky or not ethical. But his group notes that 80 percent of known extinctions over the past 500 or so years have occurred on islands, whicharealso home to 40 percent of species now considered at risk of extinction. That makes it important at least to begin to study the potential of synthetic biodiversity conservation.

Even if conservationists ultimately balk at these new technologies, business interests are already bringing synbio into the field for commercial purposes. For instance, a Pennsylvania State University researcher recently figured out how to use CRISPR gene editing to turn off genes that cause supermarket mushrooms to turn brown. The U.S. Department of Agriculturelast year ruledthat these mushrooms would not be subject to regulation as a genetically modified organism because they contain no genes introduced from other species.

With those kinds of changes taking place all around them, conservationists absolutely must engage with the synthetic biology community, says Redford, and if we dont do so it will be at our peril. Synbio, he says, presents conservationists with a huge range of questions that no one is paying attention to yet.

Richard Conniff is a National Magazine Award-winning writer whose articles have appeared in The New York Times, Smithsonian, The Atlantic, National Geographic, and other publications. His latest book is House of Lost Worlds: Dinosaurs, Dynasties, and the Story of Life on Earth. He is a frequent contributor to Yale Environment 360. More about Richard Conniff

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Should Genetic Engineering Be Used as a Tool for Conservation? - Yale Environment 360

DARPA created the Safe Genes program to gain a fundamental understanding of how gene editing technologies function; devise means to safely,A responsibly, and predictably harness them for beneficial ends; and address potential health and security concerns related to their accidental or intentional misuse. DARPA announced awards to seven teams that will pursue that mission, led by: The Broad Institute of MIT and Harvard; Harvard Medical School; Massachusetts General Hospital; Massachusetts Institute of Technology; North Carolina State University; University of California, Berkeley; and University of California, Riverside. DARPA plans to invest $65 million in Safe Genes over the next four years as these teams work to collect empirical data and develop a suite of versatile tools that can be applied independently or in combination to support bio-innovation and combat bio-threats.

UC Berkeleys Jennifer Doudna, who co-invented CRISPR-Cas9 gene editing, will investigate whether these gene editing tools might someday be capable of disabling bioterrorism threats, such as novel infectious agents or weapons employing CRISPR itself.

Scientists have also uncovered numerous variants of the Cas9 protein that have potential use in research or medical therapy, plus proteins called anti-CRISPRs that throw a wrench into the Cas machinery and stop gene editing. The UC Berkeley-led collaboration will explore the potential of all of these.

Our focus is not only to make new Cas proteins that are more accurate, but also ones that dont necessarily cut the genome, said Kyle Watters, a postdoctoral researcher in Doudnas lab who is overseeing some of the work. These engineered Cas proteins might instead prevent certain genes from being expressed, for example, so that even though they change fundamental processes in your body, they are not ultimately changing the blueprint of your DNA.

This could involve targeting messenger RNA, the working copy of the gene used to build proteins, or recruiting enzymes to modify the epigenome chemical signals like methyl groups that signal the cell whether to transcribe genes or leave them alone.

The researchers hope to generate new and better tools from these specialized Cas enzymes, develop anti-CRISPR proteins as a kill switch to halt gene editing a sort of fail-safe mechanism and explore new ways of delivering fully functional CRISPR-Cas complexes into live cells.

Gene editing technologies have captured increasing attention from healthcare professionals, policymakers, and community leaders in recent years for their potential to selectively disable cancerous cells in the body, control populations of disease-spreading mosquitos, and defend native flora and fauna against invasive species, among other uses. The potential national security applications and implications of these technologies are equally profound, including protection of troops against infectious disease, mitigation of threats posed by irresponsible or nefarious use of biological technologies, and enhanced development of new resources derived from synthetic biology, such as novel chemicals, materials, and coatings with useful, unique properties.

Achieving such ambitious goals, however, will require more complete knowledge about how gene editors, and derivative technologies including gene drives, function at various physical and temporal scales under different environmental conditions, across multiple generations of an organism. In parallel, demonstrating the ability to precisely control gene edits, turning them on and off under certain conditions or even reversing their effects entirely, will be paramount to translation of these tools to practical applications. By establishing empirical foundations and removing lingering unknowns through laboratory-based demonstrations, the Safe Genes teams will work to substantially minimize the risks inherent in such powerful tools.

The field of gene editing has been advancing at an astounding pace, opening the door to previously impossible genetic solutions but without much emphasis on how to mitigate potential downsides, said Renee Wegrzyn, the Safe Genes program manager. DARPA launched Safe Genes to begin to refine those capabilities by emphasizing safety first for the full range of potential applications, enabling responsible science to proceed by providing tools to prevent and mitigate misuse.

Each of the seven teams will pursue one or more of three technical objectives: develop genetic constructsbiomolecular instructionsthat provide spatial, temporal, and reversible control of genome editors in living systems; devise new drug-based countermeasures that provide prophylactic and treatment options to limit genome editing in organisms and protect genome integrity in populations of organisms; and create a capability to eliminate unwanted engineered genes from systems and restore them to genetic baseline states. Safe Genes research will not involve any releases of organisms into the environment; however, the researchperformed in contained facilitiescould inform potential future applications, including safe, predictable, and reversible gene drives.

During the course of the program, teams will engage with potential stakeholders, including government regulators, to increase the value of the science and to shape experiments around their questions and concerns. Additionally, as an aid to policymakers, the teams will establish models for incorporating stakeholder engagement into future decisions on whether and how to apply such tools.

Part of our challenge and commitment under Safe Genes is to make sense of the ethical implications of gene editing technologies, understanding peoples concerns and directing our research to proactively address them so that stakeholders are equipped with data to inform future choices, Wegrzyn said. As with all powerful capabilities, society can and should weigh the risks and merits of responsibly using such tools. We believe that further research and development can inform that conversation by helping people to understand and shape what is possible, probable, and vulnerable with these technologies. Gene editing is truly a case where you cant easily draw a line between ethics and pure technology developmenttheyre inextricableand were hopeful that the model we establish with Safe Genes will guide future research efforts in this space.

The efforts funded under the Safe Genes program fall into two broad categories: gene drive and genetic remediation technologies, and in vivo therapeutic applications of gene editors in mammals.

* A team led by Dr. Amit Choudhary (Broad Institute/Brigham and Womens Hospital-Renal Division/Harvard Medical School) is developing means to switch on and off genome editing in bacteria, mammals, and insects, including control of gene drives in a mosquito vector for malaria, Anopheles stephensi. The team seeks to build a general platform for the rapid and cost-effective identification of chemicals that will block contemporary and next-generation genome editors. Such chemicals could propel the development of therapeutic applications of genome editors by limiting off-target effects or protect against future biological threats. The team will also construct synthetic genome editors for precision genome engineering. * A Harvard Medical School team led by Dr. George Church seeks to develop systems to safeguard genomes by detecting, preventing, and ultimately reversing mutations that may arise from exposure to radiation. This work will involve creation of novel computational and molecular tools to enable the development of precise editors that can distinguish between highly similar genetic sequences. The team also plans to screen the effectiveness of natural and synthetic drugs to inhibit gene editing activity. * A Massachusetts General Hospital (MGH) team led by Dr. Keith Joung aims to develop novel, highly sensitive methods to control and measure on-target genome editing activityand limit and measure off-target activityand apply these methods to regulate the activity of mosquito gene drive systems over multiple generations. State-of-the-art technologies for measuring on- and off-target activity require specialized expertise; the MGH team hopes to enable orders of magnitude higher sensitivity than what is available with existing methods and make this process routine and scalable. The team will also develop novel strategies to achieve control over genome editors, including drug-regulated versions of these molecules. The team will take advantage of contained facilities that simulate natural environments to study how drive systems perform in mosquitos under conditions approximating the real world. * A Massachusetts Institute of Technology (MIT) team led by Dr. Kevin Esvelt has been selected to pursue modular daisy drive platforms with the potential to safely, efficiently, and reversibly edit local sub-populations of organisms within a geographic region of interest. Daisy drive systems are self-exhausting because they sequentially lose genetic elements until the drive system stops spreading. In one proposed variant, natural selection is anticipated to favor the edited or original version depending on which is in the majority, keeping genetic alterations confined to a specified region and potentially allowing targeted populations of organisms to be restored to wild-type genetics. MIT plans to conduct the majority of its work in nematodes, a simple type of worm that reproduces rapidly, enabling high-throughput testing of different drive configurations and predictive models over multiple generations. The team then aims to adapt this system in the laboratory for up to three key mosquito species relevant to human and animal health, gradually improving performance in mosquitos through an iterative cycle of model, test, and refine. * A North Carolina State University (NCSU) team led by Dr. John Godwin aims to develop and test a mammalian gene drive system in rodents. The teams genetic technique targets population-specific genetic variants found only in particular invasive communities of animals. If successful, the work will expand the tools available to manage invasive species that threaten biodiversity and human food security, and that serve as potential reservoirs of infectious diseases affecting native animal and human populations. The team also plans to develop mathematical models of how drives would function in mice, and then perform testing in contained, simulated natural environments to gauge the robustness, spatial limitation, and reversibility of the drives. * A University of California, Berkeley team led by Dr. Jennifer Doudna will investigate the development of novel, safe gene editing tools for use as antiviral agents in animal models, targeting the Zika and Ebola viruses. The team will also aim to identify anti-CRISPR proteins capable of inhibiting unwanted genome-editing activity, while developing novel strategies for delivery of genome editors and inhibitors. * A University of California, Riverside team led by Dr. Omar Akbari seeks to develop robust and reversible gene drive systems for control of Aedes aegypti mosquito populations, to be tested in contained, simulated natural environments. Preliminary testing will be conducted in high-throughput, rapidly reproducing populations of yeast as a model system. As part of this effort, the team will establish new temporal and environmental, context-dependent molecular strategies programmed to limit gene editor activity, create multiple capabilities to eliminate unwanted gene drives from populations through passive or active reversal, and establish mathematical models to inform design of gene drive systems and establish criteria for remediation strategies. In support of these goals, the team will sample the diversity of wild populations of Ae. aegypti.

The teams intend to refine their research over the course of the program, building initial mathematical models of gene editing systems, testing them in insect and animal models to validate hypotheses, and feeding the results back into the simulations to tune parameters. Teams will also incorporate insights garnered from engagement with regulators and in some cases from local communities considering gene editing applications, and may run additional experiments to collect data that address concerns and could inform future regulatory reviews.

Given the potential of gene editing systems to broadly impact national security, health, and the environment, DARPA is committed to a high level of transparency and engagement in its Safe Genes research. The program will work with independent experts to help DARPA and the teams think through Legal, Ethical, Environmental, Dual-Use, and Responsible innovation (LEEDR) issues. In a separate but related effort, DARPA previously co-funded a National Academies of Sciences, Engineering, and Medicine report on gene drives to help initiate the development of a framework for considering the implications of advances in gene editing, and to make recommendations on a responsible way forward.

One aspect of Safe Genes that Im most proud of is that were involving potential stakeholders from the beginning, many of whom are already considering gene editing technologies as options for responding to different health and environmental challenges but who have questions about how solutions involving gene editors would actually work, said Wegrzyn. DARPA sees their involvement in the Safe Genes program as invaluable for developing a model in which consideration of societal impact isnt an afterthought, but instead a foundation on which science advances.

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DARPA funds $65 million for safer genetic engineering and fight ... - Next Big Future

MELBOURNE: Researchers have found a solution to reduce coral bleaching by genetically engineering the micro-algae found in corals, enhancing their stress tolerance to ocean warming.

These micro-algae are called Symbiodinium, a genus of primary producers found in corals that are essential for reef health and, thereby, critical to ocean productivity, said researchers from University of New South Wales in Australia.

Symbiodinium photosynthesise to produce molecules that feed the corals, which is necessary for corals to grow and form coral reefs.

Coral bleaching is caused by changes in ocean temperatures which harm Symbiodinium, leading corals to lose their symbiotic Symbiodinium and therefore starve to death.

Different species of Symbiodinium have large genetic variation and diverse thermal tolerances which effect the bleaching tolerance of corals.

The researchers used sequencing data from Symbiodinium to design genetic engineering strategies for enhancing stress tolerance of Symbiodinium, which may reduce coral bleaching due to rising ocean temperatures.

"Very little is known about Symbiodinium, thus very little information is available to improve coral reef conservation efforts," said Rachel Levin from The University of New South Wales, Australia.

"Symbiodinium is very biologically unusual, which has made it incompatible with well-established genetic engineering methods," said Levin.

"We therefore aimed to overcome this roadblock by conducting novel genetic analyses of Symbiodinium to enable much needed research progress," she said.

The researchers have now highlighted key Symbiodinium genes that could be targeted to prevent coral bleaching.

"We have developed the first, tailored genetic engineering framework to be applied to Symbiodinium. Now this framework must be comprehensively tested and optimised. This is a tall order that will be greatly benefited by collaborative efforts," researchers said.

"Symbiodinium that have been genetically enhanced to maintain their symbiosis with corals under rising ocean temperatures has great potential to reduce coral bleaching globally," they said.

"If lab experiments successfully show that genetically engineered Symbiodinium can prevent coral bleaching, these enhanced Symbiodinium would not be immediately released onto coral reefs," Levin added.

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'Superalgae' to protect world's corals from bleaching - Economic Times