GMO “Kill Switches”

Scientists design bacteria reliant upon synthetic amino acids to contain genetically modified organisms.

By Kerry Grens | January 21, 2015

WIKIMEDIA, MATTOSAURUSOne of the biggest concerns about genetically modified organisms (GMOs) is that they can infiltrate wild populations and spread their altered genes among naturally occurring species. In Nature today (January 21), two groups present a new method of containing GMOs: by making some of their essential proteins reliant upon synthetic amino acids not found outside of the laboratory.

“What really makes this a valuable step change is that kill switches beforehand were very susceptible to mutation or other conditions, such as metabolic cross feeding, from basically inactivating them,” said Tom Ellis, a synthetic biologist at Imperial College London who was not involved in the studies. The new approach circumvents some of those problems by making it extremely unlikely for the genetically modified bacteria to be able to survive outside of the conditions dictated by their custom-designed genomes.

Both research teams—one led by George Church at Harvard Medical School and the other by Farren Isaacs at Yale University—based their work on so-called genetically recoded organisms (GROs), bacterial genomes that have had all instances of a particular codon replaced by another. Church and Isaacs, along with their colleagues, had previously developed this concept in collaboration. Since then, their respective groups designed the replacement codons to incorporate a synthetic amino acid, and engineered proteins essential to the organism to rely upon the artificial amino acid for proper function.

“Here, for the first time, we’re showing that we’re able to engineer a dependency on synthetic biochemical building blocks for these proteins,” Isaacs told reporters during a conference call.

Both teams found that the cells perished in environments lacking the synthetic amino acid. Although the technology is not ready for industrial-scale deployment, the scientists suggested that such an approach could be applied as a safeguard against the escape of GMOs.

“It really addresses a long-standing problem in biotechnology, by engineering a really compelling solution to engineering biocontainments or biological barriers that limit the spread and survival of organisms in natural environments, and along the way also endow these organisms with new and expanded biological function,” added Isaacs.

Dieter Söll, a Yale chemist who also works on genetic recoding, said the method “led to tremendous stringencies in terms of biocontainment. . . . If this is done, let’s say, with three different essential proteins you can really get a stringency that I thought earlier was not possible to get.” Ellis added that such a system could also be combined with other kill switches to establish additional layers of safety.

GROs are resistant against multiple viruses, Church noted during the call, and fail at horizontal gene transfer—one of the ways genetically engineered DNA could migrate into a natural population.

Although the basic concept was similar between the two studies, each used a different synthetic amino acid and focused on different essential proteins. The GROs Church and Isaacs designed were not optimized for any particular application. For use in, say, dairy starter cultures, the system would have to be engineered in Lactobacillus instead of E. coli, for instance, and undergo additional safety testing. “We could redo this very easily with another compound,” said Church.

The next step for Church’s team is to build a GRO that has not one replacement codon, but seven. “Once this gets to a different enough genetic code there will be a barrier unlike any that’s ever existed in the kingdoms of life,” he said.

D. Mandell et al, “Biocontainment of genetically modified organisms by synthetic protein design,” Nature, doi:10.1038/nature14121, 2014.

A.J. Rovner et al., “Recoded organisms engineered to depend on synthetic amino acids,” Nature, doi:10.1038/nature14095, 2014.

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Avatar of: Dr Edo

Dr Edo

Posts: 30

January 22, 2015

A potential fly in the ointment is the vast milieu of different organisms and genes, plasmids and phages found in a sewage treatment plant and the incredible rate of gene exchange that is driven by that treatment process.  This happens all over the nation.  The impact by sewage treatments can change much of the discussion but this seems to be a taboo subject within the governmental regulatory communities, which are supposedly there to be protecting citizens. This resultant material from this sewage processing (completely uncontrolled) is then dumped into the waterways of the nation from which people obtain their drinking water. We are finding, for example, antibiotic resistant genes in this nation's drinking water. The standards are just not there to deal with this, so it continues unabated and with the complete knowledge and non-action by the regulators.

As an example of gene exchange, sewer plants actually generate and then disburse antibiotic resistant pathogens and their genes to the environment via their effluents, see EPA study: This cited paper is a peer reviewed published version of the internal EPA study. The study was undertaken by the US-EPA in the late 1970's. That study cites various prior studies finding similar responses dating back into the 1950's. Thus, the fact that sewer plants  generate and then release multi-drug resistant pathogens is not new information. While this is not something new, it is a fact something that has been long ignored (some say "hidden") by those presumably charged with protecting public health and that includes the sewer districts and policy makers.

This "non-action" was a topic of particular interest  during the 2006 Environmental Law Conference at Yosemite. An analysis of the federal Safe Drinking Water Act (SDWA) by one of the US/EPA drinking water toxicologists bears on this point. “Bottom line on almost all of the 'emerging' contaminants that have attracted attention: It will be a long time, if ever, before they are regulated under the SDWA.” 

Thus, whether GMOs or antibiotic resistant genes in our environment, the industry controls many of these regulatory agencies as their wholly owned subsidiaries and thus those regulators do not work for you but industry. You support this through your taxes.

See also

Avatar of: James V. Kohl

James V. Kohl

Posts: 531

January 23, 2015

This indirect claim is included:  Amino acid substitutions differentiate cell types.

Differentiation naturally occurs via the biophyscially constrained chemistry of protein folding. Physical and chemical constraints link nutrient-dependent RNA-directed DNA methylation to the RNA-mediated events that differentiate cell types via amino acid substitutions in all cells of all individuals of all species. 

See Dr. Edo's comment.

Symbiosis links light-induced amino acid substitutions in plants and animals to nutrient-dependent pheromone-controlled interactions in species from microbes to man. For an example of what can happen in one microbe due to a single amino acid substitution see: The host metabolite D-serine contributes to bacterial niche specificity through gene selection. (That suggests Lenski's E. coli did not mutate and evolve.)

For an example that extends light-induced amino acid substitutions to the nutrient-dependent chemistry of symbiosis via the pheromone-controlled physiology of reproduction in the bioluminescent microbes of squid, see Microbiology: Here's looking at you, squid.

For examples from model organisms that extend what we detailed about RNA-mediated cell type differentiation in the molecular epigenetics section of our 1996 Hormones and Behavior review, see Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

If ecological variation does not lead to ecological adaptation via the conserved molecular mechanisms of RNA-mediated amino acid substitutions in all genera, we have nothing to fear from the Big Bang cosmologists and evolutionary theorists who have ignored the nutrient-dependent pheromone-controlled chemistry of life that enables its biodiversity.

Alternatively, there may be problem if, for example, Life is physics and chemistry and communication.

Amino acid substitutions alter the ability of organisms to communicate in symbiotic relationships that may lead to the physiopathology of organisms like "Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7," which is responsible for outbreaks of bloody diarrhea.

Other microbes have beneficial or deleterious effects, but so far they do not appear to link mutations to evolution.except in science fiction novels and evolutionary theories. Their deleterious effects tend to kill people who cannot quickly ecologically adapt and maintain their thermodynamic cycles of protein biosynthesis and degradation in the context of their organism-level thermoregulation despite the presence of the pathogen.

January 24, 2015

Interesting concepts. But in the wild, the phenomenon of alternate pathways to bypass biological blocks or barrier is not uncommon ;clinical conditions are well known that are due to inheritable biological/biochemical blocks just as spontaneous bypass pathways emerge to these genetically determined blocks that either minimize the original disease( forme froste) or lead to emergence of an entirely different clinical syndrome. If this can happen in the wild, how non-negotiable are these so called "Kill Switches" in GRO; inspite of layers of stringencies,it is imaginable that sufficient biological plasticities are present in the recoded forms to make bypass or escape phenomenon a distinct and scary possibility.
Avatar of: James V. Kohl

James V. Kohl

Posts: 531

January 24, 2015

Biocontainment of genetically modified organisms by synthetic protein design

The authors detail how ecological variation is linked from atoms to ecosystems via nutrient-dependent amino acid substitutions that stabilize protein folding, which they compare to mutations that perturb protein folding.

They attest to the limited probability that mutations will lead to the escape from biophysical constraints that link the nutrient-dependent amino acid substitutions to the pheromone-controlled physiology of reproduction in species from microbes to man via conserved molecular mechanisms.  

Simply put, they refute claims of mutation-driven evolution with experimental evidence of epigenetically effected nutrient-dependent pheromone-controlled RNA-mediated DNA stability in the organized genomes of their GMOs.

They indirectly express hope that biologically uniformed experts will believe their experimental evidence. I suspect that the biologically uniformed will continue to believe that "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world." (p. 199) Mutation-Driven Evolution

Indeed, this experimental evidence will probably scare anyone who has been taught to believe in pseudoscientific nonsense and failed to learn how ecological variation leads to ecological adapations. Simply put, the biophysically constrained chemistry of protein folding links RNA-mediated events to cell type differentiation in all cells of all individuals of all species via the conserved molecular mechanisms that enable nutrient-dependent amino acid substitutions. But the evolution industry is supported by the biologically uninformed majority.

Avatar of: pbourguignon


Posts: 1

January 26, 2015

There is a misconception in Mandell et al., as the incorporated aminoacid is not bringing a novel catalysis to the cell that would be required for proliferation as claimed. Yet, the recoded strain reported in Rovner et al enables further constructions while preserving the recoding, a true achievement that will certainly realize a great potential in future.

The conceptual originality of Mandell et al. should also be asserted in the light of the works of Herdewijn and Marliere in Europe, who explored this type of strain constructions already in the early nineties (Phenotypic suppression by incorporation of an alien amino acid, Lemeignan et al., 1993), but also provided in-depth discussions of "synthetic auxotrophy" already 5 years ago in "The farther, the safer: a manifesto for securely navigating synthetic species away from the old living world" (Marliere, 2009) and "Toward Safe Genetically Modified Organisms through the Chemical Diversification of Nucleic Acid" (Herdewijn and Marliere, 2009).

Avatar of: James V. Kohl

James V. Kohl

Posts: 531

Replied to a comment from pbourguignon made on January 26, 2015

March 2, 2015

Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system was reported as Evolutionary Rewiring as if mutations led to the re-evolution of the flagellum in Pseudomonas "over-the-weekend."

Journal article excerpt: "... this system enables us to understand the adaptive process in detail at the genetic and phenotypic level. We identified a tractable model for gene network evolution and observed, in real time, the rewiring of gene networks to enable the incorporation of a modified component (NtrC′) creating a novel regulatory function by a highly repeatable two-step evolutionary pathway with the same point mutations often recurring in independent lineages."

If the model is a tractable model for such rapid gene network evolution, what does it tell us about biocontainment?

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