Regulating engineered microbes for release into the environment

Microbes—tiny living things like bacteria and fungi, often consisting of a single cell or colonies of cells—are found everywhere from the tropics to the Arctic and Antarctica. They are as diverse as they are numerous, and many perform functions that are essential to the health of ecosystems as well as our own bodies.

Humans have long used microbes to achieve their goals—making beer and yogurt are among the earliest examples. The advent of synthetic biology in the early 21st century has dramatically increased our ability to engineer microbes to have specific, useful traits. This technological revolution is opening up new scientific perspectives and enabling innovations that have the potential to transform medicine, agriculture, and environmental management. It is also raising important new policy issues.

John Marken, a research assistant professor at Caltech’s Resnick Sustainability Institute, points out that synthetic biology efforts over the past 20 years have been directed primarily at “making sure that we can create reliable, predictable, and effective designs for genetically engineered microbes.” But, says Marken, “the more I got involved in synthetic biology as a graduate student, the more I realized there was an elephant in the room. Everyone was talking about all these fantastic applications for genetically engineered microbes, but no one seemed to ask whether it would be legal to release them into the environment to do the jobs we imagined for them.”

To help create a framework for safe and responsible research and application of microbial engineering technologies, Caltech’s Ronald and Maxine Linde Center for Science, Society, and Policy (LCSSP) today released a report with policy recommendations aimed at creating clear and consistent regulations while building a solid scientific knowledge base on microbial engineering.

Frederick Eberhardt, professor of philosophy and co-director of LCSSP with Michael Alvarez, professor of political and computational science at Flintridge, says the Linde Policy Center works to “build connections between the spectacular science that’s being done here at Caltech and the impact that science can have on regulation, policy, and society at large. Of course, we want to find avenues where science can and should impact regulation, but we also want to create a space for nonscientists and policymakers to say, ‘Here’s a problem that regulation has to solve when a new product or tool is introduced to the market. Can you help us better understand and quantify what the real impact will be on society or the ecosystem in the real world?’ We want to encourage research in which the policy challenge becomes part of the initial research question.”

Promising new applications

The development of recombinant DNA in the 1970s made it possible for the first time to create microbes designed to perform specific functions. For example, the insulin needed by diabetics was once extracted from the pancreas of pigs or cows, but is now produced by inserting a human insulin-producing gene into bacteria, which can replicate rapidly and produce 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, deleting, or transposing sections of DNA to give the microbes the ability to perform new functions that benefit humanity.

“We can create useful machines from biological components,” says Richard Murray, the Thomas E. and Doris Everhart Professor of Control, Dynamic Systems, and Bioengineering and William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering. “We can think of DNA as a programming language that we use to create helpful organisms.”

The potential applications for engineered microbes are, in a word, vast. They include repairing environmental damage, extracting desirable resources (biomining), detecting toxins or diseases in inorganic and organic environments (including the human body), creating and producing medicines, and enabling the cultivation of more resilient crops on fewer acres. And that’s just the beginning.

But with new potential comes risk. Once released into the environment, microbes can reproduce, spread, and potentially mutate. In other words, the microbes we design and release into the environment—known as engineered microbes for environmental release (EMER)—will go on to live and create futures outside the lab that are not yet fully understood.

Engineering safety

When possible (though not always possible), scientists design microbes to be self-limiting, surviving only as long as needed and only in the areas into which they are released.

For example, Smruthi Karthikeyan, a Gordon and Carol Treweek assistant professor of environmental science and engineering and a William H. Hurt postdoctoral fellow, has been working on oil spill remediation using engineered microbes. “In the past, people would add a ton of chemical dispersants to the area with the hopes of breaking down the oil into simpler compounds that would be easier to degrade. But what happened was that those dispersants ended up doing more harm than good. The chemicals were really toxic to the water community and the workers who were applying them, and they weren’t even that effective. But looking at the oil spills, we found that certain microbes were thriving in the oil. Their genetic makeup allowed them to produce biosurfactants, organic dispersants that, like detergents or soaps, can break down the oil. Our goal was to isolate the surfactant that those microbes were making and engineer the microbes to enhance that effect.”

But what happens to these modified microbes after the oil spill is cleaned up? Karthikeyan explains: “These microbes are almost undetectable when there is no more oil to consume. For many microbes, if the compounds or contaminants they interact with are not available, it is a burden for them to continue to carry genes that degrade those compounds. In a clean environment, it is no longer energetically advantageous for these microbes to carry additional genes that are no longer useful.”

In another area of ​​research, Gözde Demirer, a Clare Boothe Luce assistant professor of chemical engineering, is developing engineered microbes to increase crop yields and reduce reliance on chemical fertilizers, which are relatively expensive and harmful to the environment and human health. Safety is improved, Demirer says, by “developing containment approaches for engineered microbes. We’re finding ways to make engineered microbes dependent on specific plants for survival, so that the microbes don’t spread beyond the fields and die off once the crops are harvested.”

Using scientific potential while ensuring public safety

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

Existing laws regulate the use of genetically modified microbes, but as Murray explains, “A lot of those laws were written 30 years ago when the scientific possibilities we have today were simply not on anyone’s radar. The added complication is that in the United States we don’t have a single agency that deals with bioengineering. Instead, we have a patchwork of laws and agencies that do different things. Imagine, for example, that I want to put a microbe into cows that will help them produce better milk. That microbe will go into the waste stream and into the environment. Does that mean the appropriate 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 drugs?”

To begin to address the issues surrounding genetically modified microorganism research, the Linde Policy Center and the Resnick Sustainability Institute hosted a symposium in February on the challenges of developing and regulating EMER, which brought together representatives from regulatory agencies, industrial biotechnologists, and academic scientists.

The discussion and deliberations of the symposium entitled “Paths to the Safe and Effective Implementation of Microbial Engineering Technologies” formed the basis of a policy report by the Linde Policy Center.

The report calls for the creation of a program to “help small/first-time EMERs navigate the biotechnology regulatory framework” and the creation of an environmental biotechnology regulatory authority that would establish risk assessment guidelines and ensure “sequential assessments with increasingly rigorous standards” as new EMERs are introduced to the market.

The report also recommended:

• Infrastructure for EMER assessment in closed environments that simulate natural environments
• Public repository of information about EMERs undergoing field testing
• Funding for basic research aimed at assessing the potential risks and benefits of emergencies

Finally, the report recommends that regulatory agencies at both the state and federal levels “promote early and regular interaction among regulators, potential EMER developers, and the broader public.”

Marken hopes that the improved regulatory framework will help streamline regulatory decision-making for newly developed microbes. “With the right research in this direction, we will be able to better understand what types of data should and should not be collected to make an informed, evidence-based assessment of the risks associated with releasing EMER into a given environment.”

LCSSP distributed its report to the public today and earlier today to those who attended the February symposium, who in turn will share it with colleagues in academia and government. “We’ve sent the report to people in the White House and on Senate committees,” Marken says. “It should help inform policy by showing that scientific experts and regulators are on the same page about what it takes to safely introduce engineered microbes into the environment.”