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GE regulation: More may be necessary, but need not inhibit innovation

Genetic engineering (GE) allows us to create organisms that can may be sorely needed in coming years: drought-resistant corn to avoid famine in the climate-changed era, malaria-resistant mosquitoes to quell an epidemic that kills a million people per year, ponds of synthetic algae that pump out biofuels are just a few innovations.

But a new branch of genetic engineering, synthetic biology, is stirring particular concern and controversy. Synbio, as it is often called, can draw on transgenics, molecular biology, population biology and ecology. It evokes in critics fears of Frankenstein’s continual quest to tinker with the ‘natural order’ of life (whatever that may mean). Critics are particularly concerned because, they say, it remains largely unregulated. They believe unsupervised distribution of synthetic organisms has the potential for severe unintended consequences.

Although synthetic biology products have been on the market for years, corporate genetically modified (GM) crops being among the first, we are just now beginning to see products come out of the so-called do-it-yourself biology (DIYbio) community. This is a movement that has arisen unexpectedly over the past few years and is composed of hobbyists and entrepreneurs, holding PhDs or trained informally, who do not conduct their experiments in corporate, government or university facilities. The movement has been spurred by falling lab equipment costs coupled with an increase in on-line access as well as the availability of community lab spaces—all of which has provided a breeding ground for biotech innovations.

One of the first GE organisms to come from the DIYbio community is the Glowing Plant: plants engineered to express a firefly gene (think bioluminescent novelty gardens or trees replacing streetlamps). The group behind it fundraised on the crowd-sourcing website Kickstarter and pledged to send seeds of glowing, engineered roses and Arabidopsis plants (of the mustard family) to those who donated.

The prospect of the uncontrolled release of thousands of engineered plants made by so-called ‘garage scientists’ raised concerns among anti-GMO activists and some scientists. The latest Time magazine suggest it has even started a new culture war. Obscured by the hyperbole were otherwise reasonable concerns of unintended impacts on the environment: What if the glowing plants hybridize with native, non-GE roses and spread the gene? What if, by some unintended impact of the engineering process, the glowing plants are rendered more fit and able to take over the ecosystem? Could the glowing gene somehow spread to other plant species?

Even those who see such scenarios as unlikely might ask: Shouldn’t the glowing plants be, at least, tested to evaluate these potential consequences prior to release?

All GE animals (glowing fish, malaria-resistant mosquitoes, hypothetical fanged monsters) must be approved by the Food and Drug Adminstration before they can be released in to the wild or marketed for a specific purpose.

However, the regulations for GE plants are more lax and generally non-existent for GE microorganisms (viruses and bacteria). Environmental groups such as the Friends of the Earth and ETC group wrote to the United States Department of Agriculture, one of the governmental bodies that regulates GM crops, demanding that it stop the sale of the glowing plants. But the USDA has no explicit legal authority to assess or regulate these innovations.

As long as a GE plant or microbe does not produce a specific pesticide regulated by the Enviromental Protection Agency or does not contain genes from a USDA-defined plant pest, no approval or review is required to release them to the wild. As the Glowing Plant does not meet either criteria, it is beyond the jurisdiction of the government.

Many scientists believe the current oversight situation is more than adequate—the fears they say are insignificant relative to the benefits. Tougher regulations would yield few protections and squelch innovation. Others are not so sure.

Though, the introduction of the Glowing Plant has energized the discussion over whether this regulatory gap should be filled, it is far from the first GE product to pass through it. At least ten GE crops have hit the market without regulation, including varieties that breed faster and are herbicide tolerant – even another breed of glowing plant (created by BioGlow). However, these were done quietly by private companies. What makes the Glowing Plant a centerpiece for the debate is that its creators publicized their entire process from the gene-insertion design to plans for release.

Another factor is that, in making their techniques and process publicly available, they are seen as champions of DIY genetic engineering and as encouraging other researchers to tinker with GE organisms- something that makes some more formally trained scientists nervous.

“I worry about the garage scientist, about the do-your-own scientist, about the person who just wants to try and see if they can do it,” noted Dr. Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at University of Minnesota, in a New York Times article. Osterholm, commenting on fears that individuals may use published sequences of mammalian H5N1 to recreate the virus, raised the concern that even without malintent, the mutant virus created in an insecure, makeshift lab could escape and pose a threat to public health.

More likely possibilities include untrained hobbyists and even innovative highschoolers throwing GE seeds in the compost bin or pouring GE algae down the drain that could have some influence on the surrounding environment.

The increased possibility of these scenarios have many people and even some supporters of non-professional GE research asking whether it is time for the creation and release of all GE organisms to be regulated. And, if so, what should those regulations entail?

Although every new technology will impact the environment, GE organisms have the potential to survive in the environment and to compete successfully with their non-GE counterparts. In addition, engineered genes could, theoretically, be passed to non-GE counterparts through various forms of mating. Such uncontrolled spread of a gene through a population is irreversible with current technologies. Pro-regulators argue that to ensure that a product’s benefits outweigh its potential harm, each new GE breed’s capacity to alter the ecosystem should be fully evaluated before it is released.

Not all scientists agree that such risks are outsized or unmanageable, nor does the federal government at this point. Many of the imagined scenarios–like a mutant flu coming from a garage or a GE crop wiping out the native plant population—are farfetched and therefore, regulations to control them are unnecessary. After all, we have had GM crops for years (as well as breed-creating hybridization methods since the beginning of human agriculture) with little noticeable problems. Furthermore, most amateur scientists don’t have access to the expertise or sophisticated equipment to make highly complex GE organisms of consequence.

Sarah Kellogg articulates this view of DIY science in a Washington Lawyer article describing it as being ‘akin to home woodworking and gardening, albeit with more far-reaching economic and educational potential.’ From this perspective, cumbersome regulations that require expensive biosecurity infrastructure or detailed risk assessments might unnecessarily deter innovators and delay getting novel, beneficial products to the market.

Given the legitimate concerns on both sides, how might useful regulation look in practice?

There are two things to be considered:

  1. containment of GE organisms during the research phase
  2. intentional release of the final product into nature

Containment: How might we deter sloppy practices while protecting the access of responsible scientists of all backgrounds to tools they need to ‘tinker’ and innovate? 

Given the potential for escaped GE organisms to spread irretrievably through the wild (with or without consequence), we might reasonably consider precautions that would limit the possibility of prototypes escaping during the tinkering/research phase.

This could be done simply by requiring that all GE products be confined to a designated lab space and that experimental waste be sterilized before disposal. Sterilization could be done with any manner of standard procedures such as running it through an autoclave. Individuals can buy autoclaves on-line for less than $1000 and they are a standard feature in community labs spaces, such as Genspace and Biocurious. Alternatively, biohazard waste disposal can be outsourced to any number of companies.

This requirement would sufficiently reduce the risk of viable prototypes escaping. Specific guidelines for the methods and sterilization temperatures required for different types of organisms (such as spores or Achaea that can survive high temperatures and other extreme conditions) would have to be set for this strategy to work.

One could argue that the cost to access an autoclave or other sterilizing services/equipment could be prohibitive to amateurs. However, it is likely an insignificant fraction of the cost of the gene constructs and equipment used to create the organisms in the first place. If a hobbyist or entrepreneur can afford to create the organisms, the relatively minor extra cost of trash disposal is unlikely to be a prohibitive obstacle.

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In the case of engineered air-borne bacteria and viruses a discussion of air-flow containment is warranted.

Work with pathogens spurs additional considerations to containment. Members of the general public cannot just buy most pathogens, but they can, theoretically, access the genes and, as is Dr. Osterholm’s fear, use the genes to re-create versions of the unavailable pathogens from otherwise harmless organisms.

Currently, labs where scientists are working with microbes and that receive government funding must adhere to specific biosafety levels (BSL1-4) depending on the pathogenicity of the microbe one is working with. At the BSL-3 level, which is required for air-borne and potentially fatal microbes like H5N1 flu, the scientist must work in a infrastructure that has controlled airflow and two sets of self-closing and locking doors at each entrance with highly restricted access—a facility that costs millions of dollars.

Given the possibility of pathogen creation, should those in non-governmental labs who opt to work with pathogen genes be held to BSL-like requirements?

Although this scenario makes for colorful discussion, it is highly unlikely. Also, creative researchers may just use a few genes of a pathogen for non-virulent purposes. Extending the biosecurity restrictions to projects that merely use the genes of pathogens could be considered overkill. Requiring the same expensive biosafety infrastructure for an entire Ebola virus (BSL-4) as for a mail-ordered version of its single gene could be seen as unnecessary and cost-prohibitive. Rather, when known pathogen genes are involved, the containment needed for a project could be reviewed on a case-by-case basis in order to set containment requirements.

Release: How might we reduce risk of eco-system disruption while allowing novel products to get to their market in a timely manner? 

Regulation proponents want to require that all GE organisms be assessed for their potential for ecological disruption before they are released in mass. A governing body could then determine whether the potential for benefit outweighs a product’s potential for ecological damage. Ideally, such a committee would include genomic scientists who understand the mechanisms of gene spread and expression, environmentalists who understand the dynamics of ecology interactions, and experts in the specific organisms modified.

Any time you release something in to nature, it is a bit of a gamble, although quite small in most cases. How could such risk assessments be done in the lab? There certainly are some relevant factors that can be measured in short-term lab experiments.

Researchers could be required to quantify changes in the GE organism’s production of known toxic substances or other harmful metabolites associated with it or the donor organism.

An often-expressed concern is that GE organisms will overtake non-GE breeds that occur naturally and reduce ecological diversity. We have no clear examples of this happening to date and such scenarios have been evaluated and dismissed during the approval process of GM crops now on the market. But it remains a concern. To the degree that such risks are serious, researchers could assess this possibility by measuring the differences in growth metrics and pest/disease susceptibility between the to-be-released organism and its non-GE counterparts. This would at least estimate the ability of the organism to outcompete non-GE breeds in the short term.

An indicator that requiring basic measurements need not deter innovation is that  Glowing Plant has opted to do them voluntarily, even with their limited budget.

“While we don’t expect to have to go through USDA approval, we are still doing the same kinds of tests,” writes Antony Evans, Glowing Plant CEO, referring to the USDA’s Animal and Plant Health Inspection Service risk assessment protocols for corn and rose breeds.

The tests that they claim are ongoing do offer examples of what might be required of other similar ad hoc research groups. They could evaluate whether there is an increase in growth rate or biomass production in mutants versus wild-type; whether there are significant differences in pest or disease susceptibilities; and whether there are differences in physical or reproductive strength (measured by plant height, flower stem length, flower height, flower diameter, petal length and width, number of pistils, number of stamens, pollen viability, pollen grain germination, and pollen diameter). They could also measure any difference in the production of typical metabolites that might mark unseen physiological changes.

In addition to determining the evolutionary fitness of a GE organism, it is reasonable for developers to also quantify and report the transmissibility of the inserted genes to offspring with non-GE counterparts or to other organisms in its environment. The latter is common in species of bacteria that can transfer sections of their genome through mere contact.

This likely won’t burden or delay research as transmissibility metrics can be observed from experiments the developers would likely do anyway in attempts to ensure the survival of their organisms and stability of the inserted gene construct.

The degree to which a GE organism is more fit, produces more chemicals, or can transfer its engineered gene, can then inform the need for out-of-lab field trials.

Some policy researchers propose that GMO developers should also assess the mutation rates and likelihood of GE organisms to evolve in nature through lengthy field trials. However, such a requirement for all GE organisms seems unnecessary. Most mutations that accrue will likely be deleterious rendering the inserted genes inert as opposed to actually conferring any additional “super powers” or pest characteristics to the GE organism. Following an organism through the generations necessary to actually see such rare events, much less quantify their probability in nature is impractical. Doing such tests properly could take years and would be an unnecessary roadblock for getting technologies to the market.

Can we at least affect the odds of unintended impacts?

So far there have not been any observable ill effects of GM organisms in nature. This may be due to the fact that the GE process is inherently benign.

Another factor to consider is that, up until now, the majority of GM crops created have fallen under governmental jurisdiction. Traditional GE methods, such as those used by companies such as Monsanto, require an experimental trick that allows you to insert genes with the help of the bacteria Agrobacterium, which happens to be on the USDA’s regulated pest list. Therefore, the government has played a role in ensuring that the vast majority of currently available GM crops were strictly contained and trialed before release.

Other methods that do not require Agrobacterium have only recently become available and allowed GE organisms to be made without government oversight. These methods include the so-called gene-gun used to make the Glowing Plant. It is impossible to know how much influence the government has had in keeping potentially harmful crops from entering the market and whether the risk of unintended consequences is raised now that crops can be made without this oversight.

Also, there have not been any harmful creations from the DIYbio community, whether intentional or unintentional. This could either be due to the exemplary responsibility demonstrated by this small first generation community as well as their limited access to materials. It may also be due to the inherent benign nature of genetic manipulation.

However, as synthetic biology moves in to more diverse communities, the educational benefits will rise along with the potential risks,of GE seeds accidentally getting into a “neighbor’s garden”.. As more entrepreneurs of varying degrees of training and responsibility obtain the means to create complex organisms the potential for beneficial innovations will increase along with the organisms that are simply bad or unvetted ideas – a malaria-resistant mosquito that still bites and happens to produce more offspring that are harder to kill. The consequences of such happenings may be significant or infinitesimally small- it cannot be predicted for sure.

It is this author’s view that filling in the regulation gaps to incentivize simple containment practices and allow educated assessment of potential harm will reduce risks with minimal compromise to innovation. Whether one agrees with this stance or not, it may, at least, be time to revisit the question of whether regulations need to be revised to fit our modern reality. Even if the conclusion, after careful consideration, is to keep things as they are.

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