Regulating Engineered Microbes for Environmental Release

Microbes—tiny living things like bacteria and fungi, often made up of a single cell or a colony of cells—can be found everywhere from the tropics to the Arctic and Antarctic. They are as varied as they are numerous, and many perform functions that are vital to the health of ecosystems as well as our own bodies.

Humans have been using microbes to do their bidding for a very long time—the production of beer and yogurt are some of the earliest examples. The emergence of synthetic biology in the early 2000s dramatically escalated our ability to engineer microbes to have specific, useful characteristics. This technological revolution opens new scientific vistas and makes possible innovations with the potential to transform medicine, agriculture, and environmental management. It also raises important new policy considerations.

John Marken, a postdoctoral research associate with the Resnick Sustainability Institute at Caltech, points out that efforts in synthetic biology over the past 20 years have been primarily directed toward "being sure that we can make reliable, predictable, and effective designs for engineered microbes." But, Marken says, "The more I became involved in synthetic biology as a graduate student, the more I realized that there was an elephant in the room. Everybody was talking about all these fantastic applications for engineered microbes, but no one seemed to be asking if it would be legal to release them into the environment to do the sort of jobs we were imagining for them."

To help create a framework for safe and responsible research and use of engineered microbial technologies, Caltech's Ronald and Maxine Linde Center for Science, Society, and Policy (LCSSP) has today released a report with policy recommendations geared toward creating clear and consistent regulations while simultaneously building a solid scientific knowledge base about engineered microbes.

Frederick Eberhardt, professor of philosophy and co-director of the LCSSP along with Michael Alvarez, the Flintridge Professor of Political and Computational Social Science, says the Linde Policy Center works to "build links between the spectacular science that is done here at Caltech and the impact that science can have on regulation, policy, and society in general. Obviously, we want to find the pathways where science can and should influence regulation, but we also want to create a space for nonscientists and policymakers to say, 'Here is an issue that regulation needs to address when a new product or tool is commercialized. Can you help us better understand and quantify what the actual real-world impact on society or an ecosystem will be?' We want to encourage research where the policy challenge becomes part of the initial research question."

Promising new applications

With the development of recombinant DNA in the 1970s, it became possible for the first time to create designer microbes to fulfill specific functions. For example, the insulin needed by diabetics used to be harvested from the pancreas of pigs or cows but is now produced by inserting the human insulin-producing gene into bacteria that can quickly replicate and create more of the hormone, which is then purified for human use.

Now, the field of synthetic biology has made it possible to "program" microbes. This involves editing, removing, or transposing pieces of DNA to give the microbes the ability to perform new functions that are beneficial for humanity.

"We have the ability to make useful machines out of biological components," says Richard Murray, the Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering, and the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering. "We can think about DNA as the programming language we use to create helpful organisms."

Potential applications for engineered microbes are, in a word, vast. They range from remediating environmental damage, extracting desired resources (biomining), detecting toxins or medical conditions in both inorganic and organic environments (including the human body), creating and manufacturing medicines, and making it possible to grow hardier crops on fewer acres. And this is just the beginning.

However, along with new potential comes risk. Once released into the environment, microbes can reproduce, spread, and potentially mutate. In other words, the microbes we engineer and release into the environment—known as engineered microbes for environmental release (EMERs)—will lead lives and create futures outside the lab that are not yet fully known to us.

Engineering safety

Where possible—and it is not always possible—scientists are engineering microbes to be self-limiting, to persist only as long as they are needed and only within the areas to which they have been released.

For example, Smruthi Karthikeyan, the Gordon and Carol Treweek Assistant Professor of Environmental Science and Engineering, and a William H. Hurt Scholar, has worked on remediation of oil spills using engineered microbes. "In the past, people would add a ton of chemical dispersants to the area with the hope that they would break down the oil into simpler compounds that degrade more easily. But it turned out these dispersants ultimately did more harm than good. The chemicals were really toxic to the aquatic community and to the workers who deployed them, and they were not even that effective. But looking at oil spills, we found that certain microbes were thriving in oil. Their genetic composition allowed them to produce biosurfactants, organic dispersants that, like detergents or soaps, can break down oil. Our goal then was to isolate the surfactant that these microbes were producing and engineer the microbes to strengthen this effect."

But what happens to these engineered microbes after they have cleaned up an oil spill? Karthikeyan explains, "These microbes are nearly undetectable when there is no more oil to consume. For a lot of microbes, if the compounds or pollutants they interact with are not available, it is a burden for them to continue to carry the genes that degrade these compounds. In a clean environment, it is no longer energetically favorable for these microbes to have extra genes that are no longer useful."

In another area of research, Gözde Demirer, the Clare Boothe Luce Assistant Professor of Chemical Engineering, develops engineered microbes to improve crop yields and reduce dependence on chemical fertilizers, which are comparatively expensive and damaging to the environment and human health. Safety is enhanced, Demirer says, by "developing containment approaches for engineered microbes. We are finding ways to make engineered microbes depend on specific plants to survive, so that microbes will not spread beyond cultivated fields and will die out when crops are harvested."

Harnessing scientific potential while ensuring public safety

Notwithstanding researchers' commitment to engineering microbes for safety, it has not always been easy to assure government regulators and the public that releasing engineered microbes into the environment can be less dangerous and more effective than alternative courses of action or no action at all.

Existing regulations govern the use of engineered microbes, but as Murray explains, "Many of these regulations were written 30 years ago when the scientific capability we have today just was not on anyone's radar. A further complication is that in the United States, we don't have a single agency that deals with bioengineering. Instead, we have a patchwork of statutes and agencies that do different things. Imagine, for example, that I want to introduce a microbe into cows that will help them make better milk. This microbe will end up in the waste stream and go out into the environment. So, does that mean that the relevant agency is the USDA [U.S. Department of Agriculture], which normally regulates cows? Or would it go through the FDA [Food and Drug Administration], which regulates veterinary medicines?"

To begin addressing such questions surrounding the research of genetically engineered microbes, the Linde Policy Center, along with the Resnick Sustainability Institute, hosted a symposium in February on the challenges associated with developing and regulating EMERs that included representatives from regulatory agencies, biotechnologists from the industrial sector, and academic scientists.

Discussion and deliberation from the symposium, "Pathways Towards the Safe and Effective Deployment of Engineered Microbial Technologies," informed the Linde Policy Center's policy report.

Specifically, the report calls for a program to "aid small/first-time EMER developers in navigating the biotechnology regulatory framework" and the creation of an environmental biotechnology regulation office that would establish guidelines for assessing risk while also providing "sequential assessments with increasingly rigorous standards" as new EMERs enter the pipeline.

The report further recommends:

• An infrastructure for evaluating EMERs in contained conditions that simulate natural environments
• A public repository of information on EMERs undergoing field trials
• Funding for basic scientific research directed at assessing the potential risks and benefits associated with EMERs

Finally, the report recommends that regulatory agencies at both the state and federal level should "promote the early and regular interaction between regulators, potential developers of EMERs, and the broader publics."

Marken hopes that an improved regulatory structure will help streamline the regulatory decision-making process for newly engineered microbes. "With proper research in this direction, we will be able to better understand what types of data do and do not need to be collected in order to make informed, evidence-based assessments of the risks associated with releasing an EMER into a particular environment."

The LCSSP disseminated its report to the public today and earlier to those who participated in the February symposium, who will in turn share it with colleagues from academia and government. "We have sent this report out to people who work at the White House and on Senate committees," Marken says. "It should help to create better policy by demonstrating that scientific experts and regulators are saying the same things about what is needed to safely introduce engineered microbes to the environment."